A novel rearrangement in the system 3-[aryl(chloro)methyl]quinoxalin-2(1H)- one- α-picoline as a simple and efficient route to indolizin-2- ylbenzimidazoles

Article abstract of DOI:10.1007/s11172-009-0271-4

A reaction of 3-(α-chlorobenzyl)quinoxalin-2(1 H)-one with α-picoline gives 2-(3-phenyl-indolizin-2-yl)benzimidazole as a result of a ring-contracting rearrangement involving the fragment C(2)-C(3)-C(Cl)Ph of the quinoxaline system and the fragment N=CH-M

Full text of DOI:10.1007/s11172-009-0271-4

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1986—1990, September, 2009
1986
A novel rearrangement in the system
3ꢀ[aryl(chloro)methyl]quinoxalinꢀ2(1H)ꢀone—αꢀpicoline
as a simple and efficient route to indolizinꢀ2ꢀylbenzimidazoles
V. A. Mamedov, D. F. Saifina, A. T. Gubaidullin, A. F. Saifina, I. Kh. Rizvanov, and V. R. Ganieva
A. E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 1872. Eꢀmail: mamedov@iopc.ru
A reaction of 3ꢀ(αꢀchlorobenzyl)quinoxalinꢀ2(1H)ꢀone with αꢀpicoline gives 2ꢀ(3ꢀphenylꢀ
indolizinꢀ2ꢀyl)benzimidazole as a result of a ringꢀcontracting rearrangement involving the
fragment C(2)—C(3)—C(Cl)Ph of the quinoxaline system and the fragment N=CH—Me of
the αꢀpicoline system. Possible pathways of this reaction are discussed.
Key words: 3ꢀ(αꢀchlorobenzyl)quinoxalinꢀ2(1H)ꢀone, αꢀpicoline, ring contraction, rearꢀ
rangement, 2ꢀ(3ꢀphenylindolizinꢀ2ꢀyl)benzimidazole, IR spectroscopy, 1H NMR spectroscopy,
Xꢀray diffraction analysis.
The benzimidazole fragment is contained in many
physiologically active compounds, including vitamin B12,1
antiviral2,3 and antitumor agents,4—7 drugs used in veteriꢀ
nary medicine,8—11 and fungicides.12 The most commonly
used methods for the synthesis of the benzimidazole sysꢀ
tem include reactions of 1,2ꢀphenylenediamines and their
derivatives with various carboxylic acid derivatives.13—15
However, the scope of these methods is limited by low
yields of the target products or the impossibility of introꢀ
ducing the benzimidazole fragment into various heteroꢀ
cycles. If a heterocyclic system itself is difficult to obtain
and cannot be functionalized with required groups, introꢀ
duction of the benzimidazole fragment becomes a more
complicated problem for synthetic chemists.
Scheme 1
In the present work, we proposed a simple and effiꢀ
cient route to 2ꢀ(indolizinꢀ2ꢀyl)benzimidazoles via a novel
rearrangement in the system 3ꢀ(αꢀchlorobenzyl)quinoxꢀ
alinꢀ2(1H)ꢀone—αꢀpicoline.
A reaction of 3ꢀ(αꢀchlorobenzyl)quinoxalinꢀ2(1H)ꢀ
one (1)16 with αꢀpicoline (2) in its boiling solution for 9 h
afforded 2ꢀ(3ꢀphenylindolizinꢀ2ꢀyl)benzimidazole 3 in
high yield (Scheme 1). The molecular formula of comꢀ
pound 3 was determined from elemental analysis data and
mass spectra; its structure was proved by IR and 1H NMR
spectroscopy and Xꢀray diffraction.
Compound 3 forms monoclinic crystals (space group
P21); the independent part of the unit cell consists of the
Cl– anion and two molecules of compound 3, one of
them being in the protonated form (Fig. 1).
Imaginary superposition of two crystallographically
independent molecules shows that their conformations
are identical. In molecules A and B, the benzimidazole
and indolizine planes make torsion angles of 31.0(1) and
30.9(1)° and the angle between the phenyl substituent
and the indolizine plane is 59.7(2) and 59.6(2)°, respecꢀ
tively. The N(13A)—C(18A) and N(13B)—C(18B) bonds
(1.404(4) and 1.408(4) Å, respectively) are somewhat
longer than characteristic bond lengths of this type.
The crystal structure 3 shows intermolecular interacꢀ
tions of the N—H...Cl, N—H...N, and π...π types. Two
crystallographically independent molecules are linked by
the hydrogen bond N—H...N with the following paramꢀ
eters: d(H(1A)...N(1B)), 1.86 Å; d(N(1A)...N(1B)),
2.693(3) Å; the angle N(1A)—H(1A)...N(1B) 151°. Molꢀ
ecules A and B are united into πꢀdimeric molecules through
pair π...πꢀcontacts between the phenyl (C(19)—C(24))
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1924—1928, September, 2009.
1066ꢀ5285/09/5809ꢀ1986 © 2009 Springer Science+Business Media, Inc.

Synthesis of 2ꢀ(indolizinꢀ2ꢀyl)benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1987
C(23B)
C(15B)
C(24B)
C(19B)
C(22B)
C(21B)
C(14B)
N(13B)
C(16B)
C(17B)
C(20B)
C(12B)
C(18B)
C(11B)
C(2B)
Cl(1)
C(10B)
N(1B)
C(9B)
C(8B)
C(7B)
C(5A)
C(4A)
N(3B)
C(4B)
C(5B)
C(10A)
C(18A)
N(3A)
C(17A)
C(6A)
C(7A)
C(2A)
C(6B)
C(11A)
C(12A)
C(16A)
C(15A)
N(13A)
C(8A)
C(9A)
N(1A)
C(14A)
C(19A)
C(20A)
C(21A)
C(24A)
C(23A)
C(22A)
Fig. 1. ORTEP diagrams of structure 3 in the crystal. The nonꢀhydrogen atoms are indicated with thermal displacement ellipsoids
(p = 30%) and the hydrogen atoms are indicated with circles of conventional radii.
and imidazole aromatic systems (N(1)—C(9)). The shortꢀ
est distance between the planes of these rings is 3.68 Å
and the corresponding dihedral angle is 15.5°. The shortꢀ
est distances between the atoms of the interacting rings are
as follows: N(1A)...C(24B), 3.328(4) Å; C(2A)...C(24B),
3.240(4) Å; N(3A)...C(24B), 3.420(4) Å; C(4A)...C(23B),
3.268(5) Å; C(9A)...C(23B), 3.394(5) Å. The resulting
πꢀdimers are united through N—H...Cl interactions into
helical chains along the crystallographic axis 0b (Fig. 2).
The parameters of the N—H...Cl interactions are as
follows: d(H(3A)...Cl(1)), 2.26 Å; d(N(3A)...Cl(1)),
3.071(3) Å; the angle N(3A)—H(3A)...Cl(1), 151° and
d(H(3B)...Cl´(1)), 2.24 Å; d(N(3B)...Cl´(1)), 3.070(3) Å;
the angle N(3B)—H(3B)...Cl´(1), 155° (the symmetry
operation code is 2 – x, 1/2 + y, 1 – z). It should be noted
that this compound crystallizes in a chiral group, forming
supramolecular structures as levorotary helices composed
of Hꢀbonded molecules.
In the crystal of compound 3, such supramolecular
structures are packed in a parallel hexagonal way in the
plane a0c with a packing factor of 66.1%.
Structure 3 implies that the formation of two new (benzꢀ
imidazole and indolizine) heterocyclic systems involves
the fragments C(2)—C(3)—C(Cl)Ph and N=CH—Me
of the starting quinoxaline and αꢀpicoline systems, reꢀ
spectively.
During the reaction under study, we observed comꢀ
plete dissolution of compound 1 in boiling αꢀpicoline
with immediate formation of many crystals, which graduꢀ
ally dissolved on further reflux. After the reaction mixture
was refluxed for 1 h, the yield of the resulting crystalline
product with a distinct melting point was 37% with reꢀ
spect to the starting compounds. The 1H NMR spectrum
of this product shows three groups of signals for the
pyridinium, phenyl, and phenylene rings at δ 7.99—8.71,
Fig. 2. Chain formation in the crystal structure 3 by means of
π...πꢀcontacts and N—H...Cl and N—H...N interactions (they
are indicated with dashed lines).

1988
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Mamedov et al.
7.17—7.37, and 6.33—6.74, respectively. In addition,
the spectrum contains three singlets at δ 6.53, 7.08, and
10.94 and two doublets at δ 3.83 and 4.37 (AB system,
2J = 18.3 Hz). The signals for the phenylene protons
are shifted upfield compared to those for the starting comꢀ
pound (δ 7.33—7.83),16 which suggests the participation
of the azomethine C atom in the reaction. As the result,
the imino N atom becomes an electronꢀdonating amino
N atom. Based on these data, we formulated a firstꢀstep
intermediate as spiro compound 4 (Scheme 2), which is
confirmed by the formation of spiro compounds like strucꢀ
ture 4 in reactions of quinoxalinones with other binucleoꢀ
philic reagents.17—19 The spiro structure was also conꢀ
firmed by IR and mass spectra (see Experimental).
Under milder reaction conditions than are required
for the formation of a spiro compound or its rearrangeꢀ
ment into a benzimidazole derivative, we isolated and
characterized a firstꢀstep product resulting from nucleoꢀ
philic displacement of the Cl atom by the pyridine N
atom of αꢀpicoline. For instance, when 3ꢀ(αꢀchloroꢀ
benzyl)quinoxalinꢀ2(1H)ꢀone (1) was stirred in αꢀpicoline
at 50 °C for 3 h (Scheme 4), the crystals that formed were
assigned structure 5 (1H NMR). However, we failed to
isolate this compound in the individual state because the
reaction proceeds to the formation of spiro compound 4
even under sufficiently mild conditions. According to the
1H NMR data, the integral intensity of its signals is 3% of
the integral intensity of the signals for the major product.
Further heating of compound 5 in αꢀpicoline with stirring
results in the formation of either spiroquinoxaline 4 or a
benzimidazole derivative, depending on the reaction temꢀ
perature and time.
Scheme 2
Scheme 4
Spiro compound 4 was converted into 2ꢀ(3ꢀphenylꢀ
indolizinꢀ2ꢀyl)benzimidazole 3 in high yields not only in
boiling αꢀpicoline (method B) but also in acetic acid
(method C) (Scheme 3).
The formation of a rearrangement product can be repꢀ
resented by Scheme 5. According to this scheme, the
initial step involves nucleophilic displacement of the Cl
atom by the pyridine N atom, which is followed by a
cascade transformation that includes (1) dehydrochlorinꢀ
Scheme 3
Scheme 5

Synthesis of 2ꢀ(indolizinꢀ2ꢀyl)benzimidazoles
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1989
quinoxalinꢀ2(1H)ꢀone (1) (0.5 g, 1.9 mmol) in αꢀpicoline
(6 mL) was refluxed for 1 h. The crystals that formed were
filtered off, washed with PriOH (3×10 mL), and dried in air.
The yield of analytically pure compound 4 was 0.25 g (37%),
m.p. 270—272 °C. Found (%): C, 69.19; H, 4.87; Cl, 9.65;
N, 11.73. C21H18ClN3O. Calculated (%): C, 69.32; H, 4.99;
Cl, 9.74; N, 11.55. IR, ν/cm–1: 692, 742, 777, 1118, 1311, 1368,
1419, 1502, 1612, 1628, 1678, 2971, 3026, 3115, 3166. 1H NMR,
δ: 3.88 (AB system, 1 H, CHAHB, JA,B = 18.3 Hz); 4.37 (AB
system, 1 H, CHAHB, JA,B = 18.3 Hz); 6.34 (d, 1 H, H(8),
J = 7.7 Hz); 6.53 (s, 1 H, CH); 6.55 (ddd, 1 H, H(6), J = 7.5 Hz,
J = 7.2 Hz, J = 1.5 Hz); 6.66 (ddd, 1 H, H(7), J = 7.7 Hz,
J = 7.3 Hz, J = 1.5 Hz); 6.73 (dd, 1 H, H(5), J = 7.7 Hz, J = 1.1 Hz);
7.08 (br.s, 1 H, N(1)H); 7.18 (dd, 2 H, oꢀHPh, J = 7.9 Hz,
J = 1.3 Hz); 7.29—7.37 (m, 3 H, oꢀHPh, pꢀHPh); 8.01 (dd, 1 H,
H(5´), J = 7.3 Hz, J = 6.6 Hz); 8.33 (d, 1 H, H(3´), J = 8.1 Hz);
8.56 (d, 1 H, H(6´), J = 6.2 Hz); 8.69 (dd, H(4´), J = 7.7 Hz,
J = 7.7 Hz); 10.94 (br.s, 1 H, NH). MS (EI), m/z (Irel (%)): 328 (8);
327 [M]•+ (33); 309 (10); 308 (17); 299 (8); 235 (5); 221 (19);
220 (100); 208 (30); 207 (14); 193 (6); 192 (16); 191 (47); 182
(13); 180 (7); 154 (7); 91 (8); 65 (7).
ation with abstraction of a methyl H atom of αꢀpicoline,
(2) intramolecular nucleophilic addition of the methylꢀ
idene C atom of the picoline fragment to the azomethine
C atom of the quinoxaline system (spiro compound B),
(3) cleavage of the N(1)—C(2) bond (Nꢀsubstituted
oꢀphenylenediamine C), (4) closure of a fiveꢀmembered
ring (benzimidazoline D), and (5) elimination of water.
It should be noted that 3ꢀ[aryl(chloro)methyl]ꢀ and
3ꢀ(αꢀchlorophenethyl)quinoxalinꢀ2(1H)ꢀones and their
derivatives also react with αꢀpicoline to give the correꢀ
sponding 2ꢀ(3ꢀarylindolizinyl)ꢀ and 2ꢀ(3ꢀbenzylindolꢀ
izinyl)benzimidazoles in high yields. These data pointing
to the general character of the reaction under study will
be discussed elsewhere.
Experimental
Melting points were determined on a Boetius hotꢀstage
microscope. IR spectra were recorded on a Vectorꢀ22 FTIRꢀ
spectrometer (Bruker) in KBr pellets. Mass spectra (EI) were
measured on a TRACE MS quadrupole mass spectrometer
(ThermoQuest) (direct inlet probe, water cooling). 1H NMR
spectra were recorded on a Bruker MSLꢀ400 spectrometer
(400.13 MHz) in DMSOꢀd6. Chemical shifts are given on the
δ scale with the residual signal of DMSO (δH 2.54) as the interꢀ
nal standard.
2ꢀMethylꢀ1ꢀ[(2ꢀoxoquinoxalinꢀ3ꢀyl)(phenyl)methyl]pyriꢀ
dinium chloride (5). 3ꢀ(αꢀChlorobenzyl)quinoxalinꢀ2(1H)ꢀone
(1) (0.3 g, 1.1 mmol) was stirred in αꢀpicoline (5 mL) at 50 °C
for 3 h. The crystals that formed were filtered off and dried in
air. The yield was 0.13 g (29%), m.p. 195—197 °C. IR, ν/cm–1
:
560, 692, 756, 1147, 1421, 1454, 1478, 1500, 1573, 1612, 1625,
1
1661, 2684, 2738, 2788, 2856, 2927, 3034. H NMR, δ: 3.04
(s, 3 H, CH3); 7.35 (dd, 1 H, H(5´), J = 7.7 Hz, J = 7.3 Hz);
7.52—7.69 (m, 8 H, 4 H, C6H4, H(6), H(7), H(8), H(3´));
7.88 (s, 1 H, CH); 8.03 (dd, 1 H, pꢀHPh, J = 7.0 Hz, J = 6.6 Hz);
8.24 (d, 1 H, H(5), J = 7.7 Hz); 8.63 (d, 1 H, H(6´), J = 6.2 Hz);
8.64 (t, 1 H, H(4´), J = 7.0 Hz); 13.12 (br.s, 1 H, NH).
Singleꢀcrystal Xꢀray diffraction analysis of compound 3 was
performed at the Xꢀray Diffraction Division of the Collective
Use Center of the Spectroanalytical Center based on the Difꢀ
fraction Investigations Laboratory of the A. E. Arbuzov Institute
of Organic and Physical Chemistry (Kazan Research Center,
Russian Academy of Sciences).
Space group C2221 we assigned initially to semihydrochloride
3•0.5HCl was wrong because the Cl atom occupies a special
position in the unit cell so that one crystallographically indeꢀ
pendent molecule of 2ꢀ(3ꢀphenylindolizinꢀ2ꢀyl)benzimidazole
semihydrochloride in the asymmetric part of the unit cell bears a
fractional negative charge. In addition, the amino H atom of the
benzimidazole fragment was disordered over two positions and
half the positive charge should be acquired by this molecule for
charge compensation. Among lower symmetries searched
for with the PLATON program, we chose a monoclinic primiꢀ
tive cell with the chloride anion and two crystallographically
independent molecules of compound 3 in the independent part,
one molecule being in the protonated form.
2ꢀ(3ꢀPhenylindolizinꢀ2ꢀyl)benzimidazole (3). A. 3ꢀ(αꢀChloroꢀ
benzyl)quinoxalinꢀ2(1H)ꢀone (1) (0.3 g, 1.1 mmol) was refluxed
in αꢀpicoline (6 mL) for 9 h. The reaction mixture was evapoꢀ
rated to dryness in a water aspirator vacuum and treated with
water. The crystals that formed were filtered off, washed
with 5% aqueous NaHCO3 (3×10 mL), dried in air, and recrysꢀ
tallized from MeCN. The yield of free base 3 was 0.27 g (78%),
m.p. 246—248 °C. Found (%): C, 81.44; H, 4.82; N, 13.74.
C21H15N3. Calculated (%): C, 81.53; H, 4.89; N, 13.58. IR,
ν/cm–1: 700, 746, 1116, 1251, 1274, 1334, 1448, 1596, 1626,
1668, 2854, 2924, 3058. 1H NMR, δ: 6.72 (dd, 1 H, H(6´),
J = 7.0 Hz, J = 6.6 Hz); 6.92 (dd, 1 H, H(7´), J = 6.6 Hz, J = 6.2 Hz);
7.16 (s, 1 H, H(1´)); 7.27—7.31 (m, 2 H, H(4), H(7)); 7.51—7.53
(m, 2 H, H(5), H(6)); 7.54—7.60 (m, 5 H, Ph); 7.67 (d, 1 H,
H(8´), J = 9.2 Hz); 8.07 (d, 1 H, H(5´), J = 7.3 Hz). MS (EI),
m/z (Irel (%))*: 310 (12); 309 [M]•+ (62); 308 (100); 307 (15);
306 (7); 216 (7); 154.5 (23); 154 (18); 153 (6); 152 (5); 83 (5);
57 (5).
B. A solution of compound 4 (0.2 g, 0.55 mmol) was reꢀ
fluxed in αꢀpicoline (7 mL) for 8 h. The reaction mixture was
evaporated to dryness and treated with water. The crystals that
formed were filtered off and recrystallized from MeCN. The
yield of compound 3 was 0.15 g (90%).
C. A solution of compound 4 (0.2 g, 0.55 mmol) was reꢀ
fluxed in acetic acid (7 mL) for 10 h. The reaction mixture was
evaporated to dryness and treated with water. The crystals that
formed were filtered off, dried in air, and recrystallized from
MeCN. The yield of compound 3 was 0.13 g (79%).
Crystals of the semihydrochloride of compound 3 (C21H15N3),
C21H16N3+•Cl–, are monoclinic. At 20 °C, the unit cell
parameters are a = 10.3623(8) Å, b = 16.436(1) Å, c = 11.1739(9) Å,
3
β = 117.625(1)°, V = 1686.1(2) Å , Z = 2, dcalc = 1.290 g cm–3
,
space group P21. The unit cell parameters and the intensities of
13 765 reflections (7130 independent reflections (Rint = 0.0319),
4877 reflections with I ≥ 2σ) were measured at 23 °C on a Bruker
Smart Apex II automatic diffractometer fitted with a CCD
area detector (MoꢀKα radiation, graphite monochromator,
3´ꢀPhenylꢀ1´,2´,3´,1,2ꢀpentahydrospiro[quinoxalineꢀ2,2´ꢀ
indolizin]ꢀ3(4H)ꢀone (4). A suspension of 3ꢀ(αꢀchlorobenzyl)ꢀ
* Here and in the mass spectrum of compound 4, the ion peaks
with Irel < 5% are omitted.

1990
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Mamedov et al.
λ = 0.71073 Å, ω scan mode, –13 ≤ h ≤ 13, –20 ≤ k ≤ 20, –14 ≤ l ≤ 14,
2.22° ≤ θ ≤ 26.99°). An absorption correction was applied
semiempirically with the SADABS program20 (μ(Mo) = 1.54 cm–1).
The structure was solved by the direct methods and refined by
the leastꢀsquares method first isotropically and then anisotropiꢀ
cally (for all nonꢀhydrogen atoms) with the SHELXTL21 and
WinGX programs.22 The hydrogen atoms at the N atoms of the
benzimidazole system were located from difference electronꢀ
density maps and refined with fixed coordinates. The other H
atoms were located geometrically and refined using appropriate
riding models. Final residuals are R = 0.0543 and Rw = 0.1099
for 4877 independent reflections with F2 ≥ 4σ, GOOF = 1.133,
the number of parameters refined is 442. The unit cell paramꢀ
eters were collected, indexed, and refined and the data obtained
were processed with the APEX2 program.23 Intermolecular inꢀ
teractions were analyzed, and the molecular structures were
drawn, with the PLATON program.24 Atomic coordinates and
thermal parameters have been deposited with the Cambridge
Crystallographic Data Center (http://www.ccdc.cam.ac.uk;
CCDC no. 695 324).
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~
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00613ꢀa)
and the Federal Target Program “Investigations and deꢀ
velopments in the priority scientific and technical fields of
Russia for 2007—2012” (State Contract No. 02.512.11.2237).
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Received August 12, 2008;
in revised form December 1, 2008