Intramolecular redox cyclization reaction access to cinnolines from 2-nitrobenzyl alcohol and benzylamine via intermediate 2-nitrosobenzaldehyde

Abstract

A transition-metal-free intramolecular redox cyclization reaction for the synthesis of cinnolines has been developed from 2-nitrobenzyl alcohol and benzylamine. Mechanistic investigations disclosed the involvement of a key intramolecular redox reaction, followed by condensation, azo isomerization to hydrazone, cyclization, and aromatization to form the desired products. Notably, the formation of intermediate 2-nitrosobenzaldehyde and (E)-2-(2-benzylidenehydrazineyl) benzaldehyde plays an important role in this transformation.

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Cinnolines are important nitrogen-containing heterocyclic organic compounds which have attracted widespread attention in the field of organic, materials and pharmaceutical chemistry.¹ They are known to display interesting biological activities such as inhibitory activity toward CSF-1R,² antitumor,³ antiviral,⁴ anti-inflammatory⁵ and sedative effects⁶ (Fig. 1).

Fig. 1 Bioactive cinnoline derivatives.

The classical synthetic approaches to cinnolines start from N-phenylhydrazones or N-phenylazo compounds via Rh-catalyzed C–H activation,⁷ Pd-catalyzed annulation,⁸ or Cu-catalyzed C–H functionalization/cyclization strategies.⁹ For example, in 2012, Ge's group reported a Cu-catalyzed aerobic intramolecular dehydrogenative cyclization reaction of N-methyl-N-phenylhydrazones for the formation of cinnolines (Scheme 1a).¹⁰ Subsequently, Lin and coworkers described a Rh-catalyzed redox-neutral annulation of azo and diazo compounds through a tandem C–H activation and C–N bond formation strategy (Scheme 1b).¹¹ More recently, Xu et al. developed a copper-catalyzed aerobic annulation involving a dehydrogenative amination to afford cinnolines (Scheme 1c).¹² Interestingly, Wang's group reported a Cu-catalyzed cascade cyclization to achieve regioselective synthesis of functionalized cinnolines (Scheme 1d).¹³ Although great achievements have been made,¹⁴ the development of a novel transition-metal-free mediated reaction from simple substrates to obtain the cinnoline framework is highly desirable. For example, in 2016, Wang and coworkers developed a one-pot cascade reaction for the construction of 4-amido-cinnoline derivatives (Scheme 1e).¹⁵ In our previous works, we developed a novel transition-metal-free multicomponent coupling cyclization reaction for synthesis of cinnoline derivatives.¹⁶ Inspired by these works, herein, we reported a transition-metal-free intramolecular redox cyclization reaction for straightforward access to cinnolines from 2-nitrobenzyl alcohol and benzylamine (Scheme 1f).

Scheme 1 Strategic access to cinnolines.

Initially, the reaction was investigated using 2-nitrobenzyl alcohol (1a) and benzylamine (2a) as model substrates (Table 1). The desired product, 3-phenylcinnoline (3aa), was furnished with 15% yield when the reaction proceeded in the presence of 20.0 equiv. of KOH at 100 °C for 3 h in ⁱPrOH (entry 1). At the same time, 2-phenylquinazoline (4) was also obtained in 12% yield. Unfortunately, the target product 3aa was not obtained when the reaction proceeded in H₂O (entry 2). Intriguingly, the yield of 3-phenylcinnoline (3aa) was increased to 36% when the reaction was carried out in the mixed solvent ⁱPrOH/H₂O (5 : 1) at 100 °C for 3 h (entry 3). Encouraged by this result, we continued to optimize the reaction conditions. Several bases, solvents, and temperatures were examined, and the results were summarized in Table 1. Remarkably, when the reaction was conducted in the presence of C_SOH·H₂O, the yield of 3aa was given to 56% (entry 4). Other bases (NaOH and LiOH) were found to give lower yields (entries 5 and 6). However, we did not detect the desired product when using some inorganic bases (K₂CO₃, Cs₂CO₃ and Na₂CO₃) and organic bases (DABCO, t-BuOK and DBU) (entries 7–12). Next, the amount of C_SOH·H₂O was examined (entries 13–15). The reaction could proceed smoothly with 59% yield, when only 3.0 equiv. of C_SOH·H₂O was used in the reaction (entry 15). Subsequently, examination of different mixed solvents (MeOH/H₂O, DMSO/H₂O, dioxane/H₂O, EtOAc/H₂O, THF/H₂O and EtOH/H₂O) revealed that EtOH/H₂O was the best choice for the reaction, and the corresponding yield increased to 63% (entries 16–21). Following the above investigations, the ratio of EtOH/H₂O was evaluated (entries 22–26), and a higher yield (81%) was observed with the ratio 2 : 1 (entry 23). Temperature screening suggested that neither a rise nor a drop of the temperature promoted the reaction (entries 27 and 28).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent (ratio)	Base (equiv.)	T (°C)	Yield^b (%)
				3aa	4
a Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (1.5 mmol, 3.0 equiv.), base (1.5 mmol, 3.0 equiv.) and solvent (6 ml) heated in oil bath for 3 h in sealed tube.b Isolated yields.
1	^iPrOH	KOH (20)	100	15	12
2	H2O	KOH (20)	100	0	0
3	^iPrOH/H2O (5/1)	KOH (20)	100	36	20
4	^iPrOH/H2O (5/1)	CSOH·H2O (20)	100	56	19
5	^iPrOH/H2O (5/1)	NaOH (20)	100	35	21
6	^iPrOH/H2O (5/1)	LiOH (20)	100	42	10
7	^iPrOH/H2O (5/1)	K2CO3 (20)	100	0	0
8	^iPrOH/H2O (5/1)	Cs2CO3 (20)	100	0	0
9	^iPrOH/H2O (5/1)	Na2CO3 (20)	100	0	0
10	^iPrOH/H2O (5/1)	DABCO (20)	100	0	0
11	^iPrOH/H2O (5/1)	t-BuOK (20)	100	0	0
12	^iPrOH/H2O (5/1)	DBU (20)	100	0	0
13	^iPrOH/H2O (5/1)	CSOH·H2O (10)	100	57	25
14	^iPrOH/H2O (5/1)	CSOH·H2O (5)	100	55	27
15	^iPrOH/H2O (5/1)	CSOH·H2O (3)	100	59	22
16	MeOH/H2O (5/1)	CSOH·H2O (3)	100	17	<5
17	DMSO/H2O (5/1)	CSOH·H2O (3)	100	<5	51
18	Dioxane/H2O (5/1)	CSOH·H2O (3)	100	41	<5
19	EtOAc/H2O (5/1)	CSOH·H2O (3)	100	0	0
20	THF/H2O (5/1)	CSOH·H2O (3)	100	0	0
21	EtOH/H2O (5/1)	CSOH·H2O (3)	100	63	31
22	EtOH/H2O (3/1)	CSOH·H2O (3)	100	67	23
23	EtOH/H2O (2/1)	CSOH·H2O (3)	100	81	<5
24	EtOH/H2O (1/1)	CSOH·H2O (3)	100	73	<5
25	EtOH/H2O (1/2)	CSOH·H2O (3)	100	<5	<5
26	EtOH/H2O (1/3)	CSOH·H2O (3)	100	<5	<5
27	EtOH/H2O (2/1)	CSOH·H2O (3)	90	70	11
28	EtOH/H2O 2/1)	CSOH·H2O (3)	110	74	<5

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After optimizing the reaction conditions, we explored the substrate scope of benzylamine (2), as shown in Table 2. It is noteworthy that the electronic properties of the substituents on the aromatic ring system were shown to have a significant influence on the efficiency of this transformation. The benzylamine bearing electron-neutral (H) and electron-donating groups (2-Me, 3-Me, 4-Me, 3,4-2Me, 2-OMe, 4-OMe, –NH₂, 3,4-(OCH₂O)–) attached to the benzene ring, transformed smoothly into the corresponding products in moderate to good yields (53–81%; 3aa–3ai). Much to our satisfaction, halo-substituted (2-Br, 3-Br, 4-Br, 2-Cl, 4-Cl, 4-F, 4-I) substrates were also compatible, giving moderate yields (45–60%; 3aj–3ap). Fortunately, heterocyclic substituents (3-pyridyl, 4-pyridyl, 2-furyl, 2-thienyl) were also compatible, affording the expected products (3aq–3at) in 45–56% yields. In addition, naphthyl group substrates were also compatible, affording the expected products 3au and 3av in 46% and 50% yields, respectively. However, when the substrate was 2-aminoacetonitrile, the desired product 3ax was not afforded.

Table 2 Scope of benzylamine^a

a Reaction conditions: 1a (1.0 mmol, 1.0 equiv.), 2 (3.0 mmol, 3.0 equiv.) and C_SOH·H₂O (3.0 mmol, 3.0 equiv.) was stirred in EtOH/H₂O (4 ml/2 ml) at 100 °C heated in oil bath for 3 h in sealed tube. Isolated yields.

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Encouraged by the results described above, the scope of 2-nitrobenzyl alcohol (1) was subsequently examined (Table 3). At first, electron-donating substituted 2-nitrobenzyl alcohols 1b and 1c were explored, and the corresponding products 3ba and 3ca were obtained in 63% and 51% yields, respectively. Halo-substituted (2-Br, 4-Br, 2-Cl, 4-Cl, 5-Cl) groups substrates were also compatible, affording the expected products (45–50%; 3da–3ha). In addition, when the substrate was secondary alcohol 1i, the desired product 3ia was not afforded.

Table 3 Scope of 2-nitrobenzyl alcohol^a

a Reaction conditions: 1 (0.5 mmol, 1.0 equiv.), 2a (1.5 mmol, 3.0 equiv.) and C_SOH·H₂O (1.5 mmol, 3.0 equiv.) was stirred in EtOH/H₂O (4 ml/2 ml) at 100 °C heated in oil bath for 3 h in sealed tube. Isolated yields.

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To gain insights into the reaction process, control experiments were performed (Scheme 2). The reaction of 2-nitrobenzyl alcohol 1a converted to 2-nitrosobenzaldehyde 5 in 33% yield under the standard conditions (eqn 1). Later, the reaction between compound 5 and 2a proceeded to give the target product 3aa in 39% yield (eqn 2). To our surprise, when the reaction was carried out in EtOH/H₂O at 100 °C for 20 min in the presence of 3.0 equiv. C_SOH·H₂O, the desired product (3aa) was obtained in 20% yield together with unexpected (E)-2-(2-benzylidenehydrazineyl) benzaldehyde 6 (16%) (eqn 3). Moreover, compound 6 converted to the desired product 3aa in excellent yield (90%) under standard conditions (eqn 4). These results identified that compounds 5 and 6 were very probably intermediates for this reaction.

Scheme 2 Control experiments.

On the basis of the above-mentioned experimental results, a possible mechanism for this reaction is proposed as shown in Scheme 3 (using 3aa as an example). Initially, 2-nitrobenzyl alcohol 1a undergoes deprotonation in the presence of C_SOH·H₂O to form 2-nitrosobenzaldehyde 5,¹⁷ which is generated in situ via intramolecular redox reaction. Subsequently, intermediate 5 reacts with benzylamine 2a through a condensation reaction with elimination of H₂O to afford (E)-2-(benzyldiazenyl)benzaldehyde C. Meanwhile, ortho-azo intermediate C is isomerized to form (E)-2-(2-benzylidenehydrazineyl) benzaldehyde 6. Subsequently, hydrazone 6 undergoes an intramolecular cyclization process to afford intermediate D. Finally, intermediate D is converted to the desired product 3aa through an aromatization reaction with elimination of H₂O.

Scheme 3 A possible mechanism.

In order to demonstrate the potential applications for organic synthesis, the reaction of 2-nitrobenzyl alcohol (1a) and benzylamine (2a) was performed on a gram scale (Scheme 4). To our satisfaction, the reaction was carried out very well, and the 3aa was furnished in 57% yield.

Scheme 4 Gram scale experiment.

In summary, we have developed a novel transition-metal-free intramolecular redox cyclization reaction for the efficient synthesis of cinnoline derivatives by simple treatment with C_SOH·H₂O in EtOH/H₂O. This method obtained 2-nitrobenzaldehyde intermediate by intramolecular redox reaction of 2-nitrobenzyl alcohol, which then condenses with benzylamine, followed by azo is isomerized to form hydrazone, cyclization, and aromatization processes to form cinnoline compounds. Further studies on this method for the synthesis of other bioactive compounds and applications are in progress in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (Grant 21801022) for financial support. This work was also sponsored by CNPC Innovation Found (2021DQ02-0203).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2ra06523a

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