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by employing various aliphatic, aromatic, and hetero-aromatic
amino acids. In all the amino acids the regioselectivity was
achieved in nucleophilic substitution reaction. The chiral elements
were introduced into the difluorobenzodiamines 12 by using the
chiral amino acids. Furthermore the different diamino-heterocy-
cles namely piperazine, diazepine, and 4-aminomethylpiperidines
were used in combination with the above amino acid to construct
the scaffold diversity. All the substrates reacted efficiently to deli-
ver the final cyclized products with no substantial difference in the
yields. Table 1 describes the scope of developed methodology and
the diversity elements of the scaffold.
We have successfully developed a rapid and efficient solution
synthesis of benzimidazole linked pyrrolo[1,2-a]benzimidazol-
ones, pyrido[1,2-a]benzimidazolones, and isoindo[1,2-a]benzimi-
dazoles with three sets of diversity on ionic liquid support. A
cascade reaction was systematically applied to furnish diverse het-
erocyclic molecular libraries with IL-supported synthesis from an
IL-fluoro scaffold (TFNB) moiety which was indispensable for the
method in view of its double reactive sites. Guanidine linked di-
fluoro-2-quinoxalinones 10 were directly obtained by concomitant
intramolecular cyclization after reduction, whereas the stable
difluorobenzodiamines 12 was further released from the ionic li-
quid support after precipitation.
9. Gierczyk, B.; Eitner, K.; Schroeder, G.; Przybylski, P.; Brzezinski, B. J. Mol. Struct.
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14. General procedure for the synthesis of 10 and 12: IL-supported compound 1 (1 g)
was added to a 50 ml flask with 0.11 g of TFNB 2 (3 equiv, 0.59 mmol) and TEA
0.16 mL (6 equiv, 1.15 mmol) in 10 ml acetonitrile. The reaction mixture was
heated for 30 min under microwave in open vessel condition. After the
completion of reaction, ether was added to the reaction mixture to precipitate
the two isomers of the IL-supported compounds 3 and 4 and washed with
ether (30 mL ꢁ 2). IL-supported compounds 3 and 4 dissolved in acetonitrile
(10 mL), piperazine or homopiperazine or aminomethylpiperidine (3 equiv,
0.57 mmol), and 0.18 ml TEA (6 equiv, 1.18 mmol) were stirred at room
temperature for 8 h, then ether was added to the reaction mixture to
precipitate the IL-supported compounds 5 and 6. IL-supported compounds
This approach provides a high speed path for the rapid synthesis
of bis-heterocyclic libraries with a high degree of structural diver-
sity. The powerful potential of multidisciplinary synthetic ap-
proach, integrating ionic liquid support, and microwave synthesis
with multistep synthesis has great potential to produce biologi-
cally interesting molecules for drug discovery.
Acknowledgments
5
and
6
dissolved in acetonitrile (10 mL) with 0.20 g of N,N0-di-tert-
(3 equiv, 0.56 mmol)
butoxycarbonyl-1H-benzotriazole-1-carbox-amidine
7
The authors thank the National Science Council of Taiwan for
the financial assistance. This work is particularly supported by
‘Center for Bioinformatics Research of Aiming for the Top Univer-
sity Program’ of the National Chiao Tung University and Ministry
of Education, Taiwan, ROC.
and 0.16 ml TEA (6 equiv, 1.15 mmol) were stirred at room temperature for
18 h. The ether (50 mL) was added after the reaction was completed. The
precipitation was filtered, and dried under high vacuum to give guanidinyl
compounds 8 and 9. IL-supported compounds 8 and 9 dissolved in methanol
(10 mL) with 233 mg of powder Zn and 112 mg of NH4COOH (10 equiv,
1.79 mmol) were stirred at room temperature for 1 h. Monitoring the reaction
progress by TLC showed that compound 10 was released from ionic
liquid support. The filtrate was concentrated after precipitation, dried
well and submitted to spectrum analysis. Further purification by column
chromatography furnished the pure guanidinyl heterocyclic linked
quinaxolinones 10 as a liquid. Compound 10a: 1H NMR (300 MHz, CDCl3) d
10.18 (s, –NH), 8.95 (s, 1H), 7.39–7.35 (m, 2H), 7.32–7.30 (m, 1H), 7.20–7.17
(m, 2H), 6.40 (d, J = 11.2 Hz, 1H), 4.05–3.91 (m, 2H), 3.71 (m, 4H), 3.19 (m, 4H),
2.86–2.78 (dd, J = 13.3, 10.8 Hz, 1H), 1.50 (s, 18H); 13C NMR (75 MHz, CDCl3) d
168.5, 164.7, 160.4, 159.2, 155.9, 152.8, 149.3, 136.1, 135.9, 129.2, 128.9, 128.6,
Supplementary data
Supplementary data associated with this article can be found,
127.1, 126.7, 120.2, 118.0, 99.9, 97.8, 50.8, 44.5, 39.9, 31.1, 29.6, 28.0; IR (cmꢂ1
,
References and notes
neat): 3275, 2924, 2852, 1678; MS (ESI-MS) m/z: 601 [M+H] +; HRMS Calcd for
+
C
30H38F2N6O5: m/z 600.2872; Found 601.2948 [M+H]
. The IL-supported
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compound 11 was cleaved in methanol (10 mL) and 26 mg KCN (3 equiv,
0.40 mmol) for 18 h. Ether (50 mL) was added to precipitate IL-1 and the
filtrate was concentrated to give compounds 12 as a liquid. Compound 12a: 1
H
NMR (300 MHz, CDCl3) d 7.31–7.22 (m, 3H), 7.17–7.15 (m, 2H), 6.25–6.20 (dd,
J = 12.3, 2.0 Hz, 1H), 4.31 (t, J = 6.1 Hz, 1H), 3.63 (s, 3H), 3.38–3.20 (m, 4H), 3.07
(d, J = 6.5 Hz, 2H), 2.81–2.76 (m, 4H), 1.50 (s, 18H); 13C NMR (75 MHz, CDCl3) d
173.7, 167.7, 148.9, 145.6, 143.8, 142.6, 136.4, 132.4, 128.7, 128.4, 126.8, 114.8,
114.5, 110.2, 97.5, 83.3, 52.8, 51.8, 49.9, 46.2, 38.6; IR (cmꢂ1, neat): 2871, 1737;
MS (ESI-MS) m/z: 633 [M+H+]; HRMS Calcd for C31H42F2N6O6: m/z 632.3134;
Found 633.3211 [M+H+].