A diels-alder strategy for the building of imidazo[4,5-g]quinoline-4,9- dione derivatives

Article abstract of DOI:10.1002/ejoc.200400803

Benzimidazole-4,7-diones 3a and 3b were synthesized and submitted to hetero Diels-Alder reactions with azadienes 4 and 5 to afford imidazo[4,5-g]quinoline- 4,9-diones 6-9. The structure of the latter was assigned by X-ray diffraction, ¹H NMR NO

Full text of DOI:10.1002/ejoc.200400803

FULL PAPER
A Diels–Alder Strategy for the Building of Imidazo[4,5-g]quinoline-4,9-dione
Derivatives
Frédéric Alvarez,[a] Abbas Taleb,[a] Jacques Gentili,[a] Pascal Nebois,*[a] Raphaël Terreux,[a]
Monique Domard,[a] Alain Thozet,[b] Daphné Merle,[b] Houda Fillion,[a] and
Nadia Walchshofer[a]
Keywords: Benzimidazole / Cycloaddition / Nitrogen heterocycles / Quinones
Benzimidazole-4,7-diones 3a and 3b were synthesized and
submitted to hetero Diels–Alder reactions with azadienes 4
and 5 to afford imidazo[4,5-g]quinoline-4,9-diones 6–9. The
structure of the latter was assigned by X-ray diffraction, 1H
NMR NOE DIFF experiments or by a molecular dynamics
study.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
derivative and require the building of the imidazole ring.
However, quinoline derivatives can be obtained by a Diels–
Alder reaction of 1-azadienes[4] with a dienophile.[5–9] We
wish to report here our results concerning this alternative
strategy based on hetero Diels–Alder reactions between
benzimidazole-4,7-diones I as dienophiles and α,β-unsatu-
rated N,N-dimethylhydrazones.
Introduction
We are engaged in a program directed at searching for
new antiparasitic compounds. Recently,[1] we described the
activity of some benzimidazole-4,7-diones of general for-
mula I (Figure 1) as Toxoplasma gondii purine nucleoside
phosphorylase inhibitors. In order to determine structure-
activity relationships, we planned the synthesis of imidazo-
quinolinediones II and III as tricyclic derivatives of qui-
nones I.
Results and Discussion
The synthesis of the benzimidazolequinones 3a and 3b
was carried out as outlined in Scheme 1.
Figure 1. Benzimidazolediones I and imidazoquinolinediones II–III.
All the syntheses of the few imidazoquinolinediones de-
scribed in the literature[2,3] start from a quinoline-5,8-dione
Scheme 1. Synthesis of benzimidazoledione derivatives 3.
[a] Université Claude Bernard Lyon 1, ISPB, EA 3741 “Eco-
systèmes et Molécules Bioactives”,
Thus, treatment of 4,7-dimethoxybenzimidazole (1)[10]
with NaH in DMF and subsequent addition of the appro-
priate alkylating agent afforded the N-substituted benzimid-
azoles 2a[11] and 2b. Attempts to transform compound 2a
directly into quinone 3a by treatment with ceric ammonium
nitrate (CAN) failed because a dimerization process oc-
8 avenue Rockefeller, 69373 Lyon Cedex 08, France
E-mail: Nebois@univ-lyon1.fr
Nadia.Walchshofer@univ-lyon1.fr
[b] Université Claude Bernard Lyon 1, Laboratoire de crystallogra-
phie associé au CNRS,
43 boulevard du 11 novembre 1918, 69622 Villerbanne Cedex,
France
E-mail: thozet@cdlyon.univ-lyon1.fr
Eur. J. Org. Chem. 2005, 1903–1908
DOI: 10.1002/ejoc.200400803
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1903

P. Nebois et al.
FULL PAPER
curred, a phenomenon already described for dimethoxyben- 5 in both cases. As for azadienes 4 and 5, we have previously
zene derivatives.[12] The use of AgO/HNO3 as oxidant[13] reported that the largest values of the HOMO orbital coeffi-
was also unsuccessful as a 40% yield of the desired quinone cients (Scheme 2) are situated at C-4.[18] Therefore, com-
was obtained mixed with a dimerized product. Finally, qui- pounds 6 and 8 would be the major regioisomers. More-
nones 3a and 3b were obtained by demethylation of com- over, the small difference between the orbital coefficient val-
pounds 2a and 2b with hydrogen bromide followed by oxi- ues for azadiene 4 could explain the weak regioselectivity
dation with K2Cr2O7. This method provided quinones 3a observed in its reaction with quinone 3a.
and 3b in good overall yields (58 and 62% respectively, cal-
culated from 2a and 2b).
In order to unambiguously establish the structure of the
different regioisomers, we first envisaged an X-ray diffrac-
The hetero Diels–Alder reactions of 3a and 3b with azad- tion study. Unfortunately, attempts to obtain suitable crys-
ienes 4[14] and 5[15] are described in Scheme 2 and Table 1. tals of 6–9 only succeeded for 8b (Figure 2), which only
In all cases, the primary tetrahydro cycloadducts were not allowed us to assign the structure of regioisomers 8b and
detected.
9b.
Starting from azadiene 4, the Diels–Alder reaction with
quinone 3a, carried out in acetonitrile in the presence of
acetic anhydride,[16] gave a mixture of dihydro cycloadducts
and fully aromatized products. A further addition of man-
ganese dioxide to the reaction mixture provided the re-
gioisomeric compounds 6 and 7 in good yields with a poor
regioselectivity (46:54).
On the other hand, the reaction of azadiene 5 with qui-
nones 3a or 3b in ethanol afforded directly a mixture of the
aromatized compounds 8a + 9a or 8b + 9b, respectively,
with better regioselectivities than observed with azadiene 4
and quinone 3a. All the regioisomers were separated by col-
umn chromatography on silica gel and identified.
Figure 2. X-ray crystal structure of 8b (anisotropically refined
The regiochemistry of the Diels–Alder reaction can be
predicted by frontier molecular orbital (FMO) theory.
Therefore, we calculated the primary orbital coefficients for
quinones 3a and 3b by the semi-empirical PM3 method.[17]
atoms shown as 50% displacement ellipsoids).
1
A 2D H-13C NMR HMBC correlation experiment was
The calculations (Scheme 2) indicate that the largest performed on compound 8a but the detected H-13C coup-
1
LUMO orbital coefficients of quinones 3 are located at C- lings were not helpful for a structural determination.
Scheme 2. Synthesis of imidazoquinolinediones 6–9.
Table 1. Synthesis of imidazoquinolinediones 6–9.
Quinone
Azadiene
Conditions
Products
Yield [%]
63
Ratio
3a
4
MeCN, Ac2O, room temp., 48 h
then MnO2, room temp., 24 h
EtOH, room temp., 4 h
6 + 7
6/7 = 46:54
3a
3b
5
5
8a + 9a
8b + 9b
59
85
8a/9a = 69:31
8b/9b = 68:32
EtOH, room temp., 4 h
1904
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Eur. J. Org. Chem. 2005, 1903–1908

Diels–Alder Strategy for Imidazo[4,5-g]quinoline-4,9-dione Derivatives
FULL PAPER
1
We then carried out H NMR NOE DIFF experiments
on the diacetoxy derivatives 10–13, which were obtained
following a known procedure[19] (Scheme 3).
1
Figure 3. H NMR NOE DIFF experiments performed on 13.
We next turned our attention to the 1H NMR spectra of
the diacetoxy derivatives 10 and 11, where the benzylic pro-
tons show different signals for these regioisomers: a singlet
at δ = 5.58 ppm for one of them, and two doublets at δ =
5.44 and 5.59 ppm for the other. This different behavior was
assumed to come from a conformational restriction in 11,
leading to a nonchemical equivalence of the benzylic pro-
tons. In order to confirm this hypothesis, we performed a
comparative molecular dynamic study on 10 and 11 (Fig-
ure 4). As expected, compound 11 shows a weaker oscilla-
tion of the dihedral angle ψ2 compared to that of com-
pound 10, thereby establishing the structural assignment.
Scheme 3. Synthesis of the diacetoxy derivatives of compounds 6,
7, 8a, 9a. (i): Ac2O, Zn/AcONa.
Conclusions
Using this methodology, we were able to assign only the
structure of compound 13 (Figure 3), and therefore those
An effective procedure using a Diels–Alder methodology
of 8a and 9a. For the others, the NOE DIFF experiments has been developed for the synthesis of imidazoquinoline-
were inconclusive. dione derivatives. The regiochemistry of the cycloadditions
Figure 4. Plotting of dihedral angle (ψ) values vs. time for compound 10 and 11 during molecular modelling simulation.
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Eur. J. Org. Chem. 2005, 1903–1908
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1905

P. Nebois et al.
FULL PAPER
[M+]; C14H15N3O2S requires 289.0885. C14H15N3O2S·0.2H2O
(292.96): calcd. C 57.40, H 5.29, N 14.34, S 10.94; found C 57.36,
H 4.96, N 14.63, S 11.06.
of azadiene 5 with quinones 3 agrees with the calculations
of the semi-empirical method PM3, but that of azadiene 4
with quinone 3a seems to be in contradiction. The differ-
ence between the orbital coefficient values of N-1 and C-4
for azadiene 4 is smaller than that for azadiene 5, which
could explain this result. A biological evaluation of imid-
azoquinolinediones 6–9 and efforts to improve the regiose-
lectivity of the [4+2] cycloadditions between benzimidazole-
4,7-diones and azadienes are underway.
1-Benzyl-1H-benzimidazole-4,7-dione (3a): A solution of 1-benzyl-
4,7-dimethoxy-1H-benzimidazole (2a; 1.61 g, 6 mmol) in aqueous
48% HBr (40 mL) was heated to reflux for 4 h. After cooling to
4 °C over 12 h, the precipitate was filtered off and dissolved in
water (50 mL). Then, an aqueous solution of 6.7 n HCl (1.05 mL),
an aqueous solution of 0.3 m K2Cr2O7 (4.8 mL), sodium acetate
(1.61 g, 19.6 mmol), and CH2Cl2 (100 mL) were added successively.
Stirring was maintained for 30 min. The aqueous layer was then
extracted with CHCl3 (5×30 mL) and the combined organic layers
were dried with Na2SO4. After removing the solvents, the residue
was purified by column chromatography (ethyl acetate). Quinone
Experimental Section
General Remarks: Melting points were measured with a Büchi ap-
paratus (capillary tube). The 1H (300 MHz) and 13C NMR
(75 MHz) spectra were recorded with a Bruker AM 300 spectro-
photometer. The chemical shifts are reported in ppm (δ) relative to
tetramethylsilane (TMS) as an internal reference. The infrared
spectra were recorded with a Perkin–Elmer 1310 spectrometer.
Mass spectra (EI) were recorded with a GC/MS Nermag R10–10
spectrometer. Elemental analyses were performed at the Centre de
Microanalyse du CNRS at Solaize (France). The coefficients of the
molecular frontier orbitals and the conformational energy were
computed with the PM3 semi-empirical method of the Sybyl[20]
molecular modelling package. The global charge of the molecule
was set to neutral, and the electronic configuration was set to the
ground state. Starting from a PM3 energetically minimized confor-
mation, a short molecular dynamics (100 ps) was made at constant
energy and volume (NVE) using the molecular mechanics method.
Calculations were carried out with the Merck Force Field
(MMFF94)[21] and a conformation was sampled every 0.5 ps. The
electrostatic cut-off was set to 16 Å and the dielectric constant was
set to 80 and varies with distance. Atomic partial charges were
calculated using the algorithm included with the MFF94 force
field. All calculations were carried on an SGI O2 workstation.
3a was obtained in 58% yield (0.83 g). M.p. 163 °C. IR (KBr): ν =
˜
1
1660 cm–1. H NMR (CDCl3): δ = 5.53 (s, 2 H, CH2N), 6.64 (d, J
= 10.3 Hz, 1 H, 5-H or 6-H), 6.71 (d, J = 10.3 Hz, 1 H, 5-H or 6-
H), 7.28–7.31 (m, 2 H, ArH), 7.35–7.39 (m, 3 H, ArH), 7.78 (s, 1
H, 2-H) ppm. 13C NMR (CDCl3): δ = 50.32, 128.02, 128.96,
129.27, 130.07, 134.57, 136.22, 136.75, 142.54, 143.08, 178.49,
180.81 ppm. C14H10N2O2 (238.24): calcd. C 70.58, H 4.23, N 11.76;
found C 70.48, H 4.27, N 11.86
1-[(2-Methylthiazol-4-yl)methyl]-1H-benzimidazole-4,7-dione (3b):
Compound 3b was obtained from 2b as described for 3a. Yield:
0.96 g (62%) after purification by column chromatography (ethyl
acetate/methanol, 9:1). M.p. 152–153 °C (dec.). IR(KBr): ν =
˜
1
1680 cm–1. H NMR (CDCl3): δ = 2.68 (s, 3 H, 2Ј-CH3), 5.57 (s, 2
H, CH2N), 6.63 (d, J = 10.4 Hz, 1 H, 5-H or 6-H), 6.70 (d, J =
10.4 Hz, 1 H, 5-H or 6-H), 7.24 (s, 1 H, 5Ј-H), 7.99 (s, 1 H, 2-H)
ppm. 13C NMR (CDCl3): δ = 19.21, 45.75, 118.07, 136.11, 136.79,
143.63 (2 C), 148.79 (2 C), 167.53, 178.59, 180.82 ppm. EI-MS:
m/z
=
259.0413 [M+]; C12H9N3O2S requires 259.0415.
C12H9N3O2S·0.1H2O (261.08): calcd. C 55.20, H 3.55, N 16.09, S
12.36; found C 54.88, H 3.09, N 15.98, S 12.50.
3-Benzyl-8-methyl-3H-imidazo[4,5-g]quinoline-4,9-dione (6) and 1-
Benzyl-8-methyl-1H-imidazo[4,5-g]quinoline-4,9-dione (7): Acetic
anhydride (1.02 g, 9.95 mmol) and a solution of azadiene 4 (0.70 g,
6.3 mmol) in dry acetonitrile (5 mL) were added dropwise to a solu-
tion of quinone 3a (1 g, 4.2 mmol) in the same solvent (140 mL).
The reaction mixture was stirred for 48 h. Manganese dioxide
(3.60 g, 41.6 mmol) was then added and stirring was maintained
for 24 h. This mixture was filtered and concentrated. The residue
was purified by column chromatography (dichloromethane/ace-
tone, 67:33) to give 6 and 7 (0.8 g, 63% overall yield).
1-Benzyl-4,7-dimethoxy-1H-benzimidazole (2a): A solution of 4,7-
dimethoxy-1H-benzimidazole (1; 1.78 g, 10 mmol) in dry DMF
(250 mL) was added dropwise, over 15 min, to a suspension of NaH
(60% in mineral oil; 0.425 g, 10.6 mmol) in the same solvent
(10 mL). The reaction mixture was stirred for 15 min and benzyl
bromide (1.62 g, 9.47 mmol) was added. After stirring for 12 h,
DMF was removed under vacuum. The residue was then dissolved
in dichloromethane (250 mL), washed with a saturated aqueous
K2CO3 solution (3×250 mL), and dried with Na2SO4. Evaporation
of the solvent led to a residue which was purified by column
chromatography (ethyl acetate) to afford 2a (2.06 g, 81%). M.p.
6: Yield: 0.37 g (29%). M.p. 278–280 °C. IR (KBr): ν = 1680 cm–1.
˜
1H NMR (CDCl3): δ = 2.90 (d, J = 0.6 Hz, 3 H, 8-CH3), 5.67 (s,
2 H, CH2N), 7.36–7.39 (m, 5 H, ArH), 7.89 (s, 1 H, 2-H), 7.43 (dq,
J = 4.9 and 0.6 Hz, 1 H, 7-H), 8.80 (d, J = 4.9 Hz, 1 H, 6-H) ppm.
13C NMR (CDCl3): δ = 22.62, 50.72, 128.31, 128.89, 129.18,
130.73, 131.12, 134.53, 144.30, 144.85, 150.08, 151.57, 152.24,
155.04, 174.37, 180.05 ppm. C18H13N3O2 (303.31): calcd. C 71.27,
H 4.32, N 13.85; found C 70.85, H 4.46, N 13.60.
166 °C. IR (KBr): ν = 2800, 1600 cm–1. 1H NMR (CDCl3): δ =
˜
3.78 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3) 5.65 (s, 2 H, CH2N), 6.54
(d, J = 8.5 Hz, 1 H, 5-H or 6-H), 6.59 (d, J = 8.5 Hz, 1 H, 5-H or
6-H), 6.99–7.11 (m, 3 H, ArH), 7.14–7.23 (m, 1 H, ArH), 7.81 (s,
1 H, 2-H) ppm.
4,7-Dimethoxy-1-[(2-methylthiazol-4-yl)methyl]-1H-benzimidazole
(2b): Compound 2b was obtained as described for compound 2a
(alkylating agent: 4-chloromethyl-2-methylthiazole) and purified by
column chromatography (ethyl acetate/methanol, 9:1). The product
7: Yield: 0.43 g (34%). M.p. 243–245 °C. IR (KBr): ν = 1660,
˜
1690 cm–1. 1H NMR (CDCl3): δ = 2.85 (d, J = 0.6 Hz, 3 H, 8-
CH3), 5.67 (s, 2 H, CH2N), 7.31–7.39 (m, 5 H, ArH), 7.85 (s, 1 H,
2-H), 7.41 (dq, J = 2.1 and 0.6 Hz, 1 H, 7-H), 8.83 (d, J = 2.1 Hz,
1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 22.48, 50.36, 127.78,
127.90, 128.61, 129.01, 130.72, 132.06, 134.60, 143.03, 144.50,
149.99, 150.95, 152.46, 176.65, 177.95 ppm. C18H13N3O2 (303.31):
calcd. C 71.27, H 4.32, N 13.85; found C 71.02, H 4.50, N 13.57.
was isolated as a brownish oil (1.89 g, 69%). IR (film): ν = 2800,
˜
1
1510 cm–1. H NMR (CDCl3): δ = 2.65 (s, 3 H, 2Ј-CH3), 3.82 (s, 3
H, OCH3), 3.93 (s, 3 H, OCH3), 5.62 (s, 2 H, CH2N), 6.50 (d, J =
8.5 Hz, 1 H, 5-H or 6-H), 6.55 (d, J = 8.5 Hz, 1 H, 5-H or 6-H),
6.70 (s, 1 H, 5Ј-H), 7.88 (s, 1 H, 2-H) ppm. 13C NMR (CDCl3): δ
= 19.08, 46.44, 55.89, 56.00, 102.21, 103.79, 115.43, 124.64, 135.58,
141.69, 142.75, 146.11, 152.14, 166.73 ppm. EI-MS: m/z = 289.0885
3-Benzyl-7-methyl-3H-imidazo[4,5-g]quinoline-4,9-dione (8a) and 1-
Benzyl-7-methyl-1H-imidazo[4,5-g]quinoline-4,9-dione (9a): A solu-
1906
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Diels–Alder Strategy for Imidazo[4,5-g]quinoline-4,9-dione Derivatives
FULL PAPER
tion of azadiene 5 (0.252 g, 2.25 mmol) in dry ethanol (2.2 mL) was
added dropwise to a solution of quinone 3a (0.357 g, 1.5 mmol) in
the same solvent (11 mL). Stirring was maintained for 4 h. The
precipitate was then filtered off, washed with ethanol, and purified
by column chromatography (ethyl acetate/petroleum ether, 9:1) to
afford 8a and 9a (0.27g, 59% overall yield).
4 Hz, 1 H, 6-H13C NMR (CDCl3): δ = 21.08, 21.33, 21.66, 50.56,
119.31, 126.37 (2 C), 126.94, 128.57, 128.64, 128.81, 129.53, 129.58
(2 C), 134.54, 136.09, 136.36, 140.01, 148.81, 149.65; 169.62,
169.97 ppm. EI-MS: m/z = 389.1375 [M+]; C22H19N3O4 requires
389.1375.
4-(Acetyloxy)-1-benzyl-8-methyl-1H-imidazo[4,5-g]quinolin-9-yl
8a: Yield: 0.187 g (41%). M.p. 258–260 °C. IR (KBr): ν =
˜
Acetate (11): Compound 11 was prepared as above from 7 (0.019 g,
1665 cm–1. 1H NMR (CDCl3): δ = 2.53 (d, J = 0.6 Hz, 3 H, 7-
CH3), 5.69 (s, 2 H, CH2N), 7.28–7.40 (m, 5 H, ArH), 7.90 (s, 1 H,
2-H), 8.35 (dq, J = 1 and 0.6 Hz, 1 H, 8-H), 8.81 (d, J = 2.1 Hz, 1
H, 6-H) ppm. 13C NMR (CDCl3): δ = 19.20, 51.23, 128.78, 129.36,
129.63, 129.95, 132.63, 134.88, 135.52, 139.00, 144.43, 144.67,
147.04, 154.87, 175.15, 178.34 ppm. C18H13N3O2 (303.31): calcd. C
71.27, H 4.32, N 13.85; found C 71.05, H 4.29, N 13.79.
1
76% yield). IR (KBr): ν = 1765 cm–1. H NMR (CDCl ): δ = 2.19
˜
3
(s, 3 H, 4-OCOCH3), 2.65 (s, 3 H, 9-OCOCH3), 2.75 (d, J = 0.7 Hz,
3 H, 8-CH3), 5.44 (d, J = 16.1 Hz, 1 H, CH2N), 5.59 (d, J =
16.1 Hz, 1 H, CH2N), 7.38 (dq, J = 4 and 0.7 Hz, 1 H, 7-H), 7.13–
7.41 (m, 5 H, ArH), 7.98 (s, 1 H, 2-H), 8.75 (d, J = 4 Hz, 1 H, 6-
H) ppm. 13C NMR (CDCl3): δ = 21.38, 23.29 (2 C), 50.29, 120.71,
123.71, 126.76 (2 C), 127.97, 128.33, 128.87, 129.64 (2C), 135.78,
136.04, 137.70, 139.35, 142.56, 149.24, 149.61; 169.85, 170.13 ppm.
EI-MS: m/z = 389.1372 [M+]; C22H19N3O4 requires 389.1375.
9a: Yield: 0.083 g (18%). M.p. 298–300 °C. IR (KBr): ν = 1680,
˜
1700 cm–1. 1H NMR (CDCl3): δ = 2.53 (d, J = 0.6 Hz, 3 H, 7-
CH3), 5.66 (s, 2 H, CH2N), 7.32–7.43 (m, 5 H, ArH), 7.90 (s, 1 H,
2-H), 8.27 (dq, J = 2.3 Hz and 0.6 Hz, 1 H, 8-H), 8.85 (d, J =
2.3 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 18.76, 50.65,
127.91, 128.92, 129.25, 129.56, 131.32, 134.48, 134.52, 138.02,
144.47, 144.87, 146.75, 154.83, 175.70, 176.99 ppm. EI-MS: m/z =
4-(Acetyloxy)-3-benzyl-7-methyl-3H-imidazo[4,5-g]quinolin-9-yl
Acetate (12): Compound 12 was prepared as above from 8a
1
(0.012 g, 47% yield). IR (KBr): ν = 1770 cm–1. H NMR (CDCl ):
˜
3
δ = 2.29 (s, 3 H, 4-OCOCH3), 2.54 (d, J = 0.6 Hz, 3 H, 7-CH3),
2.62 (s, 3 H, 9-OCOCH3), 5.59 (s, 2 H, CH2N), 7.17–7.35 (m, 5 H,
ArH), 8.04 (s, 1 H, 2-H), 8.09 (dq, J = 2.2 and 0.6 Hz, 1 H, 8-H),
8.74 (d, J = 2.2 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 19.35,
20.79, 21.41, 50.32, 119.90, 126.53, 126.66 (2 C), 127.37, 127.99,
128.85 (2 C), 129.63 (2 C), 130.28, 134.38, 135.68, 135.97, 149.02,
303.1008
[M+];
C18H13N3O2
requires
303.1008.
C18H13N3O2·0.2H2O (306.91): calcd. C 70.43, H 4.40, N 13.69;
found C 70.31, H 4.21, N 13.64.
7-Methyl-3-[(2-methylthiazol-4-yl)methyl]-3H-imidazo[4,5-g]quino-
line-4,9-dione (8b) and 7-Methyl-1-[(2-methylthiazol-4-yl)methyl]-
1H-imidazo[4,5-g]quinoline-4,9-dione (9b): Compounds 8b and 9b
were obtained from quinone 3b and azadiene 5 (0.413 g, 85% over-
all yield) as described above for compounds 8a and 9a. They were
purified by column chromatography (dichloromethane/acetone,
1:1).
152.12, 168.86, 169.42 ppm. EI-MS: m/z
=
389.1378 [M+];
C22H19N3O4 requires 389.1375.
4-(Acetyloxy)-1-benzyl-7-methyl-1H-imidazo[4,5-g]quinolin-9-yl
Acetate (13): Compound 13 was prepared as above from 9a
1
(0.017 g, 69% yield). IR (KBr): ν = 1770 cm–1. H NMR (CDCl ):
˜
3
δ = 2.24 (s, 3 H, 4-OCOCH3), 2.52 (d, J = 0.6 Hz, 3 H, 7-CH3),
2.65 (s, 3 H, 9-OCOCH3), 5.52 (s, 2 H, CH2N), 7.11–7.39 (m, 5 H,
ArH), 7.75 (dq, J = 2 and 0.6 Hz, 1 H, 8-H), 7.98 (s, 1 H, 2-H),
8.77 (d, J = 2 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 19.35,
21.06, 21.17, 50.61, 118.92, 126.92 (2 C), 128.50, 128.76, 128.83,
129.45, 129.60 (2 C), 129.67, 132.97, 135.91, 136.08, 137.30, 148.89,
8b: Yield: 0.282 g (58%). M.p. 208–210 °C. IR (KBr): ν =
˜
1670 cm–1. 1H NMR (CDCl3): δ = 2.53 (d, J = 0.6 Hz, 3 H, 7-
CH3), 2.67 (s, 3 H, 2Ј-CH3), 5.72 (s, 2 H, CH2N), 7.42 (s, 1 H, 5Ј-
H), 8.13 (s, 1 H, 2-H), 8.37 (dq, J = 2.1 and 0.6 Hz, 1 H, 8-H),
8.82 (d, J = 2.1 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 18.73,
19.05, 46.08, 118.70, 129.49, 131.84, 135.04, 138.52, 143.80, 144.93,
146.52, 148.45, 154.32, 167.22, 174.71, 177.82 ppm. C16H12N4O2S
(324.35): calcd. C 59.25, H 3.73, N 17.27, S 9.88; found C 58.78,
H 3.76, N 17.08, S 9.99.
152.53; 169.36, 169.40 ppm. EI-MS: m/z
=
389.1378 [M+];
C22H19N3O4 requires 389.1375.
X-ray Crystallographic Study: Single crystals suitable for X-ray
analysis were obtained by recrystallisation from anhydrous ethanol.
Crystal data for compound 8b: C16H12N4O2S; M = 324.36 gmol–1;
9b: Yield: 0.131 g (27%). M.p. 246–248 °C. IR (KBr): ν = 1650,
˜
1
1730 cm–1. H NMR (CDCl3): δ = 2.53 (s, 3 H, 7-CH3), 2.68 (s, 3
¯
triclinic, space group P1, a = 4.7768(4) Å, b = 9.0378(8) Å, c =
H, 2Ј-CH3), 5.69 (s, 2 H, CH2N), 7.27 (s, 1 H, 5Ј-H), 8.09 (s, 1 H,
2-H), 8.25 (d, J = 1.7 Hz, 1 H, 8-H), 8.84 (d, J = 1.7 Hz, 1 H, 6-
H) ppm. 13C NMR (CDCl3): δ = 18.74, 19.14, 46.05, 117.99,
129.49, 131.00, 134.41, 137.94, 144.60, 145.02, 146.71, 148.69,
154.75, 167.48, 175.70, 176.96 ppm. EI-MS: m/z = 324.0681 [M+];
C16H12N4O2S requires 324.0681). C16H12N4O2S (324.35): calcd. C
59.25, H 3.73, N 17.27, S 9.88; found C 59.10, H 3.65, N 17.08, S
9.69.
21.575(4) Å, α = 92.121(3)°, β = 94.092(3)°, γ = 96.668(7)°, V =
736.0(1) Å3, T = 293(2) K, Z = 2, dcalcd. = 1.463 Mgm–3, μ(Mo-Kα)
= 0.24 mm–1, 4015 reflections collected, 2892 unique (Rint = 0.082),
850 observed reflections [I Ͼ 2σ(I)]. Images were measured on a
Nonius Kappa CCD diffractometer[22] (graphite monochromator,
λ = 0.71073 Å) and data extracted using the DENZO[23] package.
Structural solution was effected using SHELXS-86[24] and refine-
ment completed with SHELXL-97.[25]
4-(Acetyloxy)-3-benzyl-8-methyl-3H-imidazo[4,5-g]quinolin-9-yl
Acetate (10): A mixture of 6 (0.020 g, 0.066 mmol), zinc powder
(0.064 mg, 0.98 mmol), sodium acetate (0.023 g, 0.28 mmol), and
acetic anhydride (2.75 mL) was stirred for 5 h. After removing the
solvent, the residue was extracted with hot CHCl3 (3×50 mL) and
the combined organic extracts were dried (Na2SO4). The solvent
was removed and the residue was purified by column chromatog-
CCDC-205609 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Eur. J. Org. Chem. 2005, 1903–1908
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1907

P. Nebois et al.
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Received: November 10, 2004
1908
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1903–1908