Formation of complex cyclic compounds via a dehydrogenative Diels–Alder reaction

Abstract

Reported herein is an unprecedented annulation strategy for macrocyclic compounds. This reaction facilitates the generation of α,3-dehydrotoluene (DHT) intermediates through a pentadehydro-Diels–Alder process, wherein subsequent DHT variants react with 1,6-diphenylhexa-1,3,5-triene to afford macrocyclic compounds with a broad substrate scope. Density functional theory computations support a zwitterionic intermediate process. Another product with a different skeleton is obtained by changing the reaction conditions.

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Protein–protein interactions (PPIs), as effective but challenging therapeutic targets, have become a common approach to treat various diseases.¹ However, owing to the inadequate size of conventional small molecules, PPIs often cannot play a role in their absorption for therapeutic purposes.² Biologics are considered the most common approach for treating diseases, with limitations such as resistance, off-target effects, high development costs, and low tissue penetration.³ Macrocycles (rings containing ≥12 atoms) as intermediates between small molecules and biologics have excellent potential given their ability to target PPIs.⁴ They are widely found in natural products and biologically active compounds.^1a,5 For example, as a potent antibiotic, erythromycin inhibits protein synthesis to treat diseases.⁶ Kendomycin, which contains a fully carbogenic skeleton, exhibits fascinating biological activity.⁷ Epothilones, cytotoxic compounds isolated from myxobacteria, exhibit potent antiproliferation activity (Fig. 1).⁸ Additionally, these structurally important compounds have vast applications, including, but not limited to, the fields of organic electronic material synthesis,⁹ fluorescence sensing,¹⁰ nanotechnology,¹¹ and supramolecular chemistry.¹²

Fig. 1 Selected natural products and biologically active compounds containing macrocyclic skeletons.

Considering their widespread applications, researchers in the field of organic synthesis have long been interested in the development of efficient methodologies for the formation of macrocyclic compounds. Generally, normal-sized rings (5–7 membered), such as type A to B, are easy to synthesize, but large rings (C to D) present a major challenge because of the interference of competing reactions (C to E, Scheme 1a).¹³ The high dilution strategy has been applied to combat this difficulty.¹⁴ Though successful in many cases, many challenges, such as high substrate dependence, low yields, and competing intermolecular coupling, arise. Exploring novel strategies for constructing macrocyclic skeletons has become one of the hot topics in organic synthesis.¹⁵ Some facile synthetic methodologies, including diversity-oriented synthesis,¹⁶ azide–alkyne cycloaddition,¹⁷ ring-closing metathesis¹⁸ (RCM) and palladium-catalyzed cross-coupling,¹⁹ have been developed. For example, Waser and his co-worker reported an RCM-based total synthesis route of one antibiotic by ring-closing olefin metathesis in 2020 (Scheme 1b).²⁰ This research achieved direct carbon–carbon bond macrocyclization reactions. Overall, despite the success of traditional strategies for macrocycle synthesis, all these strategies have some disadvantages, such as harsh reaction conditions (e.g., high temperatures), long routes and the requirement of noble metal catalysts like Pd and Ru. Therefore, the exploration of concise and metal-free methodologies for macrocyclic skeletons is highly desirable.

Scheme 1 Previous studies and our design.

Recently, Hoye's group documented a novel strategy called pentadehydro-Diels–Alder (PDDA) reaction to generate an allene intermediate that undergoes cyclization, ultimately producing particular isomeric α,3-dehydrotoluene intermediates.²¹ DHT, a reactive intermediate like benzyne, exhibiting remarkable reactivity in diradical and zwitterion variants, can be captured by various trapping agents (Scheme 1c).^22,23 This key discovery inspired a feasible idea for the construction of macrocycles owing to the high reactivity of DHT variants. The rich reactivity of conjugated alkenes, which makes them good substrates, is attributed to their unique structure. Beyond their use as dienophiles in the Diels–Alder reaction, they can also be trapped by various nucleophiles and undergo reaction.²⁴ Inspired by this advancement, we envision that the tandem cyclization between an alkene and DHT may provide a highly efficient approach for constructing macrocyclic frameworks. Specifically, we hypothesize that zwitterion intermediates attack the conjugated alkene to form a macrocyclic skeleton. Notably, such reactivities involving zwitterionic intermediates have been recently reported in the literature, which has further stimulated our interest.²⁵ Capitalizing on this proposal, we evaluated the reaction of tetraynes as PDDA-derived intermediate precursors with 1,6-diphenylhexa-1,3,5-triene. The steric hindrance between the linker and alkene, potential competing reactions, and the need for a metal-free process made the reaction challenging (Scheme 1d).

The non-nucleophilic base DBU was considered a sufficiently effective base for promoting the isomerization of tetraynes to the intermediate allenes.^22a,26 In one of our first attempts, we heated tetrayne 1a and 2 in the presence of DBU in acetonitrile (MeCN) at 95 °C for 12 h (Table 1). Unfortunately, the expected product was not observed. When the base used for this reaction was changed from DBU to Cs₂CO₃, a 1 : 1 adduct was isolated as the sole product. The absolute configuration of 3a was determined by single crystal X-ray analysis.²⁷ To our surprise, instead of the expected compound F, the terminal phenyl group of conjugated alkenes was directly inserted into the rings, forming a 14-membered macrocycle. In contrast, when the reaction was conducted without Cs₂CO₃, dihydronaphthalene derivatives were obtained via [4 + 2] cycloaddition. That is, the base could influence whether cyclization or macrocyclization occurred. To enhance the practicality of this transformation, this study investigated other reaction parameters. Increasing the reaction temperature to 100 °C gave a superior yield. A further increase to 105 °C led to a slight reduction in the yield. Subsequently, we assessed the effects of different polar solvents. A switch to toluene, chlorobenzene, or dichloromethane was found to be detrimental to the reaction. The result revealed that the optimal reaction conditions were as follows: 1.0 mmol of tetraynes reacted with 1.2 equiv. 1,6-diphenylhexa-1,3,5-triene in MeCN with Cs₂CO₃ at 100 °C for 12 h.

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Temp. (°C)	Base	Yield^b^,^c (3a, %)	Yield^b^,^d (4a, %)
a Unless otherwise noted, 1.0 equiv. (1.0 mmol) of 1a was used. b Yields of the isolated major product after column chromatography. c 1.2 equiv. of 2 was used. d 1.1 equiv. of 2 was used. DBU = 1,8-diazabicyclo[5.4.0]-7-undecene; MeCN = acetonitrile; PhCl = chlorobenzene; DCE = 1,2-dichloroethane.
1	MeCN	95	DBU	—	—
2	MeCN	95	Cs2CO3	63	—
3	MeCN	95	—	—	48
4	MeCN	100	Cs2CO3	71	—
5	MeCN	105	Cs2CO3	67	—
6	Toluene	95	Cs2CO3	—	61
7	PhCl	95	Cs2CO3	—	48
8	DCE	95	Cs2CO3	—	42
9	MeCN	90	—	—	43
10	Toluene	90	—	—	55
11	PhCl	90	—	—	45
12	DCE	90	—	—	38
13	Toluene	100	—	—	68
14	Toluene	110	—	—	62

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With the optimized reaction conditions for macrocyclization in hand, we examined the scope and generality of tetraynes. The structure of the product led us to assume that the steric hindrance between the terminal phenyl group of conjugated alkenes and different esters of tetraynes might influence the transformation. Therefore, we used tetraynes bearing different esters (Me, Et, and nPr) while keeping the aromatic group constant. Various ester-substituted tetraynes were tolerated and the corresponding macrocycles were delivered, albeit with a slight decrease in the yield (3b (70%), 3c (67%), and 3d (65%)). We then explored the scope of aromatic substituents, including electron-donating (Me, Et, and nPr) and electron-withdrawing (F and Cl) ones. Various expected products 3e–3r with different substituents on the aryl ring were readily isolated with good to excellent yields (ranging from 63% to 72%). Compound 3m was isolated with the highest yield (72%) among the examined substrates. The structures of 3c and 3k were confirmed through X-ray diffraction.²⁷ These results demonstrated the potential of the direct functionalization of existing PDDA-derived DHTs with conjugated alkenes for the synthesis of macrocyclic compounds. Moreover, we tested 4-vinylbiphenyl and 1,4-diphenyl-1,3-butadiene. Unfortunately, neither of them yielded the desired product (Table 2).

Table 2 Preparation of macrocyclic compounds 3 ^a,b

a Reaction conditions: tetraynes 1 (1.0 mmol), 1,6-diphenylhexa-1,3,5-triene 2 (1.2 mmol), MeCN (4.0 mL), stirred at 100 °C for 12 h. b Yield of the isolated product after flash column chromatography.

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Next, we explored the reactivity of the [4 + 2] cycloaddition. We hypothesized that the reaction proceeds via the HDDA-derived benzyne intermediate reported by Hoye's group in 2012.²⁸ In the absence of Cs₂CO₃, tetrayne 1a was combined with conjugated alkenes 2 having two phenyls to provide dihydronaphthalene derivatives in MeCN at 90 °C for 12 h (Table 1). No other isomeric by-products, derived from potential side reactions, were detected. We then turned our attention to the investigation of different solvents. Among the solvents tested, including toluene, chlorobenzene, and DCE, toluene proved to be the best choice. All solvents led to the formation of the same skeleton, suggesting that the solvent does not seem to be the major determining factor for this transformation. In separate attempts, increasing the reaction temperature to 100 °C improved the reaction yield. When the temperature was further increased to 110 °C, it led to a decrease in the yield. This decrease might be due to the formation of a large number of HDDA benzynes, which could form oligomeric products.

On the basis of the optimized reaction conditions, the scope of the [4 + 2] cycloaddition reaction was further investigated by constructing nine different dihydronaphthalene derivatives. As shown in Table 3, cycloaddition products 4a–4i were obtained with high yields. Tetrayne substrates bearing different esters were tolerated, providing good yields (4b (77%), 4c (80%), and 4d (70%)). Afterward, the substituted groups in the aryl ring of tetraynes were investigated under the optimized conditions. Regardless of whether electron-donating or electron-withdrawing aromatic substituents were used, the reaction afforded high yields (ranging from 68% to 82%, Table 3). The structure of product 4a was also confirmed by X-ray crystallographic analysis.²⁷

Table 3 Preparation of dihydronaphthalene derivatives 4 ^a,b

a Reaction conditions: tetraynes 1 (1.0 mmol), 1,6-diphenylhexa-1,3,5-triene 2 (1.1 mmol), toluene (4.0 mL), stirred at 100 °C for 12 h. b Yield of the isolated product after flash column chromatography.

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The reaction mechanism for the generation of the α,3-DHT intermediate has been reported by Hoye's group.^21,22a Based on these results and reports from previous work, we propose two plausible mechanistic pathways (Scheme 2). Initially, the inorganic base Cs₂CO₃ promotes the simple alkene-to-allene isomerization of parent tetrayne 1a. Then, it undergoes rapid PDDA cyclization to form particular isomeric DHT(s), including diradical and zwitterion variants.

Scheme 2 Proposed mechanism.

To gain further insights into these mechanistic pathways, we conducted density functional theory (DFT) calculations, and the computational details are shown in the SI. Following the formation of INT1_1 and INT1_3, we evaluated the two plausible pathways for the synthesis of the desired compound 3a (Scheme 3). In path a, zwitterion DHT INT1_1 attacked 1,6-diphenylhexa-1,3,5-triene 2 to form zwitterionic intermediate INT2_1via transition state TS1_1. The energy barrier was computed to be 9.3 kcal mol⁻¹. The high conjugation and delocalization of electrons within the system provided stabilization. Subsequently, INT2_1 underwent an energy-barrier-less process to generate intermediate INT3_1. The final step involved aromatization and gave the final product 3a through an exergonic step via intermediate INT3_1. In path b, the energy barrier for forming TS1_3 from INT1_3 was only 7.9 kcal mol⁻¹, lower than that in path a. However, the calculated energy barrier from INT2_3 through TS2_3 was considerably higher, reaching 55.9 kcal mol⁻¹. Thermodynamically, this transformation of path b was unfavorable.

Scheme 3 DFT based mechanistic study of the macrocyclization of PDDA-derived DHTs INT1_1 and INT1_3 with 1,6-diphenylhexa-1,3,5-triene 2 in MeCN.

Tetraynes are good HDDA substrates. First, elevated temperatures induced cycloisomerization of tetrayne 1a to form a benzyne intermediate. The diester at position X of substrate 1a accelerated the tetrayne cyclization through its electron-withdrawing effect. Meanwhile, 1,6-diphenylhexa-1,3,5-triene A underwent configuration transformation to afford B. Subsequently, the HDDA-derived benzyne engaged in a [4 + 2] cycloaddition through transition state C, furnishing the final product 4a (Scheme 4).

Scheme 4 Proposed mechanism for the [4 + 2] cycloaddition reaction to form product 4a.

In conclusion, we disclose the first synthetic example of macrocyclization by trapping DHT. The use of a strong inorganic base was critical for achieving highly efficient macrocyclization. In comparison with existing methods, this new macrocyclic strategy has many advantages, such as high atom economy, easily accessible raw materials, and no requirement of metal catalysts. The detailed investigation of the reaction mechanism was supported by computational studies through DFT. The macrocyclization process was consistent with the high activation energy computed as it was followed by an energy-barrier-less reaction. Reactions with the same substrates but under varying conditions led to the formation of distinct types of annulation products via different intermediates. Future studies will focus on expanding the alkene substrate scope.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information: all experimental procedures, characterization data (NMR data, high-resolution mass spectra data and FT-IR spectra data), and spectra. See DOI: https://doi.org/10.1039/d5ob01117e.

CCDC 2467460 (3a), 2467462 (3c), 2467461 (3k), 2471518 (3l) and 2391023 (4a) contain the supplementary crystallographic data for this paper.^27a–e

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (22071001) and the Department of Human Resources of Anhui Province.

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