Microwave-assisted [3 + 2] cycloaddition reactions of dicyanoepoxides with benzylidene Meldrum's acids

Abstract

The [3 + 2] cycloaddition of dicyanoepoxides with benzylidene Meldrum's acid under microwave irradiation and solvent-free conditions was explored for the synthesis of trioxaspirodecanes. This method presents a highly diastereo- and regioselective route to spiro cycloadducts, delivering similar stereoselectivity to conventional reflux in toluene but with shorter reaction times and improved yields.

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Introduction

The development of 1,3-dipolar reagents in [3 + 2] cycloaddition reactions is integral for the synthesis of new organic structures containing five-membered heterocycles.¹ Carbonyl ylides are among the most important 1,3-dipolar species used in the synthesis of complex compounds and are typically formed through the C–C bond heterolysis of oxiranes.² For the preparation of these ylides, a variety of reactive oxiranes, such as oxiranyl diketones, oxiranyl dicarboxylates, glycidic esters, and dicyanoepoxides, are utilized in various transformations due to their ability to undergo easy C–C bond cleavage.³

The ring-opening reaction of activated epoxides by various nucleophiles through C–O bond cleavage has been extensively studied.⁴ However, the exploration of 1,3-dipolar cycloaddition of these compounds via C–C bond cleavage in the epoxide ring (rather than C–O bond cleavage) remains challenging.⁵ For example, dicyanoepoxides have received limited attention, with only a few reports on their cycloaddition reactions, such as 1,3-dipolar cycloaddition with aldehydes, ketones, imines, and acetylenes. Therefore, further investigation into the cycloaddition behavior of dicyanoepoxides could yield valuable insights.⁶ Several methods for preparing carbonyl ylides have been proposed, including the photochemical or thermal C–C bond cleavage of oxiranes, transition metal-catalyzed decomposition of diazo compounds, thermal decomposition of oxadiazolines, and generation of iodomethyl silyl ethers with samarium.⁷ Among these, thermal C–C bond cleavage of oxiranes is the most direct and atom-economical. However, developing eco-friendly and milder methods to improve efficiency is essential. Recently, selective and efficient catalysts, such as Lewis acids and metal complexes, have been developed for [3 + 2] cycloadditions of carbonyl ylides.⁸ While Lewis acids enable milder conditions, creating a straightforward and cost-effective synthetic process remains valuable.

Microwave irradiation has gained attention as an efficient energy source for organic synthesis due to its ability to accelerate reactions with fast heating, short reaction times, and cleaner processes, making it a green, solvent-free method.^9,10 It has been widely applied to 1,3-dipolar cycloadditions, effectively promoting the in situ generation of 1,3-dipoles for subsequent reactions.¹¹ Ababsa et al. demonstrated that the diastereoselective synthesis of oxazolidines through the [3 + 2] cycloaddition of carbonyl ylides from dicyanoepoxides with imines has significantly reduced the reaction times when microwave irradiation was applied.^6b They also used this method to synthesize spirocyclic dioxolane indolinones with short reaction times and high regioselectivity (Scheme 1).^6c

Scheme 1 [3 + 2] cycloaddition reactions of dicyanoepoxides. Previous works (a and b). This work (c).

Herein, we report a microwave-assisted cycloaddition reaction of in situ-generated carbonyl ylides derived from dicyanoepoxides with benzylidene Meldrum's acids. This method facilitates the synthesis of a novel class of highly functionalized tetrahydrofurans, which are known for their significant bioactivity and presence in numerous natural products (Fig. 1).¹²

Fig. 1 Examples of biologically active highly substituted tetrahydrofurans.

Results and discussion

The desired precursors, benzylidene Meldrum's acids (1a–h) and dicyanoepoxides (2a–i), were prepared using previously reported procedures in the literature.^4f,6b,6c,13 Based on previous reports on the thermal cycloaddition of dicyanoepoxides, 3-(4-chlorophenyl)oxirane-2,2-dicarbonitrile (1b) and 4-methoxybenzylidene Meldrum's acid (2b) (1 molar equiv.) were initially treated in toluene under reflux to obtain trioxaspiro[4.5]decane (3bb). The reaction was monitored by TLC and completed after 30 hours (Table 1, entry 1). The final product was isolated as a mixture of two diastereomers in 59% yield with a 90/10 diastereomeric ratio, which was consistent with the results from the ¹HNMR data of the crude reaction mixture. Surprisingly, unlike previous reports on diastereoselectivity in dicyanoepoxide cycloadditions, the major stereoisomer in this transformation was found to be trans. The NOESY experiment revealed no correlation between H1 (singlet at 6.1) and H4 (singlet at 4.8) for the major product, but a strong correlation between these hydrogens was observed for the minor product (singlets at 5.8 and 5.1). The structure and stereochemistry of the major product were established by X-ray crystallography analysis of 3bb (Fig. 2).

Fig. 2 X-ray crystallography analysis of the major stereoisomer of 3bb.

Table 1 Screening of the reaction parameters for the cycloaddition of dicyanoepoxides with benzylidene Meldrum's acids

Entry	Conditions	trans/cis ratio^a	Yield^b
The reaction was carried out using 0.10 mmol of 1b and 2b.a The diastereomeric ratios were calculated using the ^1H NMR spectrum of the crude reaction mixture.b Isolated yields.
1	Toluene, reflux, 30 h	90/10	59%
2	Xylene, 110 °C, 30 h	55/45	28%
3	Mesitylene, 110 °C, 30 h	57/43	15%
4	DCE, reflux, 30 h	—	—
5	Dioxane, reflux, 30 h	60/40	12%
6	DMF, 110 °C, 30 h	—	—
7	Toluene, InCl3 (10% mol), reflux, 30 h	91/9	63%
8	MW, 30w, 110 °C, 120 min	88/12	74%
9	MW, 45w, 110 °C, 120 min	82/18	74%
10	MW, 60w, 110 °C, 120 min	80/20	72%
11	MW, 90w, 110 °C, 120 min	75/25	73%
12	MW, 30w, 120 °C, 120 min	82/18	74%
13	MW, 30w, 100 °C, 120 min	87/13	68%
14	MW, 30w, 110 °C, 135 min	88/12	74%
15	MW, 30w, 110 °C, 105 min	87/13	58%
16	MW, 30w, 110 °C, 120 min, (1.25 equiv. of 1b)	88/12	79%
17	MW, 30w, 110 °C, 120 min, (1.5 equiv. of 1b)	88/12	86%
18	MW, 30w, 110 °C, 120 min, (1.75 equiv. of 1b)	86/14	84%

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We conducted several experiments by varying the reaction conditions. Toluene proved to be the best solvent for this cycloaddition (Table 1, entries 2–6). Using indium chloride as an efficient Lewis acid for cycloaddition reactions resulted in a slight increase in yield and diastereoselectivity (Table 1, entry 7). To reduce the reaction time, several reactions were carried out under microwave irradiation under various conditions, including power, reaction time, equimolar ratios of starting materials, and reaction temperature (Table 1, entries 8–18). The product 3bb was obtained by conducting the reaction in a microwave without solvent at 30 W power in only 2 hours, yielding 74%. The diastereomeric ratio was almost the same as that of the conventional procedure (trans/cis = 88/12 based on the ¹H NMR of the crude product) (Table 1, entry 8). Increasing the power resulted in a decrease in the diastereomeric ratio (Table 1, entries 9–11). Additionally, screening the model reaction at different temperatures revealed that the best reaction yield was obtained at 110 °C (Table 1, entries 12 and 13). While increasing the reaction time to 135 minutes did not positively impact the reaction yield, decreasing it to 105 minutes reduced the yield to 58% (Table 1, entries 14 and 15). Finally, as depicted in entries 16–18 of Table 1, we found that 1.5 equivalents of dicyanoepoxide 1b was the optimal amount for this transformation (86% yield for the product), while both higher and lower quantities were ineffective.

Inspired by the above findings and using the optimal reaction conditions, we explored the substrate scope of the [3 + 2] cycloaddition of dicyanoepoxides with benzylidene Meldrum's acids under microwave irradiation for the synthesis of different derivatives of trioxaspirodecane (Scheme 2). A wide variety of starting materials containing different electron-withdrawing/-donating and bulky substituents on the aromatic rings were employed to produce the desired products in good to excellent yields and diastereoselectivities (54–91% yield and 70/30–94/6 diastereomeric ratios). The highest yield was obtained when chloro and bromo substituents were used on the aromatic rings (3bc, Scheme 2). The highest selectivity was achieved when 3-phenyloxirane-2,2-dicarbonitrile and indolidene Meldrum's acid were used, resulting in a 93/7 diastereomeric ratio (3ah, Scheme 2). When starting materials containing electron-withdrawing nitro groups or bulky naphthyl groups were employed in this transformation, lower yields were observed. Furthermore, the diastereoselectivity was lowered when electron donating groups on both starting materials were used (3ee, Scheme 2).

Scheme 2 Substrate scope. Conditions: 1 (0.30 mmol), 2 (0.20 mmol), microwave irradiation – 30 W, neat, at 110 °C for 120 min. ^a Isolated yield. ^b The diastereomeric ratio was assessed by ¹H NMR spectroscopy of the crude reaction mixture. ^c For comprehensive comparison between the microwave and the conventional procedure, see Table S2 in the ESI.†

Additionally, when allylidene Meldrum's acid was used as the starting material, only the five-membered ring product of the [3 + 2] cycloaddition was obtained, and the product resulting from the [4 + 3] cycloaddition reaction was not observed. The structure of this product was confirmed by X-ray crystallography (Scheme 2, 3ai). Additionally, to assess the scalability of the presented synthetic method, we performed a gram-scale synthesis of 3bb, resulting in a 78% yield (Scheme 3).

Scheme 3 Gram-scale synthesis of 3bb.

A plausible mechanism suggesting the [3 + 2] cycloaddition reaction of dicyanoepoxides is depicted in Scheme 4. The cycloaddition of dicyanoepoxides with benzylidene Meldrum's acids proceeds through a sequential two-step process. Initially, the thermal ring opening of compound A generates the carbonyl ylide intermediate Bvia C–C bond cleavage. Subsequently, the in situ generated intermediate B undergoes a [3 + 2] cycloaddition with benzylidene Meldrum's acid (C), leading to the diastereoselective formation of a spirocyclic compound D.

Scheme 4 Plausible mechanism for the cycloaddition reaction of dicyanoepoxides with benzylidene Meldrum's acids.

The possible transition state E for the favored product is likely formed with aryl groups adopting a trans configuration to minimize the energy content, which aligns with the typical pattern observed in five-membered saturated ring compounds.

To explore the synthetic applicability of the presented approach, a transesterification reaction of 3bb was carried out in the presence of methanol under acidic conditions, affording the corresponding product 4 in a 67% yield (Scheme 5).

Scheme 5 Post-reaction of compound 3bb.

Conclusion

In conclusion, we have presented a highly stereoselective approach for the synthesis of trioxaspirodecane derivatives through a [3 + 2] cycloaddition reaction of carbonyl ylides generated from dicyanoepoxides and benzylidene Meldrum's acids under microwave irradiation in a solvent-free environment. This method offers an effective means for the innovative construction of trioxaspirodecane motifs, with several advantages over classical heating in toluene under reflux conditions, including higher product yields (up to 91%), shorter reaction times (2 hours), and cleaner reactions.

Experimental

General considerations

All materials were purchased from Merck, Aldrich, and Fluka and used as received. Melting points were measured using an Electrothermal 9100 apparatus and were uncorrected. The ¹HNMR (600 MHz) and ¹³CNMR (151 MHz) spectra were run on a Bruker spectrometer using CDCl₃ and DMSO-d₆ as the solvents and Me₄Si (TMS) as the internal standard at 298 K. The chemical shifts (δ) were reported in parts per million (ppm) and coupling constants (J) were given in Hz. High-resolution mass spectra (HRMS) were recorded on an Agilent HRMS-ESI/QTOF instrument. Single crystals of 3ai and 3bb were mounted on a MiTeGen loop with grease and examined using a Bruker D8 Venture APEX diffractometer equipped with a Photon 100 CCD area detector at 296(2) K using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The structures of 3ai and 3bb have been deposited at the CCDC (CCDC deposition number for 3ai is 2390548 and that for 3bb is 2390547†).

General procedure for the preparation of the final products

Classical heating. A pressure vessel was charged with a stir bar, the corresponding alkylidene meldrum's acids (0.1 mmol, 1 equiv.), dicyanoepoxides (0.15 mmol, 1.5 equiv.) and 2 ml of toluene. The mixture was allowed to stir for 32 hours at reflux. After that, the solvent was evaporated and the residue was purified by column chromatography (n-hexane/ethyl acetate – 100 : 0 → 80 : 20).

Microwave irradiation. A microwave vial was charged with a stir bar, the corresponding alkylidene meldrum's acids (0.1 mmol, 1 equiv.) and dicyanoepoxides (0.15 mmol, 1.5 equiv.). Then, the mixture was heated to 110° C using 20 W power and allowed to stir for 120 minutes under the same conditions. After that, the residue was purified by column chromatography (n-hexane/ethyl acetate – 100 : 0 → 80 : 20).

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

Financial support from the Sultanate of Oman Research Council (TRC) (grant no. BFP/RGP/CBS/23/105) and the University of Nizwa is gratefully acknowledged.

References

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2390547 and 2390548. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4ob01702a

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