Acceptorless dehydrogenative synthesis of 2-substituted quinazolines from 2-aminobenzylamine with primary alcohols or aldehydes by heterogeneous Pt catalysts

Abstract

CeO₂-supported Pt nanoparticle catalysts enabled the acceptorless dehydrogenative synthesis of 2-substituted quinazolines from 2-aminobenzylamine with aliphatic and benzyl primary alcohols or aldehydes with low catalyst loading, wide substrate scope and good catalyst reusability, demonstrating the first acceptor-free and additive-free catalytic system for this reaction.

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Quinazolines are important compounds in organic synthesis and the industrial production of pharmaceutical compounds which show various biological activities^1–6 such as antibacterial,¹ antiviral,² antitubercular³ and anticancer^4,6 activities. Various methods have been reported for the synthesis of 2-substituted quinazolines. One of the representative methods is the oxidative condensation of 2-aminobenzylamines with aldehydes via aminal intermediates using stoichiometric amounts of toxic oxidants such as DDQ,⁷ MnO₂ (ref. 8) and NaClO.⁹ Yu et al.¹⁰ reported more atom-efficient synthesis of 2-substituted quinazolines: an aerobic oxidative process by 5 mol% CuCl/DABCO/TEMPO catalyst. Kobayashi et al. reported that Pt/Ir bimetallic nanoclusters cooperated with dimeric catechol derivative effectively catalyzed the aerobic oxidative synthesis of quinazolines from 2-aminobenzylamines and aldehydes at 35 °C under basic conditions.¹¹ Recently, Fang et al.¹² showed an anaerobic method using [Cp*IrCl₂] complex in presence of excess amount (4 equiv.) of acceptor (styrene) under basic conditions. The most attractive methodology is an anaerobic method in the absence of any oxidant (acceptor), so called dehydrogenative acceptorless coupling reactions.¹³ Considering that alcohols are more stable and readily available than aldehydes, use of primary alcohols instead of aldehydes is also an important alternative, but acceptorless methods are not reported. The only one example using the Ir-catalyst¹² with the acceptor was applicable only to an activated alcohol, benzylalcohol. As a part of our continuing interest in heterogeneous Pt catalysts for the acceptorless dehydrogenation of alcohols¹⁴ and acceptorless dehydrogenative coupling reactions,^15,16 we report herein the first acceptorless method for the synthesis of 2-substituted quinazolines from 2-aminomethyl-phenyl amine and alcohols or aldehydes using a CeO₂-supported Pt catalyst (Pt/CeO₂).

First, we studied the acceptorless dehydrogenative synthesis of 2-substituted quinazolines from 2-aminobenzylamine 1a and primary alcohols, which was unprecedented in the literature. We carried out catalyst screening tests adopting the model reaction of 1a (1 mmol) with 1-octanol (1.2 mmol) under the same conditions: reflux in mesitylene under N₂ for 48 h using 1 mol% of metal catalysts. Table 1 lists the yields of 2-substituted quinazoline 3a (the main product) and an intermediate, 2-heptyl-1,2,3,4-tetrahydro-quinazoline 2a (a byproduct). Among various transition metal nanoparticles loaded on CeO₂ (entries 1–8), Pt/CeO₂ (entry 1) showed the highest yield (90%) of 3a without forming the byproduct 2a. CeO₂ itself was inert (entry 9). The effect of support materials of Pt catalysts (entries 1, 11–17) showed that CeO₂ was the most effective support of Pt. Other supports such as TiO₂, MgO and Nb₂O₅ gave moderate yields. Consequently, Pt/CeO₂ was found to be the most effective catalyst for the dehydrogenative synthesis of 3a from 1a and 1-octanol.

Table 1 Synthesis of 3a from 1a and 1-octanol by 1 wt% metal-loaded catalysts

Entry	Catalysts	2a yield (%)	3a yield^a (%)
a Yield based on 1a determined by GC.b Tested without pre-reduction.c Catalyst amount was 197 mg.
1	Pt/CeO2	0	90
2	Pd/CeO2	0	17
3	Ir/CeO2	20	16
4	Re/CeO2	10	12
5	Rh/CeO2	18	10
6	Ru/CeO2	0	7
7	Cu/CeO2	0	0
8	Ni/CeO2	0	0
9^b	PtOx/CeO2	0	0
10^c	CeO2	0	0
11	Pt/TiO2	0	65
12	Pt/MgO	0	45
13	Pt/Nb2O5	30	43
14	Pt/Al2O3	20	26
15	Pt/ZrO2	0	24
16	Pt/SiO2Al2O3	0	18
17	Pt/SiO2	0	10
18	Pt/HBEA	0	10
19	Pt/La2O3	0	10

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It is established that the O_1s binding energy of metal oxides decreases with increase in the electron density of oxygen in the metal oxide, or in other words, basicity of the metal oxide surface.^17–19 In our previous report,¹⁹ we measured the binding energy of the O_1s electron in the support oxide by XPS analysis. XPS spectra of Nb₂O₅, TiO₂ and MgO were added to the previous results as shown in Fig. 3. The O_1s binding energy of the peak maxima decreased in the order of SiO₂Al₂O₃ > SiO₂ > γ-Al₂O₃ > Nb₂O₅ > ZrO₂ > TiO₂ > MgO > CeO₂. Fig. 4 shows the yield of 3a from 1a and 1-octanol (Table 1) as a function of the O_1s binding energy of the support oxides. There is a general tendency that the support with higher O_1s binding energy gives higher yield, which indicates that the activity increase with basicity of the support.

Fig. 1 Time course of the reaction of 1a with 1-octanol by Pt/CeO₂. Conditions are shown in Table 1.

Fig. 2 Time course of the reaction of 1a with n-octanal by Pt/CeO₂. Conditions are shown in Table 3.

Fig. 3 XPS spectra of the O(1s) core level region of the support materials.

Fig. 4 Yield of 3a for the reaction of 1a with n-octanal by Pt-loaded metal oxides as a function of O_1s binding energy of support oxides.

With the optimized catalyst in hand, we examined the substrate scope of the dehydrogenative quinazolines syntheses. Table 2 shows the isolated yields of the 2-substituted quinazolines from the reaction of 1a with different primary alcohols using 1 mol% of Pt/CeO₂. Linear and branched aliphatic alcohols (entries 1–3) were converted to the corresponding 2-substituted quinazolines in good yields (75–89%). Benzylalcohol and 4-fluoro benzylalcohol resulted in moderate yields (52, 51%). This is the first example of the acceptorless dehydrogenative synthesis of 2-substituted quinazolines from 1a and various primary alcohols.

Table 2 Synthesis of 2-substituted quinazolines from 1a and alcohols by Pt/CeO₂^a

Entry	Alcohol	Product	Isolated yield^a (%)
a Yield based on 1a determined by weight of the isolated products.b 1.5 mmol alcohol.
1			89
2			75
3			89
4^b			76
5			52
6			51

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Next, we studied the dehydrogenative synthesis of 2-substituted quinazolines from 1a and aldehydes. Table 3 summarizes the result of catalyst screening for the model reaction of 1a and n-octanal. Among various metal-loaded CeO₂ (entries 1–8) and Pt-loaded metal oxides (entries 10–16), Pt/CeO₂, Pt/TiO₂ and Pt/La₂O₃ were found to be effective exhibiting high yields (95–99%) of 1a. On the basis of the results of preliminary studies on the aldehyde scope for this reaction, we selected Pt/CeO₂ as the standard catalyst. The reaction with CeO₂ gave 20% yield of the non-dehydrogenated intermediate 2a but no yield of the dehydrogenated product 3a (entry 9).

Table 3 Synthesis of 3a from 1a and n-octanal with 1 wt% metal loaded catalysts

Entry	Catalysts	2a yield (%)	3a yield^a (%)
a Yield based on 1a determined by GC.b Catalyst amount was 197 mg.
1	Pt/CeO2	0	98
2	Pd/CeO2	0	60
3	Rh/CeO2	17	55
4	Re/CeO2	7	42
5	Ni/CeO2	22	18
6	Ir/CeO2	75	12
7	Ru/CeO2	60	12
8	Cu/CeO2	40	10
9^b	CeO2	20	0
10	Pt/TiO2	0	99
11	Pt/MgO	29	56
12	Pt/Nb2O5	0	90
13	Pt/Al2O3	0	89
14	Pt/ZrO2	0	70
15	Pt/HBEA	0	69
16	Pt/La2O3	0	95

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Table 4 shows the general applicability of the dehydrogenative synthesis of 2-substituted quinazolines from 1a and aldehydes using 1 mol% of Pt/CeO₂. Various aliphatic aldehydes including linear, branched and cyclic aldehydes (entries 1–7) were converted to the 2-substituted quinazolines in moderate to high isolated yields (50–93%). The reactions of 1a and benzaldehydes with electron-donating and electron-withdrawing substituents proceeded to give moderate to high isolated yield (entries 8–11). For the reactions with n-octanal (eqn (1)) and benzaldehyde (eqn (2)), we carried out synthesis of 2-substituted quinazolines using small amount (0.2 mol%) of the Pt/CeO₂ catalyst for 52 h, and the results showed 95 and 90% yield, corresponding to the turnover number (TON) of 470 and 450. The TON of 450 for the reaction of 1a and benzaldehyde was higher than those of the previous catalytic systems in the presence of oxidants: TONs of 19 (CuCl/TEMPO/DABCO),¹⁰ 26 ([IrCp*Cl₂]₂/KOH)¹² and 190 (PI/CB-Pt/Ir/TTSBI/K₂CO₃.¹¹

Table 4 Synthesis of 2-substituted quinazolines from 1a and aldehydes by Pt/CeO₂

Entry	Aldehyde	Product	Isolated yield^a (%)
a Yield based on 1a determined by weight of the isolated products. GC yields are in the parentheses.b 1.5 mmol aldehyde.c Reuse 1.d Reuse 2.
1			93 (95), (90),^c (90)^d
2			70
3			92
4^b			84
5^b			88
6			50
7			72
8			85
9			77
10			90
11			57

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We studied leaching test and reusability of Pt/CeO₂ for the synthesis of 3a from 1a and n-octanal. The reaction was completely terminated by removal of the catalyst from the reaction mixture after 1 h (29% yield of 3a); further heating of the filtrate for 48 h under the reflux conditions did not increased the yield. ICP-AES analysis of the filtrate confirmed that the content of Pt in the solution was below the detection limit (10 ppb). Table 4 (entry 1) includes the result of catalyst recycles. After the first cycle, the catalyst was separated from the reaction mixture by centrifugation and was dried at 90 °C for 3 h and then reduced in H₂ at 300 °C for 0.5 h. The recovered catalyst showed high yield (90%) in the second and third cycles.

Finally, we carried out mechanistic studies to discuss a possible reaction pathway. We carried out mass spectrometry analysis of gas phase products for the reaction of 1a with 1-octanol (eqn (3)) and n-octanal (eqn (4)). For the reaction of 1a with 1-octanol (eqn (3)), the yields of gas phase H₂ (87%) and 3a (90%) were close to each other. For the reaction of 1a with n-octanal (eqn (4)), the yields of gas phase H₂ (95%) was identical to that of 3a (95%). These results indicate that H₂ was generated quantitatively during the dehydrogenative coupling reactions.

The time-yield profiles for the reactions of 1a with 1-octanol (Fig. 1) and 1a with n-octanal (Fig. 2) showed typical features of consecutive reaction mechanism via intermediate 2a; the yield of 2a initially increased with time and then decreased accompanying increase in the yield of the final product 3a. The reaction of 1a and n-octanal at 155 °C in the presence of CeO₂ gave 40% yield of the cyclized intermediate 2a which was isolated and identified by NMR and GCMS (eqn (5)). The intermediate 2a underwent dehydrogenation by Pt/CeO₂ under N₂ atmosphere to give the 2-substituted quinazoline 3a in 50% yield (eqn (6)).

From these results, we propose a plausible catalytic pathway of the synthesis of 2-substituted quinazolines from 1a with alcohols or aldehydes in Scheme 1. The reaction begins with Pt-catalyzed dehydrogenation of alcohols to aldehydes with liberation of H₂. Then, CeO₂-promoted condensation of aldehydes and 2-aminobenzylamine 1a gives cyclized intermediates 2 which undergo Pt-catalyzed dehydrogenation to give 2-substituted quinazolines 3. The mechanistic role of the basic site of the support is not clear. We speculate that the basic sites promote the dehydrogenation of alcohol (step 1) and 2 (step 3) via deprotonation of these acidic molecules.

Scheme 1 A possible pathway of Pt/CeO₂-catalyzed dehydrogenative synthesis of quinazolines 3 from 1a with alcohols or aldehydes.

In summary we have developed the first acceptorless dehydrogenative synthesis of 2-substituted quinazolines from 2-aminobenzylamine and alcohols or aldehydes using Pt/CeO₂ as a reusable heterogeneous catalyst.

Acknowledgements

This work was supported by Grant-in-Aids for Scientific Research B (26289299) from MEXT (Japan), a MEXT program “Elements Strategy Initiative to Form Core Research Center” and a Grant-in-Aid for Scientific Research on Innovative Areas “Nano Informatics” (25106010) from JSPS.

References

1. P. M. S. Bedi, V. Kumar and M. P. Mahajan, Bioorg. Med. Chem. Lett., 2004, 14, 5211–5213.
2. T.-C. Chien, C.-S. Chen, F.-H. Yu and J.-W. Chern, Chem. Pharm. Bull., 2004, 52, 1422–1426.
3. P. Desai, B. Naik, C. M. Desai and D. Patel, Asian J. Chem., 1998, 10, 615–617.
4. E. A. Henderson, V. Bavetsias, D. S. Theti, S. C. Wilson, R. Clauss and A. L. Jackman, Bioorg. Med. Chem., 2006, 14, 5020–5042.
5. J. F. Mendes da Silva, M. Walters, S. Al-Damluji and C. R. Ganellin, Bioorg. Med. Chem., 2008, 16, 7254–7263.
6. H. A. Buris III, Oncologist, 2004, 9, 10–17.
7. J. J. Vandeneynde, J. Godin, A. Mayence, A. Maquestiau and E. Anders, Synthesis, 1993, 867–869.
8. Y. Y. Peng, Y. Y. Zeng, G. Y. S. Qiu, L. S. Cai and V. W. Pike, J. Heterocycl. Chem., 2010, 47, 1240–1245.
9. C. U. Maheshwari, G. S. Kumar, M. Venkateshwar, R. A. Kumar, M. L. Kantam and K. R. Reddy, Adv. Synth. Catal., 2010, 352, 341–346.
10. B. Han, X. L. Yang, C. Wang, Y. W. Bai, T. C. Pan, X. Chen and W. Yu, J. Org. Chem., 2012, 77, 1136–1142.
11. H. Yuan, W. J. Yoo, H. Miyamura and S. Kobayashi, Adv. Synth. Catal., 2012, 354, 2899–2904.
12. J. Fang, J. Zhou and Z. Fang, RSC. Adv., 2013, 3, 334–336.
13. (a) C. Gunanathan and D. Milstein, Science, 2013, 341, 249–260; (b) G. E. Dobereiner and R. H. Crabtree, Chem. Rev., 2010, 110, 681–703; (c) C. Chen and S. Hyeok Hong, Org. Biomol. Chem., 2011, 9, 20–26.
14. K. Kon, S. M. A. H. Siddiki and K. Shimizu, J. Catal., 2013, 304, 63–71.
15. S. M. A. H. Siddiki, K. Kon, A. S. Touchy and K. Shimizu, Catal. Sci. Technol., 2014, 4, 1716–17198.
16. C. Chaudhari, S. M. A. H. Siddiki, K. Kon, A. Tomita, Y. Tai and K. Shimizu, Catal. Sci. Technol., 2014, 4, 1064–1069.
17. Y. Nagai, T. Hirabayashi, K. Dohmae, N. Takagi, T. Minami, H. Shinjoh and S. Matsumoto, J. Catal., 2006, 242, 103–109.
18. A. Y. Stakheev, Y. Zhang, A. V. Ivanov, G. N. Baeva, D. E. Ramaker and D. C. Koningsberger, J. Phys. Chem. C, 2007, 111, 3938–3948.
19. K. Shimizu, K. Ohshima, Y. Tai, M. Tamura and A. Satsuma, Catal. Sci. Technol., 2012, 2, 730–738.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra09205h

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