Three-component tandem benzyl-C(sp³)–H functionalization via thermally generated arynes with phenazine

Abstract

A rare strategy for three-component tandem benzyl-C(sp³)–H functionalization via thermally generated arynes with phenazine without a catalyst was developed for the first time. A series of novel fused N,N′-disubstituted dihydrophenazine derivatives were synthesized with excellent yield and high atomic utilization. Deuterium-labelling studies suggested that the formation of carboanion intermediates has a significant role in the reaction. Our data enrich the field of C(sp³)–H functionalization and promote the development of aryne chemistry.

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Introduction

Carbon–hydrogen bond functionalization is a breakthrough technology in organic chemistry.^1,2 It was weaned from the dependence on the pre-modification of functional groups in traditional organic synthesis. Functionalization of carbon–hydrogen bonds provides an efficient and facile strategy for the construction of complex molecular skeletons.³ It is of great importance in organic synthesis,⁴ drug development⁵ and material sciences.⁶ Several types of C–H bond functionalization,⁷ mainly transition metal (Rh,⁸ Pd,⁹ Au,¹⁰ Ru,¹¹ Ir,¹² Fe,¹³ Ag¹⁴ and Cu¹⁵) catalysis, electrocatalysis,¹⁶ photocatalysis,¹⁷ and acid/base-catalysis¹⁸ have been described. Transition metal-catalyzed C–H functionalization is one of the most mainstream methods.¹⁹ The C–H bond functionalization reaction carried out by transition metals and their complexes as catalysts operates by reducing the energy barrier of the C–H bond²⁰ by coordination of the directing group on substrates or promoting C–H bond cleavage through changes in the redox state of metals.²¹ Classification of C–H bond functionalization can be divided into C(sp)–H, C(sp²)–H and C(sp³)–H bond functionalization according to hybridization of the carbon atom.²² Typically, the C(sp)–H (alkyne C–H) bond can be activated readily by transition metals or strong bases thanks to the higher bond energy and weak acidity of the alkyne hydrogen. Although successful C–H sp–sp³ cross-coupling is difficult to achieve, it has been reported in recent years.²³ Functionalization of C(sp²)–H bonds (alkenyl/aromatic C–H bonds) is challenging, yet prevalent.²⁴ The C–H bonds on both sides of the plane of the alkene can be attacked by various reagents readily,²⁵ while the aromatic stabilization energy needs to be overcome during activation of the aromatic C–H bond for the surrounding aromatic π-electron clouds.²⁶

Su and co-workers developed Cu–Pd bimetallic catalysts for multiple remote C(sp³)–H functionalizations of aliphatic ketones.²⁷ They overcame the challenge of continuous dehydrogenation and desaturation of terminal unsubstituted alkyl chains in aliphatic ketones (Scheme 1a). Furthermore, metal-free C(sp³)–H functionalization has also received considerable interest recently. A successful, metal-free three-component alkyl-C(sp³)–H functionalization reaction of arylacetylenes with phthalazines in dichloromethane or acetonitrile (Scheme 1b) has been reported by Chenoweth's group.²⁸ Likewise, intramolecular hydride transfer to arynes-enabled redox-neutral and transition metal-free C(sp³)–H functionalization of amines (Scheme 1c) was disclosed by Jones’ group,²⁹ which generated a new C(sp³)–C(sp³/sp²/sp) bond to nitrogen in a single synthetic operation. Reports have been published on the C(sp³)–H bond functionalization reaction mediated by arynes synthesized via conventional approaches.³⁰ However, the realization of benzyl-C(sp³)–H functionalization via benzynes generated through the hexadehydro-Diels–Alder reaction is pending.

Scheme 1 Examples of C(sp³)–H bond functionalization and our work.

Extremely low stability and highly unsaturated cyclic intermediates-benzyne intermediates³¹ possess high reactivity which can be captured by various reagents readily and generated by the hexadehydro-Diels–Alder reaction³² (thermal cycloisomerization) of a 1,3-diyne or remotely chained diynophile. Herein, we report an unprecedented strategy (Scheme 1d) based on our previous work:³³ three-component tandem benzyl-C(sp³)–H functionalization via thermally generated arynes with phenazine. Tetrayne substrates were reacted with phenazine under a series of benzylic solvents only by heating, and generated a novel fused N,N′-disubstituted dihydrophenazine derivative³⁴ in the absence of a catalyst. We have provided a convenient method for the synthesis of dihydrophenazine derivatives, and simultaneously enriched the field of C–H bond functionalization and promoted the development of aryne chemistry.

Results and discussion

Initially, we blended a tetrayne substrate (1a) and phenazine (2a) with 3 mL of toluene under heating and observed the reaction. A new yellow-green and fluorescent spot was observed after the thin-layer chromatography analysis of a brown-green reaction mixture had been carried out. We cultured a single crystal of 4a and the structure of the final product was confirmed by X-ray diffraction.³⁷ Through analyses of the single crystal structure of the target product, we found that formation of this compound involved a three-component tandem reaction. Most strikingly, toluene was also involved in the reaction as one of the reactants. Meanwhile, a very rare case of benzyl-C(sp³)–H functionalization occurred in the absence of a cocatalyst. This is different from the previously reported benzylic C–H (activation/functionalization) mediated by metal catalysis.³⁵

Having established the feasibility of this type of reaction, we used a tetrayne with the same aromatic group but containing different esters (OMe, OEt, or OⁱPr) to react (Table 1). If the ester substituent on tetraynes was changed, the yield of the target product (4a, 4b and 4c) fluctuated slightly (range from 77% to 84%), which indicated that the tetraynes of different esters had little effect on the yield of the product. Next, we investigated the applicability of the reaction (Table 2). Tetrayne substrates with different aromatic substituents under optimized conditions were employed (see SI). The tetrayne with different electron-donating (p-Me, p-Et, p-ⁿPr and m-Me) or electron-withdrawing (p-Cl, p-F and m-Cl) groups of the aromatic substituents reacted with phenolazine and toluene to undergo a three-component tandem reaction to afford a series of N,N′-disubstituted dihydrophenazine derivatives (4d–4r). Target compounds (e.g., 4f, 4g, 4h, 4k, 4q and 4r) with different electron-donating aryl-substitutes were isolated in good yields (71% to 80%). Compounds (e.g., 4d, 4e, 4i, 4l, 4m and 4p) with various electron-withdrawing aryl-substitutes were isolated in good yields (75% to 88%). In addition, the structures of 4d and 4j were confirmed³⁷ by X-ray diffraction.

Table 1 Three-component tandem reaction via different tetraynes^a,b

a Conditions: tetraynes 1a–1c (1.0 equiv.), phenazine 2a (1.0 equiv.), 3a toluene (3.0 mL), and stirred at 120 °C for 3 h. b Yield of isolated product after flash column chromatography.

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Table 2 Three-component tandem reaction via different tetraynes^a,b

a Conditions: tetraynes 1d–1r (1.0 equiv.), phenazine 2a (1.0 equiv.), 3a toluene (3.0 mL), and stirred at 120 °C for 3 h. b Yield of isolated product after flash column chromatography.

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We also explored the applicability of this type of reaction to various benzylic solvents (Table 3). First, we screened several types of commonly used organic solvents but lacking a CH₃-group (chlorobenzene, 1,2-dichloroethane, 1,2-dichlorobenzene) blended with tetrayne, phenolazine or toluene under heating (120–130 °C). Disappointingly, we did not obtain the target products. A reason for this phenomenon might have been that the introduction of different solvents broke the dual equilibrium of the original reaction solvent as the reactant and reaction medium, so the reaction could not occur. Subsequently, we replaced toluene with CH₃CN and mixed it with tetrayne or phenazine under heating (120–130 °C), but again the target product could not be obtained. We speculated that it was hard for the benzyne intermediate after tetrayne cycloisomerization to obtain protons from these solvents, which hampered the formation of carbon anions and the target product could not be obtained. Therefore, we chose mesitylene (3b), m-xylene (3c) or 4-chlorotoluene (3d) to react with tetrayne and phenazine. To our delight, as shown in Table 3, the reaction was effective in mesitylene, m-xylene and 4-chlorotoluene to afford the desired benzyl-C(sp³)–H functionalization products, respectively (4s–4x, 4y–4A and 4B–4D) in good yields (70% to 85%), and the structures of 4x, 4A and 4B were confirmed by X-ray diffraction (Table 4).³⁷

Table 3 Scope of application of the reaction substrate^a,b

a Conditions: tetraynes 1s–1D (1.0 equiv.), phenazine 2a (1.0 equiv.), 3b, 3c and 3d (3.0 mL), and stirred at 120 °C for 3 h. b Yield of isolated product after flash column chromatography.

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Table 4 Scope of application of the reaction substrate^a,b

a Conditions: tetraynes 1E–1G (1.0 equiv.), phenazine 2a (1.0 equiv.), 3e (3.0 mL), stirred at 120 °C for 2 h. b Yield of isolated product after flash column chromatography.

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We also investigated the compatibility of ethylbenzene and cumene for the reaction. Ethylbenzene could also react with tetrayne and phenozine if stirred at 120 °C for 2 h and we obtained the target products 4E, 4F and 4G efficiently (yields ranging from 71% to 75%). We confirmed the structures of 4F through X-ray diffraction.³⁷ It is notable that the reaction site was a methylene carbon (benzyl carbon) that connected directly to the benzene ring. Conversely, we did not observe the three-component products of the cumene if we lengthened the reaction time or increased the reaction temperature. This effect may have been caused by two reasons. First, the methyl group is an electron-donating group. The more methyl groups obtained, the greater is the likelihood of negative charge being more concentrated, which contributes to greater destabilization of the carbon anion. The second reason is the influence of steric hindrance elicited by the isopropyl group.

Interestingly, 4H (72%) and 4I′ (11%) were invested in various reaction types of products that were different from the above reactions if phenazine was replaced with 1-methoxyphenazine (Scheme 2). Besides, the structures of 4H and 4I′ were confirmed by X-ray diffraction.³⁷ The reason underlying this phenomenon may have been a p–π conjugate effect arising through the large π bond of the phenazine ring with the methoxy group. This would have contributed to the nucleophilicity of the phenazine ring being enhanced, so a cycloaddition reaction would be more likely to occur.

Scheme 2 Reaction of 1-methoxyphenazine with tetrayne.

After considering the above experimental examples, depicted in Scheme 3a is the possible mechanism of the three-component tandem benzyl-C(sp³)–H functionalization via thermally generated arynes with phenazine.^28,29 Taking the synthesis of compound 4a as an example, tetrayne 1a undergoes cycloisomerization under thermal conditions to form the benzyne intermediate INT1. Then, the lone-pair electrons of the N atom in phenazine (2a) attack the benzyne to generate the intermediate INT2 (INT2′). The aryl anion part of the intermediate INT2 (INT2′) has higher basicity. The highly basic phenyl anion abstracts the benzylic proton of the solvent under certain conditions³⁶ and undergoes the transition state TS1 while generating the intermediates INT3 and INT4. When intermediate INT3 is formed, the positive charge delocalizes to the para-position N atom through the conjugated system, which reduces the electron cloud density of N atoms significantly and presents a partial positive charge. Simultaneously, an electrostatic attraction is formed with the negative charge of INT4 while reducing the functionalization energy of the reaction (charge matching drives a nucleophilic attack). This leads to the N atom in the para-position becoming more likely to react with the carbon anion (INT4) and compound 4a is generated eventually.

Scheme 3 Proposed mechanism.

To gain insight into the mechanism of three-component tandem benzyl-C(sp³)–H functionalization via thermally generated arynes with phenazine, a deuterium-labelling experiment was conducted (Scheme 3b). The deuterium-labelled product 4J was isolated in 76% yield under optimized reaction conditions (see SI), and we confirmed the structure of 4J through NMR spectroscopy. Fig. 1 shows the ¹H NMR spectra of compound 4c and compound 4J. Compound 4J was the deuterated product of compound 4c.

Fig. 1 Comparison of ¹H NMR spectra.

Compared with compound 4c, the ¹H NMR spectrum signal peaks of a (–CH_2, 2H), b (–Ar, 4H), c (–Ar, 1H) and d (–Ar, 1H) in the deuterated product 4J disappeared, which verified the rationality of the proposed mechanism. These results indicated that the formation of carbanion intermediates was crucial to achieve benzyl-C(sp³)–H functionalization.

Conclusions

We created an efficient three-component tandem benzyl-C(sp³)–H functionalization through thermally generated arynes with phenazine. In this strategy, activation of the benzylic-C(sp³)–H bond was only by heating and a catalyst was not needed. A series of novel fused N,N′-disubstituted dihydrophenazine derivatives were synthesized with excellent yield and high atomic utilization. The reaction possessed good tolerance of functional groups: a series of target compounds could be obtained in good yield and high atomic utilization for tetrayne substrates with different substituents and benzylic solvents. Deuterium-labelling studies supported the rationality of the proposed possible reaction mechanism, while affirmed that the formation of carboanion intermediates had a significant role in the reaction. We have provided a feasible method for the synthesis of dihydrophenazine derivatives and ultimately enriched the field of C(sp³)–H functionalization while promoting the development of aryne chemistry. Further work on the application of dihydrophenazine derivatives is ongoing in our group.

Author contributions

All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts of interest to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Crystallographic data for compounds 4a, 4d, 4j, 4x, 4A, 4B, 4F, 4H and 4I′ (CCDC 2493648, 2493649, 2493650, 2493651, 2493652, 2493653, 2493654, 2493655 and 2493656) have been deposited in the Cambridge Crystallographic Data Center. Supplementary information is available. See DOI: https://doi.org/10.1039/d5ob01818h.

CCDC 2493648 (4a), 2493649 (4d), 2493650 (4j), 2493651 (4x), 2493652 (4A), 2493653 (4B), 2493654 (4F), 2493655 (4H) and 2493656 (4I′) contain the supplementary crystallographic data for this paper.^37a–i

Acknowledgements

The authors thank the National Natural Science Foundation of China (22071001) and Department of Human Resources of Anhui Province for financial support.

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