A facile approach for the synthesis of novel xanthene derivatives with Vilsmeier–Haack reagent

Article abstract of DOI:10.1007/s10593-019-02416-6

[Figure not available: see fulltext.] A series of new derivatives of formylxanthenes have been synthesized via the reaction of substituted 1,3-benzoxazines with Vilsmeier–Haack reagent. It has been shown that 1,3-benzoxazines unsubstituted in the aromatic

Full text of DOI:10.1007/s10593-019-02416-6

DOI 10.1007/s10593-019-02416-6
Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
A facile approach for the synthesis of novel xanthene derivatives
with Vilsmeier–Haack reagent
Oleg K. Farat1*, Ivan V. Ananyev2,3, Svetlana A. Varenichenko4,
Ekaterina V. Zaliznaya4, Victor I. Markov4
1
Chemistry Department, M. V. Lomonosov Moscow State University,
1–3 Leninskie Gory, Moscow 119991, Russia; е-mail: faratok@mail.ru
2
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova St., Moscow 119334, Russia; е-mail: i.ananyev@gmail.com
Plekhanov Russian University of Economics,
36 Stremannyy Pereulok, Moscow 115093, Russia; е-mail: i.ananyev@gmail.com
Ukrainian State University of Chemical Technology,
8 Gagarin Ave., Dnipro 49005, Ukraine; е-mail: markov@email.dp.ua
3
4
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(1), 38–46
Submitted November 24, 2018
Accepted December 24, 2018
A series of new derivatives of formylxanthenes have been synthesized via the reaction of substituted 1,3-benzoxazines with Vilsmeier–
Haack reagent. It has been shown that 1,3-benzoxazines unsubstituted in the aromatic part and 6-bromo-1,3-benzoxazines are rearranged
into xanthene derivatives under heating at 80°C for 1.5 h. Substitution at the C-8 position of 1,3-benzoxazines, especially with electro-
negative groups significantly inhibits the reaction. So, the presence of iodine atoms at the C-6 and C-8 positions leads to increase in reac-
tion time up to 8 h, the presence of bromine atom in the C-8 position requires heating up to 100°C for 11 h.
Keywords: Vilsmeier–Haack reagent, xanthene derivatives, crystal structure, rearrangement.
It is hard to overestimate the value of the Vilsmeier–
Haack reaction for modern organic chemistry. It is an
effective tool for introduction of formyl group into the
activated aromatic and heteroaromatic compounds. More-
over, the scope of application of the Vilsmeier–Haack
reagent goes far beyond formylation reaction. This reagent
is used for chlorination, as well as various condensations,
cyclizations, and rearrangements.1–6
In our previous works, we have shown that under the
influence of this reagent, substituted spiropyrimidines are
rearranged into derivatives of acridine,7,8 quinoline, and
benzothiazine.9 It has been also found that substituted
1,3-benzoxazines under the Vilsmeier–Haack reaction
conditions are transformed into formylxanthene deriva-
tives, and derivatives of 3,1-benzoxazines – into acridine
derivatives.10 Derivatives of formylxanthene fluoresce in
the yellow-green spectrum region in MeCN solution.11
Dyes with a high extinction coefficient were obtained on
the basis of these aldehydes by the Knoevenagel and Schiff
reactions.11,12 Thus, an increase in the number of examples
of the new rearrangement of 1,3-benzoxazine derivatives in
the Vilsmeier–Haack reaction is an extremely urgent task.
In this paper, the results of the further study of the
formylation of 1,3-benzoxazine derivatives are presented.
Derivatives of 1,3-benzoxazines have been obtained
through the interaction of substituted salicylamides with
cyclic ketones in PhMe in the presence of p-TsOH with
water removal with a Dean–Stark trap (Scheme 1).10
Amides 2 and 6 were obtained through alkylation of
unsubstituted salicylamide 1 by corresponding alcohol in
concentrated H2SO4.
The yields of 1,3-benzoxazines range from good to
excellent. The structures of the synthesized compounds
have been established by a complex of spectral methods.
1
The analysis of H and 13C NMR spectra revealed that
1,3-benzoxazines obtained from 4-substituted cyclo-
0009-3122/19/55(1)-0038©2019 Springer Science+Business Media, LLC
38

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
Scheme 1
hexanones exist as a mixture of two stereoisomers. The
mixture of isomers of compounds 8–10, 13–15, 17, 19, 22,
23 was reacted with the Vilsmeier–Haack reagent without
prior separation.
latter exhibits the envelope conformation with the C-4 atom
being out of the mean-square plane of the cycle by 0.7 Å.
Noteworthy, the C(6)–C(7)–N(1)–C(19) torsion angle in
compound 26 is 56°, while the corresponding angle in the
The interaction of 1,3-benzoxazines 7–23 with the
Vilsmeier–Haack reagent resulted in previously unknown
derivatives 24–40. The reaction products were isolated as
intermediate perchlorate salts, which were further subjected
to hydrolysis with NaOH solution to obtain relevant formyl
derivatives (Scheme 2).
The structures of the obtained compounds 24–40 were
1
confirmed by H and 13C NMR spectroscopy and mass
spectrometry. Additionally, X-ray diffraction analysis was
made for compound 26 (Fig. 1). Chiral compounds 25–27,
30–32, 34, 36, 39, 40 have been obtained as racemic
mixtures.
The X-ray diffraction analysis revealed that the crystal
structure of compound 26 is quite similar to that of non-
substituted N'-(4-formyl-2,3-dihydro-1H-xanthen-9-yl)-N,N-
dimethylimidoformamide published earlier.10 The dimethyl-
amidine fragment in compound 26 is in the trans location
to the substituted C-4 atom of the hydrogenated cycle. The
Figure 1. Molecular structure of compound 26 with atoms repre-
sented by thermal vibration ellipsoids of 50% probability.
39

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
Scheme 2
non-substituted derivative10 is 295° that makes the structu-
res of these compounds different in the sense of planar
chirality, though similar in the sense of the intermediate
dimethylamidine fragment rotation. The preference of this
intermediate conformation can be rationalized in terms of
the interplay between 1) stereoelectronic interaction involving
lone pair of the imide nitrogen atom, π-conjugation
between the dimethylamidine fragment and the xanthene
moiety, and steric repulsion (the in-plane conformation
with the C(6)–C(7)–N(1)–C(19) torsion angle equal to 0°
or 180°) and 2) the π-conjugation between lone pair of
the imide nitrogen atom and the xanthene moiety (the
C(6)–C(7)–N(1)–C(19) torsion angle is equal to 90° or
270°). The PBE1PBE/6-311+G(d) relaxed scan of the
isolated molecule 26 along the C(6)–C(7)–N(1)–C(19)
torsion angle coordinate (36 steps by 10°) demonstrated
that the rotation of the dimethylamidine fragment is not
followed by conformational changes of the hydrogenated
cycle and has two energy barriers of 4.0 and 6.2 kcal/mol
for the C(6)–C(7)–N(1)–C(19) angle being equal, respec-
tively, to 180° and 0°.
In its turn, the energy minimum corresponds to the
C(6)–C(7)–N(1)–C(19) angle being equal to 56° and 308°,
while no more minimums were observed which could
correspond to the structures with pronounced π-conjugation
between lone pair of the imide nitrogen atom and the
xanthene moiety. Note that the fully optimized geometry of
the isolated molecule 26 corresponds to the energy mini-
mum according to the second derivative matrix analysis
and is nearly the same as the molecular geometry in crystal
even without accounting for nonspecific solvation; no
additional
noncovalent
intramolecular
interactions
stabilizing the observed conformation were found between
the dimethylamidine fragment and the xanthene moiety
40

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
Scheme 3
according to the ''Atoms in Molecules'' approach.13 The
intermolecular contacts are practically of the same nature in
both compound 26 and the non-substituted derivative,
although the topology of crystal packing differs signi-
ficantly. While in the non-substituted derivative the
stacking-stabilized supramolecular dimers (interplane
distance is 3.65 Å) form layers by weaker CH···O inter-
actions (H···O distance is 2.28 Å with normalized C–H
distances), the most shortened contacts in compound 26
correspond to the multiple CH···π (H···C distances are
2.79–2.86 Å with normalized C–H distances) stacking
(interplane distance is 3.25 Å) and CH···O interactions
(H···O distances are 2.35–2.58 Å with normalized C–H
distances) which bound molecules into chains with parallel
planes of xanthene moieties. These chains interact with each
other by weaker CH···O (2.71 Å) and H···H interactions to
give 3D crystal structure.
The rate of this rearrangement is influenced by sub-
stituent in the aromatic cycle of benzoxazines. Derivatives
7–15, 20–23 are rearranged into substituted formyl
derivatives 24–32, 37–40 through processing with a triple
excess of the Vilsmeier–Haack reagent at 80°C for 1.5 h.
The increasing electronegativity of atoms in C-6 and C-8
positions of substituted 1,3-benzoxazines significantly
inhibits the reaction. So, the presence of iodine atoms in
these positions (compounds 16 and 17) leads to an increase
in the reaction time up to 8 h, while the presence of
bromine atoms in C-6 and C-8 positions (compounds 18
and 19) requires heating up to 100°C for 11 h.
The key stage of the reaction is the electrophilic
disclosure of the oxazine cycle with the formation of
imidoyl chloride A. The electron lone pair of oxygen atom
attacks σ*-orbital of C–N bond, which leads to breaking of
this bond and formation of oxonium cation B. The bromine
atom only in the C-6 position of 1,3-benzoxazines 20–23
does not affect the reaction rate since it is located far from
the cyclic oxygen atom affecting the stability of the cation
B (Scheme 3). More harsh reaction conditions for obtaining
derivatives 33–36 are caused by the halogen atoms in the
C-8 position, which destabilize cation B due to a negative
inductive effect. The initial stages of the reaction mecha-
nism are presented in Scheme 3 (the complete reaction
mechanism is reported in the literature10).
This paper presents novel examples of rearrangement of
1,3-benzoxazines into substituted xanthenes under the
action of the Vilsmeier–Haack reagent. It has been
established that the presence of the bromine atom in the
C-6 position of 1,3-benzoxazine derivatives has no effect
on the reaction conditions, while the iodine and bromine
atoms in the C-6 and C-8 positions of the respective
derivatives require more harsh reaction conditions. The
structure of the synthesized compounds has been confirmed
by the physicochemical analysis data including X-ray
diffraction. The obtained derivatives of xanthenes can be
used as molecular building blocks for organic synthesis and
as organic fluorophores.
Experimental
1H and 13C NMR spectra were recorded on a Bruker
Avance II 400 spectrometer (400 and 101 MHz, respec-
tively; compounds 2, 6, 8, 9, 11, 12, 19, 24–29) or a Bruker
Avance 600 spectrometer (600 and 151 MHz, respectively;
compounds 10, 13–18, 20–23, 30–40) in CDCl3 or DMSO-d6
1
with TMS as internal standard. The H and 13C NMR
spectra for compounds 17, 22, and 23 are presented for the
predominant isomer. The FAB mass spectra (compounds 6,
11, and 28) were recorded on a VG7070 spectrometer.
Desorption of the ions from the solution of the samples in
meta-nitrobenzyl alcohol was realized with a beam of
argon atoms with 8 keV energy. The EI mass spectra (other
compounds) were recorded on a Kratos MS 30 instrument
with direct injection of the sample, ionization chamber
temperature 250°C, ionization energy 70 eV. Elemental
analysis was performed on a LECO CHN-900 instrument.
Melting points were determined using an Electrothermal
9100 Digital Melting Point apparatus and were uncor-
rected. Completion of the reactions and purity of the
obtained compounds were monitored by TLC on Merck
Silica gel 60 F-254 plates, eluent CHCl3–МеOH, 9:1.
All reagents of analytical grade were purchased from
commercial suppliers and used without any further
purification, unless stated otherwise. Compounds 3,14 4,15
and 516 were obtained by known procedures.
2-Hydroxy-3,5-di(propan-2-yl)benzamide (2). i-PrOH
(3 ml, 0.04 mol) was slowly added to concentrated H2SO4
(8 ml) with stirring and ice-cooling. Salicylamide (1) (2 g,
0.015 mol) was added to the resulting solution. The
reaction mixture was heated at 80°C for 1.5 h. Then the
reaction mixture was left for 12 h at room temperature,
poured onto ice, amide 2 was filtered off, dried, and
crystallized from n-hexane. Yield 2.26 g (70%), light-gray
powder, mp 116–117°C (mp 116–117°C17). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 12.30 (1H, br. s, OH);
7.25 (1H, d, 4J = 2.0, H-6); 7.07 (1H, d, 4J = 2.0, H-4); 6.34
3
(2H, br s, NH2); 3.38 (1H, sept, J = 6.9, CH(CH3)2); 2.85
3
3
(1H, sept, J = 6.9, CH(CH3)2); 1.26 (6H, d, J = 6.9,
CH(CH3)2); 1.24 (6H, d, J = 6.9, CH(CH3)2). 13C NMR
3
spectrum (CDCl3), δ, ppm: 173.6; 157.8; 138.4; 137.6;
129.9; 120.9; 112.0; 33.6; 26.6; 24.1; 22.4. Mass spectrum,
m/z (Irel, %): 221 [М]+ (92), 161 (100).
5-tert-Butyl-2-hydroxybenzamide (6). t-BuOH (11 ml,
0.12 mol) and MeOH (5 ml) were slowly added to
concentrated H2SO4 (24 ml) with stirring and ice-cooling.
Salicylamide (1) (6 g, 0.04 mol) was added to the resulting
41

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
solution. The reaction mixture was stirred at room
H Ar); 2.40–2.28 (2.39H, m, CH2); 1.74–1.68 (1.50H, m,
CH2); 1.62–1.56 (2.82H, m, CH2); 1.51–1.18 (4.2H, m,
CH, CH2); 0.86–0.78 (9H, m, 3CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 166.4; 166.0; 159.1; 158.6; 137.7; 132.0;
130.7; 129.0; 124.8; 124.6; 120.1; 120.0; 91.6; 90.6; 47.4;
46.7; 39.2; 39.1; 37.5; 35.6; 27.2; 27.1; 25.3; 25.2; 11.1;
11.0. Mass spectrum, m/z (Irel, %): 287 [М]+ (26), 174
(100). Found, %: C 75.39; H 8.83; N 4.90. C18H25NO2.
Calculated, %: C 75.22; H 8.77; N 4.87.
temperature for 5 h. Then the reaction mixture was left for
12 h at room temperature, poured onto ice, amide 6 was
filtered off, dried, and crystallized from n-hexane. Yield
3.4 g (40%), white powder, mp 165–167°C. 1H NMR
spectrum (DMSO-d6), δ, ppm: 12.81 (1H, s, OH); 8.45 (1H,
br. s, NH2); 7.80 (1H, br. s, NH2); 7.79 (1H, d, 4J = 2.4, H-6);
7.41 (1H, dd, 3J = 8.6, 4J = 2.4, H-4); 6.78 (1H, d, 3J = 8.6,
H-3); 1.25 (9H, s, t-Bu). 13C NMR spectrum (DMSO-d6),
δ, ppm: 172.2; 158.7; 140.6; 130.9; 124.5; 116.7; 113.6;
34.0; 31.3. Mass spectrum, m/z (Irel, %): 194 [М+H]+ (100).
Found, %: C 68.51; H 7.89; N 7.30. C11H15NO2.
Calculated, %: C 68.37; H 7.82; N 7.25.
6-tert-Butylspiro[1,3-benzoxazine-2,1'-cyclohexan]-
4(3H)-one (11). Yield 1.77 g (65%), white powder, mp 215–
1
216°C (i-PrOH). H NMR spectrum (DMSO-d6), δ, ppm
4
(J, Hz): 8.61 (1H, br. s, NH); 7.72 (1H, d, J = 1.9,
3
4
Synthesis of spirans 7–23 (General method). A mixture
of the corresponding salicylamide 1–6 (0.010 mol), ketone
(0.012 mol), and p-TsOH·H2O (0.03 mol) in PhMe (45 ml)
was refluxed for 8 h with continuous removal of water with
a Dean–Stark trap. Then solvent was evaporated to dryness
under reduced pressure, the solid residue was washed with
5% aqueous NaOH solution and filtered off.
H-5 Ar); 7.72 (1H, dd, J = 8.4, J = 1.9, H-7 Ar); 6.93
3
(1H, d, J = 8.4, H-8 Ar); 1.97–1.95 (2H, m, CH2); 1.65–
1.49 (7H, m, CH2); 1.24–1.22 (1H, m, CH2); 1.27 (9H, s,
t-Bu). 13C NMR spectrum (DMSO-d6), δ, ppm: 161.3;
152.7; 143.8; 131.4; 122.9; 117.0; 116.4; 87.3; 35.4; 34.0;
31.1; 24.2; 21.4. Mass spectrum, m/z (Irel, %): 274 [М+H]+
(100). Found, %: C 74.76; H 8.57; N 5.21. C17H23NO2.
Calculated, %: C 74.69; H 8.48; N 5.12.
Spiro[1,3-benzoxazine-2,1'-cycloheptan]-4(3H)-one (7).
Yield 2.10 g (91%), white powder, mp 157–158°C (154–
6,8-Diisopropylspiro[1,3-benzoxazine-2,1'-cycloheptan]-
4(3H)-one (12). Yield 2.68 g (85%), white powder, mp 138–
140°C (aqueous MeOH). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.62 (1H, d, 4J = 2.0, H Ar); 7.47 (1H, br. s,
1
156°C18) (aqueous MeOH). H and 13C NMR spectral data
are identical to those reported in literature.18
4'-Methylspiro[1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-
one (8). Yield 2.19 g (95%), white powder, mp 148–156°C
4
NH); 7.22 (1H, d, J = 2.0, H Ar); 3.29–3.26 (1H, m,
1
(mp 150–165°C19) (aqueous MeOH). H NMR spectrum
CH(CH3)2); 2.90–2.86 (1H, m, CH(CH3)2); 2.29–2.23 (2H,
m, CH2); 2.01–1.95 (2H, m, CH2); 1.70–1.52 (8H, m, CH2);
(CDCl3), δ, ppm (J, Hz): 7.92–7.88 (1H, m, H Ar); 7.80–
7.70 (0.62H, br. s, NH); 7.65–7.57 (0.33H, br. s, NH); 7.50–
7.40 (1H, m, H Ar); 7.09–7.01 (1H, m, H Ar); 6.97 (0.63H,
3
3
1.25 (6H, d, J = 6.9, CH(CH3)2); 1.24 (6H, d, J = 6.9,
CH(CH3)2). 13C NMR spectrum (CDCl3), δ, ppm: 163.3;
150.8; 141.6; 136.3; 129.7; 122.1; 116.6; 91.4; 39.8; 33.5;
28.7; 26.7; 23.9; 22.6; 21.3. Mass spectrum, m/z (Irel, %):
315 [М]+ (32), 205 (100). Found, %: C 76.25; H 9.33;
N 4.48. C20H29NO2. Calculated, %: C 76.15; H 9.27; N 4.44.
6,8-Diisopropyl-4'-methylspiro[1,3-benzoxazine-2,1'-
cyclohexan]-4(3H)-one (13). Yield 2.65 g (84%), white
powder, mp 126–134°C (aqueous MeOH). 1H NMR spectrum
(CDCl3), δ, ppm: 7.62–7.60 (1H, m, H Ar); 7.47 (0.6H, br. s,
NH); 7.31 (0.4H, br. s, NH); 7.23 (0.64H, s, H Ar); 7.20
(0.38H, s, H Ar); 3.33–3.30 (0.64H, m, CH(CH3)2); 3.24–
3.21 (0.38H, m, CH(CH3)2); 2.90–2.85 (1H, m, CH(CH3)2);
2.31–2.29 (1.48H, m, CH); 2.19–2.15 (0.89H, m, CH); 1.78–
1.72 (1.54H, m, CH); 1.62–1.37 (4.63H, m, CH); 1.30–1.22
(12H, m, CH(CH3)2); 0.98–0.94 (3H, m, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 163.8; 163.4; 151.2; 150.6;
141.8; 136.5; 136.4; 130.0; 129.7; 122.4; 122.3; 116.9;
115.0; 87.8; 87.1; 35.9; 35.3; 33.7; 31.2; 30.8; 30.6; 30.0;
27.1; 26.4; 24.1; 23.0; 22.7; 22.1; 21.0. Mass spectrum, m/z
(Irel, %): 315 [М]+ (34), 258 (100). Found, %: C 76.28; H 9.35;
N 4.47. C20H29NO2. Calculated, %: C 76.15; H 9.27; N 4.44.
4'-tert-Butyl-6,8-diisopropylspiro[1,3-benzoxazine-2,1'-
cyclohexan]-4(3H)-one (14). Yield 3.50 g (98%), white
powder, mp 177–184°C (aqueous MeOH). 1H NMR spectrum
(CDCl3), δ, ppm: 7.62–7.61 (1H, m, H Ar); 7.38 (0.29H,
br. s, NH); 7.30 (0.62H, br. s, NH); 7.23 (0.67H, s, H Ar);
7.20 (0.33H, s, H Ar); 3.35–3.32 (0.68H, m, CH(CH3)2);
3.24–3.21 (0.33H, m, CH(CH3)2); 2.90–2.85 (1H, m,
CH(CH3)2); 2.37–2.35 (1.54H, m, CH); 2.31–2.29 (0.77H,
m, CH); 1.80–1.78 (0.76H, m, CH); 1.71–1.67 (2.17H, m,
3
3
d, J = 8.2, H Ar); 6.92 (0.33H, d, J = 8.2, H Ar); 2.27–
2.32 (1.33H, m, CH2); 2.20–2.15 (0.72H, m, CH2); 1.83–
1.68 (1.45H, m, CH2); 1.66–1.25 (5.60H, m, CH2); 0.97
3
3
(1.90H, d, J = 6.5, CH3); 0.96 (1.10H, d, J = 6.5, CH3).
13C NMR spectrum (CDCl3), δ, ppm: 163.2; 155.8; 155.5;
134.5; 134.4; 127.6; 127.5; 121.6; 121.5; 117.0; 116.9; 88.4;
87.4; 40.7; 35.7; 35.1; 34.6; 21.7; 20.9. Mass spectrum, m/z
(Irel, %): 231 [М]+ (45), 121 (100).
4'-tert-Butylspiro[1,3-benzoxazine-2,1'-cyclohexan]-
4(3H)-one (9). Yield 2.70 g (99%), white powder, mp 220–
225°C (mp 208–215°C20) (aqueous MeOH). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.93–7.90 (1.89H, m,
NH and H Ar); 7.46–7.42 (1H, m, H Ar); 7.07–7.03 (1H,
3
m, H Ar); 6.96 (0.62H, d, J = 8.1, H Ar); 6.92 (0.37H, d,
3J = 8.1, H Ar); 2.37–2.28 (2.10H, m, CH); 1.81–1.35
(6.30H, m, CH); 1.14–1.05 (1.06H, m, CH); 0.90 (5.65H, s,
t-Bu); 0.88 (3.35H, s, t-Bu). 13C NMR spectrum (CDCl3),
δ, ppm: 163.2; 156.0; 155.5; 134.5; 134.3; 127.6; 121.6;
121.5; 117.6; 117.0; 116.9; 88.5; 87.4; 47.0; 46.4; 36.2;
32.2; 27.5; 27.4; 22.7; 22.6. Mass spectrum, m/z (Irel, %):
273 [М]+ (25), 174 (100).
4'-(2-Methylbutan-2-yl)spiro[1,3-benzoxazine-2,1'-cyclo-
hexan]-4(3H)-one (10). Yield 2.58 g (90%), white powder,
mp 155–162°C (aqueous MeOH). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 8.09 (0.56H, br. s, NH); 7.97
(0.30H, br. s, NH); 7.92–7.88 (0.97H, m, H Ar); 7.82
3
(0.20H, d, J = 6.9, H Ar); 7.48–7.43 (1H, m, H Ar); 7.23
3
(0.20H, d, J = 6.9, H Ar); 7.08–7.03 (0.88H, m, H Ar);
3
3
6.97 (0.60H, d, J = 8.0, H Ar); 6.92 (0.33H, d, J = 8.0,
42

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
CH); 1.56–1.45 (3.10H, m, CH); 1.33–1.28 (0.88H, m,
8.01 (0.80H, br. s, NH); 7.97 (1H, s, H Ar); 7.84 (0.20H,
br. s, NH); 7.79 (1H, s, H Ar); 2.28–2.10 (2H, m, CH2);
1.90–1.80 (1H, m, CH); 1.65–1.47 (6H, m, 3CH2); 1.00–
0.97 (3H, m, CH3). 13C NMR spectrum (CDCl3), δ, ppm:
161.3; 151.8; 139.7; 129.6; 120.1; 114.2; 112.2; 90.0; 89.2;
35.9; 34.7; 31.1; 30.2; 29.5; 22.0; 20.5. Mass spectrum, m/z
(Irel, %): 389 [М]+ (35), 279 (100). Found, %: C 43.29;
H 3.93; N 3.62. C14H15Br2NO2. Calculated, %: C 43.22;
H 3.89; N 3.60.
CH); 1.28–1.25 (12H, m, 2CH(CH3)2); 0.89 (5.97H, s,
t-Bu); 0.88 (2.89H, s, t-Bu). 13C NMR spectrum (CDCl3),
δ, ppm: 163.8; 151.4; 150.5; 141.8; 136.5; 136.4; 130.1;
129.8; 122.4; 122.3; 116.9; 87.9; 87.1; 47.2; 46.3; 36.3;
33.7; 32.4; 32.3; 27.7; 27.5; 27.3; 26.3; 24.1; 23.1; 23.0;
22.9; 22.6. Mass spectrum, m/z (Irel, %): 357 [М]+ (41), 138
(100). Found, %: C 77.35; H 9.90; N 3.96. C23H35NO2.
Calculated, %: C 77.27; H 9.87; N 3.92.
4'-(2-Methylbutan-2-yl)-6,8-diisopropylspiro[1,3-benz-
oxazine-2,1'-cyclohexan]-4(3H)-one (15). Yield 3.23 g
(87%), white powder, mp 152–160°C (aqueous MeOH).
1H NMR spectrum (CDCl3), δ, ppm: 8.03 (0.54H, br. s,
NH); 7.82 (0.51H, br. s, NH); 7.62 (1H, s, H Ar); 7.25–
7.23 (0.61H, m, H Ar); 7.14–7.11 (0.54H, m, H Ar); 3.37–
3.19 (1H, m, CH(CH3)2); 2.91–2.89 (1H, m, CH(CH3)2);
2.39–2.31 (3H, m, CH, CH2); 1.75–1.45 (6H, m, 3CH2);
1.30–1.23 (14H, m, CH2, 2CH(CH3)2); 0.86–0.80 (9H, m,
3CH3). 13C NMR spectrum (CDCl3), δ, ppm: 164.1; 163.7;
151.4; 150.5; 142.0; 141.8; 136.7; 136.4; 130.4; 129.5;
129.0; 126.0; 125.7; 122.4; 122.3; 116.4; 116.0; 115.0;
114.9; 88.0; 87.3; 44.5; 43.3; 36.3; 36.1; 34.6; 33.6; 32.7;
27.2; 26.2; 24.3; 24.1; 24.0; 23.0; 22.5; 22.4; 22.3; 21.4;
19.7; 8.1. Mass spectrum, m/z (Irel, %): 371 [М]+ (59), 152
(100). Found, %: C 77.68; H 10.11; N 3.82. C24H37NO2.
Calculated, %: C 77.58; H 10.04; N 3.77.
6-Bromospiro[1,3-benzoxazine-2,1'-cycloheptan]-4(3H)-
one (20). Yield 2.48 g (80%), white powder, mp 168–170°C
1
(DMF). H NMR spectrum (CDCl3), δ, ppm: 8.02 (1H, s,
H-5 Ar); 7.59 (1H, br. s, NH); 7.52 (1H, d, 3J = 8.6, H-7 Ar);
3
6.83 (1H, d, J = 8.6, H-8 Ar); 2.26–2.22 (2H, m, CH2);
2.00–1.96 (2H, m, CH2); 1.68–1.54 (8H, m, 4CH2). 13C NMR
spectrum (CDCl3), δ, ppm: 161.6; 154.8; 137.3; 130.3;
119.1; 114.0; 92.6; 39.7; 28.4; 21.3. Mass spectrum, m/z
(Irel, %): 311 [М(81Br)]+ (18), 309 [М(79Br)]+ (20), 111
(100). Found, %: C 54.29; H 5.23; N 4.58. C14H16BrNO2.
Calculated, %: C 54.21; H 5.20; N 4.52.
6-Bromospiro[1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-
one (21). Yield 2.75 g (93%), white powder, mp 186–189°C
1
(DMF). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 8.24
(1H, br. s, NH); 8.01 (1H, s, H-5 Ar); 7.52 (1H, d, 3J = 8.6,
H-7 Ar); 6.85 (1H, d, 3J = 8.6, H-8 Ar); 2.12–2.10 (2H, m,
CH2); 1.73–1.60 (7H, m, CH2); 1.39–1.37 (1H, m, CH).
13C NMR spectrum (CDCl3), δ, ppm: 162.0; 154.7; 137.1;
130.2; 119.0; 114.0; 88.4; 35.9; 24.5; 21.8. Mass spectrum,
m/z (Irel, %): 297 [М(81Br)]+ (22), 295 [М(79Br)]+ (20), 97
(100). Found, %: C 52.90; H 4.88; N 4.80. C13H14BrNO2.
Calculated, %: C 52.72; H 4.76; N 4.73.
6,8-Diiodospiro[1,3-benzoxazine-2,1'-cycloheptan]-4(3H)-
one (16). Yield 3.35 g (69%), white powder, mp 182–185°C
1
(DMF). H NMR spectrum (CDCl3), δ, ppm: 8.16–8.15
(3H, m, NH, H Ar); 2.32–2.28 (2H, m, CH2); 1.95–1.91
(2H, m, CH2); 1.80–1.72 (4H, m, 2CH2); 1.63–1.58 (4H, m,
2CH2). 13C NMR spectrum (CDCl3), δ, ppm: 163.6; 157.8;
153.8; 139.3; 122.2; 96.4; 89.1; 87.4; 42.8; 30.9; 24.1.
Mass spectrum, m/z (Irel, %): 483 [М]+ (76), 373 (100).
Found, %: C 34.99; H 3.23; N 3.02. C14H15I2NO2. Calcu-
lated, %: C 34.81; H 3.13; N 2.90.
6-Bromo-4'-methylspiro[1,3-benzoxazine-2,1'-cyclo-
hexan]-4(3H)-one (22). Yield 3.07 g (99%), white powder,
mp 166–175°C (DMF). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 8.24 (1H, br. s, NH); 8.01 (1H, s, H-5 Ar);
7.53 (1H, d, 3J = 8.6, H-7 Ar); 6.87 (1H, d, 3J = 8.6, H-8 Ar);
2.27–2.25 (2H, m, CH2); 1.64–1.56 (4H, m, 2CH2); 1.51–
1.42 (1H, m, CH); 1.39–1.30 (2H, m, CH2); 0.95 (3H, d,
3J = 6.2, CH3).13C NMR spectrum (CDCl3), δ, ppm: 162.2;
154.6; 137.3; 130.3; 119.1; 114.1; 88.1; 35.6; 31.0; 30.1;
21.8. Mass spectrum, m/z (Irel, %): 311 [М(81Br)]+ (98), 309
[М(79Br)]+ (100). Found, %: C 54.33; H 5.25; N 4.58.
C14H16BrNO2. Calculated, %: C 54.21; H 5.20; N 4.52.
6-Bromo-4'-tert-butylspiro[1,3-benzoxazine-2,1'-cyclo-
hexan]-4(3H)-one (23). Yield 3.00 g (85%), white powder,
mp 225–230°C (DMF). 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 8.10 (1H, br. s, NH); 8.02 (1H, s, H-5 Ar);
6,8-Diiodo-4'-methylspiro[1,3-benzoxazine-2,1'-cyclo-
hexan]-4(3H)-one (17). Yield 4.64 g (96%), white powder,
mp 220–226°C (DMF). 1H NMR spectrum (CDCl3),
δ, ppm: 8.15 (2H, s, H Ar); 7.83 (1H, s, NH); 2.31–2.18
(2H, m, CH2); 1.70–1.47 (6H, m, 3CH2); 1.37–1.24 (1H, m,
CH); 1.02–0.98 (3H, m, CH3). 13C NMR spectrum (CDCl3),
δ, ppm: 161.5; 154.9; 150.7; 136.5; 119.6; 89.3; 86.0; 84.5;
35.9; 31.0; 30.2; 21.9. Mass spectrum, m/z (Irel, %): 483
[М]+ (100). Found, %: C 34.95; H 3.20; N 2.95. C14H15I2NO2.
Calculated, %: C 34.81; H 3.13; N 2.90.
6,8-Dibromospiro[1,3-benzoxazine-2,1'-cyclohexan]-
4(3H)-one (18). Yield 3.23 g (86%), white powder, mp 215–
3
3
7.53 (1H, d, J = 8.6, H-7 Ar); 6.86 (1H, d, J = 8.6,
H-8 Ar); 2.27–2.25 (2H, m, CH2); 1.64–1.56 (4H, m,
2CH2); 1.51–1.42 (1H, m, CH); 1.39–1.30 (2H, m, CH2);
0.89 (9H, s, t-Bu). 13C NMR spectrum (CDCl3), δ, ppm:
162.1; 154.6; 137.1; 130.3; 119.1; 114.1; 88.0; 46.4; 36.2;
32.3; 27.5; 22.7. Mass spectrum, m/z (Irel, %): 353
[М(81Br)]+ (7), 351 [М(79Br)]+ (5), 138 (100). Found, %:
C 58.10; H 6.36; N 4.07. C17H22BrNO2. Calculated, %:
C 57.96; H 6.30; N 3.98.
1
217°C (DMF). H NMR spectrum (CDCl3), δ, ppm: 8.23
(1H, br. s, NH); 7.97 (1H, s, H Ar); 7.79 (1H, s, H Ar);
2.20–2.18 (2H, m, CH2); 1.79–1.67 (7H, m, CH2); 1.34–
1.32 (1H, m, CH2). 13C NMR spectrum (CDCl3), δ, ppm:
161.3; 151.8; 139.7; 129.6; 120.0; 114.1; 112.1; 89.5; 36.1;
24.5; 21.8. Mass spectrum, m/z (Irel, %): 375 [М]+ (63), 97
(100). Found, %: C 41.70; H 3.54; N 3.75. C13H13Br2NO2.
Calculated, %: C 41.63; H 3.49; N 3.73.
6,8-Dibromo-4'-methylspiro[1,3-benzoxazine-2,1'-cyclo-
hexan]-4(3H)-one (19). Yield 3.46 g (89%), white powder,
Synthesis of compounds 24–40 (General method). The
Vilsmeier–Haack reagent was prepared from POСl3
(2.75 ml, 0.03 mol) and DMF (4.61 ml, 0.06 mol) with ice-
1
mp 180–184°C (DMF). H NMR spectrum (CDCl3), δ, ppm:
43

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
cooling. Compound 7 (2.31 g, 0.01 mol) was added to the
N'-[2-(4-Formyl-2-methylbutan-2-yl)-2,3-dihydro-1H-
xanthen-9-yl]-N,N-dimethylimidoformamide (27). Yield
2.11 g (60%), yellow powder, mp 153–155°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.25
Vilsmeier–Haack reagent. The reaction mixture was heated
and stirred on a water bath at 80°C for 1.5 h. Then the
reaction mixture was cooled to 10°C and treated with an
ice-cold 15% aqueous NaClO4 solution (10 ml). The
precipitate of the organic salt was filtered off, dried, and
washed with PhMe. The organic salt was dissolved in hot
DMF (5 ml). To the obtained solution, an aqueous 15%
NaOH solution (1.5 ml) was added, and the mixture was
stirred vigorously at 60–75°C for 5 min. The precipitated
solid of compound 24 was filtered off. If no solid precipi-
tated, the solution was cooled to the room temperature and
water was added.
3
(1H, s, CHO); 7.47 (1H, d, J = 7.7, H Ar); 7.37 (1H, s,
3
3
CH); 7.31 (1H, t, J = 7.5, H Ar); 7.11 (1H, d, J = 7.7,
H Ar); 7.08 (1H, t, 3J = 7.0, H Ar); 3.13 (3H, s, CH3); 3.08
(3H, s, CH3); 2.84–2.73 (2H, m, CH2); 1.95–1.91 (2H, m,
CH2); 1.83–1.79 (1H, m, CH); 1.41–1.34 (2H, m, CH2);
3
0.89 (6H, s, 2CH3); 0.82 (3H, d, J = 6.6, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 186.5; 163.2; 153.4; 152.4;
146.7; 129.9; 123.9; 123.1; 121.2; 115.0; 114.0; 110.8;
40.1; 39.3; 34.5; 34.3; 32.6; 25.7; 24.0; 23.9; 22.1. Mass
spectrum, m/z (Irel, %): 352 [М]+ (100). Found, %: C 75.08;
H 8.05; N 7.99. C22H28N2O2. Calculated, %: C 74.97;
H 8.01; N 7.95.
Similarly compounds 25–32, 37–40 were obtained. For
compounds 33 and 34, the reaction time was increased to
8 h. Compounds 35, 36 were obtained at 100°C for 11 h.
N'-(6-Formyl-7,8,9,10-tetrahydrocyclohepta[b]chromen-
11-yl)-N,N-dimethylimidoformamide (24). Yield 1.92 g
(65%), yellow powder, mp 120–123°C (aqueous MeOH).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.26 (1H, s,
N'-(7-tert-Butyl-4-formyl-2,3-dihydro-1H-xanthen-9-yl)-
N,N-dimethylimidoformamide (28). Yield 2.03 g (60%),
1
yellow powder, mp 125–127°C (hexane). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 10.12 (1H, s, CHO); 7.75 (1H,
3
4
CHO); 7.50 (1H, d, J = 7.0, H Ar); 7.35 (1H, s, CH); 7.32–
s, CH); 7.55 (1H, d, J = 2.4, H-8 Ar); 7.46 (1H, dd,
4
3
7.27 (1H, m, H Ar); 7.08–7.04 (2H, m, H Ar); 3.11 (3H, s,
CH3); 3.08 (3H, s, CH3); 2.63–2.61 (4H, m, 2CH2); 1.82–
1.74 (4H, m, 2CH2). 13C NMR spectrum (CDCl3), δ, ppm:
187.5; 167.4; 153.2; 152.5; 150.4; 130.1; 124.4; 122.8;
120.9; 116.0; 115.1; 40.1; 34.3; 28.0; 25.9; 25.3; 19.7.
Mass spectrum, m/z (Irel, %): 296 [М]+ (100). Found, %:
C 73.12; H 6.83; N 9.51. C18H20N2O2. Calculated, %:
C 72.95; H 6.80; N 9.45.
3J = 8.6, J = 2.4, H-6 Ar); 7.18 (1H, d, J = 8.6, H-5 Ar);
3.06 (3H, s, CH3); 3.04 (3H, s, CH3); 2.54–2.51 (2H, m,
CH2); 2.28 (2H, t, 3J = 5.9, CH2); 1.58–1.52 (2H, m, CH2);
1.27 (9H, s, t-Bu). 13C NMR spectrum (DMSO-d6), δ, ppm:
184.0; 162.8; 154.8; 147.9; 147.2; 145.5; 127.5; 120.1;
119.9; 114.8; 110.6; 108.7; 39.6; 34.2; 33.8; 31.1; 24.8;
21.1; 20.3. Mass spectrum, m/z (Irel, %): 339 [М+H]+ (100).
Found, %: C 74.60; H 7.78; N 8.32. C21H26N2O2. Calcu-
lated, %: C 74.53; H 7.74; N 8.28.
N'-(4-Formyl-2-methyl-2,3-dihydro-1H-xanthen-9-yl)-
N,N-dimethylimidoformamide (25). Yield 2.16 g (73%),
yellow powder, mp 124–126°C (aqueous MeOH). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 10.20 (1H, s, CHO);
N'-(6-Formyl-2,4-diisopropyl-7,8,9,10-tetrahydrocyclo-
hepta[b]chromen-11-yl)-N,N-dimethylimidoformamide
(29). Yield 2.20 g (58%), yellow powder, mp 110–112°C
3
4
1
7.51 (1H, dd, J = 7.8, J = 1.5, H Ar); 7.40 (1H, s, CH);
7.35–7.32 (1H, m, H Ar); 7.15–7.12 (1H, m, H Ar); 7.11–
7.08 (1H, m, H Ar); 3.15 (3H, s, CH3); 3.09 (3H, s, CH3);
2.74–2.70 (2H, m, CH2); 2.04–1.99 (1H, m, CH); 1.93–
1.87 (1H, m, CH); 1.77–1.69 (1H, m, CH); 1.05 (3H, d,
3J = 6.6, CH3). 13C NMR spectrum (CDCl3), δ, ppm: 186.0;
163.4; 153.4; 152.3; 130.0; 123.9; 123.1; 121.0; 115.4;
113.0; 109.8; 40.3; 34.3; 33.1; 29.1; 26.5; 20.9. Mass
spectrum, m/z (Irel, %): 296 [М]+ (100). Found, %: C 73.10;
H 6.84; N 9.52. C18H20N2O2. Calculated, %: C 72.95;
H 6.80; N 9.45.
(aqueous MeOH). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 10.31 (1H, s, CHO); 7.34 (1H, s, CH); 7.21 (1H, d,
4J = 1.9, H-1 Ar); 7.12 (1H, d, 4J = 1.9, H-3 Ar); 3.48–3.41
(1H, m, CH(CH3)2); 3.13 (3H, s, CH3); 3.09 (3H, s, CH3);
2.93–2.84 (1H, m, CH(CH3)2); 2.66–2.61 (4H, m, 2CH2);
3
1.83–1.74 (4H, m, 2CH2); 1.27 (6H, d, J = 6.9, CH(CH3)2);
3
1.23 (6H, d, J = 6.9, CH(CH3)2). 13C NMR spectrum
(CDCl3), δ, ppm: 187.0; 168.0; 153.0; 151.7; 147.9; 143.2;
134.8; 129.8; 125.5; 122.1; 119.1; 115.6; 40.1; 39.9; 33.8;
28.2; 26.7; 25.9; 25.3; 24.0; 22.5; 19.8. Mass spectrum, m/z
(Irel, %): 380 [М]+ (100). Found, %: C 75.90; H 8.54; N 7.40.
C24H32N2O2. Calculated, %: C 75.75; H 8.48; N 7.36.
N'-(2-tert-Butyl-4-formyl-2,3-dihydro-1H-xanthen-9-yl)-
N,N-dimethylimidoformamide (26). Yield 2.70 g (80%),
yellow powder, mp 167–170°C (aqueous MeOH). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 10.24 (1H, s, CHO);
N'-(4-Formyl-5,7-diisopropyl-2-methyl-2,3-dihydro-1H-
xanthen-9-yl)-N,N-dimethylimidoformamide (30). Yield
2.39 g (63%), yellow powder, mp 165–167°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.26
(1H, s, CHO); 7.36 (1H, s, CH); 7.20 (1H, s, H-8 Ar); 7.12
(1H, s, H-6 Ar); 3.46–3.44 (1H, m, CH(CH3)2); 3.14 (3H, s,
CH3); 3.08 (3H, s, CH3); 2.89–2.88 (1H, m, CH(CH3)2);
2.71–2.69 (2H, m, CH2); 2.03–2.00 (1H, m, CH); 1.92–
1.89 (1H, m, CH); 1.77–1.69 (1H, m, CH); 1.27 (6H, d,
3J = 6.9, CH(CH3)2); 1.23 (6H, d, 3J = 6.9, CH(CH3)2); 1.05
3
4
7.48 (1H, dd, J = 7.8, J = 1.2, H Ar); 7.38 (1H, s, CH);
7.34–7.29 (1H, m, H Ar); 7.12 (1H, d, 3J = 8.1, H Ar); 7.08
(1H, t, J = 7.7, H Ar); 3.13 (3H, s, CH3); 3.08 (3H, s,
3
CH3); 2.89–2.77 (2H, m, CH2); 1.95–1.87 (2H, m, CH2);
1.81–1.76 (1H, m, CH); 0.95 (9H, s, t-Bu). 13C NMR
spectrum (CDCl3), δ, ppm: 186.4; 163.1; 153.4; 152.3;
146.7; 139.8; 123.8; 123.0; 121.1; 115.4; 113.8; 110.6;
41.8; 40.1; 34.2; 32.1; 27.3; 26.0; 22.4. Mass spectrum, m/z
(Irel, %): 338 [М]+ (61), 281 (100). Found, %: C 74.60;
H 7.78; N 8.32. C21H26N2O2. Calculated, %: C 74.53;
H 7.74; N 8.28.
3
(3H, d, J = 6.3, CH3). 13C NMR spectrum (CDCl3),
δ, ppm: 185.9; 163.7; 153.3; 147.8; 143.4; 134.9; 129.8;
125.4; 120.4; 122.3; 119.0; 109.5; 40.3; 36.0; 33.9; 33.2; 30.5;
29.3; 27.1; 26.8; 22.5; 21.1. Mass spectrum, m/z (Irel, %):
44

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
380 [М]+ (84), 351 (100). Found, %: C 75.97; H 8.55; N 7.43.
N'-(5,7-Dibromo-4-formyl-2,3-dihydro-1H-xanthen-
9-yl)-N,N-dimethylimidoformamide (35). Yield 2.11 g
(48%), yellow powder, mp 190–193°C (aqueous MeOH).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.35 (1H, s,
CHO); 7.59 (1H, s, H Ar); 7.56 (1H, s, H Ar); 7.37 (1H, s,
CH); 3.10 (3H, s, CH3); 3.07 (3H, s, CH3); 2.52–2.49 (2H,
m, CH2); 2.43–2.40 (2H, m, CH2); 1.66–1.63 (2H, m, CH2).
13C NMR spectrum (CDCl3), δ, ppm: 187.4; 161.8; 153.8;
148.1; 144.6; 135.0; 125.9; 124.2; 115.5; 113.7; 112.1; 109.8;
40.3; 34.4; 25.4; 21.0; 20.3. Mass spectrum, m/z (Irel, %):
440 [М]+ (100). Found, %: C 46.50; H 3.71; N 6.45.
C17H16Br2N2O2. Calculated, %: C 46.39; H 3.66; N 6.36.
N'-(5,7-Dibromo-4-formyl-2-methyl-2,3-dihydro-1H-
xanthen-9-yl)-N,N-dimethylimidoformamide (36). Yield
2.04 g (45%), yellow powder, mp 145–148°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.36
C24H32N2O2. Calculated, %: C 75.75; H 8.48; N 7.36.
N'-(2-tert-Butyl-4-formyl-5,7-diisopropyl-2,3-dihydro-
1H-xanthen-9-yl)-N,N-dimethylimidoformamide (31).
Yield 3.38 g (80%), yellow powder, mp 185–188°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.28
(1H, s, CHO); 7.35 (1H, s, CH); 7.18 (1H, s, H-8 Ar); 7.11
(1H, s, H-6 Ar); 3.45–3.43 (1H, m, CH(CH3)2); 3.13 (3H, s,
CH3); 3.07 (3H, s, CH3); 2.90–2.80 (2H, m, CH(CH3)2);
1.95–1.90 (2H, m, CH2); 1.33–1.28 (7H, m, CH, 2CH(CH3)2);
3
1.23 (6H, d, J = 6.5, 2CH(CH3)2); 0.95 (9H, s, t-Bu).
13C NMR spectrum (CDCl3), δ, ppm: 185.9; 163.8; 153.4;
148.1; 147.8; 143.4; 134.9; 125.4; 120.5; 118.9; 113.3;
110.2; 42.1; 34.3; 33.9; 32.2; 27.4; 27.2; 26.2; 24.2; 24.0;
22.6; 22.5. Mass spectrum, m/z (Irel, %): 422 [М]+ (35), 57
(100). Found, %: C 76.80; H 9.10; N 6.67. C27H38N2O2.
Calculated, %: C 76.74; H 9.06; N 6.63.
4
(1H, s, CHO); 7.61 (1H, d, J = 2.3, H Ar); 7.57 (1H, d,
N'-[4-Formyl-5,7-diisopropyl-2-(2-methylbutan-2-yl)-
2,3-dihydro-1H-xanthen-9-yl]-N,N-dimethylimidoform-
amide (32). Yield 2.83 g (65%), yellow powder, mp 168–
170°C (aqueous MeOH). 1H NMR spectrum (CDCl3),
δ, ppm: 10.30 (1H, s, CHO); 7.36 (1H, s, CH); 7.19 (1H, s,
H-8 Ar); 7.12 (1H, s, H-6 Ar); 3.48–3.44 (1H, m, CH(CH3)2);
3.14 (3H, s, CH3); 3.08 (3H, s, CH3); 2.90–2.80 (3H, m,
CH); 1.98–1.92 (2H, m, CH2); 1.65–160 (1H, m, CH); 1.30–
1.26 (2H, m, CH2); 1.26–1.24 (6H, m, 2CH3); 1.23–1.20
(6H, m, 2CH3); 0.84 (6H, s, 2CH3); 0.84–0.81 (3H, m,
CH3). 13C NMR spectrum (CDCl3), δ, ppm: 185.9; 163.7;
153.3; 148.1; 147.8; 138.8; 134.9; 125.4; 120.5; 118.9;
113.4; 110.4; 43.5; 39.5; 36.4; 32.6; 27.2; 26.2; 25.7; 24.1;
24.0; 23.0; 22.6; 22.5; 22.1. Mass spectrum, m/z (Irel, %):
436 [М]+ (100). Found, %: C 77.20; H 9.30; N 6.49.
C28H40N2O2. Calculated, %: C 77.02; H 9.23; N 6.42.
N'-(6-Formyl-2,4-diiodo-7,8,9,10-tetrahydrocyclohepta-
[b]chromen-11-yl)-N,N-dimethylimidoformamide (33).
Yield 2.63 g (48%), yellow powder, mp 151–155°C
4J = 2.3, H Ar); 7.36 (1H, s, CH); 3.12 (3H, s, CH3); 3.09
(3H, s, CH3); 2.71–2.65 (2H, m, CH2); 2.05–1.87 (2H, m,
CH2); 1.72–1.69 (1H, m, CH); 1.05 (3H, d, 3J = 6.5, CH3).
13C NMR spectrum (CDCl3), δ, ppm: 187.2; 161.3; 153.6;
147.8; 144.5; 135.1; 125.7; 124.0; 115.4; 113.5; 111.7; 109.6;
40.3; 34.3; 33.8; 29.5; 26.7; 20.6. Mass spectrum, m/z (Irel, %):
454 [М]+ (100). Found, %: C 47.76; H 4.06; N 6.25.
C18H18Br2N2O2. Calculated, %: C 47.60; H 3.99; N 6.17.
N'-(2-Bromo-6-formyl-7,8,9,10-tetrahydrocyclohepta-
[b]chromen-11-yl)-N,N-dimethylimidoformamide (37).
Yield 2.06 g (55%), yellow powder, mp 168–171°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.23
(1H, s, CHO); 7.61 (1H, d, 4J = 2.3, H-1 Ar); 7.37 (1H, dd,
4
3J = 8.6, J = 2.3, H-3 Ar); 7.34 (1H, s, CH); 6.94 (1H, d,
3J = 8.6, H-4 Ar); 3.12 (3H, s, CH3); 3.08 (3H, s, CH3);
2.61–2.58 (4H, m, 2CH2); 1.80–1.74 (4H, m, 2CH2).
13C NMR spectrum (CDCl3), δ, ppm: 187.7; 166.8; 153.4;
151.5; 149.1; 132.8; 129.6; 127.8; 126.8; 122.9; 116.8;
116.7; 40.2; 34.5; 28.1; 25.8; 25.6; 19.8. Mass spectrum,
m/z (Irel, %): 376 [М(81Br)]+ (97), 374 [М(79Br)]+ (100).
Found, %: C 57.70; H 5.12; N 7.51. C18H19BrN2O2.
Calculated, %: C 57.61; H 5.10; N 7.47.
1
(aqueous MeOH). H NMR spectrum (CDCl3), δ, ppm:
10.52 (1H, s, CHO); 7.96 (1H, s, H Ar); 7.74 (1H, s, H Ar);
7.32 (1H, s, CH); 3.11 (3H, s, CH3); 3.09 (3H, s, CH3);
2.63–2.57 (4H, m, 2CH2); 1.83–1.74 (4H, m, 2CH2).
13C NMR spectrum (CDCl3), δ, ppm: 189.1; 165.9; 153.6;
151.6; 148.2; 146.4; 133.1; 123.9; 117.5; 116.9; 86.3; 83.3;
40.3; 34.5; 28.1; 25.9; 25.7; 19.6. Mass spectrum, m/z
(Irel, %): 548 [М]+ (75), 504 (100). Found, %: C 39.61;
H 3.37; N 5.18. C18H18I2N2O2. Calculated, %: C 39.44;
H 3.31; N 5.11.
N'-(7-Bromo-4-formyl-2,3-dihydro-1H-xanthen-9-yl)-
N,N-dimethylimidoformamide (38). Yield 2.77 g (77%),
yellow powder, mp 180–182°C (aqueous MeOH). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 10.20 (1H, s, CHO);
7.61 (1H, d, 4J = 2.4, H-8 Ar); 7.38 (1H, s, CH); 7.37 (1H,
dd, 3J = 8.6, 4J = 2.4, H-6 Ar); 6.96 (1H, d, 3J = 8.6, H-5 Ar);
3
3.11 (3H, s, CH3); 3.08 (3H, s, CH3); 2.51 (2H, t, J = 6.1,
N'-(4-Formyl-5,7-diiodo-2-methyl-2,3-dihydro-1H-
xanthen-9-yl)-N,N-dimethylimidoformamide (34). Yield
2.80 g (51%), yellow powder, mp 168–171°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.44
(1H, s, CHO); 7.98 (1H, s, H Ar); 7.74 (1H, s, H Ar); 7.34
(1H, s, CH); 3.12 (3H, s, CH3); 3.08 (3H, s, CH3); 2.71–
2.64 (2H, m, CH2); 2.03–1.87 (2H, m, CH2); 1.73–1.65
CH2); 2.41 (2H, t, 3J = 6.0, CH2); 1.67–1.61 (2H, m, CH2).
13C NMR spectrum (CDCl3), δ, ppm: 186.4; 162.5; 153.6;
151.2; 145.3; 132.3; 126.5; 123.0; 116.8; 115.5; 113.2;
111.1; 40.5; 33.8; 25.3; 20.8; 20.1. Mass spectrum, m/z
(Irel, %): 362 [М(81Br)]+ (98), 360 [М(79Br)]+ (100). Found, %:
C 56.65; H 4.80; N 7.61. C17H17BrN2O2. Calculated, %:
C 56.52; H 4.74; N 7.75.
3
(1H, m, CH); 1.04 (3H, d, J = 6.3, CH3). 13C NMR
N'-(7-Bromo-4-formyl-2-methyl-2,3-dihydro-1H-xanthen-
9-yl)-N,N-dimethylimidoformamide (39). Yield 2.63 g
(70%), yellow powder, mp 251–254°C (aqueous MeOH).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.22 (1H, s,
CHO); 7.62 (1H, d, 4J = 2.3, H-8 Ar); 7.39 (1H,
spectrum (CDCl3), δ, ppm: 187.8; 161.9; 153.7; 151.2;
146.2; 144.7; 132.9; 124.0; 113.5; 111.3; 86.5; 83.5; 40.4;
34.4; 33.2; 29.0; 26.6; 20.9. Mass spectrum, m/z (Irel, %):
548 [М]+ (82). Found, %: C 39.58; H 3.35; N 5.17.
C18H18I2N2O2. Calculated, %: C 39.44; H 3.31; N 5.11.
4
dd,3J = 8.6, J = 2.3, H-6 Ar); 7.36 (1H, s, CH); 6.98 (1H,
45

Chemistry of Heterocyclic Compounds 2019, 55(1), 38–46
3
d, J = 8.6, H-5 Ar); 3.13 (3H, s, CH3); 3.09 (3H, s, CH3);
References
2.72–2.67 (2H, m, CH2); 2.04–1.85 (2H, m, CH2); 1.82–
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1.78 (1H, m, CH); 1.05 (3H, d, J = 6.5, CH3). 13C NMR
3
spectrum (CDCl3), δ, ppm: 186.5; 162.4; 153.5; 151.2;
145.5; 132.4; 126.5; 123.0; 116.9; 115.6; 113.3; 110.4;
40.2; 33.1; 30.0; 29.0; 26.5; 20.9. Mass spectrum, m/z (Irel, %):
376 [М(81Br)]+ (84), 374 [М(79Br)]+ (82), 29 (100). Found, %:
C 57.81; H 5.18; N 7.55. C18H19BrN2O2. Calculated, %:
C 57.61; H 5.10; N 7.47.
2. Seybold, G. J. J. Prakt. Chem. 1996, 338, 392.
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xanthen-9-yl)-N,N-dimethylimidoformamide (40). Yield
3.35 g (80%), yellow powder, mp 137–140°C (aqueous
MeOH). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.22
7. Markov, V. I.; Farat, O. K.; Varenichenko, S. A.; Velikaya, E. V.
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3
(1H, s, CHO); 7.59 (1H, s, H-8 Ar); 7.38 (1H, d, J = 8.6,
3
9. Markov, V. I.; Farat, O. K.; Varenichenko, S. A.; Velikaya, E. V.;
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H-6 Ar); 7.36 (1H, s, CH); 6.99 (1H, d, J = 8.6, H-5 Ar);
3.13 (3H, s, CH3); 3.08 (3H, s, CH3); 2.84–2.77 (2H, m,
CH2); 1.94–1.88 (2H, m, CH2); 1.70–1.65 (1H, m, CH); 0.94
(9H, s, t-Bu). 13C NMR spectrum (CDCl3), δ, ppm: 186.7;
162.5; 153.6; 151.3; 145.3; 132.5; 126.5; 123.0; 117.1; 115.7;
114.5; 111.3; 41.8; 32.2; 27.5; 27.4; 23.7; 26.3; 22.4. Mass
spectrum, m/z (Irel, %): 418 [М(81Br)]+ (80), 416 [М(79Br)]+
(77), 57 (100). Found, %: C 60.59; H 6.12; N 6.80.
C21H25BrN2O2. Calculated, %: C 60.44; H 6.04; N 6.71.
X-ray diffraction study of compound 26. Crystals
(C21H26N2O2, Mr 338.44) are monoclinic, space group P21/c, at
120 K: a 11.2411(7), b 9.9313(6), c 17.2530(11) Å;
β 106.6430(10)°; V 845.4(2) Å3; Z 4; dcalc 1.218 g/cm–3;
µ(MoKα) 0.078 mm–1; F(000) 728. Intensities of 23262
reflections were measured with a Bruker APEX 2 Duo
diffractometer (CCD detector) (λ(MoKa) 0.71073 Å,
ω-scans, 2θ < 60°), and 5367 independent reflections
(Rint 0.0400) were used in further refinement. The structure
was solved by direct method and refined by the full-matrix
least-squares technique against F2 in the anisotropic-
isotropic approximation. The H(C) atom positions were
calculated, these atoms were refined in the isotropic
approximation within the riding model. For compound 26,
the refinement converged to wR2 0.1314 and GOF 1.024
for all independent reflections (R1 0.0461 was calculated
against F for 3927 observed reflections with I > 2σ(I)). All
crystallography calculations were performed using the
SHELX software.21,22 The DFT calculations were carried
out using the Gaussian 09 program,23 the ''Atoms in
Molecules'' analysis was performed within the MultiWFN
program.24 Crystal data were deposited at the Cambridge
Crystal Database (deposit CCDC 1866102).
13. The Quantum Theory of Atoms in Molecules: From Solid
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1
Supplementary information file containing H and 13C
NMR spectra and mass spectra of all synthesized com-
pounds (except compounds 32, 36, 37, 40) is available at
the journal website at http://link.springer.com/journal/10593.
I. V. Ananyev is thankful to the Russian Foundation for
Basic Research (project № 18-33-20075) for the financial
support of X-ray diffraction studies and DFT calculations.
Authors are grateful to Dr. N. E. Borisova for NMR
studies. The NMR measurements were supported by the
Laboratory of Magnetic Tomography and Spectroscopy of
Chemical Department of the Moscow State University.
24. Lu, T.; Chen, F. J. Comput. Chem. 2012, 33, 580.
46