Synthesis of 5-substituted 8,8-dimethyl-8,9-dihydro-3H,7H-[1,2]oxazino[5,4, 3-de]quinolin-3-ones

Article abstract of DOI:10.1007/s10593-013-1170-z

The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8- tetrahydroquinoline-4-carboxylic acids with hydroxylamine results in the formation of 5-substituted 8,8-dimethyl-8,9-dihydro-3H,7H-[1,2]ox-azino[5,4,3- de]quinolin-3-ones. The structure of the 5-phenyl derivative has been established by X-ray structural analysis. A possible mechanism of the reaction has been proposed on the basis of nonempirical quantum-chemical calculations.

Full text of DOI:10.1007/s10593-013-1170-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
SYNTHESIS OF 5-SUBSTITUTED 8,8-DIMETHYL-
8,9-DIHYDRO-3H,7H-[1,2]OXAZINO[5,4,3-de]QUINOLIN-3-ONES
D. A. Rudenko1, P. A. Slepukhin2, V. I. Karmanov3, S. N. Shurov1*,
M. I. Vakhrin1, and Yu. A. Shchurov1
The reaction of 2-substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids with
hydroxylamine results in the formation of 5-substituted 8,8-dimethyl-8,9-dihydro-3H,7H-[1,2]ox-
azino[5,4,3-de]quinolin-3-ones. The structure of the 5-phenyl derivative has been established by X-ray
structural analysis. A possible mechanism of the reaction has been proposed on the basis of
nonempirical quantum-chemical calculations.
Keywords: hydroxylamine, 8,8-dimethyl-8,9-dihydro-3H,7H-[1,2]oxazino[5,4,3-de]quionolin-3-ones,
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids, quantum-chemical calculation.
One method for the construction of 1,2-oxazine ring is the interaction of 1,4-dicarbonyl compounds
with hydroxylamine. However, ring closure is not always observed in these reactions, hence the initially formed
oximes must be additionally cyclized [1-3]. In cases where the 1,4-dicarbonyl unit is part of a cyclic system,
reaction with hydroxylamine enables the synthesis of heterocycles containing a 1,2-oxazine [4].
2-Substituted 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-4-carboxylic acids 1a-g, obtained by the
reaction of 3-amino-5,5-dimethylcyclohex-2-enone with acyl(aroyl)pyruvic acids [5], are 1,4-dicarbonyl
compounds suitable as starting reagents in the synthesis of tricyclic heterocycles.
It has been found that the reaction of acids 1a-g with hydroxylamine, generated in situ from its
hydrochloride, leads to 5-substituted 8,8-dimethyl-8,9-dihydro-3H,7H-[1,2]oxazino[5,4,3-de]quionolin-3-ones 6a-g.
The compounds 6a-g are colorless crystalline substances, soluble in hot DMF and DMSO, and poorly
soluble in common organic solvents and water. Yields, melting points, and the elemental analyses of the
synthesized compounds 6a-g are given in Table 1.
_______
*To whom correspondence should be addressed, e-mail: seshurov@yandex.ru.
1Perm State National Research University, 15 Bukireva St., Perm 614990, Russia.
2Institute of Organic Synthesis, Ural Branch, Russian Academy of Science, 22 S. Kovalevskoi St.,
Yekaterinburg 620041, Russia; e-mail: slepukhin@iso.uran.ru.
3Institute of Technical Chemistry, Ural Branch, Russian Academy of Science, 3 Akademika Koroleva St., Perm
614013, Russia; e-mail: karmanovvi@rambler.ru.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1651-1656, October, 2012.
Original paper submitted February 8, 2012.
0009-3122/13/4810-1539©2013 Springer Science+Business Media New York
1539

Formation of the reaction products 6a-g can be explained by hydroxylamine nitrogen atom attack on
ketone carbonyl of the acid 1a-g and proton transfer from the nitrogen atom to the carbonyl oxygen atom
(intermediates 2a-g). Then in the intermediates 2a-g, the oxygen atom of the hydroxyamino group attacks the
carbon of the carboxyl group, which leads to the intermediates 4a-g. The latter then successively eliminates two
molecules of water to give the intermediates 5a-g and then the reaction products 6a-g.
OH
COOH
HO
O
OH
OH
N
N
COOH
N
Me
Me
+
Me
Me
Me
Me
N
R
N
R
N
R
9a–g
–H2O
8a–g
7a–g
–H2O
2
O
COOH
O
OH
O
3
O
1N
OH
R
HN
OH
H2NOH
Me
Me
4
9
EtOH
, 3 h
Me
Me
Me
5
N
R
1a–g
8
N
R
Me
N
7 6a–g
6
2a–g
–H2O
H
O
=/
O
OH
OH
OH
O
OH
O
O
HN
HN
HN
OH
OH
Me
Me
–H2O
Me
Me
Me
Me
N
R
N
R
4a–g
N
5a–g
R
3a–g
a R = t-Bu, b R = Ph, c R = 4-MeC6H4, d R = 4-MeOC6H4, e R = 4-EtOC6H4,
f R = 4-BrC6H4, g R = 4-ClC6H4
With the objective of elucidating the fundamental possibility of the proposed scheme, we carried out
calculations of the total energy, electronic and geometric characteristics of the intermediates 2b, 5b, and also the
intermediates 7b-9b using the CCP MO LCAO nonempirical method in the 6-31G(d) basis set.
According to the calculations, the distance lO···C between the reaction centers in intermediate 2b is 3.319 Ǻ,
and the values of the charges on the carboxyl group oxygen and carbon according to Löwdin are respectively -
0.458 and 0.296 a.u., which does not inhibit them becoming close enough to form an O–C bond. This
intermediate may be stabilized by an intramolecular hydrogen bond C(5)–O–H···O–CO–C(4), as indicated by
the calculated interatomic distance lH···O of 2.094 Ǻ.
Modeling of the nucleophilic attack on the carbon atom of the carboxylic acid allowed us to identify an
activated complex 3b, which corresponds to the transition state of this reaction. An interatomic distance lO···C
equal to 1.708 Ǻ corresponds to the maximum on the potential curve, while C=O bond length is increased to
1.289 Ǻ. The calculated lO···H bond length is equal to 1.004 Ǻ, and the interatomic distance lH···O=C is shortened to
1.241 Ǻ. The charge on the oxygen atom is practically unchanged (q(O) = -0.461 a.u.), but the charge on the
carbon atom increased to 0.371 a.u.
Thus, as the reaction centers approach, a proton is transferred from the hydroxyamino group oxygen
atom to the carbonyl oxygen atom. Further shortening of the lO···C distance leads to the formation of intermediate
4b, in which the length of the N–O–C bond becomes equal to 1.400 Ǻ. The lengths of the newly formed C–O
and O–H bonds are equal to 1.374 and 0.952 Ǻ, respectively.
1540

TABLE 1. Physicochemical Characteristics of the Synthesized Compounds 6a-g
Found, %
——————
Com-
pound
Empirical
formula
Mp, °С
Yield, %
Calculated, %
C
H
N
C16H20N2O2
C18H16N2O2
C19H18N2O2
C19H18N2O3
C20H20N2O3
C18H15BrN2O2
C18H15ClN2O2
70.31
70.56
73.95
73.96
7.17
7.40
5.43
5.52
5.87
5.92
5.69
5.63
5.99
5.99
3.95
4.07
4.53
4.63
10.05
10.29
9.61
9.58
9.00
9.14
8.64
8.69
8.30
8.33
7.75
7.55
8.40
8.57
28-29
96
81
86
90
70
80
88
6a
6b
6c
6d
6e
6f
162-163
215-16
74.22
74.49
70.55
70.79
71.54
71.41
58.37
58.24
216-217
179-180
220-221
226-227
66.11
66.16
6g
The most probable direction for the dehydration of intermediate 4b is the formation of intermediate 5b,
which, according to calculations, is more stable by 13.9 kJ/mol than the alternative intermediate 9b.
The oximes 7b and 8b, potentially formed through dehydration of the key intermediate 2b, were not
observed in the reaction mixture.
1
The structures of reaction products 6a-g were established by the data of IR, H and 13C NMR
1
13
spectroscopy (Tables 2 and 3). The assignments of H and C NMR signals were based on heteronuclear 2D
13
1H–13C gHSQC and gHMBC experiments. For example, of the two C NMR signals at 174.3 and 163.1 ppm
exhibited by compound 6a, the weaker signal is assigned to atom C–5 by analogy with the α-carbon
TABLE 2. IR and 1H NMR Spectra of Compounds 6a–g
IR spectrum,
1Н NMR spectrum δ, ppm (J, Hz)
, cm–1
Com-
C=S,
C=N
8-(СН3)2 7-CH2 9-CH2
H-4
pound
C=O
R
(6H, s)
2H, s) (2H, s) (1H, s)
1596
1591
1742
1747
1.08
1.10
2.98
3.05
2.75
2.78
7.87
8.37
1.39 (9Н, s, C(CH3)3)
6a
6b
7.54–7.56 (3Н, m, H Ph);
8.22–8.26 (2Н, m, H Ph)
2.39 (3Н, s, СН3);
1588
1584
1588
1745
1741
1742
1.10
1.10
1.10
3.03
3.02
3.02
2.77
2.76
2.76
8.31
8.27
8.26
6c
6d
6e
7.36 (2Н, d, J = 8.4, H Ar);
8.14 (2Н, d, J = 8.4, H Ar)
3.86 (3Н, s, ОСН3);
7.09 (2Н, d, J = 8.9, H Ar);
8.21 (2Н, d, J = 8.9, H Ar)
1.37 (3Н, t, J = 6.9, ОСН2СН3);
4.14 (2Н, q J = 6.9, ОСН2СН3);
7.07 (2Н, d, J = 9.0, H Ar);
8.19 (2Н, d, J = 9.0, H Ar)
7.73 (2Н, d, J = 8.9, H Ar);
8.19 (2Н, d, J = 8.9, H Ar)
7.58 (2Н, d, J = 8.8, H Ar);
8.25 (2Н, d, J = 8.8, H Ar)
1585
1588
1746
1746
1.11
1.11
3.05
3.05
2.78
2.78
8.38
8.37
6f
6g

1541

1542

in the pyridine molecule. At the same time, this signal appears as a cross peak in the 2D gHMBC spectrum with
the protons of the tert-butyl substituent. The corresponding signals of the carbon atoms of the methylene groups
were assigned from the 2D gHSQC spectra on account of the direct constants of the spin-spin interactions
similar to other carbon atoms bound with hydrogen atoms.
Fig. 1. Molecular structure of compound 6b with atoms represented by thermal vibration elipsoids of 50%
probability (the EtOAc molecule found in the composition of the crystal is not shown).
Monocrystal X-ray diffraction study of compound 6b also confirmed the proposed product structure for
the reaction discussed (Fig. 1). The compound crystallized in the centrosymmetric space group of the triclinic
class. The fused heterocyclic fragment is planar within limits of 0.04 Ǻ, but the phenyl substituent is at an angle
of 7.2° relative to that plane. The distribution of bond lengths in the oxazine ring allows its characterization as a
system of conjugated multiple bonds, but not as an aromatic system. At the same time, the bond lengths in the
pyridine ring are noticeably equalized. The molecular packing is formed by molecule layers with planes of the
fused heterocyclic systems at an angle of 55.86° relative to the [1 0 0] plane. There are no conspicuous close
contacts in the packing.
Thus the reaction studied is a convenient and effective method for the preparation of annelated three-
membered heterocyclic compounds containing an oxazine unit. The quantum-chemical calculations did not
contradict the proposed reaction scheme.
EXPERIMENTAL
1
13
IR spectra of nujol suspensions were recorded with a Bruker IFS 66ps spectrometer. H and C NMR
spectra in DMSO-d6 with HMDS as internal standard were recorded with a Varian Mercury 300 Plus
spectrometer (300 and 75 MHz, respectively). Elemental analysis was carried out with a LECO CHNS-932
apparatus. Melting points were determined with a PTP apparatus. Purity of the compounds synthesized was
confirmed by HPLC (Agilent 1260 chromatograph, MeCN eluent, detection at 254 and 300 nm). Quantum-
chemical calculations were carried out with the Firefly suite of software [6] on a Toshiba Portege M400 PC.
The starting acids 1a-g were prepared by a known method [5].
5–Substituted
8,8-Dimethyl-8,9-dihydro-3H,7H-[1,2]oxazino[5,4,3-de]quinolin-3-ones
6a-g
(General Method). H2NOH·HCl (1.0 g, 14.4 mmol) was ground in a mortar with anhydrous NaOAc (1.18 g,
14.4 mmol), the mixture was transferred to a glass beaker and boiled in EtOH (10 ml) for 1 min. The hot
solution was filtered, and the corresponding acid 1a-g (2.0 mmol) was added to the filtrate and refluxed for 3 h.
The reaction mixture was cooled, the precipitate was filtered off and washed on the filter with hot EtOH.
1543

X-ray Structural Study of Compound 6b. A crystal was grown from EtOAc as a 1:1 solvate,
empirical formula C18H16N2O2·C4H8O2 (M 380.45). Crystals of compound 6a were triclinic, space group P1; a
6.0405(6), b 11.845(11), c 12.0501(12) Ǻ, α 117.838(10)°, β 93.803(10)°, γ 95.908(8)°, V 751.92(13) Ǻ3, dcalc
1.291 g/cm3, Z 2. The unit cell parameters and the set of experimental reflections were measured by a standard
method [7] with an automatic four-cycle Xcalibur 3 diffractometer with a CCD detector by ω/2θ-scanning
method with monochromatic MoKα irradiation over the interval of angles 3.35<θ<28.28. Reflections (5129)
were measured, of which 3401 were independent (Rint 0.0204), 1605 with I > 2σ(I). The completeness of the
experiment for θ 25.50° was 95.5%. Correction for absorption was not used (μ 0.085 mm-1). The structure was
determined by a direct statistical method and was refined by complete matrix least squares method with respect
to F2 in the anisotropic approximation for all non-hydrogen atoms. Hydrogen atoms were placed in
geometrically calculated positions and refined in isotropic approximation. All calculations were carried out with
the SHELXTL suite of software (8). The final results of the refinement were R1 0.0428, wR2 0.0929 for
reflections with I > 2σ(I), R1 0.1049, wR2 0.1036 for all reflections, S 1.005. The maximum and minimum peaks
of the residual electronic density were 0.189 and -0.174 e·Ǻ-3. The results of the X-ray structural study have
been deposited at the Cambridge Crystallographic Data Center (CCDC 903807).
REFERENCES
1.
2.
3.
4.
5.
A. Maeder, Helv. Chim. Acta, 29, 120 (1946).
M. Masaki, H. Matsucubo, K. Masuzawa, Y. Chigira, and M. Ohta, J. Heterocycl. Chem., 2, 376 (1965).
B. Hardegger and S. Shatzmiller, Helv. Chim. Acta, 59, 2499 (1976).
C. P. Sakthidharan and N. Sampathkumar, Heterocycl. Lett., 1, 43 (2011).
D. A. Rudenko, S. N. Shurov, M. I. Kodess, M. A. Ezhikova, and A. N. Vasyanin, Zh. Org. Khim., 48,
803 (2012).
6.
A. A. Granovsky, Firefly version 7.1.G, http://classic.chem.msu.su/gran/firefly/index.html
(application date: 07.02.2012).
7.
8.
CrysAlis Pro, Version 171.33.66, Oxford Diffraction Ltd.
G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., A64, 112 (2008).
1544