Copper-catalyzed intermolecular cyclization of nitriles and 2-aminobenzylamine for 3,4-dihydroquinazolines and quinazolines synthesis via cascade coupling and aerobic oxidation

Abstract

A copper-catalyzed cascade coupling and aerobic oxidation of aromatic nitriles and 2-aminobenzylamine for the synthesis of 3,4-dihydroquinazolines and quinazolineshas been achieved. The catalytic system, characterized by not adding additives and using molecular oxygen as the sole oxidant, exhibited exquisite substrate specificity and operated under mild conditions through inherently “green” processes.

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Among pharmaceutical substances, the N-heterocycles comprise an important class.¹ A recent survey found that more than 70% of the top-selling proprietary drugs contain N-heterocycles in their structures.² As such, 2-substituted quinazolines and 3,4-dihydroquinazolines have been widely used in organic synthesis and medicinal chemistry as building blocks because of their biological and therapeutic activities (Fig. 1).^3,4 For example, quinazolines are used as ligands for benzodiazepine and GABA receptors in the CNS system⁵ or as DNA binders.⁶ There are some synthetic strategies available for the synthesis of quinazolines^7,8 involving several substrates such as 2-halophenylmethanamines⁹ or 2-aminobenzoketones¹⁰ or amidines¹¹ or 2-aminobenzaldehydes¹² (Scheme 1). Despite these advances, the reported synthetic approachs suffer from some drawbacks that nonrenewable oxidant has to be used and the yields are not satisfactory. Unfortunately, few methods are reported for synthetic approaches to 3,4-dihydroquinazolines until now,^11a,13 and this transformation is considered to be a big challenge. Therefore, novel and efficient methods for the synthesis of 2-substituted quinazolines and 3,4-dihydroquinazolines that are compatible with various functional groups and proceed under mild conditions remain highly desirable. Herein, we report the transformations of various nitriles with 2-aminobenzylamine via copper-catalyzed cascade coupling to synthesize 3,4-dihydro-quinazolines and aerobic oxidative process to produce 2-substituted quinazolines. The catalytic system, characterized by not adding additives and using molecular oxygen as the sole oxidant, exhibited exquisite substrate specificity and operate under mild conditions through inherently “green” processes. Particularly, the present method could provide a practical route for synthesis of 3,4-dihydroquinazolines for the first time.

Fig. 1 This work and general methods for the synthesis of quinazolines and 3,4-dihydroquinazolines.

Scheme 1 Quinazolines as core structures in drugs.

To standardize the reaction conditions a series of experiments were performed with variation of reaction parameters such as catalyst, solvent and temperature for are presentative coupling of benzonitrile 1a and 2-aminobenzylamine 2. As shown in Table 1, screening of various copper catalysts (entries 1–9) revealed that Cu^II(L₁)₂ displayed greater catalytic reactivity for the transformations (entry 6). Only a trace amount of target product was observed in the absence of copper catalyst (entry 10). Optimization of different solvents revealed that EtOH, dioxane and CH₃CN were inferior to toluene in the reaction (entries 11–13). There action temperature was also varied, and 110 °C gave the best result (compare entries 14–16). Accordingly, the optimized reaction conditions are as follows: Cu^II(L₁)₂ (10 mol%), under air atmosphere in toluene at 110 °C.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Temp (°C)	Yield^b (%)
a The reaction conditions were as follow: a mixture of benzonitrile (1a, 1 mmol), 2-aminobenzylamine (2, 1.25 mmol), catalyst (0.1 mmol), solvent (2 mL) were heated in a 10 mL flask for 12 h under air.b Yield of the isolated pure product.c n.d. = not detected.
1	CuCl2	EtOH	75	n.d.
2	CuBr2	EtOH	75	n.d.
3	CuI2	EtOH	75	n.d.^c
4	Cu(OAc)2	EtOH	75	20
6	Cu^II(L1)2	EtOH	75	60
7	Cu^II(L2)2	EtOH	75	<5
8	Cu^II(L3)2	EtOH	75	13
9	Cu^II(L4)2	EtOH	75	38
10	—	EtOH	75	n.d.
11	Cu^II(L1)2	CH3CN	75	62
12	Cu^II(L1)2	Toluene	75	65
13	Cu^II(L1)2	Dioxane	75	55
14	Cu^II(L1)2	Toluene	90	72
15	Cu^II(L1)2	Toluene	100	75
16	Cu^II(L1)2	Toluene	110	81

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With the optimized reaction conditions established, the scope and generality of the reaction were investigated (Table 2). There action showed high functional group tolerance and proved to beaquitegeneral method for the preparation of dihydroquinazoline 3. In general, the electron-deficient aromatic nitriles showed better reactivity and provided higher yields than electron-rich ones, and the reactions were insensitive to the steric hindrance of the substituents on the aromatic rings. The nitriles possessing phenyl, pyridyl, and thienyl groups underwent the desired reaction to give the corresponding dihydroquinazolines 3a–3e in good yields. However, 2-(pyridin-3-yl)-3,4-dihydroquinazoline 3c was obtained in trace amounts due to the volatility of dihydroquinazoline. Nitriles with fluoro, chloro, bromo, nitro, and trifluoromethyl groups on the phenyl ring reacted smoothly to give the corresponding dihydroquinazolines 3f–3o in excellent yields in the reactions. The ability to incorporate C–Br and C–Cl bonds makes this method appealing, since it offers an opportunity for further transformation. An extensive investigation of the reaction showed that dinitriles were converted into the respective monodyhydroquinazolines with excellent chemoselectivity (3p–3s). It is note worthy that mixtures of dinitriles (1 mmol) with double 2-aminobenzylamine (2.5 mmol) gave only 2-substitutedmonodihydroquinazolines, which is of practical significance because the remaining nitrile group can be converted into other important functional groups. Even if sterically bulky aromatic nitriles such as 3,4,5,6-tetrafluorophthalonitrile 1s was used, the corresponding 3s were obtained in 89% yields. Unfortunately, couplings of 2-aminobenzylamine with alkyl nitriles did not work by using a similar procedure.

Table 2 Copper-catalyzed cascade coupling for synthesis of 2-substituted 3,4-dihydroquinazolines^a,b

a The reaction conditions were as follow: 1 (1 mmol), 2 (1.25 mmol), Cu^II(L₁)₂ (0.1 mmol) in 2 mL toluene at 110 °C under air.b Yield of the isolated pure product.c Reaction time is 6 h.d Reaction time is 8 h.

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Next, we continued our investigation by studying the conversion of 1 and 2 to the desired quinazolines 4 using a combination of a copper catalyst together with O₂ as the sole oxidant (Table 3). Satisfactorily, quinazolines could be obtained smoothly with good results. These results that showed electron-withdrawing groups had more favorable effects than electron-donating groups. As is depicted in Table 3, nitriles with fluoro, chloro, nitro, and trifluoromethyl groups on the phenyl ring reacted smoothly to give the corresponding products in high yields. These functional groups provide ample opportunity for further synthetic manipulations. The introduction of fluorine atoms or fluorine-containing groups into heterocyclic rings has made possible the discovery of new bioactive products. We then succeeded in performing the reaction to demonstrate the practicability of the developed method in a one-pot fashion, and our oxidation reaction could provide a useful route for drug discovery. Similarly, copper-catalyzed aerobic oxidation of 2-aminobenzylamine with alkyl nitrile was not effective under this set of conditions.

Table 3 Copper-catalyzed aerobic oxidation for synthesis of 2-substituted quinazolines^a,b

a Reaction conditions: 1 (1 mmol), 2 (1.25 mmol), Cu^II(L₁)₂ (0.1 mmol) in 2 mL toluene under oxygen atmosphere at 110 °C.b Yield of the isolated pure product.c Reaction time is 6 h.

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To gain more insight into the mechanism of the reaction, when 3a was treated under oxygen atmosphere for 6 h, 98% yield of aromatized quinazoline 4a could be obtained. However, when 3a was treated in the absence of Cu^II(L₁)₂, 4a was obtained in 42% yield (Scheme 2). This result indicated that the 3,4-dihydroquinazolines 3 was probably an intermediate in the synthesis of quinazoline 4, and the copper catalyst serves a double catalytic function for both cascade coupling and aerobic oxidation.

Scheme 2 The oxidation of 3,4-dihydroquinazoline to synthesize quinazoline.

A tentative mechanism is depicted in Scheme 3. First, the nitrile 1 is activated by Cu^II(L₁)₂ to give intermediate A.¹⁴ Nucleophilic addition of A with 2-aminobenzylamine 2 provides B. Intramolecular cycloaddition of B provides C, intermediate C releases Cu^II(L₁)₂ and NH₃ to afford 3. As part of our ongoing effort, we also calculate the Fukui function (f⁺) of the compound 3 (Fig. 2), the result proved the tentative mechanism. The nitrogen atom of tertiary amines 3 coordinate to Cu^II(L₁)₂ to give D by a ligand-exchange reaction. Then the intermediate D through deprotonation to form E. Finally, after deprotonation would liberate quinazolines 4 and the reoxidation of the Cu(I) complex to the Cu(II) complex would close the catalytic cycle.¹⁵

Scheme 3 Possible mechanism for synthesis of 3,4-dihydroquinazolines and quinazolines.

Fig. 2 The Fukui function (f⁺) of the compound 3a.

Conclusions

In summary, we have developed a novel and efficient method for synthesis of 3,4-dihydroquinazolines and quinazolines from aromatic nitriles and 2-aminobenzylamine via copper-catalyzed cascade coupling and aerobic oxidation without addition of any base or additive. This method features demonstrated that: (1) the copper catalyst serves double catalytic function for both cascade coupling and aerobic oxidation; (2) the use of oxygen as the terminal oxidant and the one-pot method can be employed for the reactions. Further studies on the scope of the substrates, applications, and the precise mechanism are underway in our laboratory.

Acknowledgements

We thank the National Natural Science Foundation of China (NSFC 21272184; 20972124 and 21143010) and the Shaanxi Provincial Natural Science Fund Project (no. 2012JQ2007) for financial support.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, copies of ¹HNMR, ¹³C NMR and IR spectra. CCDC 977533 and 977534. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra09240f

‡ Cheng Li and Shujian An contributed equally to this work.

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