Selective monobromination in the series of quinoid pyrido[1,2-a] benzimidazole derivatives

Full text of DOI:10.1134/S1070428009030208

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 460–462. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © O.Yu. Slabko, I.N. Tyshchenko, V.A. Kaminskii, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 3,
pp. 470–472.
SHORT
COMMUNICATIONS
Selective Monobromination in the Series of Quinoid
Pyrido[1,2-a]benzimidazole Derivatives
O. Yu. Slabko, I. N. Tyshchenko, and V. A. Kaminskii
Far East State University, ul. Oktyabr’skaya 27, Vladivostok, 690600 Russia
e-mail: slabko@chem.dvgu.ru
Received November 19, 2007
DOI: 10.1134/S1070428009030208
Bromo-substituted quinoid compounds are wide-
spread in nature (examples are alkaloids discorhabdins,
verongiaquinol, components of plant pigments, etc.),
and they exhibit pronounced antibacterial activity [1].
Synthetic analogs of natural compounds could also be
expected to display various kinds of biological activity.
Furthermore, regioselective introduction of bromine
atoms into quinoid ring should make further nucleo-
philic functionalization of the bromination products
more unambiguous with a view to obtain compounds
having pharmacophoric groups. On the other hand,
heterocyclic compounds whose molecules contain
quinoid fragments are convenient substrates for vari-
ous transformations due to their fairly rare ability to
undergo functionalization under mild conditions by the
action of both nucleophilic and electrophilic reagents,
as well as of radical species.
reactions follow the addition–elimination pattern, and
in most cases the process is difficult to terminate at the
stage of formation of monohalo derivative, so that
polyhalogenated products are formed. Published data
on the halogenation of heterocyclic quinone imines are
rather scanty. Most examples refer to halogenation of
phenothiazinones and phenazinones [3]. However,
halogenation of such systems is sufficiently selective
only in the presence of an oxidant; otherwise, mixtures
of polyhalo derivatives are obtained. Moreover, there
are no data on the bromination of such rare quinoid
compounds as heterocyclic methylenequinone imines.
Bromination of quinone imines I of the pyrido-
[1,2-a]benzimidazole series with a solution of bromine
in carbon tetrachloride was not selective, and it re-
sulted in the formation of a mixture of 3,9-di- and
3,8,9-tribromo-substituted quinoid derivatives which
were difficult to separate by chromatography; the reac-
tion was carried out in the absence of an oxidant [4].
Halogenation of para-quinones and quinone imines
has been studied in sufficient detail [2]. As a rule, such
Scheme 1.
Ph Br
N
O
Br2, DMF
Ph
Ph
N
N
R
O
R'
IIa, IIb
Ph
Ph Br
N
Br
O
N
R
R'
1,4-Dioxane·Br2, DMF
Ia, Ib
IIa, IIb
+
Ph
N
R
R'
IIIa, IIIb
RR′ = (CH2)4 (a); R = Ph, R′ = H (b).
460

SELECTIVE MONOBROMINATION IN THE SERIES OF QUINOID PYRIDO...
461
Scheme 2.
NC
NC
Ph
N
Ph
N
Br
CN
CN
Br2, DMF
Ph
Ph
N
N
R
R
R'
R'
IVa, IVb
Va, Vb
RR′ = (CH2)4 (a); R = Ph, R′ = H (b).
With a view to enhance the regioselectivity of bromi-
nation of heterocyclic quinones we were the first to use
a milder brominating agent, namely 1,4-dioxane–bro-
mine complex in chloroform. However, analogous
results were obtained.
Thus, the use of a solution of bromine in DMF
ensures regioselective bromination of quinone imines
of the pyrido[1,2-a]benzimidazole series with forma-
tion of 6-bromo-substitued derivatives. Analogous re-
sults were obtained in ethanol as solvent, but the con-
version was not complete because of poor solubility of
the initial quinone imines. It may be concluded that the
regioselectivity in the examined reactions is deter-
mined mainly by solvent polarity rather than by the
reagent nature. We believe that polar solvents induce
polarization of bromine molecule so that the latter
becomes capable of forming a complex at the N10
nitrogen atom (Brδ––Brδ+···N10). Decomposition of the
complex is accompanied by bromine addition at the
nearest nucleophilic carbon atom (C9 in the quinoid
fragment). The C9 atom in molecules IVa and IVb is
shielded by the cyano groups; therefore, bromine atom
adds at the other nearest carbon atom in position 2.
The bromination of Ia and Ib with a solution of
bromine in dimethylformamide gave the corresponding
9-bromo derivatives IIa and IIb as the major products.
The reactions took 2 h at room temperature, and the
substrate-to-reagent ratio was 1:2. In the reactions of
the same substrates with 1 or 2 equiv of dioxane di-
bromide mixtures of 9-mono- (IIa, IIb) and 2,9-di-
bromo derivatives (IIIa, IIIb) at a ratio of 1:2 were
formed, and we failed to find conditions ensuring pre-
dominant formation of one or another product.
We also examined bromination of [4,4a-dihydro-
pyrido[1,2-a]benzimidazol-8(3H)-ylidene]malononi-
triles IVa and IVb with a solution of bromine in DMF.
We previously showed [4] that bromination of IVa and
IVb with a solution of bromine in chloroform at a sub-
strate-to-reagent ratio of 1:2 results in quantitative for-
mation of the corresponding 2,9-dibromo derivatives.
The bromination of the same substrates in DMF at
room temperature (reaction time 2 h) gave exclusively
[2-bromo-1,3-diphenyl-4,4a-dihydropyrido[1,2-a]benz-
imidazol-8(3H)-ylidene]malononitriles Va and Vb.
To conclude, the proposed procedure makes it pos-
sible to introduce bromine atoms into different posi-
tions of quinoid pyrido[1,2-a]benzimidazole deriva-
tives, depending on the solvent nature, which is pro-
mising from the viewpoint of subsequent selective
functionalization of these compounds.
Initial compounds Ia, Ib [5], IVa, and IVb [6] were
synthesized according to known methods.
According to the IR data, the quinoid structure was
conserved in the bromination products, and their
1H NMR spectra were also consistent with the assumed
Bromination of compounds I and IV with a solu-
tion of bromine in dimethylformamide (general
procedure). A solution of an equimolar amount of
bromine in 5 ml of DMF was added dropwise over
a period of 15 min to a solution of 0.24 mol of com-
pound Ia or IVa or 0.33 mol of Ib or IVb in 5 ml of
DMF under stirring at room temperature. The mixture
was stirred for 1 h, an additional 1 equiv of bromine in
DMF was added, and the mixture was stirred until the
initial compound disappeared according to the TLC
data. The mixture was then diluted with two volumes
of water, and the red (compounds II) or violet (V)
precipitate was filtered off, washed with water, and
dried. The products were purified by preparative thin-
1
structures. The H NMR spectra of mixtures of com-
pounds II and III contained doublets from 2-H and
7-H in II and doublets from 6-H and 7-H in III, the
latter being twice as intense, while no 9-H signal was
observed. The spectra of compounds Va and Vb lacked
doublet signal assignable to olefinic proton on C2,
while signals from protons in the quinoid fragment
remained almost unchanged. The chemical ionization
mass spectra of all compounds II, III, and V contained
peaks from the [M + H]+ pseudomolecular ions with
m/z values corresponding to the calculated ones.
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SLABKO et al.
462
layer chromatography (II) or by heating in boiling
acetone–hexane (1:10) over a period of 30 min to
remove impurities (V).
Bromination of compounds Ia and Ib with
1,4-dioxane–bromine complex in DMF. An equi-
molar amount of dioxane dibromide was added under
stirring to a solution of 0.1 g of compound Ia
(0.24 mmol) or Ib (0.33 mmol) in 5 ml of DMF. The
mixture was stirred for 1 h, an additional equivalent of
dioxane dibromide was added, and the mixture was
stirred for 1 h until the initial compound disappeared
(TLC). The mixture was then diluted with two vol-
umes of water, and the red precipitate was filtered off,
washed with water, and dried. We failed to separate
compounds II and III by chromatography.
9-Bromo-4,4a-tetramethylene-1,3-diphenyl-
3,4,4a,8-tetrahydropyrido[1,2-a]benzimidazol-8-one
1
(IIa). Yield 68%, mp 177–179°C. H NMR spectrum,
δ, ppm: 1.50–2.25 m (9H), 3.73 d.d (1H, 3-H, J = 9.1,
4.7 Hz), 6.03 d (1H, 2-H, J = 4.7 Hz), 6.84 d (1H, 7-H,
J = 9.6 Hz), 7.15–7.30 m (11H, 6-H, C6H5). Found, %:
C 69.35; H 5.05; N 5.63. Mass spectrum: m/z 471
[M + H]+. C27H23BrN2O. Calculated, %: C 68.79;
H 4.92; N 5.94. M 471.39.
1
The H NMR spectra were recorded on a Bruker
9-Bromo-1,3,4a-triphenyl-3,4,4a,8-tetrahydro-
AC-250 spectrometer at 250 MHz using DMSO-d6 as
solvent and tetramethylsilane as internal reference. The
elemental compositions were determined on a Flash
EA 1112 CHN/MAS200 analyzer. HPLC analysis was
performed on a an HP 1100 LC/MSD system (Hypersil
ODS column, 4×125 mm; eluent propan-2-ol–water,
60:40, flow rate 0.3 ml/min; temperature 55°C, diode
matrix; atmospheric pressure chemical ionization).
pyrido[1,2-a]benzimidazol-8-one (IIb). Yield 84%,
mp 183–185°C. H NMR spectrum, δ, ppm: 1.68 d.d
1
(1H, 4-Hax, J = 11.8, –13.2 Hz), 3.48 d.d (1H, 4-Heq,
J = 7.1, –13.2 Hz), 3.63 q.d (1H, 3-H, J = 11.8, 7.1,
3.3 Hz), 5.98 d (1H, 2-H, J 3.3 Hz), 6.82 d (1H, 7-H,
J = 9.9 Hz), 7.15–7.65 m (16H, 6-H, C6H5). Found, %:
C 70.58; H 4.39; N 5.53. Mass spectrum: m/z 491
[M + H]+. C29H21BrN2O. Calculated, %: C 70.59;
H 4.29; N 5.68. M 493.39.
REFERENCES
(2-Bromo-4,4a-tetramethylene-1,3-diphenyl-
3,4,4a,8-tetrahydropyrido[1,2-a]benzimidazol-8-yli-
dene)malononitrile (Va). Yield 72%, mp 251–253°C.
1H NMR spectrum, δ, ppm: 1.50–2.40 m (9H), 3.96 d
(1H, 3-H, J = 9.9 Hz), 4.85 d (1H, 9-H, J = 1.7 Hz),
7.07 d (1H, 6-H, J = 9.6 Hz), 7.37 d.d (1H, 8-H, J =
9.6, 1.7 Hz), 7.20–7.60 m (10H, C6H5). Found, %:
C 69.84; H 4.79; N 10.66. Mass spectrum: m/z 519
[M + H]+. C30H23BrN4. Calculated, %: C 69.37;
H 4.46; N 10.79. M 519.43.
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1
(Vb). Yield 75%, mp 257–259°C. H NMR spectrum,
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δ, ppm: 1.98 d.d (1H, 4-Hax, J = 12.9; –12.4 Hz),
3.41 d.d (1H, 4-Heq, J = 6.1, –12.4 Hz), 3.65 d.d (1H,
3-H, J = 12.9, 6.1 Hz), 4.92 s (1H, 9-H), 7.04 d (1H,
6-H, J = 9.9 Hz), 7.15–7.65 m (16H, 7-H, C6H5).
Found, %: C 71.37; H 4.12; N 10.08. Mass spectrum:
m/z 541 [M + H]+. C32H21BrN4. Calculated, %:
C 70.99; H 3.91; N 10.35. M 541.44.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009