A. K. Yadav et al. / Tetrahedron Letters 53 (2012) 859–862
861
Table 2
References and notes
Yields of the compounds 9a–e and 11a–e
1. Llinas-Brunet, M.; Bailey, M. D.; Ghiro, E.; Gorys, V.; Halmos, T.; Poirier, M.;
Rancourt, J.; Goureare, N. J. Med. Chem. 2004, 47, 6584.
Product
R1
R2
Yielda (%)/Time (min)
[BMIM]Br
9
[BMIM]BF4
[BMIM]OTf
2. Frutos, R. P.; Haddad, N.; Houpis, I. N.; Johnson, M.; Smith-Keenan, L. L.; Fuchs,
V.; Yee, N. K.; Farina, V.; Faucher, A.-M.; Brochu, C.; Hache, B.; Duceepe, J.-S.;
Beaulieu, P. Synthesis 2006, 256. and the references cited therein.
3. Huang, L.-J.; Hsich, M.-C.; Teng, C.-M.; Lee, K.-H.; Kno, S.-C. Bioorg. Med. Chem.
1998, 6, 1657.
4. Gasparotto, V.; Castagliuolo, I.; Chiarelotto, G.; Pezzi, V.; Montanaro, D.; Brun,
P.; Palu, G.; Viola, G.; Ferlin, M. G. J. Med. Chem. 2006, 49, 1910. and the
references cited therein.
11
11
a
b
c
d
e
H
CH3
H
H
H
H
H
CH3
OCH3
Cl
87/120
91/120
94/120
72/120
78/120
90/90
85/90
83/90
78/90
75/90
93/90
88/90
85/90
80/90
77/90
5. Osawa, T.; Ohta, H.; Akmoto, K.; Harada, K.; Soga, H.; Jinno, Y. EP 0343574,
1994.
a
Isolated yield after purification.
6. Ruchelman, A. L.; Singh, S. K.; Ray, A.; Wu, X. H.; Yang, J.-M.; Li, T.-K.; Liu, A.;
Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2003, 11, 2061.
7. (a) Theeraladanon, C.; Arisawa, M.; Nishidi, A.; Nakagawa, M. Tetrahedron 2004,
60, 3017; (b) Nishida, A.; Sorimachi, H.; Iwaida, M.; Matsumizu, M.; Kawate, T.;
Na Kagawa, M. Synlett 1998, 389.
Table 3
Recyclability data for product 4a and 5a
8. Wentland, M. P.; Perni, R. B.; Dorff, P. H.; Brundage, R. P.; Castaldi, M. J.; Bailey,
T. R.; Carabatean, P. M.; Baeon, E. R.; Young, D. C.; Woods, M. G.; Rosi, D.; Drozd,
M. L.; Kullnig, R. K.; Dutko, F. J. J. Med. Chem. 1993, 36, 1580.
9. Schmidt, R. D. Taschenatlas der Biotechnologie and Gentechnik; Wiley-VCH:
Weinheim, 2002.
10. Tazkoparan, B.; Ertan, M.; Kelichen, P.; Demirdamar, R. IL Farmaco 1999, 54,
588. and the references cited therein.
11. Uwe, K.; Jochem, H. German patent Wo 2003089441A1 Oct 30, 2003.
12. Singh, H. P.; Sharma, C. S.; Gautam, C. P. Middle East J. Scientific Res. 2009, 4, 203.
13. Price, C. C.; Roberts, R. M. J. Am. Chem. Soc. 1946, 68, 1204.
14. Biere, H.; Seelen, W. Liebigs Ann. Chem. 1976, 1972.
Product
Cycle
Yielda (%)/Time (min)
[BMIM]BF4
[BMIM]Br
[BMIM]OTf
4a
0
1
2
0
1
2
87/120
83/120
79/120
—
—
—
—
—
—
85/120
79/120
76/120
—
—
—
90/120
85/120
80/120
5a
a
15. (a) Li, J. J. Conard–Limpach Reactions in Name Reactions: A Collection of Detailed
Reaction Mechanisms, 2nd ed.; Springer: Berlin, 2003; (b) Zewge, D.; Chem, C.-
Y.; Deer, C.; Domer, P. G.; Hughes, D. L. J. Org. Chem. 2007, 72, 4276. and the
references cited therein.
Isolated yield after purification.
We have attempted the cyclization of 4a–e in [BMIM]Br/BF4/
OTf at temperatures 40 2 °C, 80 2 °C with any of these three
ILs. However at 80 2 °C when cyclization was attempted with
[BMIM]BF4/OTf, we have obtained the products 5a–e in excellent
yields. This behavior appears to be due to the coordinating strength
between the cation, viz. [BMIM]+ and anion BrÀ/BFÀ4 /OTfÀ. As BFÀ4
and OTfÀ are weakly coordinated20 BrÀ > BFÀ4 > OTf–, the cyclization
occurs smoothly with [BMIM]BF4/OTf. The better results of
cyclization with anion OTfÀ in comparison to BFÀ4 are in conso-
nance with this preposition.
Next, we have attempted this methodology with 2-aminothia-
zole 6/2-aminobenzothiazole 7a–e, reactant 2 and 3 in the pres-
ence of [BMIM]Br under nitrogen atmosphere at 40 2 °C to
afford thiazolo-2-amino/benzothiazolyl-2-aminomethylene-1,3-
dioxane-4,6-dione 8/9a–e in excellent yields. These compounds
upon subsequent cyclization, as described above, afford 5H-thiaz-
olo[3,2-a]pyrimidine-5-one 10 in an 88% yield/4H-pyrimido
[2,1-b]benzothiazol-4-ones 11a–e in good yields (Scheme 2,
Table 2).
A general method for the synthesis of these compounds is pre-
sented.21 All these compounds 4a–e, 5a–e, 8, 9a–e, and 11a–e were
characterized by IR, 1H NMR, 13C NMR, mass spectroscopy and
elemental analysis.22
We have studied the recyclability of the regenerated ionic
liquids for the products 4a and 5a. The yields of the products in
two cycles are presented in Table 3.
From the data presented in Table 3, it is clear that the yields of the
products 4a and 5a decrease in various cycles, yet the regenerated
ionic liquid can be reused with reasonably good success. Thus, this
procedure is advantageous over the reported conventional methods.
In conclusion, we have developed an environmentally benign
efficient methodology for the clean synthesis of 4(1H)-quinolones,
5H-thiazolo[3,2-a]pyrimidin-5-ones and 4H-pyrimido[3,2-a]ben-
zothiazol-4-ones.
16. Heindel, N. D.; Kennewell, P. D.; Fish, V. B. J. Heterocyl. Chem. 1969, 6, 77.
17. Rotzoll, S.; Reinke, H.; Fischer, C.; Langer, P. Synthesis 2009, 69.
18. Huang, X.; Lia, Z. J. Org. Chem. 2002, 67, 6731. and the references cited therein.
19. Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron Lett. 2009, 50, 5031.
20. Bini, R.; Bortolini, O.; Chiappe, C.; Pieraccini, D.; Siciliano, T. J. Phys. Chem. B.
2007, 111, 598–604.
21. (a) Typical experimental procedure for the synthesis of 4a–e: A mixture of
appropriate aniline
1
(5 mmol), Meldrum’s acid
2
(6 mmol), trimethyl
round
orthoformate (15 mmol) and [BMIM]Br (3 mL) is taken in
3
a
bottomed flask with the provision to perform the reaction under nitrogen
atmosphere. The contents of the flask were stirred magnetically at 40 2 °C.
The progress of the reaction was monitored on a TLC plate (Merck Silica gel
60F254) in pet.ether–ethyl acetate (8:2) and the visualization was accomplished
in an iodine chamber/UV-light. After the completion of the reaction, water
(10 mL) was added to it. The organic compound was precipitated, which was
filtered on a Buckner funnel applying vacuum. The product, so obtained, was
purified by crystallization with methanol/column chromatography (Merck
Silica gel 60–120 mesh) and elution of the product was carried out by
pet.ether–ethylacetate (8:2).
(b) Typical experimental procedure for the cyclization of 4a–e: Compound 4a–
e (5 mmol) and [BMIM]BF4/OTf (3 mL) were taken in a round bottomed flask
having provision to carry out the reaction under nitrogen atmosphere. The
contents of the flask were stirred magnetically at 80 2 °C. The progress of the
reaction was monitored on a TLC plate in pet.ether–ethyl acetate (8:2). After
completion of the reaction, the product was extracted with ethyl acetate
(3 Â 10 mL). The solvent was recovered under reduced pressure (5 mm of Hg).
The pasty mass thus obtained was extracted with diethyl ether (3 Â 10 mL),
dried over anhydrous sodium sulphate and ether was distilled. The product so
obtained was purified by crystallization with ethanol/column chromatography
(Merck Silica gel 60–120 mesh) and eluting TLC product with pet.ether–
ethylacetate (8:2).
22. Details of analytical data of compounds 4a,b, 5a,b,d,e, 8, 11a,b; Compound 4a.
5{(Phenylamino)methylene}-2,2-dimethyl, 1,3-dioxane-4,6-dione: Yellow
solid, mp 135–136 °C, Characteristic IR (KBr pellet, cmÀ1) 3169, 3067, 1728,
1675, 1630, 1608, 1440, 1270, 1028. 1H NMR (300 MHz, CDCl3) d 1.74 (s, 6H,
2 Â CH3), 7.18 (d, 3J = 7.8 Hz, 2H, Ar), 7.15 (dd, 3J = 7.6, 2H, Ar), 7.12 (dd, 1H, Ar),
8.68 (d, 3J = 13.9 Hz, 1H, @CH), 11.43 (br d, 3J = 13.8 Hz, 1H, NH). 13C NMR
(75 MHz, CDCl3) d = 27.1, 87.2, 105.4, 116.9, 125.2, 127.4, 131.5, 136.2, 137.6,
152.6, 163.6, 165.7. Anal. Calcd for C13H13NO4: C, 63.15; H, 5.26, N, 5.66%.
Found: C, 63.12; H, 5.18; N, 5.60%.
Compound 4b. 5{[(2-Methylphenyl)amino]methylene}, 2,2-dimethyl-1,3-
dioxane-4,6-dione: yellow solid, mp 142–143 °C, Characteristic IR (KBr pellet,
cmÀ1) 3165, 3058, 2985, 1722, 1672, 1640, 1609, 1440, 1270, 1025. 1H NMR
(300 MHz, CDCl3) d 1.76 (s, 6H, 2 Â CH3), 3.33 (d, 3H, CH3), 7.02 (d, 3J = 7.6 Hz,
1H, Ar), 7.15 (dd, 2H, Ar), 7.19 (d, 3J = 7.6 Hz, 1H, Ar), 8.65 (d, 3J = 13.9 Hz, 1H, –
CH), 11.40 (d, 3J = 13.9 Hz, 1H, NH). 13CNMR (75 MHz, CDCl3) d 21.1, 27.1, 87.1,
105.3, 117.4, 124.8, 127.5, 131.3, 136.7, 137.5, 152.7, 163.6, 165.7. Anal. Calcd
for C14H15NO4: C, 64.36; H, 5.74; N, 5.36%. Found: C, 64.28; H, 5.79; N, 5.44%.
Compound 5a. Quinolin-4(1H)-one: brownish solid, mp 190–191 °C,
Characteristic IR (KBr pellet, cmÀ1) 3240, 3080, 3150, 1640, 824. 1H NMR
(300 MHz, CDCl3) d 6.12 (d, 2J = 7.5 Hz, 1H, CH), 7.37 (dd, 3J = 7.5 Hz, 2H, Ar),
Acknowledgments
We thank the head, Chemistry Department, the University of
Rajasthan, Jaipur for providing laboratory facilities. Financial assis-
tance from UGC, New Delhi is thankfully acknowledged.