Synthesis and properties of 1,3-diaryl-5,6-dihydro-8h-imidazo-[2,1-c]-1,4-oxazinium bromides

Article abstract of DOI:10.1023/B:COHC.0000003529.60667.25

It has been established that the condensation of 3-(4-methoxyphenylamino)-5,6-dihydro-2H-1,4-oxazine with substituted phenacyl bromides occurs at the exocyclic nitrogen atom with formation of 3-aryl-3-hydroxy-1-(4-methoxyphenyl)-2,5,6,8-tetrahydro-3H-imidazo[2,1-c]-1, 4-oxazinium bromides. By treatment of the latter with acetic anhydride 3-aryl-1-(4-methoxyphenyl)-5,6-dihydro-8H-imidazo[2,1-c]-1,4-oxazinium bromides are formed. The structures of the compounds synthesized were determined via ¹H NMR spectroscopy and X-ray diffraction.

Full text of DOI:10.1023/B:COHC.0000003529.60667.25

Chemistry of Heterocyclic Compounds, Vol. 39, No. 8, 2003
SYNTHESIS AND PROPERTIES OF
1,3-DIARYL-5,6-DIHYDRO-8H-IMIDAZO-
c
[2,1- ]-1,4-OXAZINIUM BROMIDES
A. M. Demchenko1, N. A. Shtil2, A. P. Andrushko2, A. N. Krasovsky2, A. N. Chernega3,
E. B. Rusanov3, V. V. Pirozhenko3, and M. O. Lozinskii3
It has been established that the condensation of 3-(4-methoxyphenylamino)-5,6-dihydro-2H-1,4-oxazine
with substituted phenacyl bromides occurs at the exocyclic nitrogen atom with formation of 3-aryl-3-
hydroxy-1-(4-methoxyphenyl)-2,5,6,8-tetrahydro-3H-imidazo[2,1-c]-1,4-oxazinium
bromides.
By
treatment of the latter with acetic anhydride 3-aryl-1-(4-methoxyphenyl)-5,6-dihydro-8H-
imidazo[2,1-c]-1,4-oxazinium bromides are formed. The structures of the compounds synthesized were
determined via 1H NMR spectroscopy and X-ray diffraction.
Keywords: heterocyclic amidines, 3-(4-methoxyphenylimino)-5,6-dihydro-2H-1,4-oxazine, substituted
phenacyl bromides, 3-ethoxy-5,6-dihydro-2H-1,4-oxazine, exocyclic nitrogen atom, alkylation.
In a continuation of our work on the properties of heterocyclic N-aryl(alkyl)amidines [1,4], we have
studied the alkylation of 3-(4-methoxyphenylamino)-5,6-dihydro-2H-1,4-oxazine (1) with substituted phenacyl
bromides. The initial products of the reaction are the salts 2a-e in 48-78% yield (Table 1). 3-Aryl-1-(4-
methoxyphenyl)-5,6-dihydro-8H-imidazo[2,1-c]-1,4-oxazinium bromides 3a-e are obtained when the initial salts
are refluxed with acetic anhydride. The structures of the reaction products 2a-e were investigated by IR and
1H NMR spectroscopy. For example the stretching bands of the CO group in the range 1650-1750 cm-1 and of
the NH group in the 3300-3500 cm-1 are absent from the IR spectra of products 2a-e, while the characteristic
1
absorption bands of the associated OH group appear in the range 3060-3100 cm-1. In the H NMR spectra of
DMSO-d6 solutions, the signals of the methylene group of the oxazine ring occur in the range 3.01-4.48 ppm.
The two-proton singlet of the 8-CH2 group is found in the 4.38-4.48 ppm region. The signals of the methoxy
groups are recorded at 3.81-3.84 ppm. As a result of the presence of an asymmetric carbon atom in compounds
2, the methylene groups in the second position in the systems appear as characteristic AB systems in the
4.46-4.95 ppm (J = 16.8-17.4 Hz). The one-proton singlet of the OH group is observed in the 8.11-8.30 ppm
region (this assignment is confirmed by disappearance of this signal when the spectra are recorded for a second
time in the presence of a small amount of D2O) (Table 2). Thus compounds 2a-e are 1,3-diaryl-2,5,6,8-
tetrahydro-3H-imidazo[2,1-c]-1,4-oxazinium bromides. It is interesting to note that these salts dissolve well in
chloroform as well as in polar solvents.
__________________________________________________________________________________________
1
T. G. Shevchenko Chernigov Pedagogical University, Chernigov 14013, Ukraine; e-mail:
2
3
demch@cn.relc.com. Chernigov Technological University, Chernigov 14027, Ukraine. Institute of Organic
Chemistry, Ukraine National Academy of Sciences, Kiev 02094, Ukraine; e-mail: iochkiev@ukrpack.net.
Translated from Khimii Geterotsiklicheskikh Soedinenii, No. 8, 1239-1245, August, 2003. Original article
submitted February 13, 2001.
1084
0009-3122/03/3908-1084$25.00©2003 Plenum Publishing Corporation

OMe
OMe
OMe
+
+
N
_
N
Ac2O
ArCOCH2Br
O
O
Br
N
N
OH
NH
O
R
R
N
_
Br
1
R
2a–c
R
3a–c
2, 3 a R = 4-Me; b R = 4-Br; c R = 2-F,4-OMe; d R = 3,4-OCH2CH2O; e R = 4-Ph
Compounds 3a-e were obtained by refluxing salts 2a-e in Ac2O. The structures of the imidazolinium salts
obtained were also determined by 1H NMR spectroscopy. The disappearance of the asymmetric center on going
from compounds 2 to products 3 led to a considerable simplification of the proton spectra of the latter. For
example the methylene groups of the oxazine ring appear as two triplets and a singlet at 4.18, 4.33, and 5.1 ppm.
It should be noted that the data from the spectral studies do not determine unambiguously which of the
nitrogen atoms is alkylated. Therefore an X-ray crystallographic of compound 3a was carried out which showed
that alkylation occurred at the exocyclic nitrogen atom to give 3-aryl-3-hydroxy-1-(4-methoxyphenyl)-2,5,6,8-
tetrahydro-3H-imidazo[2,1-c]-1,4-oxazinium bromides, 3a-e.
TABLE 1. Characteristics of Compounds 1, 2a-e, and 3a-e
Empirical
formula
Found N, %
Compound
mp, °C
Yield, %
——————
Calculated N, %
C11H14N2O2·HBr
C20H23N2O3·Br
C19H20BrN2O3·Br
C20H22FN2O4·Br
C21H23N2O5·Br
C25H25N2O3·Br
C20H21N2O2·Br
C19H18BrN2O2·Br
C20H20FN2O3·Br
C21H21N2O4·Br
C25H23N2O2·Br
9.98
9.76
173-174
206-207
206-207
202-203
176-177
213-215
213-214
230-231
209-210
212-213
241-242
78
65
75
68
64
78
50
62
48
53
62
1
6.50
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
6.68
5.84
5.79
6.03
6.18
5.96
6.05
5.97
5.82
6.72
6.98
5.76
6.01
6.26
6.44
6.51
6.29
5.88
6.05
1085

TABLE 2. IR and 1H NMR Spectra of Compounds 1, 2a-e, and 3a-e
IR spectrum,
1H NMR spectra, δ, ppm (J, Hz)
Com-
ν, cm-1
pound
MeO (s) OCH2 (s)
OCH2–CH2N
OCH2–CH2N
OH (s)
НAr (m)
Other signals
9.58 (s, 1H, NH)
3.80
3.81
4.68
4.42
3.33 (t, J = 5.1)
3.01-3.42 (m)
3.95 (t, J = 5.1)
7.06-7.28 (4H)
7.10-7.72 (8H)
1
2a
1630; 3060-3070
3.97 (m)
8.16
2.36 (s, 3H, CH3); 4.69 and 4.87 (dd,
J = 17.4, 2H, CH2N)
1620; 3060-3070
1635; 3080-3090
3.81
3.84
4.43
4.44
3.05-3.43 (m)
3.07-3.69 (m)
4.00 (m)
8.30
8.24
7.09-7.32 (8H)
6.68-7.86 (7H)
4.46 and 4.86 (dd, J = 16.8, 2H, CH2N)
2b
2c
4.08-4.39 (m)
3.86 (s, 3H, OCH3); 4.58 and 4.82 (dd,
J = 17.1, 2H, CH2N)
1630; 3090
3.81
4.38
3.05-3.42 (m)
3.98 (m)
8.11
8.27
6.95-7.58 (7H)
4.29 (s, 4H, OCH2CH2O); 4.67 and 4.83
2d
(dd, J = 17.1, 2H, CH2N)
1620; 3090-3100
1620
3.82
3.82
3.86
3.85
3.84
3.86
4.48
5.09
5.09
5.12
5.21
5.13
3.08-3.50 (m)
4.03 (m)
7.09-7.85 (13H)
7.19-7.71 (8H)
7.19-7.82 (8H)
6.85-8.02 (7H)
7.02-7.75 (7H)
7.21-7.95 (13H)
4.75 and 4.95 (dd, J = 17.1, 2H, CH2N)
2.41 (s, 3H, CH3); 8.24 (s, 1H, CHN)
8.32 (s, 1H, CHN)
2e
3a
3b
3c
3d
3е
4.18 (t, J = 4.5)
4.18 (t, J = 4.2)
4.19 (t, J = 4.5)
4.18 (t, J = 4.5)
4.20 (t, J = 4.8)
4.30 (t, J = 4.5)
4.33 (t, J = 4.2)
4.33 (t, J = 4.5)
4.36 (t, J = 4.5)
4.42 (t, J = 4.8)
1620
1640
1610
1610
3.86 (s, 3H, OCH3); 8.31 (s, 1H, CHN)
4.27 (s, 4H, OCH2CH2O); 8.22 (s, 1H, CHN)
8.37 (s, 1H, CHN)

Fig. 1. General view of the molecule of 3-(4-methylphenyl)-1-(4-methoxyphenyl)-5,6-dihydro-
8H-imidazo[2,1-c]-1,4-oxazinium bromide (3a).
The overall shape of molecule 3a is shown in Fig.1, and its basic geometric parameters are shown in
Table 3. The central five-membered ring N(1)C(3)N(2)C(5)C(6) is planar withing limits of 0.010 A, while atoms C(2),
C(4), C(7), and C(14) are displaced from this plane by 0.212, -0.022, -0.015, and 0.130 A respectively. Distribution
of bond lengths in this ring indicate significant delocalization of electron density which is a characteristic trait
of the structure of similar systems [2]. The benzene rings C(7-12) and C(14-19) are twisted in the same direction
relative to the five membered ring, forming bifacial angles of 17.8 and 17.3° with it. The torsion angles in the
six-membered ring O(1)C(1)C(2)N(1)C(3)C(4) (O(1)C(1)C(2)N(1) 54.4(5), C(1)C(2)N(1)C(3 ) -16.3 (5), C(2)N(1)C(3)C(4) -9.0(5),
N(1)C(3)C(4)O(1) -4.2(5), C(3)C(4)O(1)C(1) 44.4(4), C(4)O(1)C(1)C(2) -72.0(4)°) indicate considerable nonplanarity.
Calculated Kremer–Pople modification parameters [5] (S 0.85, θ 43.1°, ψ 20.9°) show that this heterocycle has
a somewhat distorted half-chair conformation.
Fig. 2. Crystallographic packing of compound 3a (view along the c axis).
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TABLE 3. Basic Bond Lengths (d) and Bond Angles (ω) in the Cation of
Compound 3a
Bond
d, Å
Angle
ω, deg.
O(1)–C(4)
O(1)–C(1)
O(2)–C(17)
O(2)–C(20)
N(1)–C(3)
N(1)–C(6)
N(1)–C(2)
N(2)–C(3)
N(2)–C(5)
N(2)–C(14)
C(1)–C(2)
C(3)–C(4)
C(5)–C(6)
C(6)–C(7)
1.398(4)
1.423(5)
1.356(4)
1.433(5)
1.335(4)
1.400(4)
1.475(5)
1.342(4)
1.384(4)
1.443(4)
1.501(5)
1.497(5)
1.342(5)
1.468(5)
C(4)–O(1)–C(1)
C(17)–O(2)–C(20)
C(3)–N(1)–C(6)
C(3)–N(1)–C(2)
C(6)–N(1)–C(2)
C(3)–N(2)–C(5)
C(3)–N(2)–C(14)
C(5)–N(2)–C(14)
O(1)–C(1)–C(2)
N(1)–C(2)–C(1)
N(1)–C(3)–N(2)
N(1)–C(3)–C(4)
N(2)–C(3)–C(4)
O(1)–C(4)–C(3)
C(6)–C(5)–N(2)
C(5)–C(6)–N(1)
C(5)–C(6)–C(7)
N(1)–C(6)–C(7)
111.8(3)
117.1(3)
109.2(3)
121.4(3)
128.8(3)
107.7(3)
128.0(3)
124.1(3)
108.2(3)
108.2(3)
108.3(3)
121.6(3)
130.0(3)
111.5(3)
109.0(3)
105.7(3)
128.5(3)
125.9(3)
In the crystal of compound 3a the cations are associated in centrosymmetric dimeric pairs with the
aromatic systems N(1)C(3)N(2)C(5-12) placed in parallel at a distance of 3.434(5) A in a head to tail arrangement
(Fig. 2). These cationic dimers are organized in layers separated by layers of anions. No short contacts were
observed between cations and anions.
EXPERIMENTAL
IR spectra of KBr disks were taken on a UR-20 instrument. 1H NMR spectra of DMSO-d6 solutions with
TMS as internal standard were recorded on a Bruker instrument (300 MHz). Constants, yields, and elemental
analyses of new compounds are given in Tables 1 and 2.
The X-ray Structural Analysis of Compound 3a was carried out at room temperature on an automatic
four circle Enraf-Nonius CAD-4 diffractometer (λMoKα radiation, relative rate of scanning ω/2θ = 1.2,
θmax = 24°, segment of sphere 0
h
11, -11
k
11, -10
l 11). To determine the parameters of the
≤ ≤
≤
≤
≤
≤
elementary cell and the orientation matrix for a monocrystal of compound 3a with linear dimensions 0.22 × 0.38
× 0.47 mm, 22 reflexions with 12 < θ < 13° were used. A total of 2850 reflexions were collected, of which 2667
were symmetrically independent (average R factor 0.020). Crystals of compound 3a are triclinic, a = 9.652(2),
b = 9.690(1), c = 9.847(1) Å; α = 79.42(1), β = 73.08(1), γ = 85.09(1)°; V = 863.2(2) Å3; Z = 2; dcalc
=
1.544 g/cm3; µ = 2.397 mm-1; F(000) = 412; space group P1 (No.2). The structure was solved by direct methods
and refined by least squares in the full-matric anisotropic approximation using the SHELXS and SHEXL 93
programs [6, 7]. For the refinement 2304 reflexions with I > 2σ(I) were used (310 parameters were refined, with
number of reflexions per parameter 7.43; the weighting used was ω = 1/[σ2(Fσ2) + (0.060P)2 + 0.217P], where
P = (Fσ2 + 2Fc2)/3, ratio of maximum/mean shift to error in the last cycle 0.013/0.001). Corrections for
anomalous dispersion were introduced , but errors for absorption were not taken into account. All hydrogen
atoms were revealed objectively in the electron density difference syntheses and were refined isotropically. The
1088

final values of the residual factors were R1(F) = 0.0387, Rw(F2) = 0.0933, GOOF 1.065. The residual electron
densities from the Fourier difference series were 0.69 and -0.64 e/A3. The complete set of X-ray structural data
has been deposited in the Cambridge Structural Data Bank (register No. 145573).
3-(4-Methoxyphenylamino)-5,6-dihydro-2H-oxazine-1,4 (1). 3-Ethoxy-5,6-dihydro-2H-1,4-oxazine
[8] (14.2 g, 0.11 mol) was added to anisidinium chloride (16 g, 0.1 mol) at 20°C. The reaction mixture was kept
at room temperature for 24 h, after which the residue was triturated with ether, filtered, and sissolved in water
(20 ml). 50% Sodium hydroxide solution (10 ml) was added to the solution. The oily layer was extracted with
chloroform, the chloroform was evaporated in vacuum, the residue was ground with a minimum amount of
ether, filtered, washed with hexane, and used in further syntheses.
3-Aryl-3-hydroxy-1-(4-methoxyphenyl)-2,5,6,8-tetrahydro-3H-imidazo[2,1-c]-1,4-oxazinium Bromides
(2a-e). Morpholinimine (1) (2.06 g, 0.01 mol) was added to a solution of an α-halo ketone (0.01 mol) in ethyl
acetate (30 ml). The mixture was refluxed until a precipitate began to form (1-2 h). The mixture was then
cooled, the precipitate was filtered off, washed with ether, and crystallized from ethanol.
3-Aryl-1-(4-methoxyphenyl)-5,6-dihydro-8H-imidazo[2,1-c]-1,4-oxazinium Bromides (3a-e). Acetic
anhydride (30 ml) was added to a bromide 2a-e (0.01 mol) and the mixture was refluxed for 5 h. The Ac2O was
then evaporated in vacuum, the oily residue was ground with acetone, filtered, and crystallized from 2-propanol.
REFERENCES
1.
2.
A. M. Demchenko, K. G. Chumakov, A. N. Nazarenko, A. N. Krasovsky, V. V. Pirozhenko, and
M. O. Lozinskii, Khim. Geterotsikl. Soedin., 644 (1995).
A. M. Demchenko, K. G. Chumakov, A. N. Krasovsky, E. B. Rusanov, A. N. Chernega, and
M. O. Lozinskii, Zh. Org. Khim., 67, 1886 (1997).
3.
4.
A. M. Demchenko, Dokl. Nat. Akad. Nauk Ukraine, 4, 144 (2000).
A. M. Demchenko, K. G. Chumakov, A. N. Krasovsky, V. V. Pirozhenko, and M. O. Lozinskii, Khim.
Geterotsikl. Soedin., 829 (1997).
5.
6.
N. S. Zefirov and V. A. Palyulin, Dokl. Akad, Nauk , 252, 111 (1980).
G. M. Sheldrick, SHELXS-86. Program for the Solution of Crystal Structures, Univ of Göttingen,
Göttingen, Germany, 1986.
7.
8.
G. M. Sheldrick, SHELXL-93. Program for the Solution of Crystal Structures, Univ of Göttingen,
Göttingen, Germany, 1993.
D. R. Shridar, M. Jogibhukta, P. P. Joshi, and P. Gopal Reddy, Ind. J. Chem., 20B, 132 (1981).
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