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Solid-Phase Combinatorial Synthesis of 2-Arylquinazolines and 2-Arylquinazolinones by an 4-Alkoxyaniline Linker Hideaki Hioki,* Kimihito Matsushita, Shosei Nakamura, Hiroki Horiuchi, Miwa Kubo, Kenichi Harada, and Yoshiyasu Fukuyama Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho, Tokushima 770-8514 Japan ReceiVed April 14, 2008 Quinazolines 1 and 4(3H)-quinazolinones 2 are an important class of heterocycles1 with potential pharmacological activitiesincludingantibacterial,2 antihypertensive,3 antitumor,4,5 antiinflammatory,6 and antidiabetic agents7 and protein kinase inhibitors8,9 (Figure 1). Both structural motifs are popular templates for drug discovery and have been used as scaffolds for combinatorial libraries. Thus considerable effort has been directed to combinatorial synthesis of these compounds in solution10,11 or on solid support12,13 for effective lead discovery and optimization. Previously, we developed a new aniline linker 3 suitable for the solid-phase synthesis of 2-substituted benz-fused azoles 9, such as benzothiazoles, benzimidazoles, and benzoxazoles.14,15 The linker 3 is characterized as a traceless linker, which is particularly advantageous because the functional group attached on a solid support is not necessary in the target molecules.16–18 Using the traceless aniline linker 3, we demonstrated facile combinatorial syntheses of 36 members library of these compounds 9 as shown in Scheme 1. The reaction sequence involved loading of the substrates on a solid support by an azomethine synthesis (step 1), condensation of alcohols, thiols, and amines (step 2), and oxidative release of resin-bound azomethines with various 2-heteroatom-substituted anilines (step 3). When 2-aminobenzylamines or 2-aminobenzamides are reacted with resin-bound azomethines 7 in the final step of this sequence, it would be expected to afford 2-arylquinazolines 1 and 2-arylquinazolinones 2 in the same manner as previously described. Herein, we report the preparation of libraries 1 and 2 by applying our methodology for the synthesis of benzfuzed azoles. A few examples have been reported for synthesizing 2-substituted quinazolines from corresponding 2-aminobenzylamines and aldehydes. They are generally prepared by N,N-cyclic acetalization followed by oxidation with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) or chloranil.19 It is desirable to use other oxidants at the final stage in the solid-phase synthesis, because employing these reagents may cause tedious separation of the final product and the reduced reagent (2,3-dichloro-5,6-dicyano-1,4hydroquinone or 2,3,5,6-tetrachlorohydroquinone). Thus, * Corresponding author. E-mail:
[email protected].
first we decided to explore other conditions for oxidizing N,N-acetal 10 to quinazoline 11 in solution and then to apply them to oxidative cleavage on the solid support 12. Results are shown in Table 1 and Scheme 2. N,N-Acetal 10 was prepared by simply mixing methyl 4-formylbenzoate with 2-aminobenzylamine at room temperature without any catalyst in quantitative yield. Treating 10 with DDQ gave desired 2-arylquinazoline 11 in 73% yield according to literature precedent19 (entry 1). In our previous synthesis of benz-fused azole library,14,15 air oxidation in the presence or absence of Darco KB20 (a sort of activated carbon) was shown to be effective in the oxidative cleavage from solid support. In this case, Darco KB was indispensable for air oxidation of 10 to quinazoline 11 (entries 2 and 3). Longer reaction time improved the yield up to 73% (entry 4). Next, we applied this oxidation conditions to the solid-phase synthesis of quinazoline 14. Air-oxidative cleavage of resin bound azomethine with 4 equiv of 2-aminobenzylamine also afforded quinazoline 14. (Scheme 2). Excess 2-aminobenzylamine was required because it was gradually decomposed under oxidative conditions. The excess reagent and its oxidatively decomposed products were readily removed by column chromatography. Isolated yield was 73% for the three steps. Yield was increased to 85% when solid supported azomethine 12 was treated with 2-aminobenzylamine for 18 h to form N,N-acetal 13 before addition of Darco KB which caused oxidative decomposition of unreacted 2-aminobenzylamine. On the other hand, air-oxidative coupling of 2-aminobenzamide and aldehydes to 2-arylquinazolinones are generally performed by air in the presence of p-toluenesulfonic acid,21,22 sodium hydrogen sulfite,23–25 or iodine.26 We searched for alternative additives that would accelerate the oxidative coupling 15 with 16 to give 17 in solution. As a result, in Table 2, Darco KB was found again to effectively catalyze the oxidative coupling reaction to give 17 under the same conditions as used for
Figure 1. Quinazolines 1 and quinazolinones 2. Table 1. Oxidation of N,N-Acetal 10 to Quinazoline 11
entry oxidant 1 2 3 4
DDQ air air air
additive
temp (°C)
solvent
Darco KB Darco KB
rt 100 100 100
CH2Cl2 DMF DMF DMF
10.1021/cc800056c CCC: $40.75 2008 American Chemical Society Published on Web 07/25/2008
period (h) yield (%) 2 18 2 18
73 0 57 73
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Journal of Combinatorial Chemistry, 2008 Vol. 10, No. 5 621
Scheme 1. Synthesis of the 2-Arylbenzoxazole, 2-Arylbenzothiazole, and 2-Arylbenzimidazole Library
Scheme 2. Three-Step Syntheis of Quinazoline 14 on a Solid Support
a Value refers to a yield when Darco KB and 2-aminobenzylamine were simultaneously added to 12. b Value in parenthesis refers to a yield when Darco KB was added after stirring 12 with 2-aminobenzylamine for 18 h.
Table 2. Oxidative Coupling of 2-Aminobenzamide 15 and Aldehydes 16 to 2-Arylquinazolinone 17
entry 1 2 3 a
additive
yield (%)
Darco KB TFA
0 71a 95
Darco KB was washed with CH2Cl2 and EtOAc after the reaction.
the preparation of 2-arylquinazoline 14 (entry 2). To our surprise, this reaction proceeded completely by using 5% trifluoroacetic acid (TFA), which is easily removed by simple evaporation (entry 3).27 Applying the TFA conditions to a solid-phase synthesis of quinazolinones, 18 was obtained from the resin-bound azomethine 12 in good yield under the same conditions (Table 3, entry 3). However, in the oxidative cleavage of 12 with Darco KB, the yield of 18 was affected by rising the products out from the solid-support and Darco KB with solvent, i.e., washing the products out with CH2Cl2 and ethyl acetate gave poor yield due to strong adsorption of 18 on Darco KB, whereas the use of a polar DMF improved the yield of 18 to 82%. The preference for adsorption highly depends on products, i.e., nonyl ester 17 was weakly adsorbed on Darco KB.
Table 3. Three-Step Synthesis of Quinazolinone 18 on a Solid Support
entry 1 2 3 a
additive
yield (%)
Darco KB TFA
0 82 (41)a 74
Value in parenthesis refers to a yield when Darco KB was washed with CH2Cl2 and EtOAc after the reaction. See text.
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Table 4. Three-Step Combinatorial Synthesis of Quinazolines 19 and Quinazolinones 20
Y ) H2 (19)
Y ) O (20)
R
X)H
X ) Br
X ) OMe
X)H
X ) Br
X ) OMe
OnBu SnC9H19 N(CH2CHMe2)2
82 41 33
40 17 12
79 26 17
74 68 39
77 67 24
67 61 30
Finally, combinatorial synthesis of 2-arylquinazolines and 2-arylquinazolinones was performed to demonstrate the scope and versatility of these solid phase reactions which we developed (Table 4). Nine members of solid supported azomethines 7 were prepared by previously reported methods.15 The azomethines 7 were cleaved by 2-aminobenzylamine aided with air oxidation in the presence of Darco KB for the synthesis of 2-arylquinazolines 19. On the other hand, air-oxidative cleavage of 7 with 2-aminobenzamide to form 2-arylquinazolinones 20 were performed in 5% TFA solution in stead of Darco KB because of excluding the possible adsorption on the Darco KB from the oxidation step. The reaction rate in the final step was highly dependent on the substituents at the aromatic nuclei. When X was a methoxy group, the reaction rate was the fastest of the series, whereas when X was bromine, the reaction rate was the slowest. Isolated yields after column chromatography were shown in Table 4. Esters were obtained in good yields in almost all cases. The oxidation rate to the quinazolines 19 affected the yields because air oxidation of N,N-acetal to quinazolines 19 competes with the oxidative decomposition of unreacted 2-aminobenzylamine. Thus, quinazolines 19 with a bromo group was obtained in low yields because the oxidation rate was the slowest of the series as described above. Yields of thioesters in quinazoline 19 were lower than those in quinazolinone 20 series. Amides were obtained in lower yields, indicating that substantial amount of imine-exchange reaction between 5 and diisobutylamine occurred as previously reported benz-fuzed azole series. In conclusion, we have demonstrated combinatorial synthesis of 2-arylquinazolines and 2-arylquinazolinones consisting of 18 members by using traceless 4-alkoxy aniline linker. The substrates were oxidatively released from azomethine linkage on a solid-support by 2-aminobenzylamine or 2-aminobenzamide with air. Darco KB was shown to be a effective catalyst for the air oxidation. It should be emphasized that the oxidative coupling of aromatic aldehydes with 2-aminobenzylamines or 2-aminobenzamidetosynthesize2-arylquinazolinesor2-arylquinazolinones using Darco KB is useful method not only in solidphase reaction but also in conventional solution phase one because the products are obtained by simply exposing an air atmosphere without any kinds of oxidants under neutral conditions.
Acknowledgment. This study was financially supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of the Japanese Government (No. 18590024). Supporting Information Available. General procedures for oxidative cleavage from the solid support, spectroscopic data, and 1HNMR spectra of all 18 library members. This material is available free of charge via the Internet at http:// pubs.acs.org. References and Notes (1) For a recent and general synthetic review, see:Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153–10202. (2) Kung, P. -P.; Casper, M. D.; Cook, K. L.; Wilson-Lingardo, L.; Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705–4713. (3) Hess, H. J.; Cronin, T. H.; Scriabine, A. J. Med. Chem. 1968, 11, 130–136. (4) Baek, D.; Park, Y.; Heo, H. I.; Lee, M.; Yang, Z.; Choi, M. Bioorg. Med. Chem. Lett. 1998, 8, 3287–3290. (5) Webber, S. E.; Bleckman, T. M.; Attard, J.; Deal, J. G.; Kathardekar, V.; Welsh, K. M.; Webber, S.; Janson, C. A.; Matthews, D. A.; Smith, W. W. J. Med. Chem. 1993, 36, 733– 746. (6) Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson, D. A.; Cottam, H. B. J. Med. Chem. 1999, 42, 3860–3873. (7) Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492– 1503. (8) Gibson, K. H.; Grundy, W.; Godfrey, A. A.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.; Barker, A. J.; Brown, D. S. Bioorg. Med. Chem. Lett. 1997, 7, 2723–2728. (9) Myers, M. R.; Setzer, N. N.; Spada, A. P.; Zulli, A. L.; Hsu, C. J.; Zilberstein, A.; Johnson, S. E.; Hook, L. E.; Jacoski, M. V. Bioorg. Med. Chem. Lett. 1997, 7, 417–420. (10) Carpintero, M.; Cifuentes, M.; Ferritto, R.; Haro, R.; Toledo, M. A. J. Comb. Chem. 2007, 9, 818–822. (11) Liu, J. F.; Kaselj, M.; Isome, Y.; Ye, P.; Sargent, K.; Sprague, K.; Cherrak, D.; Wilson, C. J.; Si, Y.; Yohannes, D.; Ng, S. C. J. Comb. Chem. 2006, 8, 7–10. (12) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Rao, M. V. Mini ReV. Med. Chem. 2006, 6, 71–89.
Reports (13) Kamal, A.; Shankaraiah, N.; Devaiah, V.; Reddy, K. L. Tetrahedron Lett. 2006, 47, 9025–9028. (14) Hioki, H.; Matsushita, K.; Kubo, M.; Kodama, M. J. Comb. Chem. 2006, 8, 462–463. (15) Hioki, H.; Matsushita, K.; Kubo, M.; Harada, K.; Kodama, M.; Fukuyama, Y. Tetrahedron 2007, 63, 11315–11324. (16) Blaney, P.; Grigg, R.; Sridharan, V. Chem. ReV. 2002, 102, 2607–2624. (17) Gil, C.; Bra¨se, S. Curr. Opin. Chem. Biol. 2004, 8, 230–237. (18) Bra¨se, S.; Dahmen, S. Chem.sEur. J. 2000, 6, 1899–1905. (19) Jacques, J.; Eynde, V.; Godin, J.; Mayence, A.; Maquestiau, A.; Anders, E. SYNTHESIS 1993, 867–869. (20) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5, 3713–3715. (21) Chen, K.; AlAowad, A. F.; Adelstein, S. J.; Kassis, A. I. J. Med. Chem. 2007, 50, 663–673.
Journal of Combinatorial Chemistry, 2008 Vol. 10, No. 5 623 (22) Zappala`, M.; Grasso, S.; Micale, N.; Zuccala`, G.; Menniti, F. S.; Ferreri, G.; De Sarro, G.; De Micheli, C. Bioorg. Med. Chem. Lett. 2003, 13, 4427–4430. (23) Imai, Y.; Sato, S.; Takasawa, R.; Ueda, M. SYNTHESIS 1981, 35–36. (24) Xia, Y.; Yang, Z.; Hour, M.; Kuo, S.; Xia, P.; Bastow, K. F.; Nakanishi, Y.; Nampoothiri, P.; Hackl, T.; Hamel, E.; Lee, K. Bioorg. Med. Chem. Lett. 2001, 11, 1193–1196. (25) Hour, M. -J.; Huang, L. -J.; Kuo, S. -C.; Xia, Y.; Bastow, K.; Nakanishi, Y.; Hamel, E.; Lee, K. J. Med. Chem. 2000, 43, 4479–4487. (26) Bhat, B. A.; Sahu, D. P. Synth. Commun. 2004, 34, 2169– 2176. (27) TFA did not catalyze the oxidative coupling to give quinazolines 11 at all. CC800056C
