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. 2023 Sep 12;6:194. doi: 10.1038/s42004-023-00999-y

Copper-catalyzed intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles

Can-Ming Chen 1, Ye-Nan Yang 1, Yin-Zhu Kong 1, Bo-Han Zhu 2, Peng-Cheng Qian 1,2,3,✉, Bo Zhou 1, Long-Wu Ye 1,4,✉
PMCID: PMC10497616  PMID: 37700020

Abstract

One-carbon homologation reactions based on one-carbon insertion into the N−O bond of heterocycles have received tremendous interest over the past decades. However, these protocols have to rely on the use of hazardous and not easily accessible diazo compounds as precursors, and examples of the relevant asymmetric catalysis have not been reported. Here we show that a copper-catalyzed intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles involving one-carbon insertion into the heterocyclic N−O bond via non-diazo approach. This method enables practical and atom-economic synthesis of valuable pyrrole-substituted oxadiazines in generally moderate to good yields under mild reaction conditions. In addition, the possibility of such an asymmetric formal (5 + 1) annulation also emerges.

Subject terms: Synthetic chemistry methodology, Stereochemistry, Asymmetric synthesis

One-carbon insertion into N–O bonds is widely exploited in organic synthesis, but synthetic protocols for this rely on hazardous diazo precursors that are difficult to access. Here, copper-catalyzed intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles is shown to facilitate one-carbon insertion into heterocyclic N–O bonds without the need for diazo precursors.

Introduction

Oxadiazines are a class of important heterocyclic compounds, which are widely present in drug molecules and show good activities in anticancer, antiviral, antibacterial and weed control1–14. As a result, the development of efficient methods for synthesis of oxadiazines continues to draw a great deal of interest from the synthetic community. Although a range of methods have been developed for the construction of oxadiazines15–24, only a few reports involved the synthesis of 1,2,5-oxadiazines, which are still challenging to be accessed due to the lack of efficient method.

One-carbon homologation reactions, in which a carbon chain or carbon ring is expanded by a one-carbon unit, have been widely used in complex molecule synthesis25–27. Among various types of ring-expansion reactions, the coupling of cyclic ketones with diazoalkanes, namely the Büchner-Curtius-Schlotterbeck reaction, has been intensively investigated28–30. In 2008, an important breakthrough was achieved in this regard by Davies, who demonstrated an elegant protocol on the rhodium-catalyzed ring expansion of isoxazoles via rhodium carbene intermediates insertion into the N−O bond of isoxazoles (Fig. 1a)31. Since then, a variety of reactions in which single carbon atom is inserted into the N–O bond of heterocyclic compounds have been reported32–35. However, these protocols have to rely on the use of hazardous and not easily accessible diazo compounds as precursors, which severely limit their further synthetic applications and the molecular flexibility. Moreover, to our knowledge, examples of the relevant asymmetric catalysis have not been reported. Thus, it is highly desirable to develop new methods for one-carbon ring expansion, especially those with high flexibility, efficiency, and stereoselectivity.

Fig. 1. Single carbon atom insertion into N–O bond of heterocycles.

Fig. 1

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a Rh-catalyzed formal (5 + 1) annulation of diazo compounds with isoxazoles. b Cu-catalyzed formal (5 + 1) annulation of N-propargyl ynamides with 1,2,5-oxadiazoles.

In the past decade, the chemistry of vinyl cations has received particular attention because of their unique carbene-like reactivity36,37. Recently, our group reported a copper-catalyzed diyne cyclization via vinyl cations as key intermediates, providing a variety of polycyclic pyrrole derivatives38–47. In particular, the related catalytic asymmetric transformations were established via a remote control of enantioselectivity. Inspired by these results and by our recent study of the development of ynamide chemistry for heterocycle synthesis48–65, we envisioned that the vinyl cations generated from copper-catalyzed diyne cyclization might be trapped by 1,2,5-oxadiazoles, eventually leading to valuable 1,2,5-oxadiazines via one-carbon homologation (Fig. 1b). Herein, we describe such a copper-catalyzed one-carbon ring expansion of 1,2,5-oxadiazoles through vinyl cation intermediates generated from N-propargyl ynamides, thus constituting an intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles.

Results and discussion

Screening of reaction conditions

To prohibit the background C–H insertion reaction38, 2,6-dimethylphenyl-substituted N-propargyl ynamide 1a was first chosen as the model substrate to react with 1,2,5-oxadiazole 2a under our previous related reaction conditions38–47, and selected results are listed in Table 1. To our delight, the expected 1,2,5-oxadiazine 3a was indeed formed in 37% yield in the presence of 10 mol % of CuOTf as catalyst (Table 1, entry 1). Subsequent screening of other copper catalysts (Table 1, entries 2–3) revealed that Cu(MeCN)4PF6 was the best catalyst to deliver the desired product 3a in 53% yield (Table 1, entry 3). In addition, the use of other typical solvents such as DCM, CHCl3, PhMe and PhCl led to decreased yields (Table 1, entries 4–7). Of note, the formation of byproducts decreased with the increase of the equiv of 2a, and 5 equiv of 2a was found to be the most appropriate (Table 1, entries 8–9). Gratifyingly, the reaction could be significantly promoted by the addition of 12 mol % of NaBArF4 (Table 1, entry 10), and the yield of the reaction could be further increased to 72% under nitrogen atmosphere (Table 1, entry 11). Of note, it was found that the temperature had very slight impact on the yield of 3a (Table 1, entries 12–13).

Table 1.

Optimizations of reaction conditionsa.

graphic file with name 42004_2023_999_Taba_HTML.gif
Entry Catalyst Reaction conditions Yield (%)b
1 CuOTf DCE, 40 °C,6 h 37
2 Cu(MeCN)4BF4 DCE, 40 °C, 6 h 41
3 Cu(MeCN)4PF6 DCE, 40 °C, 6 h 53
4 Cu(MeCN)4PF6 DCM, 40 °C, 6 h 52
5 Cu(MeCN)4PF6 CHCl3, 40 °C, 10 h 30
6 Cu(MeCN)4PF6 PhMe, 40 °C, 10 h 28
7 Cu(MeCN)4PF6 PhCl, 40 °C, 9 h 47
8c Cu(MeCN)4PF6 DCE, 40 °C, 6 h 38
9d Cu(MeCN)4PF6 DCE, 40 °C, 6 h 52
10e Cu(MeCN)4PF6 DCE, 40 °C, 4 h 68
11e Cu(MeCN)4PF6 DCE, 40 °C, N2, 4 h 72
12e Cu(MeCN)4PF6 DCE, 20 °C, N2, 12 h 71
13e Cu(MeCN)4PF6 DCE, 60 °C, N2, 2 h 70
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aReaction conditions: 1a (0.05 mmol), 2a (2–10 equiv), catalyst (0.005 mmol), solvents (1 mL), 40–60 °C, 2–12 h, in vials.

bMeasured by 1H NMR using 1,3,5-trimethoxybenzene as internal reference.

c2 equiv of 2a was used.

d10 equiv of 2a was used.

e12 mol % of NaBArF4 was added.

Ns = 4-nitrobenzenesulfonyl.

Reaction scope study

With the optimized reaction conditions in hand (Table 1, entry 11), the scope of this copper-catalyzed formal (5 + 1) annulation was explored. As depicted in Fig. 2, in general, ynamides with different N-protecting groups, such as Ns, Ts, Bs and MBS groups, could proceed smoothly to provide the corresponding 1,2,5-oxadiazines 3a–3d in 61–72% yields (see Supplementary Data 1, 2). In addition, various aryl-substituted ynamides (R1 = Ar) bearing both electron-donating and -withdrawing groups on the aromatic ring were tolerated for this reaction, leading to the expected products 3e–3i in 64–76% yields. Moreover, the reaction occurred efficiently for a variety of aryl-substituted N-propargyl ynamides (R2 = Ar), producing the target oxadiazines 3j–3o in 55–84% yields. Interestingly, 2-thienyl-substituted and alkenyl-substituted ynamides were also suitable substrates to deliver the desired products 3p (78%) and 3q (57%), respectively. Of note, 2-methylphenyl-substituted N-propargyl ynamide 1r was also tolerated to afford the expected 3r in 61% yield while the use of phenyl-substituted N-propargyl ynamide 1 s only led to complicated mixtures. Moreover, the cyclopropyl-substituted ynamide could also be smoothly converted into the expected product 3t in 51% yield. Particularly, this formal (5 + 1) annulation was also extended to other aryl-substituted 1,2,5-oxadiazoles, allowing the formation of the corresponding products 3u–3 v in 62–73% yields. Finally, the methyl-substituted 1,2,5-oxadiazole was tolerated in this reaction, and the expected product 3w was formed in 56% yield. The structure of product 3a was further confirmed by X-ray diffraction analysis (Fig. 3). Thus, this protocol provides a unique way for rapid and efficient assembly of 1,2,5-oxadiazine derivatives, which are not readily accessible by known methods. It is notable that the use of the alkyl-substituted ynamide 1 y (R2 = alkyl) as substrate and the relevant thiadiazole and triazole as nucleophiles only led to complicated mixtures under the optimal and related conditions.

Fig. 2. Reaction scope study.

Fig. 2

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Copper-catalyzed synthesis of oxadiazines 3. Reaction conditions: 1 (0.1 mmol), 2 (0.5 mmol), Cu(MeCN)4PF6 (10 mol %), NaBArF4 (12 mol %), DCE (2 mL), 40 °C, N2, 3–12 h, in Schlenk tubes; yields are those for the isolated products.

Fig. 3. Crystal structure.

Fig. 3

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Structure of compound 3a in its crystal form. Thermal ellipsoids are shown at 50% probability.

Inspired by the above results, we then explored the chiral copper-catalyzed asymmetric formal (5 + 1) annulation. Although direct asymmetric catalysis based on the reaction of N-propargyl ynamide 1a and 1,2,5-oxadiazole 2a failed to give promising enantioselectivity (<20% ee), the use of the steric group-substituted N-propargyl ynamide 1x as substrate could lead to moderate enantioselectivity bases on our recent study on the chiral copper-catalyzed atroposelective diyne cyclization45. As depicted in Fig. 4, we were pleased to find that the use of bisoxazoline (BOX) ligand L* as the chiral ligand resulted in the formation of the desired chiral oxadiazine 3x in 57% yield and 4:1 d.r. with 60% ee.

Fig. 4. Asymmetric copper-catalyzed formal (5 + 1) annulation.

Fig. 4

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Chiral oxadiazine 3x was obtained in 57% yield with 60% ee.

Synthetic applications

To further demonstrate the utility of this annulation reaction, we carried out several synthetic transformations of the pyrrole-substituted oxadiazine 3a, as illustrated in Fig. 5. First, the preparative-scale reaction of ynamide 1a was conducted under the standard conditions, and the desired product 3a was formed in 72% yield. In addition, the Ns group of 3a could be readily removed to deliver product 4a in 77% yield. Interestingly, the treatment of 4a with 5 equiv of KOH led to the formation of the corresponding N-oxide compound 5a in 95% yield via a ring contraction way.

Fig. 5. Preparative-scale reaction and product elaboration.

Fig. 5

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a Preparative-scale reaction of 1a. b Transformation of 3a into 4a and 5a.

Plausible reaction mechanism

On the basis of the above experimental results and our previous study on the copper-catalyzed cyclization of N-propargyl ynamides38–47, a plausible reaction mechanism to rationalize the formation of pyrrole-substituted oxadiazine 3a is shown in Fig. 6. First, catalytic Cu(I) species coordinate with the electron-richer amide-tethered C–C triple bond of ynamide 1a, generating the precursor A, which subsequently undergoes nucleophilic attack by another C−C triple bond to produce the key vinyl cation intermediate B. Then, the vinyl cation is trapped by oxadiazole 2a, providing intermediate C. Next, ring-opening of oxadiazole, followed by 6π electrocyclization, leads to donor/donor copper carbene intermediate E. Finally, intermediate E undergoes [1,4]-H shift and demetallation to furnish the corresponding product 3a. On the other hand, by using chiral copper catalyst, chiral product 3x can be obtained via asymmetric atroposelective cyclization through a remote control of enantioselectivity.

Fig. 6. Mechanistic hypothesis.

Fig. 6

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Plausible catalytic cycle.

Conclusions

In summary, we have disclosed a copper-catalyzed intermolecular formal (5 + 1) annulation of 1,5-diynes with 1,2,5-oxadiazoles, allowing the practical and atom-economic synthesis of valuable 1,2,5-oxadiazine derivatives in generally moderate to good yields under mild reaction conditions. This reaction is realized by inserting vinyl cations formed through 1,5-diyne cyclization into the N–O bond of 1,2,5-oxadiazoles. In addition, the possibility of such an asymmetric formal (5 + 1) annulation also emerges. Importantly, the protocol achieves one-carbon ring expansion of 1,2,5-oxadiazoles base on vinyl cations, and provides a rare approach to 1,2,5-oxadiazines. Further application of this type of copper-catalyzed one-carbon homologation will be pursued in our laboratory.

Methods

Materials

Unless otherwise noted, materials were obtained commercially and used without further purification. All the solvents were treated according to general methods. Flash column chromatography was performed over silica gel (300–400 mesh). See Supplementary Methods for experimental details.

General methods

1H NMR spectra and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer in chloroform-d3. For 1H NMR spectra, chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. For 13C NMR spectra, chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. Infrared spectra were recorded on a Nicolet AVATER FTIR330 spectrometer as thin film and are reported in reciprocal centimeter (cm−1). Mass spectra were recorded with Micromass QTOF2 Quadrupole/Time-of-Flight Tandem mass spectrometer using electron spray ionization. 1H NMR, 13C NMR spectra and HPLC spectra are supplied for all compounds: see Supplementary Information. See Supplementary Methods for the characterization data of compounds not listed in this part.

General procedure for the synthesis of 1,2,5-oxadiazines 3

1,2,5-oxadiazole 2 (0.5 mmol), NaBArF4 (0.012 mmol, 2.7 mg), and Cu(MeCN)4PF6 (0.01 mmol, 3.7 mg) were added in this order to the N-propargyl ynamide 1 (0.1 mmol) in DCE (2 mL) at room temperature. The reaction mixture was stirred at 40 °C and the progress of the reaction was monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (dichloromethane/hexane) to afford the desired product 3.

Supplementary information

Supporting Information (984.3KB, pdf)
42004_2023_999_MOESM2_ESM.pdf (70.8KB, pdf)

Description of additional supplementary file

Supplementary Data 1 (2.4MB, pdf)
Supplementary Data 2 (517.4KB, cif)

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (22125108 and 92056104), the President Research Funds from Xiamen University (20720210002), and NFFTBS (J1310024). We thank Mr. Zanbin Wei from Xiamen University (College of Chemistry and Chemical Engineering) for assistance with X-ray crystallographic analysis.

Author contributions

C.-M.C., Y.-N.Y., Y.-Z.K., B.-H.Z., and B.Z. performed experiments. L.-W.Y. and P.-C.Q conceived and directed the project and wrote the paper. All authors discussed the results and commented on the manuscript.

Peer review

Peer review information

Communications Chemistry thanks Thierry Ollevier and the other anonymous reviewers for their contribution to the peer review of this work.

Data availability

Data for the crystal structure reported in this paper has been deposited at the Cambridge Crystallographic Data Centre (CCDC) under the deposition number CCDC 2268060 (3a). Copies of these data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other data supporting the findings of this study, including experimental procedures and compound characterization, are available within the paper and its Supplementary Data 1, 2, or from the corresponding authors on request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Peng-Cheng Qian, Email: qpc@wzu.edu.cn.

Long-Wu Ye, Email: longwuye@xmu.edu.cn.

Supplementary information

The online version contains supplementary material available at 10.1038/s42004-023-00999-y.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information (984.3KB, pdf)
42004_2023_999_MOESM2_ESM.pdf (70.8KB, pdf)

Description of additional supplementary file

Supplementary Data 1 (2.4MB, pdf)
Supplementary Data 2 (517.4KB, cif)

Data Availability Statement

Data for the crystal structure reported in this paper has been deposited at the Cambridge Crystallographic Data Centre (CCDC) under the deposition number CCDC 2268060 (3a). Copies of these data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other data supporting the findings of this study, including experimental procedures and compound characterization, are available within the paper and its Supplementary Data 1, 2, or from the corresponding authors on request.

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