Synthesis of quinolizin-2-one and pyrido[1,2-a]azepin-2-one derivatives from difluoroboron complexes of aroylacetones and O-methyllactims

Article abstract of DOI:10.1007/s11172-011-0308-3

O-Methyllactims react at the methyl group of difluoroboron complexes of aroylacetones with the formation of condensation products, novel difluoroboron chelates of 1-aryl-4-(piperi-din-2-ylidene)butane-1,3-diones and 1-aryl-4-(azepan-2-ylidene)butane-1,3-diones, which upon the action of concentrated HCl in ethanol are transformed into the corresponding quino-lizin-2-one and pyrido[1,2-a]azepin-2-one derivatives.

Full text of DOI:10.1007/s11172-011-0308-3

Russian Chemical Bulletin, International Edition, Vol. 60, No. 10, pp. 2027—2029, October, 2011
2027
Synthesis of quinolizinꢀ2ꢀone and pyrido[1,2ꢀa]azepinꢀ2ꢀone derivatives
from difluoroboron complexes of aroylacetones and Oꢀmethyllactims
I. V. Kravtsov, S. V. Baranin, P. A. Belyakov, and V. A. Dorokhov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vador@ioc.ac.ru
OꢀMethyllactims react at the methyl group of difluoroboron complexes of aroylacetones
with the formation of condensation products, novel difluoroboron chelates of 1ꢀarylꢀ4ꢀ(piperiꢀ
dinꢀ2ꢀylidene)butaneꢀ1,3ꢀdiones and 1ꢀarylꢀ4ꢀ(azepanꢀ2ꢀylidene)butaneꢀ1,3ꢀdiones, which
upon the action of concentrated HCl in ethanol are transformed into the corresponding quinoꢀ
lizinꢀ2ꢀone and pyrido[1,2ꢀa]azepinꢀ2ꢀone derivatives.
Key words: Oꢀmethyllactims, difluoroboron chelates of aroylacetones, condensation, 1ꢀarylꢀ
4ꢀ(piperidinꢀ2ꢀylidene)butaneꢀ1,3ꢀdiones, 1ꢀarylꢀ4ꢀ(azepanꢀ2ꢀylidene)butaneꢀ1,3ꢀdiones,
quinolizinꢀ2ꢀones, pyrido[1,2ꢀa]azepinꢀ2ꢀones.
Scheme 1
In the present work, we report on a new approach to
the synthesis of quinolizinꢀ2ꢀone and pyrido[1,2ꢀa]azepinꢀ
2ꢀone derivatives from difluoroboron chelates of aroylꢀ
acetones and Oꢀmethyllactims.
It is known that Oꢀmethyllactims, widely used in
heterocyclic synthesis,1—4 react with the methyleneꢀacꢀ
tive βꢀdicarbonyl compounds at the methylene group.5,6
However, chelation of βꢀdicarbonyl compounds with
boron can dramatically change their reactivity and makes
possible transformations uncharacteristic of the free
ligands. Thus, in the framework of our studies on the apꢀ
plication of boronꢀchelates of 1,3ꢀdiketones in the synꢀ
thesis of nitrogenꢀcontaining heterocyclic compounds, we
suggested new approaches towards pyrazoles7, pyrazoloꢀ
[1,5ꢀc]pyrimidines,8 and indazoles9 based on the condenꢀ
sation of amide acetetals at the exocyclic methyl (methylꢀ
ene) group of the βꢀdiketone difluoroboron chelates and
subsequent heterocyclization of the thus obtained enaminoꢀ
diketone complexes upon the action of the corresponding
binucleophilic reactants (hydrazines, thiosemicarbazide,
aminoguanidine). A convenient method for the preparaꢀ
tion of pyridazinꢀ4ꢀone derivatives was also found,10 which
is based on the ability of the methyl group in the boron
βꢀdiketonates to undergo attacks by diazonium salts.
In continuation of these studies, in the present work
we for the first time showed that Oꢀmethyllactims 2 and 3
react at the methyl groups of difluoroboron chelates of
aroylacetones 1a,b with the formation of chelate comꢀ
plexes 4a,b and 5a,b (Scheme 1).
n = 1 (2, 4), 2 (3, 5)
R = Ph (a), 4ꢀClC6H4 (b)
i. PhMe, microwave irradiation, 7 min.
The mass spectra of the synthesized chelates are charꢀ
acterized by the presence of the peaks for the molecular
ions [M]+ and the fragment ions [M – F]+. Their 1H NMR
spectra exhibit singlets for the protons of the CH group in
both the ylidene fragment and the chelate ring at δ 4.8—4.9
and δ 5.9—6.0, respectively, as well as a broad singlet for
the proton of the NH group at δ 9.7—9.8. The signal at
δ 0.5—0.7 in the 11B NMR spectra confirms the presence
of the tetracoordinated B atom in the molecules of the
compounds obtained.
It should be taken into account that an alternative
structure of the type 6 with a competitive N,Oꢀcoordinaꢀ
tion of the B atom is possible for the compounds obtained.
Taken the product of condensation of chelate 1a with
lactim 2 as an example, we unambiguously established
The reaction was carried out in toluene in a sealed tube
under microwave irradiation for 7 min. It should be noted
that without irradiation, the reaction carried out in boiling
toluene reached completion within 50—60 h.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1990—1992, October, 2011.
1066ꢀ5285/11/6010ꢀ2027 © 2011 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 10, October, 2011
Kravtsov et al.
insoluble in diethyl ether and hexane. Their mass spectra
exhibit peaks for the molecular ions [M]+, whereas the
1H NMR spectra in CDCl3 are characterized by the presꢀ
ence of two signals for the protons of the pyridine fragꢀ
ment at δ 6.2 and 6.3. A characteristic absorption band at
1630 cm–1 is present in the IR spectra, which corresponds
to the stretching vibrations of the carbonyl group of the
pyridone fragment.
A bicyclic fragment with the bridging nitrogen atom is
a part of many alkaloids exhibiting various biological acꢀ
tivity.11 Quinolizinꢀ2ꢀone derivatives are of special interꢀ
est, since they were found to display hypoglycemic,12,13
vasculoꢀ and bronchodilating properties.14
It should be noted that the multiꢀstep methods deꢀ
scribed in the literature for the synthesis of 4ꢀmethylꢀ
6,7,8,9ꢀtetrahydroꢀ2ꢀquinolizinone from diketene and
2ꢀpyridylacetonitrile15 or methyl 2ꢀpyridylacetate16 can
be used for the preparation of neither compounds containꢀ
ing aryl substituents at position 4, nor pyrido[1,2ꢀa]azepinꢀ
2ꢀone derivatives.
In conclusion, the approach suggested by us opens
a new efficient way for the construction of the indicated
fused systems with the bridging N atom.
n = 1, 2
that it has the structure 4a and, therefore, the O,Oꢀcoordiꢀ
nation of the boron atom during reactions of difluoroꢀ
boronꢀβꢀdiketonates with Oꢀmethyllactims retained. Thus,
in the 13C NMR spectrum of the compound with the cheꢀ
late site N—B—O (the structure 6a, R = Ph) one could
expect three triplet signals (C=O, C—N, CH2—N) split
due to the remote interaction with the fluorine nuclei. In
this case, two of the signals (C=O, C—N) should be in the low
field, whereas one of them (CH2—N) should be in the high
field. However, the 13C NMR spectrum shows that only
two C atoms interact with the fluorine atoms, which are
characterized by the presence of two triplets at δ 175.3 and
168.4 with J = 1.5 Hz in the downfield region of the spectrum,
whereas the upfield region exhibits the presence of four
singlets for the carbon atoms, no one of which displays splitꢀ
ting due to the remote interaction with the fluorine nuclei.
The IR spectra of compounds 4a,b and 5a,b in KBr
pellets contain a sharp absorption band in the region
3300 cm–1, which does not disappear if the spectrum is
recorded in a dilute solutions of THF, that indicates the
Experimental
1
H and 13C NMR spectra were recorded on a Bruker WMꢀ250
...
presence of intramolecular hydrogen bond NH O.
spectrometer (250 and 63 MHz, respectively) at 25 °C, 11B NMR
spectra, on a Bruker ACꢀ200P spectrometer (64.21 MHz,
BF3•OEt2 was an external standard, the lowꢀfield signals are
given relatively to BF3•OEt2 with the "+" signs). IR spectra
were recorded on a Specord Mꢀ82 spectrometer in KBr pellets.
Mass spectra were recorded on a Kratos MSꢀ30 instrument (EI,
70 eV). Microwave irradiation was carried out in a Daewoo c.r.s.
oven (concave reflectors, a double source of waves system, 480 W).
Difluoroboron chelates of aroylacetones 1a,b were obtained
from the corresponding aroylacetones and boron trifluoride diꢀ
ethyl etherate in benzene according to the known procedure.17
6ꢀMethoxyꢀ2,3,4,5ꢀtetrahydropyridine (2) was obtained accordꢀ
ing to the published method.18 7ꢀMethoxyꢀ3,4,5,6ꢀtetrahydroꢀ
2Hꢀazepine (3) commercially available from Aldrich was used
without additional purification.
The boronꢀchelates 4 and 5 are orange crystalline subꢀ
stances soluble in dioxane, THF, benzene, poorly soluble
in ethanol, ethyl acetate, diethyl ether, chloroform, and
insoluble in hexane. The chelates are stable upon proꢀ
longed reflux in the solution of sodium acetate in EtOH.
However, treatment of the latter with concentrated hydroꢀ
chloric acid in boiling ethanol resulted in deboronation
and subsequent heterocyclization of the free ligand to the
derivatives of 6,7,8,9ꢀtetrahydroꢀ2Hꢀquinolizinꢀ2ꢀone
7a,b and 7,8,9,10ꢀtetrahydroꢀ6Hꢀpyrido[1,2ꢀa]azepinꢀ2ꢀ
one 8a,b, respectively (Scheme 2).
Scheme 2
Reaction of aroylacetone difluoroboron chelates with Oꢀmethꢀ
yllactims (general procedure). A mixture of chelate 1a,b (2 mmol)
and Oꢀmethyllactim 2 or 3 (3 mmol) in toluene (4 mL) was
irradiated for 7 min in a sealed tube in a microwave oven (480 W).
The solvent was evaporated on a rotary evaporator, ethanol
(3 mL) was added to the residue. The crystals that formed were
filtered off and recrystallized from ethyl acetate to obtain cheꢀ
lates 4a,b or 5a,b as orange crystals.
Difluoroboron chelate of 4ꢀ(piperidinꢀ2ꢀylidene)ꢀ1ꢀphenylꢀ
butaneꢀ1,3ꢀdione (4a) was obtained from difluoroboron chelate
of benzoylacetone (1a) and 6ꢀmethoxyꢀ2,3,4,5ꢀtetrahydropyriꢀ
dine (2). The yield was 41%, m.p. 209—210 °C. Found (%):
C, 61.71; H, 5.68; N, 4.58. C15H16BF2NO2. Calculated (%):
C, 61.89; H, 5.54; N, 4.81. MS, m/z (Irel (%)): 291 [M]+ (67),
271 [M – F]+ (37), 225 (44). 1H NMR (CDCl3), δ: 1.82 (m, 4 H,
2 CH2); 2.55, 3.50 (both m, 2 H each, 2 CH2); 4.82, 5.95 (both s,
n = 1 (4, 7), 2 (5, 8)
R = Ph (a), 4ꢀClC6H4 (b)
i. HCl, EtOH, reflux, 4 h.
Bicyclic compounds 7a,b and 8a,b are well soluble in
ethanol, ethyl acetate, benzene, chloroform and virtually

Quinalizinꢀ2ꢀones, pyrido[1,2ꢀa]azepinꢀ2ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 10, October, 2011
2029
1 H each, 2 CH); 7.43, 7.86 (both m, total 5 H, Ar); 9.76 (br.s, 1 H,
NH). 13C NMR (CDCl3), δ: 18.3, 21.0, 29.6, 42.4, 91.4, 94.0, 126.6,
128.3, 131.2, 133.9, 168.4 (C=O), 169.2 (C=O), 175.3. 11B NMR
(CHCl3), δ: 0.67. IR, ν/cm–1: 3316, 2960, 2876, 1552, 1448.
Difluoroboron chelate of 1ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(piperidinꢀ2ꢀ
ylidene)butaneꢀ1,3ꢀdione (4b) was obtained from difluoroboron
chelate of 4ꢀchlorobenzoylacetone (1b) and 6ꢀmethoxyꢀ2,3,4,5ꢀ
tetrahydropyridine (2). The yield was 41%, m.p. 215—216 °C.
Found (%): C, 55.09; H, 4.80; N, 4.19. C15H15BClF2NO2. Calꢀ
culated (%): C, 55.34; H, 4.64; N, 4.30. MS, m/z (Irel (%)): 325
[M]+ (4), 306 [M – F]+ (2), 259 (6). 1H NMR (CDCl3), δ: 1.83
(m, 4 H, 2 CH2); 2.55, 3.52 (both m, 2 H each, 2 CH2); 4.82,
5.91 (both s, 1 H each, 2 CH); 7.36, 7.80 (both d, 2 H each, Ar,
J = 8.8 Hz); 9.81 (br.s, 1 H, NH). 11B NMR (CHCl3), δ: 0.53.
IR, ν/cm–1: 3308, 2952, 2852, 1556, 1480.
4ꢀPhenylꢀ7,8,9,10ꢀtetrahydroꢀ6Hꢀpyrido[1,2ꢀa]azepinꢀ2ꢀ
one (8a). The yield was 77%, m.p. 153—154 °C (hexane—benzꢀ
ene, 1 : 1). Found (%): C, 80.18; H, 7.30; N, 5.65. C16H17NO.
Calculated (%): C, 80.30; H, 7.16; N, 5.85. MS, m/z (Irel (%)):
1
239 [M]+ (59), 211 (100), 182 (36). H NMR (CDCl3), δ: 1.64
(m, 6 H, 3 CH2); 2.76, 3.78 (both m, 2 H each, 2 CH2); 6.17,
6.28 (both m, 1 H each, 2 CH); 7.25, 7.40 (both m, total 5 H,
Ar). 13C NMR (CDCl3), δ: 26.2, 28.0, 28.1, 34.4, 50.0, 117.6,
118.4, 127.8, 128.3, 128.8, 134.9, 152.4, 154.3, 178.2. IR, ν/cm–1
:
3048, 2928, 1628, 1560.
4ꢀ(4ꢀChlorophenyl)ꢀ7,8,9,10ꢀtetrahydroꢀ6Hꢀpyrido[1,2ꢀa]ꢀ
azepinꢀ2ꢀone (8b). The yield was 81%, m.p. 207—208 °C (benzꢀ
ene). Found (%): C, 69.98; H, 6.00; N, 5.02. C16H16ClNO.
Calculated (%): C, 70.20; H, 5.89; N, 5.12. MS, m/z (Irel (%)):
1
273 [M]+ (100), 245 (87), 216 (20). H NMR (CDCl3), δ: 1.64
Difluoroboron chelate of 4ꢀ(azepanꢀ2ꢀylidene)ꢀ1ꢀphenylꢀ
butaneꢀ1,3ꢀdione (5a) was obtained from difluoroboron chelate of
benzoylacetone (1a) and 7ꢀmethoxyꢀ3,4,5,6ꢀtetrahydroꢀ2Hꢀ
azepine (3). The yield was 43%, m.p. 189—190 °C. Found (%):
C, 62.76; H, 6.10; N, 4.37. C16H18BF2NO2. Calculated (%): C, 62.95;
H, 5.90; N, 4.59. MS, m/z (Irel (%)): 305 [M]+ (66), 285 [M – F]+
(38), 239 (42). 1H NMR (CDCl3), δ: 1.70 (m, 6 H, 3 CH2); 2.53,
3.53 (both m, 2 H each, 2 CH2); 4.94, 6.00 (both s, 1 H each, 2 CH);
7.44, 7.88 (both m, total 5 H, Ar); 9.69 (br.s, 1 H, NH). 11B NMR
(CHCl3), δ: 0.61. IR, ν/cm–1: 3332, 2928, 2864, 1544, 1448.
Difluoroboron chelate of 4ꢀ(azepanꢀ2ꢀylidene)ꢀ1ꢀ(4ꢀchloroꢀ
phenyl)butaneꢀ1,3ꢀdione (5b) was obtained from difluoroboron
chelate of 4ꢀchlorobenzoylacetone (1b) and 6ꢀmethoxyꢀ3,4,5,6ꢀ
tetrahydroꢀ2Hꢀazepine (3). The yield was 46%, m.p. 213—214 °C.
Found (%): C, 56.42; H, 5.13; N, 4.04. C16H17BClF2NO2. Calꢀ
culated (%): C, 56.59; H, 5.05; N, 4.12. MS, m/z (Irel (%)):
339 [M]+ (65), 319 [M – F]+ (9), 273 (18). 1H NMR (CDCl3), δ:
1.70 (m, 6 H, 3 CH2); 2.50, 3.54 (both m, 2 H each, 2 CH2);
4.94, 5.96 (both s, 1 H each, 2 CH); 7.38, 7.82 (both d, 2 H each,
Ar, J = 8.8 Hz); 9.73 (br.s, 1 H, NH). 11B NMR (CHCl3),
δ: 0.55. IR, ν/cm–1: 3312, 2936, 2860, 1540, 1476.
Synthesis of 4ꢀarylꢀ6,7,8,9ꢀtetrahydroꢀ2Hꢀquinolizinꢀ2ꢀones
7a,b and 4ꢀarylꢀ7,8,9,10ꢀtetrahydroꢀ6Hꢀpyrido[1,2ꢀa]azepinꢀ2ꢀ
ones 8a,b (general procedure). Concentrated HCl (0.2 mL) was
added to a suspension of chelate 4a,b or 5a,b (1 mmol) in ethanol
(5 mL), and the reaction mixture was refluxed for 4 h, neutralꢀ
ized with 10% aqueous NaOH, and extracted with ethyl acetate.
The ethyl acetate extract was dried, the solvent was evaporated,
the residue was recrystallized from the corresponding solvent to
obtain bicyclic compounds 7a,b, 8a,b as white crystals.
(m, 6 H, 3 CH2); 2.76, 3.78 (both m, 2 H each, 2 CH2); 6.16,
6.30 (both m, 1 H each, 2 CH); 7.24, 7.40 (both m, total 4 H,
Ar). IR, ν/cm–1: 3056, 2924, 1628, 1560.
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4ꢀPhenylꢀ6,7,8,9ꢀtetrahydroꢀ2Hꢀquinolizinꢀ2ꢀone (7a). The
yield was 76%, m.p. 152—153 °C (hexane—benzene, 1 : 5).
Found (%): C, 79.76; H, 6.83; N, 6.09. C15H15NO. Calculatꢀ
ed (%): C, 79.97; H, 6.71; N, 6.22. MS, m/z (Irel (%)): 225 [M]+
1
(53), 198 (100), 169 (51). H NMR (CDCl3), δ: 1.83 (m, 4 H,
2 CH2); 2.78, 3.63 (both m, 2 H each, 2 CH2); 6.27, 6.29 (both m,
1 H each, 2 CH); 7.30, 7.50 (both m, total 5 H, Ar). IR, ν/cm–1
:
3044, 2924, 1624, 1536.
4ꢀ(4ꢀChlorophenyl)ꢀ6,7,8,9ꢀtetrahydroꢀ2Hꢀquinolizinꢀ2ꢀone
(7b). The yield was 79%, m.p. 183—184 °C (hexane—benzene,
1 : 5). Found (%): C, 69.25; H, 5.52; N, 5.25. C15H14ClNO.
Calculated (%): C, 69.37; H, 5.43; N, 5.39. MS, m/z (Irel (%)):
1
259 [M]+ (70), 232 (100), 203 (49). H NMR (CDCl3), δ: 1.85
(m, 4 H, 2 CH2); 2.80, 3.63 (both m, 2 H each, 2 CH2); 6.27,
6.31 (both m, 1 H each, 2 CH); 7.27, 7.44 (both m, total 4 H,
Ar). IR, ν/cm–1: 3036, 2948, 1636, 1540.
Received March 29, 2011;
in revised form, August 23 2011