A facile route to imidazo[1,2-a]quinolines via a domino reaction

Article abstract of DOI:10.1055/s-2008-1072572

The interaction of methyl 2,4-dioxo-2H-3,1-benzoxazine-1(4H)-acetate, 1-(3,3-dimethyl-2-oxobutyl)- and 1-(2-oxopropyl)-2H-3,1-benzoxazine-2,4(1H)- diones with substituted acetonitriles, XCH₂CN (X = CN, hetaryl), has been studied. In acetic acid in the presence of sodium acetate, imidazo[1,2-a]quinoline-2,5(1H,3H)-diones, 2-tert-butyl- and 2-methylimidazo[1,2-a]quinolin-5(3H)-ones were obtained in 60-85% yield. A reaction pathway is suggested and has been confirmed by the isolation of specific intermediates. The scope and limitations of the method are discussed. The structure of the obtained imidazo[1,2-a]quinoline derivatives has been assigned unambiguously on the basis of an X-ray crystallographic study. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072572

PAPER
1535
A Facile Route to Imidazo[1,2-a]quinolines via a Domino Reaction
F
acile Route toIm
u
idazo[1,2-
a
s
]quinoline
t
s
am T. Iminov,a Anton V. Tverdokhlebov,*b Andrey A. Tolmachev,b Yulian M. Volovenko,a
Alexander N. Kostyuk,c Alexander N. Chernega,c Eduard B. Rusanovc
a
Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
b
Fax +380(44)5373253; E-mail: atver@univ.kiev.ua
Institute of Organic Chemistry, National Academy of Sciences, Murmanska str. 5, 02094 Kiev, Ukraine
c
Received 9 January 2008; revised 4 February 2008
Over the last years, so-called domino reactions have at-
tained an increasing importance in heterocyclic chemis-
try.10 They are especially effective for the preparation of
tri- and polycyclic systems, allowing the creation of two
Abstract: The interaction of methyl 2,4-dioxo-2H-3,1-benzox-
azine-1(4H)-acetate, 1-(3,3-dimethyl-2-oxobutyl)- and 1-(2-oxo-
propyl)-2H-3,1-benzoxazine-2,4(1H)-diones with substituted
acetonitriles, XCH2CN (X = CN, hetaryl), has been studied. In ace-
tic acid in the presence of sodium acetate, imidazo[1,2-a]quinoline- or more rings at once at the expense of sequential chemi-
2,5(1H,3H)-diones, 2-tert-butyl- and 2-methylimidazo[1,2-a]quin-
olin-5(3H)-ones were obtained in 60–85% yield. A reaction path-
way is suggested and has been confirmed by the isolation of specific
tions to the synthesis of condensed nitrogen heterocycles,
intermediates. The scope and limitations of the method are dis-
cussed. The structure of the obtained imidazo[1,2-a]quinoline de-
cal transformations induced one by another. Continuing
our research work11 on the application of domino reac-
we were interested in elaborating a domino approach to
imidazo[1,2-a]quinolines as an alternative to the de-
rivatives has been assigned unambiguously on the basis of an X-ray
crystallographic study.
scribed stepwise procedures.1,3–9
Key words: cyclizations, domino reactions, heterocycles, imida-
zo[1,2-a]quinolines, nitriles
N-Alkylisatoic anhydrides are known to react with active
methylene compounds to yield quinoline derivatives.12–14
Compounds 1–3 (Scheme 1), readily available by direct
alkylation of isatoic anhydride,15 seem to be suitable ob-
jects for domino cyclizations because of the presence of
additional functionality tethered to the nitrogen. Thus,
their reaction with substituted acetonitriles 4a–e has been
examined as the possible route to imidazo[1,2-a]quino-
lines.
Imidazo[1,2-a]quinoline is a synthetically designed scaf-
fold with a broad spectrum of biological activities. Its de-
rivatives have been claimed to be contraceptive,1a
hypotensive,1b antiallergic and antiasthmatic agents.1c–e
Moreover, several prospective nonsedative anxiolytic
agents with the imidazoquinoline structure have been dis-
covered,2a and one of them, referred to as Ru 31719, is
now under clinical evaluation. Its affinity to GABA recep-
tors in the brain is being studied intensively in order to re-
veal the mechanism of action.2b–d
Three types of conditions, one acidic (i) and two basic (ii
and iii), were employed in performing the reaction. Appli-
cation of the two very similar basic media (ii and iii) was
required as the solubility of compound 1 in dioxane is too
low; therefore, N,N-dimethylformamide was used as sol-
vent for the reactions with 1. Under acidic conditions (i) it
was found that derivatives 1 and 2 react smoothly with the
nitriles 4a–e affording the imidazo[1,2-a]quinolines 5a–e
and 6a–e, respectively, in good yields. Compounds 5 and
6 were assumed to be formed by initial C-acylation of ni-
triles 4 accompanied by carbon dioxide evolution, further
intramolecular addition of the secondary amino group to
the nitrile in the intermediates A, and finally intramolecu-
lar condensation of the amino and ester or carbonyl func-
tionalities in the intermediates B. This reaction pathway
was confirmed by the isolation of specific intermediate
compounds available under basic conditions. Thus, when
compound 1 was treated with nitrile 4d under conditions
(ii), the product 8 (Figure 1) corresponding to the first step
of the reaction was obtained; at the same time, reaction of
1 with the rest of the nitriles 4a–c,e gave the expected
imidazoquinolines 5 under both conditions (i) and (ii) in
comparable yields. Similar intermediate compounds 9a,b
were obtained from anhydride 2 and nitriles 4c,d under
conditions (iii). Furthermore, the 2,3-dihydro-2-hydroxy-
imidazo[1,2-a]quinolin-5(1H)-one derivative 10 was iso-
The known syntheses of imidazo[1,2-a]quinolines usually
utilize various quinoline derivatives as starting materials.
Among them, 2-aminoquinolines are the most popular.
Thus, their reactions with a-halo carbonyl compounds1,2a,3
and related 1,2-bielectrophiles4 lead to the target system.
Furthermore, 2-aminoquinolines have been employed in
Strecker and Ugi reactions, also resulting in imidazoquin-
olines.5,6 As for other quinoline precursors, the transfor-
mation of 1-phenacylquinolinium salts into the title
system upon treatment with primary amines,7a–c
hydroxylamines7d and hydrazine derivatives,7e as well as
the condensation of 2-chloro- or 2-alkoxyquinolines with
a-amino carbonyl compounds,8 should be mentioned. Fi-
nally, a few less general approaches to imidazoquinolines
have been reported.9
SYNTHESIS 2008, No. 10, pp 1535–1540
x
x.
x
x
.
2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072572; Art ID: Z00908SS
© Georg Thieme Verlag Stuttgart · New York

1536
R. T. Iminov et al.
PAPER
O
O
N
X
i, ii or iii
– CO2
O
R
NC
4a–e
X
+
CN
NH
O
O
O
A
1–3
R
O
O
N
O
X
X
X
R = Me, t-Bu
– H2O
R = OMe
– MeOH
N
NH2
O
NH
R
N
NH
O
R
6a–e
7b,c,e
5a–e
B
R = OMe (1), t-Bu (2, 6), Me (3, 7)
4-ClC6H4
e:
N
N
N
N
N
X = a: CN
b:
c:
d:
S
N
H
S
Me
Scheme 1 Reagents and conditions: (i) AcOH, NaOAc, reflux; (ii) DMF, Et3N (cat.), 110–120 °C; (iii) dioxane, Et3N (cat.), reflux.
lated after the reaction of compounds 2 and 4e under 7b,c,e were obtained both under acidic (i) and basic (iii)
conditions (iii). Clearly, it is the intermediate compound conditions. In the case of nitriles 4a and 4d under various
corresponding to the final dehydration step. Expectedly, media complex mixtures were formed, from which we
upon heating in acetic acid all intermediate derivatives 8– failed to isolate the target imidazoquinolines. Probably,
10 were converted quantitatively into the appropriate this failure was caused by the relatively high reactivity of
imidazoquinolines 5 and 6.
the carbonyl of the acetonyl moiety. Thus, competitive at-
tack of the methylene component at both the endocyclic
and acetonyl carbonyls of derivative 3 resulted in unclear
reactions and the formation of mixtures.
It should be noted that compounds 8 and 9 exist complete-
ly in the tautomeric form with an intramolecular hydrogen
bond, as shown in Figure 1. Previously, this type of tau-
tomer has been determined by us16 and other researchers17 The structures of the prepared compounds 5–7 were ini-
as the sole form of different C-acyl derivatives of 1H- tially deduced from their H and 13C NMR spectra and
1
benzimidazole-2-acetonitrile. On the basis of those then confirmed unambiguously by an X-ray crystallo-
data,16,17 the same tautomeric form is assigned to deriva- graphic study carried out on derivative 6e (Figure 2).
tives 8 and 9.
Noteworthy, derivative 5a turned out to be described pre-
viously using another method;18 the analytical and spec-
troscopic data for 5a are in complete agreement with the
reported data. According to the crystal data, the imidazo-
quinoline core is planar (deviations from the least-square
plane do not exceed 0.03 Å). The thiazole ring is almost
coplanar with the tricycle; the angle between their planes
is 4.2°. This coplanar conformation appears due to the in-
tramolecular hydrogen bond N2–H···N3 with the length
2.73 Å and the angle 123°. Also, it results in the strong at-
tractive interaction between O1 and S1; the distance O1–
S1 is 2.77 Å, while the sum of their van der Waals radii is
3.32 Å.
Attempts to further extend the reaction to N-acetonylisa-
toic anhydride (3) led to some problems. Only derivatives
Me
R
N
N
NC
NC
N
N
H
H
O
O
NH
NH
O
COOMe
O
8
9a,b
To summarize, the present investigation has resulted in a
new approach to imidazo[1,2-a]quinolines based on the
domino principle. Sodium acetate in acetic acid should be
considered as the most general conditions for the prepara-
tion of the target compounds 5–7. On the other hand, ap-
plication of basic catalysis allowed us to obtain several
intermediate compounds 8–10, thus confirming the sug-
gested reaction pathway. It has been shown that isatoic an-
hydride derivatives containing additional electrophilic
S
C6H4(4-Cl)
N
N
NH
OH
10
Figure 1 R = a: H; b: Me
Synthesis 2008, No. 10, 1535–1540 © Thieme Stuttgart · New York

PAPER
Facile Route to Imidazo[1,2-a]quinolines
1537
1H NMR: d = 4.81 (s, 2 H, CH2), 7.41 (m, 2 H, 7,9-H), 7.76 (t,
J = 7.5 Hz, 1 H, 8-H), 8.09 (d, J = 7.5 Hz, 1 H, 6-H), 12.84 (s, 1 H,
NH).
13C NMR: d = 50.5 (1-C), 77.1 (4-C), 115.1 (CN), 116.4 (9-C),
123.0 (5a-C), 124.8 (7-C), 126.2 (6-C), 134.1 (8-C), 137.0 (9a-C),
156.6 (3a-C), 171.1 (2-CO), 175.0 (5-CO).
Anal. Calcd for C12H7N3O2: C, 64.00; H, 3.13; N, 18.66. Found: C,
63.99; H, 3.20; N, 18.58.
4-(2-Benzothiazolyl)imidazo[1,2-a]quinoline-2,5(1H,3H)-dione
(5b)
Yield: 76% (i), 73% (ii); mp >300 °C (DMF).
1H NMR: d = 4.98 (s, 2 H, CH2), 7.36 (t, J = 7.0 Hz, 1 H, HX), 7.45–
7.51 (m, 3 H, 7,9-H, HX), 7.77 (t, J = 6.5 Hz, 1 H, 8-H), 8.06 (d,
J = 7.0 Hz, 1 H, HX), 8.11 (d, J = 7.0 Hz, 1 H, HX), 8.29 (d, J = 6.5
Hz, 1 H, 6-H), 12.07 (s, 1 H, NH).
Figure 2 X-ray molecular structure of compound 6e with the atom
numbering used in the crystallographic analysis
13C NMR: d = 50.0 (1-C), 97.0 (4-C), 116.3 (9-C), 121.9 (7-CX),
122.0 (4-CX), 123.3 (5a-C), 124.4 (7-C), 124.5 (6-CX), 126.4 (6-C),
functionalities tethered to the nitrogen atom are promising
substrates for domino cyclizations. However, the range of
suitable functionalities is limited by the following require- 126.6 (5-CX), 133.4 (8-C), 133.7 (7a-CX), 136.5 (9a-C), 151.1 (3a-
CX), 152.2 (2-CX), 162.1 (3a-C), 170.5 (2-CO), 173.6 (5-CO).
ment: for a smooth reaction, the reactivity of the tethered
group should be lower than the reactivity of the isatoic an-
hydride moiety.
Anal. Calcd for C18H11N3O2S: C, 64.85; H, 3.33; N, 12.60; S, 9.62.
Found: C, 64.72; H, 3.44; N, 12.70; S, 9.41.
4-(1H-Benzimidazol-2-yl)imidazo[1,2-a]quinoline-2,5(1H,3H)-
dione (5c)
Yield: 79% (i), 65% (ii); mp >300 °C (DMF).
The starting compounds 1–3 were prepared according to the de-
scribed procedure.15 The nitriles 4a–e were either commercially
available or obtained as reported.19 All melting points were deter-
mined in open capillary tubes in a Thiele apparatus and are uncor-
rected. Elemental analyses were performed at the microanalytical
department of the Institute of Organic Chemistry, NAS, Kiev.
1H and 13C NMR spectra (400 and 100 MHz, respectively) were re-
corded on a Varian Unity plus 400 spectrometer in DMSO-d6 solu-
tions. Chemical shifts (d) are given in ppm downfield from internal
TMS. The purity of all compounds obtained was checked by
1H NMR spectroscopy and LC/MS on an Agilent 1100 instrument.
1H NMR: d = 4.73 (s, 2 H, CH2), 7.28 (m, 2 H, HX), 7.36 (m, 2 H,
7,9-H), 7.69 (t, J = 7.5 Hz, 1 H, 8-H), 7.79 (m, 2 H, HX), 8.26 (d,
J = 7.5 Hz, 1 H, 6-H), 12.82 (br s, 2 H, 2 × NH).
13C NMR: d = 50.2 (1-C), 89.6 (4-C), 114.6 (4,7-CX), 115.7 (9-C),
123.0 (5a-C), 123.4 (7-C), 123.6 (5,6-CX), 126.4 (6-C), 133.3 (8-C),
133.4 (3a,7a-CX), 137.0 (9a-C), 149.0 (2-CX), 161.5 (3a-C), 174.7
(2-CO), 177.6 (5-CO).
Anal. Calcd for C18H12N4O2: C, 68.35; H, 3.82; N, 17.71. Found: C,
68.28; H, 3.81; N, 17.51.
Reaction of Anhydrides 1–3 with Substituted Acetonitriles
4a–e; General Procedures
4-(1-Methyl-1H-benzimidazol-2-yl)imidazo[1,2-a]quinoline-
2,5(1H,3H)-dione (5d)
Yield: 71% (i), 99% (from compound 8); mp >300 °C (DMF).
Method (i): NaOAc (0.33 g, 4 mmol) was added to a soln of an an-
hydride 1–3 (4 mmol) and a nitrile 4a–e (4 mmol) in glacial AcOH
(7 mL), and the resulting mixture was refluxed for 3 h. After cooling
the mixture, the separated solid was collected by filtration, washed
with H2O (2 × 5 mL) and recrystallized from an appropriate solvent,
affording the derivative 5a–e, 6a–e, 7b,c,e.
1H NMR: d = 3.67 (s, 3 H, CH3), 4.86 (s, 2 H, CH2), 7.22 (t, J = 7.5
Hz, 1 H, HX), 7.27 (t, J = 7.5 Hz, 1 H, HX), 7.38 (t, J = 8.0 Hz, 1 H,
7-H), 7.44 (d, J = 8.0 Hz, 1 H, 9-H), 7.56 (d, J = 7.5 Hz, 1 H, HX),
7.63 (d, J = 7.5 Hz, 1 H, HX), 7.75 (t, J = 8.0 Hz, 1 H, 8-H), 8.18 (d,
J = 8.0 Hz, 1 H, 6-H), 11.33 (s, 1 H, NH).
13C NMR: d = 31.2 (CH3), 50.2 (1-C), 93.9 (4-C), 110.6 (7-CX),
116.0 (9-C), 119.0 (6-CX), 121.9 (5-CX), 122.4 (4-CX), 123.8 (7-C),
124.2 (5a-C), 126.5 (6-C), 133.1 (8-C), 136.3 (9a-C), 137.5 (7a-
CX), 142.7 (3a-CX), 148.4 (2-CX), 153.7 (3a-C), 171.4 (2-CO),
172.5 (5-CO).
Method (ii): A few drops of Et3N were added to a soln of com-
pound 1 (0.94 g, 4 mmol) and a nitrile 4a–e (4 mmol) in DMF (5
mL), and the resulting mixture was heated at 110–120 °C for 2 h.
After cooling the mixture, the precipitate formed was collected by
filtration and recrystallized (DMF) to give the derivative 5a–c,e, or
compound 8 when nitrile 4d was used as the starting material.
Method (iii): A few drops of Et3N were added to a soln of anhy-
dride 2 or 3 (4 mmol) and a nitrile 4a–e (4 mmol) in dioxane (10
mL), and the resulting mixture was refluxed for 3 h. After cooling
the mixture, the solid formed was collected by filtration and recrys-
tallized from an appropriate solvent, yielding either the derivative
6a,b, 7b,c,e (from the anhydride 2 or 3 and the corresponding nitrile
4), compounds 9a,b (from 2 and 4c,d), or the imidazoquinoline 10
(from 2 and 4e).
Anal. Calcd for C19H14N4O2: C, 69.08; H, 4.27; N, 16.96. Found: C,
68.86; H, 4.28; N, 16.90.
4-[4-(4-Chlorophenyl)-2-thiazolyl]imidazo[1,2-a]quinoline-
2,5(1H,3H)-dione (5e)
Yield: 60% (i), 66% (ii); mp >300 °C (DMF).
1H NMR: d = 4.97 (s, 2 H, CH2), 7.44 (m, 2 H, 7,9-H), 7.50 (d,
J = 7.5 Hz, 2 H, HX), 7.73 (t, J = 7.5 Hz, 1 H, 8-H), 7.86 (s, 1 H, HX),
7.94 (d, J = 7.5 Hz, 2 H, HX), 8.32 (d, J = 7.5 Hz, 1 H, 6-H), 11.48
(s, 1 H, NH).
13C NMR: d = 48.6 (1-C), 92.1 (4-C), 114.3 (5-CX), 116.1 (9-C),
122.1 (7-C), 124.1 (5a-C), 127.4 (6-C), 127.9 (3,5-CPhCl), 131.3
(2,6-CPhCl), 132.9 (1-CPhCl), 133.2 (8-C), 133.7 (4-CPhCl), 135.1 (9a-
1,2,3,5-Tetrahydro-2,5-dioxoimidazo[1,2-a]quinoline-4-carbo-
nitrile (5a)
Yield: 69% (i), 80% (ii); mp >300 °C (DMF).
Synthesis 2008, No. 10, 1535–1540 © Thieme Stuttgart · New York

1538
R. T. Iminov et al.
PAPER
2-tert-Butyl-4-[4-(4-chlorophenyl)-2-thiazolyl]imidazo[1,2-
C), 137.4 (4-CX), 154.2 (3a-C), 163.1 (2-CX), 169.5 (2-CO), 169.8
(5-CO).
a]quinolin-5(3H)-one (6e)
Yield: 66% (i), 98% (from compound 10); mp 287 °C (AcOH).
Anal. Calcd for C20H12ClN3O2S: C, 60.99; H, 3.07; N, 10.67; Cl,
9.00; S, 8.14. Found: C, 60.78; H, 3.13; N, 10.42; Cl, 8.87; S, 8.21.
1H NMR: d = 1.50 (s, 9 H, t-Bu), 7.53 (m, 3 H, 7-H, 2 × HX), 7.76
(m, 2 H, 8-H, HX), 7.97 (d, J = 8.0 Hz, 2 H, HX), 8.18 (s, 1 H, 1-H),
8.21 (d, J = 8.0 Hz, 1 H, 6-H), 8.40 (d, J = 8.0 Hz, 1 H, 9-H), 12.33
(s, 1 H, NH).
2-tert-Butyl-3,5-dihydro-5-oxoimidazo[1,2-a]quinoline-4-car-
bonitrile (6a)
Yield: 83% (i), 71% (iii); mp >300 °C (dioxane).
13C NMR: d = 29.7 (3 × CH3), 30.9 (CMe3), 94.3 (4-C), 106.2 (1-C),
111.6 (5-CX), 116.4 (9-C), 124.8 (5a-C), 125.6 (7-C), 126.9 (6-C),
127.8 (3,5-CPhCl), 129.2 (2,6-CPhCl), 131.5 (8-C), 132.6 (1-CPhCl),
132.7 (4-CPhCl), 133.8 (2-C), 140.2 (4-CX), 142.2 (9a-C), 150.2 (3a-
C), 162.7 (2-CX), 168.7 (5-CO).
1H NMR: d = 1.35 (s, 9 H, t-Bu), 7.49 (t, J = 7.5 Hz, 1 H, 7-H), 7.76
(t, J = 7.5 Hz, 1 H, 8-H), 8.06 (s, 1 H, 1-H), 8.19 (m, 2 H, 6,9-H),
12.80 (s, 1 H, NH).
13C NMR: d = 29.2 (3 × CH3), 31.2 (CMe3), 71.7 (4-C), 106.6 (1-C),
116.6 (9-C), 117.7 (CN), 124.2 (5a-C), 126.0 (7-C), 126.7 (6-C),
132.6 (8-C), 133.5 (2-C), 141.9 (9a-C), 145.2 (3a-C), 172.9 (5-CO).
Anal. Calcd for C24H20ClN3OS: C, 66.43; H, 4.65; N, 9.68; Cl, 8.17;
S, 7.39. Found: C, 66.48; H, 4.61; N, 9.89; Cl, 8.17; S, 7.54.
Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C,
72.50; H, 5.83; N, 15.85.
4-(2-Benzothiazolyl)-2-methylimidazo[1,2-a]quinolin-5(3H)-
one (7b)
Yield: 65% (i), 62% (iii); mp 252 °C (dioxane).
4-(2-Benzothiazolyl)-2-tert-butylimidazo[1,2-a]quinolin-5(3H)-
one (6b)
Yield: 84% (i), 84% (iii); mp 297 °C (dioxane).
1H NMR: d = 2.50 (s, 3 H, CH3), 7.29 (t, J = 7.0 Hz, 1 H, HX), 7.46
(t, J = 7.0 Hz, 1 H, HX), 7.55 (t, J = 8.0 Hz, 1 H, 7-H), 7.77 (t,
J = 8.0 Hz, 1 H, 8-H), 8.02 (m, 2 H, 6-H, HX), 8.14 (m, 2 H, 1-H,
HX), 8.41 (d, J = 8.0 Hz, 1 H, 9-H), 12.54 (s, 1 H, NH).
13C NMR: d = 11.2 (CH3), 94.7 (4-C), 108.1 (1-C), 116.4 (9-C),
121.0 (7-CX), 121.9 (4-CX), 123.4 (6-CX), 124.6 (5a-C), 125.8 (5-
CX), 125.9 (7-C), 127.0 (6-C), 128.1 (7a-CX), 131.9 (8-C), 132.8 (2-
C), 133.5 (3a-CX), 142.2 (9a-C), 151.7 (3a-C), 162.9 (2-CX), 169.8
(5-CO).
1H NMR: d = 1.51 (s, 9 H, t-Bu), 7.30 (t, J = 7.5 Hz, 1 H, HX), 7.44
(t, J = 7.5 Hz, 1 H, HX), 7.56 (t, J = 7.0 Hz, 1 H, 7-H), 7.79 (t,
J = 7.0 Hz, 1 H, 8-H), 7.96 (d, J = 7.5 Hz, 1 H, HX), 8.00 (d, J = 7.5
Hz, 1 H, HX), 8.20 (s, 1 H, 1-H), 8.23 (d, J = 7.0 Hz, 1 H, 6-H), 8.42
(d, J = 7.0 Hz, 1 H, 9-H), 12.65 (s, 1 H, NH).
13C NMR: d = 29.6 (3 × CH3), 31.0 (CMe3), 94.2 (4-C), 106.3 (1-C),
116.5 (9-C), 120.8 (7-CX), 121.9 (4-CX), 123.6 (6-CX), 124.8 (5a-
C), 125.8 (5-CX), 126.0 (7-C), 127.1 (6-C), 131.9 (8-C), 133.0 (7a-
CX), 133.1 (2-C), 140.5 (3a-CX), 142.7 (9a-C), 151.1 (3a-C), 163.3
(2-CX), 169.7 (5-CO).
Anal. Calcd for C19H13N3OS: C, 68.86; H, 3.95; N, 12.68; S, 9.68.
Found: C, 68.80; H, 3.86; N, 12.60; S, 9.60.
4-(1H-Benzimidazol-2-yl)-2-methylimidazo[1,2-a]quinolin-
5(3H)-one (7c)
Yield: 63% (i), 66% (iii); mp 215 °C (dioxane).
Anal. Calcd for C22H19N3OS: C, 70.75; H, 5.13; N, 11.25; S, 8.59.
Found: C, 70.64; H, 5.24; N, 11.08; S, 8.50.
4-(1H-Benzimidazol-2-yl)-2-tert-butylimidazo[1,2-a]quinolin-
5(3H)-one (6c)
Yield: 69% (i), 96% (from compound 9a); mp 215 °C (AcOH).
1H NMR: d = 2.43 (s, 3 H, CH3), 7.19 (m, 2 H, HX), 7.51 (t, J = 8.0
Hz, 1 H, 7-H), 7.72 (m, 3 H, 8-H, 2 × HX), 8.06 (s, 1 H, 1-H), 8.09
(d, J = 8.0 Hz, 1 H, 6-H), 8.40 (d, J = 8.0 Hz, 1 H, 9-H), 12.27 (br
s, 2 H, 2 × NH).
13C NMR: d = 12.3 (CH3), 89.0 (4-C), 107.7 (1-C), 116.1 (9-C),
122.2 (4,7-CX), 122.3 (5,6-CX), 124.0 (5a-C), 125.1 (7-C), 126.7 (6-
C), 131.7 (8-C), 132.0 (3a,7a-CX), 133.0 (2-C), 143.2 (9a-C), 150.8
(2-CX), 150.9 (3a-C), 168.6 (5-CO).
1H NMR: d = 1.46 (s, 9 H, t-Bu), 7.25 (m, 2 H, HX), 7.52 (t, J = 7.5
Hz, 1 H, 7-H), 7.75 (m, 3 H, 8-H, 2 × HX), 8.12 (s, 1 H, 1-H), 8.21
(d, J = 7.5 Hz, 1 H, 6-H), 8.39 (d, J = 7.5 Hz, 1 H, 9-H), 12.62 (br
s, 2 H, 2 × NH).
13C NMR: d = 30.2 (3 × CH3), 31.7 (CMe3), 88.7 (4-C), 105.3 (1-C),
116.3 (9-C), 122.7 (5,6-CX), 122.8 (4,7-CX), 123.6 (5a-C), 125.0 (7-
C), 126.7 (6-C), 131.8 (8-C), 133.6 (2-C), 143.6 (3a,7a-CX), 147.1
(9a-C), 150.7 (2-CX), 150.8 (3a-C), 168.0 (5-CO).
Anal. Calcd for C19H14N4O: C, 72.60; H, 4.49; N, 17.82. Found: C,
72.75; H, 4.40; N, 18.23.
4-[4-(4-Chlorophenyl)-2-thiazolyl]-2-methylimidazo[1,2-
a]quinolin-5(3H)-one (7e)
Yield: 76% (i), 77% (iii); mp >300 °C (dioxane).
Anal. Calcd for C22H20N4O: C, 74.14; H, 5.66; N, 15.72. Found: C,
73.92; H, 5.76; N, 15.90.
2-tert-Butyl-4-(1-methyl-1H-benzimidazol-2-yl)imidazo[1,2-
a]quinolin-5(3H)-one (6d)
Yield: 64% (i), 97% (from compound 9b); mp 264 °C (AcOH).
1H NMR: d = 2.50 (s, 3 H, CH3), 7.48–7.54 (m, 3 H, 7-H, 2 × HX),
7.75 (t, J = 7.0 Hz, 1 H, 8-H), 7.80 (s, 1 H, 5-HX), 8.09–8.13 (m, 4
H, 1-H, 6-H, 2 × HX), 8.39 (d, J = 7.0 Hz, 1 H, 9-H).
1H NMR: d = 1.20 (s, 9 H, t-Bu), 3.51 (s, 3 H, NCH3), 7.01–7.22 (m,
4 H, HX), 7.51 (t, J = 7.6 Hz, 1 H, 7-H), 7.75 (t, J = 7.6 Hz, 1 H, 8-
H), 8.06 (s, 1 H, 1-H), 8.29 (d, J = 7.6 Hz, 1 H, 6-H), 8.33 (d, J = 7.6
Hz, 1 H, 9-H), 11.99 (s, 1 H, NH).
13C NMR: d = 29.1 (3 × CH3), 31.2 (NCH3), 31.8 (CMe3), 89.6 (4-
C), 105.2 (1-C), 110.0 (7-CX), 116.3 (9-C), 121.5 (4-CX), 121.8 (6-
CX), 125.1 (7-C), 125.2 (5-CX), 125.3 (5a-C), 127.0 (6-C), 131.4 (8-
C), 133.3 (2-C), 135.6 (7a-CX), 142.7 (3a-CX), 145.4 (9a-C), 150.3
(3a-C), 150.4 (2-CX), 168.6 (5-CO).
13C NMR: d = 12.4 (CH3), 89.0 (4-C), 106.1 (1-C), 111.6 (5-CX),
118.3 (9-C), 124.0 (5a-C), 124.2 (7-C), 126.1 (6-C), 128.4 (3,5-
CPhCl), 129.2 (2,6-CPhCl), 129.4 (8-C), 131.8 (1-CPhCl), 132.6 (2-C),
134.0 (4-CPhCl), 140.2 (4-CX), 141.9 (9a-C), 149.2 (3a-C), 164.9 (2-
CX), 170.4 (5-CO).
Anal. Calcd for C21H14ClN3OS: C, 64.36; H, 3.60; N, 10.72; Cl,
9.05; S, 8.18. Found: C, 64.57; H, 3.60; N, 10.61; Cl, 9.05; S, 7.97.
Methyl N-[2-[2-Cyano-2-(1,3-dihydro-1-methyl-2H-benzimid-
azol-2-ylidene)-1-oxoethyl]phenyl]glycinate (8)
Yield: 84% (ii); mp 220 °C (DMF).
Anal. Calcd for C23H22N4O: C, 74.57; H, 5.99; N, 15.12. Found: C,
74.41; H, 5.90; N, 15.16.
Synthesis 2008, No. 10, 1535–1540 © Thieme Stuttgart · New York

PAPER
Facile Route to Imidazo[1,2-a]quinolines
1539
1H NMR: d = 3.67 (s, 3 H, NCH3), 3.97 (s, 3 H, OCH3), 4.01 (d,
J = 5.0 Hz, 2 H, CH2), 6.58 (m, 2 H, NH, 6-HPh), 6.65 (t, J = 7.0 Hz,
1 H, 4-HPh), 7.24 (t, J = 7.0 Hz, 1 H, 5-HPh), 7.35 (m, 2 H, 2 × Him),
7.55 (d, J = 7.0 Hz, 1 H, 3-HPh), 7.64 (d, J = 7.0 Hz, 1 H, Him), 7.73
(d, J = 7.0 Hz, 1 H, Him), 13.58 (s, 1 H, NH···O).
13C NMR: d = 32.4 (NCH3), 45.1 (CH2), 52.3 (OCH3), 65.9 (CCN),
110.8 (7-Cim), 111.7 (4-Cim), 113.2 (6-CPh), 115.6 (4-CPh), 121.9
(CN), 124.0 (5-Cim), 124.4 (6-Cim), 129.8 (3-CPh), 130.0 (5-CPh),
131.8 (2-CPh), 132.6 (1-CPh), 146.7 (7a-Cim), 146.8 (3a-Cim), 151.5
(2-Cim), 171.8 (COO), 190.1 (CO).
Conversion of the Intermediate Compounds 8–10 into the
Corresponding Imidazoquinolines; General Procedure
A soln of compound 8–10 (2 mmol) in AcOH (5 mL) was refluxed
for 1 h. After cooling the mixture, the precipitate formed was col-
lected by filtration and dried to give the pure derivative 5d, 6c, 6d
or 6e in nearly quantitative yield.
X-ray Crystal Structure Determination of Compound 6e
Crystallographic measurements were performed at 296 K on a
Bruker Smart APEX II diffractometer. The intensities of 11024 re-
flections (4358 unique) were collected within the range 2.1 < q <
26.5 (–17 < h < 19, –9 < k < 9, –22 < l < 22) using graphite mono-
chromated Mo–Ka radiation (l = 0.71073 Å). Crystal data:
C24H20ClN3OS, Mr = 433.94, monoclinic, a = 15.663(2) Å,
b = 7.8495(11) Å, c = 18.353(2) Å, b = 110.2°, V = 2117.2(5) Å3,
Z = 4, space group P21/n, m(Mo–Ka) = 0.300 mm–1. The structure
was solved by direct methods and refined by full-matrix least-
squares technique in anisotropic approximation using SHELXS-
9720 and SHELXL-9721 program packages. Hydrogen atoms were
located in the difference Fourier maps and refined isotropically (ex-
cluding hydrogen atoms of the t-Bu group, which were placed geo-
metrically and refined as ‘riding’ model using AFIX 137
instruction). In the refinement 2386 reflections with I > 2s(I) were
used. Convergence was obtained at R1 = 0.05 and wR2 = 0.114,
GOF = 1.02. Full crystallographic parameters have been deposited
with the Cambridge Crystallographic Data Centre under the refer-
ence number CCDC 671695. These data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk.
Anal. Calcd for C20H18N4O3: C, 66.29; H, 5.01; N, 15.46. Found: C,
66.07; H, 5.18; N, 15.51.
a-(1,3-Dihydro-2H-benzimidazol-2-ylidene)-2-[(3,3-dimethyl-
2-oxobutyl)amino]-b-oxobenzenepropanenitrile (9a)
Yield: 74% (iii); mp 268 °C (dioxane).
1H NMR: d = 1.16 (s, 9 H, t-Bu), 4.22 (d, J = 1.5 Hz, 2 H, CH2),
6.64 (t, J = 7.0 Hz, 1 H, 5-HPh), 6.70 (d, J = 7.0 Hz, 1 H, 3-HPh), 6.91
(t, J = 1.5 Hz, 1 H, NH), 7.26 (m, 3 H, 4-HPh, 2 × Him), 7.57 (m, 3
H, 6-HPh, 2 × Him), 13.00 (br s, 2 H, 2 × NH).
13C NMR: d = 26.5 (3 × CH3), 43.1 (CMe3), 48.4 (CH2), 66.6
(CCN), 112.3 (3-CPh), 112.6 (4,7-Cim), 115.1 (5-CPh), 121.4 (CN),
123.3 (1-CPh), 123.9 (5,6-Cim), 129.7 (6-CPh), 131.0 (4-CPh), 131.9
(3a,7a-Cim), 146.7 (2-CPh), 152.6 (2-Cim), 188.7 (b-CO), 211.7
(CH2CO).
Anal. Calcd for C22H22N4O2: C, 70.57; H, 5.92; N, 14.96. Found: C,
70.61; H, 5.86; N, 14.83.
a-(1,3-Dihydro-1-methyl-2H-benzimidazol-2-ylidene)-2-[(3,3-
dimethyl-2-oxobutyl)amino]-b-oxobenzenepropanenitrile (9b)
Yield: 50% (iii); mp 195 °C (dioxane).
1H NMR: d = 1.17 (s, 9 H, t-Bu), 3.97 (s, 3 H, NCH3), 4.26 (d,
J = 2.0 Hz, 2 H, CH2), 6.63 (t, J = 8.0 Hz, 1 H, 5-HPh), 6.70 (m, 2 H,
3-HPh, NH), 7.26 (t, J = 8.0 Hz, 1 H, 4-HPh), 7.34 (m, 2 H, Him), 7.55
(d, J = 8.0 Hz, 1 H, 6-HPh), 7.63 (d, J = 6.5 Hz, 1 H, Him), 7.77 (d,
J = 6.5 Hz, 1 H, Him), 13.56 (s, 1 H, NH···O).
13C NMR: d = 26.5 (3 × CH3), 32.4 (NCH3), 43.1 (CMe3), 48.5
(CH2), 65.6 (CCN), 110.7 (7-Cim), 112.3 (3-CPh), 113.3 (4-Cim),
115.2 (5-CPh), 121.9 (CN), 123.9 (1-CPh), 124.0 (6-Cim), 124.4 (5-
Cim), 129.8 (3a-Cim), 130.0 (6-CPh), 131.8 (4-CPh), 132.7 (7a-Cim),
146.6 (2-CPh), 151.6 (2-Cim), 190.2 (b-CO), 211.7 (CH2CO).
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Anal. Calcd for C23H24N4O2: C, 71.11; H, 6.23; N, 14.42. Found: C,
71.27; H, 6.30; N, 14.50.
2-tert-Butyl-4-[4-(4-chlorophenyl)-2-thiazolyl]-2,3-dihydro-2-
hydroxyimidazo[1,2-a]quinolin-5(1H)-one (10)
Yield: 69% (iii); mp 289 °C (dioxane).
1H NMR: d = 1.13 (s, 9 H, t-Bu), 4.20 (d, J = 12.5 Hz, 1 H, 1-H),
4.64 (d, J = 12.5 Hz, 1 H, 1-H), 6.82 (s, 1 H, OH), 7.35 (t, J = 7.5
Hz, 1 H, 7-H), 7.47 (d, J = 7.5 Hz, 1 H, 9-H), 7.54 (d, J = 8.5 Hz, 2
H, HX), 7.68 (t, J = 7.5 Hz, 1 H, 8-H), 7.92 (s, 1 H, 5-HX), 7.96 (d,
J = 8.5 Hz, 2 H, HX), 8.21 (d, J = 7.5 Hz, 1 H, 6-H), 9.98 (s, 1 H,
NH).
13C NMR: d = 25.0 (3 × CH3), 38.1 (CMe3), 55.0 (1-C), 94.1 (2-C),
94.2 (4-C), 112.3 (9-C), 115.4 (5-CTh), 122.8 (5a-C), 123.0 (7-C),
126.3 (6-C), 127.8 (3,5-CPhCl), 129.3 (2,6-CPhCl), 132.3 (8-C), 132.8
(1-CPhCl), 133.9 (4-CPhCl), 136.7 (4-CTh), 150.1 (9a-C), 153.1 (3a-C),
163.2 (2-CTh), 172.6 (5-CO).
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Synthesis 2008, No. 10, 1535–1540 © Thieme Stuttgart · New York

1540
R. T. Iminov et al.
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Synthesis 2008, No. 10, 1535–1540 © Thieme Stuttgart · New York