I. Cikotiene / Tetrahedron Letters 50 (2009) 2570–2572
2571
Table 1
O
S
Optimization of the reaction conditions for benzannulation
O
KSCH2CO2CH3
CH3OH
O
Entry
Solvent
Base
Yield of 2a (%)
N
N
79a
Ar
Ar
1
2
3
4
5
6
7
CH3OH
CH3OH
CH3OH
CH3OH
C2H5OH
2-C3H7OH
DMSO
CH3ONa
CH3OK
K2CO3
1a-e
90a
29a
Et3N
0a,b
C2H5OK
2-C3H7OK
K2CO3
21a
O
O
0a, 10b
38a
O
S
O
-S
N
Ar
N
a
Reactions were performed at rt.
Reaction was performed at reflux temperature.
Ar
b
2a-e
Scheme 2. A proposed mechanism for the benzannulation reaction.
try 4) while the use of potassium ethoxide or 2-propoxide in
appropriate absolute alcohols gave very low yields of 2a together
with undefined mixtures (entries 5 and 6). The reaction of 1a with
methyl mercaptoacetate using potassium deuteriomethoxide in
deuterated methanol gave the labelled product 3 (Scheme 1). Thus,
the optimal reaction conditions required 1 equiv of potassium
methoxide and 1 equiv of methyl mercaptoacetate in methanol
at room temperature. Encouraged by these results we decided to
perform the reactions of 2-arylethynylquinoline-3-carbaldehydes
1b–e with methyl mercaptoacetate. The reactions proceeded
smoothly to afford good isolated yields of 3-aryl-2-methoxycar-
bonylacridines 2b–e (Scheme 1).
It is assumed, that the benzannulation reaction proceeds via
thiepino[4,5-b]quinolines, which are formed during nucleophilic
attack on the C„C bond by methyl mercaptoacetate together with
a Dieckmann-type condensation of the formyl group with the
methylene moiety. It is believed that due to the antiaromatic char-
acter of the intermediates, 1,6-electrocyclic ring closure followed
by aromatization with elimination of sulfur proceeds very
smoothly to form the corresponding 3-aryl-2-methoxycarbonylac-
ridines 2a–e (Scheme 2). An analogous transformation from ben-
zothiepine to naphthalene derivatives was reported earlier,16 so
our proposed mechanism has good precedent for the final step.
It is noteworthy that methyl mercaptoacetate is the most effi-
cient reagent for this transformation. Other thiols such as 1-
butanethiol and benzylthiol did not undergo reaction with the
starting compounds to give acridine derivatives.
pounds should be useful for the preparation of various important
acridines. Extension of these reactions is currently underway in
our laboratory and application of this novel benzannulation meth-
odology to other carbo- or heterocyclic structures will be reported
in due course.
Acknowledgements
The author thanks M. Kreneviciene and A. Karosiene for the
recording of the NMR and IR spectra and M. Gavrilova for the ele-
mental analyses data. This work was supported by the Lithuanian
State Science and Studies Foundation, Grant No. T-09027, T-67/09.
References and notes
1. Albert, A. The Acridines, 2nd ed.; Edward Arnold: London, 1966.
2. Demeunynck, M.; Charmantray, F.; Martelli, A. Curr. Pharm. Des. 2001, 7, 1703.
3. (a) Gamage, S. A.; Figgitt, D. P.; Wojcik, S. J.; Ralph, R. K.; Ransijn, A.; Mauel, J.;
Yardley, V.; Snowdon, D.; Croft, S. L.; Denny, W. A. J. Med. Chem. 1997, 40, 2634;
(b) Bonse, S.; Santelli-Rouvier, C.; Barbe, J.; Krauth-Siegel, R. L. J. Med. Chem.
1999, 42, 5448; (c) Finlay, G. J.; Atwell, G. J.; Baguley, B. C. Oncol. Res. 1999, 11,
249.
4. (a) Belmont, P.; Bosson, J.; Godet, T.; Tiano, M. Anti-Cancer Agents Med. Chem.
2007, 7, 139; (b) Demeunynck, M. Exp. Opin. Ther. Patents 2004, 14, 55.
5. (a) Atwell, G. J.; Rewcastle, G. W.; Baguley, B. C.; Denny, W. A. J. Med. Chem.
1987, 30, 664; (b) Sourdon, V.; Mazoyer, S.; Pique, V.; Galy, J.-P. Molecules 2001,
6, 673.
6. Bernthsen, A.; Bender, F. Chem. Ber. 1883, 16, 1802.
7. (a) Gamage, S. A.; Spicer, J. A.; Rewcastle, G. W.; Denny, W. A. Tetrahedron Lett.
1997, 38, 699; (b) Albert, A.. In Heterocyclic Compounds; Elderfield, R. C., Ed.; J.
Wiley and Sons: New York, 1952; Vol. 4,.
8. Smolders, R. R.; Waefelaer, A.; Coomans, R.; Francart, D.; Hanuise, J.; Voglet, N.
Bull. Soc. Chim. Belg. 1982, 91, 33.
9. (a) Gevorgyan, V.; Yamamoto, Y. J. Organomet. Chem. 1999, 576, 232; (b)
Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263; (c) Kotha, S.; Misra, S.;
Halder, S. Tetrahedron 2008, 64, 10775.
10. Dotz, K. H.; Tomuschat, R. Chem. Soc. Rev. 1999, 28, 187.
11. Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
In summary, a novel, efficient and strightforward procedure for
the synthesis of the acridine framework via an unexpected reaction
of 2-arylethynylquinoline-3-carbaldehydes with methyl mercap-
toacetate has been developed.17–19 Taking into account that the es-
ter functionality in the molecules can undergo further
transformations, this method for the synthesis of the title com-
12. (a) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzales, J. M. Org. Lett.
2003, 5, 4121; (b) Ciufolini, M. A.; Weiss, T. J. Tetrahedron Lett. 1994, 35, 1127.
13. (a) Belmont, P.; Andrez, J.-C.; Allan, C. S. M. Tetrahedron Lett. 2004, 45, 2783; (b)
Godet, T.; Belmont, P. Synlett 2008, 2513.
14. Belmont, P.; Belhadj, T. Org. Lett. 2005, 7, 1793.
15. Patin, A.; Belmont, P. Synthesis 2005, 2400.
O
i
O
O
N
N
Ar
16. (a) Scott, G. P. J. Am. Chem. Soc. 1953, 75, 6332; (b) Dimroth, K.; Lenke, G. Chem.
Ber. 1956, 89, 2608.
Ar
1a-e
2a-e
17. Typical procedure for the preparation of 3-aryl-2-methoxycarbonylacridines 2a–e:
To a solution of 2-arylethynylquinoline-3-carbaldehyde 1a–e (0.3 mmol) in
methanol (5 mL) a solution of the potassium salt of methyl mercaptoacetate,
prepared from potassium (11.7 mg, 0.3 mmol), methyl mercaptoacetate
(31.8 mg, 0.3 mmol) and methanol (3 mL) was added. The resulting reaction
mixture was stirred for 4 h at room temperature. The solvent was evaporated
under reduced pressure, the residue washed with water, filtered and
recrystallized from an appropriate solvent to give compounds 2a–e.
18. Spectral data of selected 3-aryl-2-methoxycarbonyl acridines. Compound 2a: Yield
72 - 95%
1,2a: Ar = C6H5;
1,2b: Ar = 4-FC6H4;
1,2c
: Ar = 4-MeC6H4;
1,2d: Ar = 4-EtC6H4;
1,2e: Ar = 2-pyridyl
O
m
max/cmÀ1 1724 (C@O); dH
CD3
90%, mp 156–157 °C (from MeOH), IR (KBr)
O
(300 MHz, CDCl3): 3.94 (3H, s, OCH3); 7.37 (1H, t, J = 7.5 Hz, ArH), 7.47–7.58
(3H, m, ArH), 7.70 (1H, s, C(9)-H), 7.72–7.78 (3H, m, ArH), 7.82 (1H, d,
J = 8.7 Hz, ArH), 8.00 (1H, s, C(1)-H), 8.12 (1H, d, J = 8.7 Hz, ArH), 8.16 (1H, s,
C(4)-H); dc (75 MHz, CDCl3): 52.9, 124.5, 126.0, 126.7, 127.3, 127.7, 127.8,
128.0, 128.3, 128.7, 129.6, 129.7, 129.8, 130.2, 130.8, 135.8, 137.4, 149.0, 149.2,
163.7. (C21H15NO2 requires C, 80.49; H, 4.82; N, 4.47. Found: C, 80.54; H, 4.92;
N
D
3
Scheme 1. Reagents and conditions: (i) KSCH2CO2CH3, CH3OH, rt, 4 h.