Supported gold-catalyzed and ammonia-promoted selective synthesis of quinazolines in aqueous media

Abstract

A highly efficient and selective nitrogen source-promoted reaction for the synthesis of 2,4-disubstituted quinazolines from o-nitroacetophenones and alcohols catalyzed by Au/TiO₂ has been developed via a hydrogen-transfer strategy. This reaction has good tolerance to air and water, a wide substrate scope, and represents a new avenue for practical multiple C–N bond formation. More importantly, no additional additive, oxidant and reductant are required in the reaction and the catalyst can be recovered and reused readily.

---

Quinazolines and its derivatives are important compounds due to their widespread applications in organic synthesis and medicinal chemistry.¹ Usually, the traditional synthesis of quinazolines involves reactions of Bischler cyclization, dicarbonyl compounds with diamines and reactions from 2-aminobenzonitriles or anthranilic acids as well as N-arylbenzamides.² Recently, copper-catalyzed cascade coupling of o-halobenzaldehyde with acetamidine hydrochloride (or benzaldehyde) to synthesize quinazolines was developed.³ Also, the reactions of o-aminoacetophenones with benzaldehydes were reported for the synthesis of 2-phenylquinazolines in the presence of a nitrogen source.⁴ Very recently, new approaches for the synthesis of 2-phenylquinazolines were developed by using o-aminoacetophenones and benzylamines (or DMF) as the starting materials under the catalysis of I₂,⁵ NIS,⁶ nano-CuO⁷ and 4-hydroxy-TEMPO⁸ respectively, by our group and Han et al. Nevertheless, these methods generally involved large excess of oxidants and suffered from limitations of substrate generality and availability of starting material.

Because of the advantages of high catalytic efficiency and easy recycling, heterogeneous catalysts have been receiving more and more attention.⁹ Metal nanoparticles supported on different templates have been widely used as heterogeneous catalysts in recent years.^10,11 In particular, various heterogeneous catalytic systems for direct C–N bond formation from nitroarenes (or amines) and alcohols were successfully developed by Cao,¹² Shi,¹³ our group,¹⁴ and others.¹⁵ As an ongoing interest in the synthesis of quinazolines and the construction of a C–N bond, we herein developed a one-pot direct synthesis of 2,4-disubstituted quinazolines using o-nitroacetophenones and alcohols as the starting materials in the presence of a nitrogen source catalyzed by gold nanoparticles supported on titanium dioxide (Au/TiO₂). No additional additive, oxidant and reductant were required in this reaction. Various transformations, including dehydrogenative oxidation of alcohol and C–N bond, reduction of the nitro group and condensation of aldehyde with amine, can be achieved in this cascade reaction.

We began our study with the reaction of benzyl alcohol (1a) with o-nitroacetophenone (2a) under catalysis of Au/TiO₂ (Table 1).¹⁶ Initial experiments were performed to investigate the influence of nitrogen sources on the reaction. Moderate yields of 3aa were obtained with NH₄OAc, NH₄HCO₃ or urea as the nitrogen source, whereas the reaction could hardly take place in the presence of NH₄HSO₄ or NH₄Cl (Table 1, entries 1–5). 3aa was selectively obtained in an excellent yield of 92% when NH₃·H₂O was employed as the nitrogen source (Table 1, entry 6). However, when NaOH was added to the reaction with NH₄Cl as the nitrogen source, 75% 3aa was obtained (Table 1, entry 7). Some analyses were conducted to explain this phenomenon. No gold nanoparticle was observed in the TEM analysis and XPS test could not detect the element of gold on the surface of titanium dioxide after reaction with acidic NH₄Cl as the nitrogen source. However, a typical doublet of 4f core level bands could be observed when we added NaOH in the reaction or alkaline NH₃·H₂O was used as the nitrogen source (Fig. 1(2) and (3)). These results indicated that the catalyst could be maintained well under alkaline conditions, whereas under acidic conditions gold nanoparticles would detach from the surface of titanium dioxide. This is why an alkaline nitrogen source like NH₃·H₂O could promote the reaction, but an acidic nitrogen source was unfavorable to the reaction. 3aa was not detected in the absence of the nitrogen source (Table 1, entry 8). ¹⁵N-labeling experiment unambiguously established that the additional nitrogen atom of 3aa was derived from NH₃·H₂O.¹⁷ Subsequently, various solvents were tested in the reaction (Table 1 entries 9–15). To our delight, when toluene–water (1 : 1) was employed as the mixture solvent, 99% isolated yield was obtained (Table 1, entry 14).

Fig. 1 (1) TEM image of Au/TiO₂ before reaction; (2) TEM image of Au/TiO₂ after reaction with NH₄Cl as the nitrogen source; (3) XPS analyses of Au/TiO₂; (4) Synthesis of 3aa catalyzed by various catalysts.

Table 1 Optimization of the reaction conditions^a

Entry	N source	Solvent	Yield^b (%)
			3a	3b	3c	3aa
a The reactions were carried out with 1a (1.5 equiv., 0.75 mmol), 2a (1.0 equiv., 0.25 mmol), nitrogen source (3.0 equiv., 0.75 mmol), solvent (1.0 ml) and catalyst (Au/TiO2, metal: 0.8 mol%) for 20 h under a N2 atmosphere. b GC yield of the product is based on 2a, n.d. = not detected, isolated yield in parentheses. c NaOH (0.75 mmol) was added.
1	NH4HSO4	Toluene	<1	<1	n.d.	n.d.
2	NH4Cl	Toluene	<1	<1	n.d.	n.d.
3	NH4OAc	Toluene	35	10	3	51
4	NH4HCO3	Toluene	25	5	2	62
5	Urea	Toluene	10	4	2	57
6	NH3·H2O	Toluene	8	<1	<1	92
7^c	NH4Cl	Toluene	6	2	3	75
8	None	Toluene	51	25	8	n.d.
9	NH3·H2O	1,4-Xylene	13	<1	<1	85
10	NH3·H2O	NMP	46	4	<1	45
11	NH3·H2O	DMF	91	5	<1	<1
12	NH3·H2O	Water	2	3	8	86
13	NH3·H2O	Toluene–water (3 : 1)	3	2	<1	93
14	NH3·H2O	Toluene–water (1 : 1)	<1	<1	<1	>99 (99)
15	NH3·H2O	Toluene–water (1 : 3)	4	3	4	88

---

With the optimized conditions in hand, we then studied the activities of various catalysts (Fig. 1(4)). When other supported gold catalysts, such as Au/C, Au/ZrO₂ and Au/CeO₂, were employed in this reaction, relatively low activity and selectivity were obtained. The comparison of Au/TiO₂ with other supported gold catalysts showed that the nature of the support had a strong influence on the activity of the Au catalysts and TiO₂ was the best support for this reaction. When catalysts of Pd/C and Pd/diatomite were employed in this reaction, low conversion but good selectivity were achieved to afford 3aa in moderate yields. However, other supported metal catalysts including Pt/C, Ni/ZrO₂ and Ru/ZrO₂ presented very low activity in this reaction. No product was obtained only in the presence of TiO₂ or KAuCl₄. After catalyst screening, Au/TiO₂ showed the best catalytic efficiency and selectivity for this reaction.

After the confirmation of Au/TiO₂ as the most efficient catalyst, the substrate scope of the reaction was extended under the optimized reaction conditions (Table 2). Firstly, the electronic properties of a series of aromatic alcohols were found to have little influence on the reaction. The reactions could be carried out effectively to afford the desired products (3aa–3ca, 3ea–3ha, 3ja) with good yields regardless of the electron-donating groups or electron-withdrawing groups at the benzene ring of benzylic alcohols. However, the steric hindrance of the substituents had a negative influence on the reaction. Relatively low yields of the products (3da, 3ia) were obtained when the substituent groups appeared at the ortho-position of the benzene ring. Besides, low yields of the products (3ka, 3la) were obtained in the presence of an ester group and trifluoromethyl. This negative effect could be compensated by elevating the reaction temperature. Product 3ma was obtained readily in 89% yield when 1-naphthalenemethanol was employed. It was worth noting that aliphatic alcohols were also good substrates to afford the corresponding products (3na–3qa) in moderate to good yields. In contrast, the previous methods were limited to only 2-arylquinazolines.^4a,c,5,7,8 Excellent yields of 3ab–3ad were achieved when R² was methyl, fluoro, or chloro. When R³ was an aromatic substituent, the reaction could also give the desired products of 3ae–3ai in good yields. Nevertheless, 3aj could not be obtained, perhaps due to the steric hindrance. Moreover, 3ak–3an could also be obtained when R³ was replaced by other aliphatic groups. These results indicated that this reaction had a broad substrate scope and a variety of quinazolines could be synthesized by virtue of this developed reaction. When these reactions were performed under an air atmosphere, 3aa, 3ba, 3fa, 3ja, 3na and 3ac could still be achieved in good yields, which delivered that this reaction had good tolerance to air.

Table 2 Scope of substrates^a,b

a The reactions were carried out with 1 (1.5 equiv., 0.75 mmol), 2 (1.0 equiv., 0.25 mmol), ammonia (25% in H₂O, 3.0 equiv.), 1.0 ml of the solvent and catalyst (Au/TiO₂, Au: 0.8 mol%) for 20 h under a N₂ atmosphere. b Yield of the isolated product is based on 2. c Under air. d 150 °C.

---

The recovery and reuse of the Au/TiO₂ catalyst in the reaction could be achieved by a simple phase separation. A little loss of the catalytic activity was observed after the seventh round, as shown in Table 3. When we added some additional catalyst to keep Au loading of 0.8 mol% (Run 8), we were pleased to find that an excellent yield of 99% was obtained again. The result showed that the catalyst could be reused at least 8 times without loss of its activity.

Table 3 Recycling of Au/TiO₂ ^a

Run	1	2	3	4	5	6	7	8^c
a The reactions were carried out with 1a (1.5 equiv., 0.75 mmol), 2a (1.0 equiv., 0.25 mmol), ammonia (25% in H2O, 3.0 equiv.), 1.0 ml of the solvent and initial catalyst (Au/TiO2, Au: 0.8 mol%) for 20 h under a N2 atmosphere. b Yield of the isolated product is based on 2a. c Catalyst (Au/TiO2, Au: 0.8 mol%).
Yield (%)^b	99	99	99	99	98	96	95	99

---

Based on control experiments¹⁸ and previous reports,^12,13,14,15c the possible mechanism is depicted in Scheme 1. First of all, dehydrogenative oxidation of the alcohol (1a) into the corresponding carbonyl compound (1a′) promoted by ammonia, generates the gold-hydride species (b)^{12b,c,13c,e,19} and 2a′ is reduced into 2bin situ by b. This is the first hydrogen-transfer process and also the rate-limiting step of the reaction. Then, 2b can readily react with 1a′ to afford the corresponding imine 2c. 2c is converted to the intermediate 2d under the catalysis of gold. Subsequently, 2d can be rapidly oxidized to the product of 3aa in the presence of the gold catalyst accompanied with the generation of b. And 2a′ is again reduced into 2b by b. This is the second hydrogen-transfer process. In the whole catalytic cycle, the alcohol 1a and the intermediate 2d are used as the reductant (hydrogen donor) once and the nitrocompound 2a′ is used as the oxidant (hydrogen acceptor) twice.

Scheme 1 Plausible reaction mechanism.

In summary, we have developed a highly efficient protocol for one-pot synthesis of 2,4-disubstituted quinazolines by taking advantage of the hydrogen-transfer strategy. To the best of our knowledge, this is the first example to prepare quinazolines under catalysis of heterogeneous gold nanoparticles. By virtue of this catalytic system, the scope of alcohols and nitro compounds was extended widely to give a variety of quinazolines. It is noteworthy that no additional additive, oxidant and reductant were involved in this reaction. More importantly, all the transformations could be carried out smoothly in aqueous media and reuse of the catalyst has also been accomplished by using a simple phase separation process. Detailed mechanistic studies and other applications in organic reactions of this catalyst are in progress in our laboratory.

We are grateful to National Nature Science Foundation of China (21432009, 2127222, 91213303, 21172205).

Notes and references

1. (a) P. A. Ple, T. P. Green, L. F. Hennequin, J. Curwen, M. Fennell, J. Allen, C. Lambertvan der Brempt and G. Costello, J. Med. Chem., 2004, 47, 871; (b) L. A. Doyle and D. D. Ross, Oncogene, 2003, 22, 7340; (c) K. Waisser, J. Gregor, H. Dostal, J. Kunes, L. Kubicova, V. Klimesova and J. Kaustova, Farmaco, 2001, 56, 803; (d) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166; (e) V. Colotta, D. Catarzi, F. Varano, O. Lenzi, G. Filacchioni, C. Costagli, A. Galli, C. Ghelardini, N. Galeotti, P. Gratteri, J. Sgrignani, F. Deflorian and S. Moro, J. Med. Chem., 2006, 49, 6015.
2. (a) A. Witt and J. Bergman, Curr. Org. Chem., 2003, 7, 659; (b) D. J. Connolly, D. Cusack, T. P. O'Sullivan and P. J. Guiry, Tetrahedron, 2005, 61, 10153; (c) J. Li, X. Chen, D. Shi, S. Ma, Q. Li, Q. Zhang and J. Tang, Org. Lett., 2009, 11, 1193; (d) P. R. Marsham, A. L. Jackman, A. J. Barker, F. T. Boyle, S. J. Pegg, J. M. Wardleworth, R. Kimbell, B. M. O'Connor, A. H. Calvert and L. R. Hughes, J. Med. Chem., 1995, 38, 994.
3. (a) C. Huang, Y. Fu, H. Fu, Y. Jiang and Y. Zhao, Chem. Commun., 2008, 6333; (b) X. Liu, H. Fu, Y. Jiang and Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 348; (c) X. Yang, H. Liu, H. Fu, R. Qiao, Y. Jiang and Y. Zhao, Synlett, 2010, 101; (d) V. L. Truong and M. Morrow, Tetrahedron Lett., 2010, 51, 758; (e) J. Ju, R. Hua and J. Su, Tetrahedron, 2012, 68, 9364.
4. (a) R. Sarma and D. Prajapati, Green Chem., 2011, 13, 718; (b) Z.-H. Zhang, X.-N. Zhang, L.-P. Mo, Y.-X. Li and F.-P. Ma, Green Chem., 2012, 14, 1502; (c) Z. Chen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang and H. Wu, J. Org. Chem., 2013, 78, 11342.
5. (a) J. Zhang, D. Zhu, C. Yu, C. Wan and Z. Wang, Org. Lett., 2010, 12, 2841; (b) Y. Yan and Z. Wang, Chem. Commun., 2011, 47, 9513.
6. Y. Yan, Y. Zhang, C. Feng, Z. Zha and Z. Wang, Angew. Chem., Int. Ed., 2012, 51, 8077.
7. J. Zhang, C. Yu, S. Wang, C. Wan and Z. Wang, Chem. Commun., 2010, 46, 5244.
8. B. Han, C. Wang, R.-F. Han, W. Yu, X.-Y. Duan, R. Fan and X.-L. Yang, Chem. Commun., 2011, 47, 7818.
9. For reviews on heterogeneous catalysts, see: (a) N. Mizuno and M. Misono, Chem. Rev., 1998, 98, 199; (b) R. Akiyama and S. Kobayashi, Chem. Rev., 2009, 109, 594; (c) S. Ikegami and H. Hamamoto, Chem. Rev., 2009, 109, 583; (d) M. J. Climent, A. Corma and S. Iborra, Chem. Rev., 2011, 111, 1072 , and references therein.
10. For reviews on supported metal catalysts in nanoscale, see: (a) D. Astruc, F. Lu and J. R. Aranzaes, Angew. Chem., Int. Ed., 2005, 44, 7852; (b) J. M. Campelo, D. Luna, R. Luque, J. M. Marinas and A. A. Romero, ChemSusChem, 2009, 2, 18; (c) J. Lu and P. H. Toy, Chem. Rev., 2009, 109, 815; (d) R. J. White, R. Luque, V. L. Budarin, J. H. Clark and D. J. Macquarrie, Chem. Soc. Rev., 2009, 38, 481 , and references therein.
11. For reviews on supported gold catalysts in nanoscale, see: (a) A. S. K. Hashmi and G. J. Hutchings, Angew. Chem., Int. Ed., 2006, 45, 7896; (b) T. V. W. Janssens, B. S. Clausen, B. Hvolbaek, H. Falsig, C. H. Christensen, T. Bligaard and J. K. Norskov, Top. Catal., 2007, 44, 15; (c) B. K. Min and C. M. Friend, Chem. Rev., 2007, 107, 2709; (d) A. Corma and H. Garcia, Chem. Soc. Rev., 2008, 37, 2096; (e) G. J. Hutchings, Chem. Commun., 2008, 1148; (f) A. Corma, A. Leyva-Pe'rez and M. J. Sabater, Chem. Rev., 2011, 111, 1657, and references therein; For selected examples of supported gold heterogeneous catalysts: (g) A. Corma and P. Serna, Science, 2006, 313, 332; (h) H. Miyamura, R. Matsubara, Y. Miyazaki and S. Kobayashi, Angew. Chem., Int. Ed., 2007, 46, 4151; (i) A. Grirrane, A. Corma and H. Garcia, Science, 2008, 322, 1661; (j) T. Mitsudome, A. Noujima, T. Mizugaki, K. Jitsukawa and K. Kaneda, Green Chem., 2009, 11, 793; (k) S. Kegnæs, J. Mielby, U. V. Mentzel, C. H. Christensen and A. Riisager, Green Chem., 2010, 12, 1437.
12. (a) H. Sun, F. Z. Su, J. Ni, Y. Cao, H. Y. He and K. N. Fan, Angew. Chem., Int. Ed., 2009, 48, 4390; (b) L. He, X. B. Lou, J. Ni, Y. M. Liu, Y. Cao, H. Y. He and K. N. Fan, Chem. – Eur. J., 2010, 16, 13965; (c) C. H. Tang, L. He, Y. M. Liu, Y. Cao, H. Y. He and K. N. Fan, Chem. – Eur. J., 2011, 17, 7172; (d) J. Huang, L. Yu, L. He, Y. M. Liu, Y. Cao and K. N. Fan, Green Chem., 2011, 13, 2672; (e) H. Huang, J. Huang, Y. M. Liu, H. Y. He, Y. Cao and K. N. Fan, Green Chem., 2012, 14, 930.
13. (a) F. Shi, Q. Zhang, Y. Ma, Y. He and Y. Deng, J. Am. Chem. Soc., 2005, 127, 4182; (b) X. Cui, F. Shi and Y. Deng, Chem. Commun., 2012, 48, 7586; (c) Q. Peng, Y. Zhang, F. Shi and Y. Deng, Chem. Commun., 2011, 47, 6476; (d) X. Cui, X. Dai, Y. Zhang, Y. Deng and F. Shi, Chem. Sci., 2014, 5, 649; (e) X. Cui, C. Zhang, F. Shi and Y. Deng, Chem. Commun., 2012, 48, 9391; (f) X. Cui, Y. Zhang, F. Shi and Y. Deng, Chem. – Eur. J., 2011, 17, 2587.
14. (a) Y. Wang, D. Zhu, L. Tang, S. Wang and Z. Wang, Angew. Chem., Int. Ed., 2011, 50, 8917; (b) L. Tang, H. Sun, Y. Li, Z. Zha and Z. Wang, Green Chem., 2012, 14, 3423; (c) L. Tang, X. Guo, Y. Li, S. Zhang, Z. Zha and Z. Wang, Chem. Commun., 2013, 49, 5213; (d) X. Guo, L. Tang, Y. Yang, Z. Zha and Z. Wang, Green Chem., 2014, 16, 2443; (e) L. Tang, X. Guo, Y. Yang, Z. Zha and Z. Wang, Chem. Commun., 2014, 50, 6145.
15. (a) F. Gelman, J. Blum and D. Avnir, New J. Chem., 2003, 27, 205; (b) C. Gonzalez-Arellano, K. Yoshida, R. Luque and P. L. Gai, Green Chem., 2010, 12, 1281; (c) A. Corma, T. Ródenas and M. J. Sabater, Chem. – Eur. J., 2010, 16, 254; (d) C.-C. Lee and S.-T. Liu, Chem. Commun., 2011, 47, 6981; (e) K. Shimizu, K. Shimura, M. Nishimura and A. Satsuma, ChemCatChem, 2011, 3, 1755; (f) R. Cano, D. J. Ramón and M. Yus, J. Org. Chem., 2011, 76, 5547; (g) Y. Shiraishi, M. Ikeda, D. Tsukamoto, S. Tanaka and T. Hiraiai, Chem. Commun., 2011, 47, 4811; (h) J.-F. Soulé, H. Miyamura and S. Kobayashi, J. Am. Chem. Soc., 2011, 133, 18550; (i) W.-J. Yoo, H. Yuan, H. Miyamura and S. Kobayashi, Adv. Synth. Catal., 2011, 353, 3085.
16. See ESI† for detailed experiments and characterization of metal nanoparticles supported on different templates.
17. For detailed ¹⁵N-labeling experiment and NMR data, see ESI.†.
18. See control experiments in the ESI.†.
19. (a) A. Abad, C. Almela, A. Corma and H. Garcia, Chem. Commun., 2006, 3178; (b) F. Z. Su, L. He, J. Ni, Y. Cao, H. Y. He and K. N. Fan, Chem. Commun., 2008, 3531.

---

Footnotes

† Electronic supplementary information (ESI) available: Experimental details, characterization of catalysts and characterization of products. See DOI: 10.1039/c4qo00278d

‡ These authors contributed equally to this work.

---