Copper-catalyzed crosscoupling of vinyl nitrenes and CF₃-carbenes to synthesize CF₃-2-azadienes

Abstract

A unique and efficient copper catalytic system has been established to synthesize fluorinated 2-azadienes from isoxazoles and CF₃-N-tosylhydrazones via crosscoupling reactions of vinyl nitrenes with CF₃-carbenes. A proposed reaction pathway involves the tandem cleavage of N–O/C–N bonds and formation of a C–N double bond. The developed method features a broad substrate scope, easy handling, step economy, and well-defined regio- and stereoselectivities.

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Introduction

The eternal pursuit of organic chemists is the construction of aggregated functional molecules from simple and easily available substrates with high chemo- and regioselectivities.¹ The past few decades have witnessed remarkable progress in reactions involving reactive species such as carbenes and nitrenes to design key skeletons owing to well-established catalytic systems based on transition metals.² Notably, while carbenes and nitrenes are employed to participate in various unique and efficient transformations, including C–X bond (X = H, N, O, etc.) insertions,³ ylide formations,⁴ and cycloadditions,⁵ they are prone to undergo homocoupling reactions yielding undesired products (Fig. 1A).⁶ Although several researchers have applied this homocoupling strategy to prepare highly functionalized alkenes,⁷ crosscoupling reactions of carbenes with nitrenes have received limited exploration, perhaps due to chemo- and regioselective issues of these highly reactive species.⁸ We have envisioned that suitable precursors might be essential for realizing such nonhomocoupling reactions of carbenes with nitrenes.

Fig. 1 Reactions involving coupling of carbene and nitrene precursors.

Inspired by recent works of Wang and Bi and spurred on by our previous results, we have developed interest in α-fluoroalkyl-N-tosylhydrazones. This interest is also driven by the balance between the reactivity and stability of their carbene precursors, attributed to the unique effect of the fluoride group.⁹ Furthermore, employing α-CF₃-N-tosylhydrazones as carbene precursors offers the possibility of not only coupling them with nitrenes but also introducing CF₃ groups into molecules, which are difficult to achieve using other available methods.¹⁰ Conversely, several representative nitrene precursors, such as azides,¹¹ arylsulfonyl hydroxylamines,¹² amines,¹³ and nitro compounds,¹⁴ take part in amination reactions through denitrogenation, α-elimination, oxidation, and deoxygenation reduction processes. For instance, the Chiba and Jiao groups employed vinyl azides as vinyl nitrene precursors to synthesize aza-heterocycles and N-containing molecules.¹⁵ Despite these achievements, many of these reactions involve toxic substances, harsh reaction conditions, and high potential risk of explosion.¹⁶ In our continuing interest in 2H-azirine and isoxazole chemistry,¹⁷ we envisioned that isoxazoles, as easily available and bench-stable heterocycles, could be used as vinyl nitrene precursors to react with α-CF₃-N-tosylhydrazones through the tandem cleavage of N–O/C–N bonds and formation of a C–N double bond (Fig. 1B).¹⁸ Herein, we disclose a unique and efficient copper catalytic system for synthesizing fluorinated 2-azadienes from isoxazoles and CF₃-N-tosylhydrazones via crosscoupling reactions of fluoroalkyl carbenes with vinyl nitrenes (Fig. 1C). Notably, CF₃-2-azadienes are key skeletons that can not only be applied in diverse organic transformations, including nucleophilic addition, aziridination, and aza-Diels–Alder cyclization reactions,¹⁹ but also be potentially applied in biological and materials science.²⁰

Results and discussion

We employed isoxazole 1a and CF₃-N-tosylhydrazone 2a as model substrates to synthesize fluorinated aza-containing molecules (Table 1). Initially, various copper catalysts were screened with K₂CO₃ as the base in toluene at 90 °C; the results showed copper catalyst to be essential for this transformation, and Cu(I) and Cu(II) performed well at generating 1-CF₃-2-aza-1,3-diene 3aa with yields of 29%–57% (Table 1, entries 1–8). NMR spectroscopy and single-crystal X-ray data were collected to determine the structure and geometry of 3aa (CCDC 2246278†). As CuCl₂ worked more efficiently than other catalysts, various solvents were investigated in the presence of CuCl₂ and K₂CO₃ (Table 1, entries 9–13). This investigation revealed that aromatic solvents such as xylene and PhCF₃ were more compatible with this reaction than DCM, THF, and hexane. PhCF₃ stood out with a high product yield of 68% occurring in its presence (Table 1, entry 13). To our delight, modifying the reaction temperature to 110 °C further significantly increased the reaction yield to 82% (Table 1, entries 14–16). Examination of other bases, however, failed to improve the reaction efficiency (Table 1, entries 17–20), causing retention of the starting material in the absence of the base (Table 1, entry 20).

Table 1 Comparison of the reaction conditions for copper-catalyzed ring opening of isoxazoles^a

Entry	Catalyst	Solvent	Base	Temp. (^°C)	Yield^b (%)
a Unless otherwise specified, the reactions were performed using 1a (0.20 mmol), 2a (0.40 mmol), copper catalyst (10 mol%), base (2.5 equiv.), and solvent (2.0 mL) at 110 °C in a sealed tube until 1a was consumed completely according to thin later chromatography analysis. b Isolated yield. Tol. = toluene, Hex. = hexane.
1	CuCl	Tol.	K2CO3	90	45
2	CuBr	Tol.	K2CO3	90	50
3	CuI	Tol.	K2CO3	90	33
4	Cu(OAc)2	Tol.	K2CO3	90	29
5	Cu(acac)2	Tol.	K2CO3	90	44
6	Cu(OTf)2	Tol.	K2CO3	90	29
7	CuBr2	Tol.	K2CO3	90	54
8	CuCl2	Tol.	K2CO3	90	57
9	CuCl2	DCM	K2CO3	90	37
10	CuCl2	THF	K2CO3	90	0
11	CuCl2	Hex.	K2CO3	90	16
12	CuCl2	Xylene	K2CO3	90	56
13	CuCl2	PhCF3	K2CO3	90	68
14	CuCl2	PhCF3	K2CO3	80	40
15	CuCl2	PhCF3	K2CO3	100	74
16	CuCl 2	PhCF 3	K 2 CO 3	110	82
17	CuCl2	PhCF3	Na2CO3	110	41
18	CuCl2	PhCF3	Cs2CO3	110	30
19	CuCl2	PhCF3	^tBuOK	110	25
20	CuCl2	PhCF3	—	110	0

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With the established catalytic system in hand, we then investigated the reaction substrate scope, specifically testing various substituted 5-methoxyl-isoxazoles 1 and CF₃-N-tosylhydrazones 2 (Table 2). At the outset, diverse functional isoxazoles 1 were examined (Table 2-A). The results showed that reactions with these substrates proceeded smoothly under the standard reaction conditions to afford 2-aza-1,3-dienes in moderate-to-good yields. Aryl-substituted isoxazoles with different alkyl groups inserted into the aromatic ring all worked well, generating desired product yields of 63%–82% (3aa–3ea); a phenyl-substituted substrate also reacted to afford the corresponding product, but in a lower yield (3fa, 50%). Subsequently, we investigated electronic effects by examining various substituted isoxazoles including electron-donating (–OMe and –OPh) and electron-withdrawing (–CF₃) substituents. Electron-rich substrates generally gave higher yields (3ga–3ia, 53%–81%) than electron-poor ones (3ja, 55%). Aromatic-substituted isoxazoles bearing halides (–F, –Cl, –Br, and –I) were quite compatible with this modular catalytic system and delivered the corresponding fluorinated azadienes in moderate-to-good yields (3ka–3na, 54%–72%). Notably, these halogenic functionalities are widely employed in transition-metal-catalyzed coupling reactions.²¹ Herein, naphthyl-substituted isoxazole 1o also worked well and afforded a product with 73% yield (3oa). Additionally, the furyl and thienyl heterocyclic groups survived this mild reaction system and offered the corresponding 2-aza-1,3-dienes in 75% and 77% yields, respectively (3pa and 3qa). Alkyl-substituted isoxazoles including bulky, cyclic, and linear groups also reacted smoothly and provided desired products with yields of 54%–70% (3ra–3ta). Notably, E and Z isomers of the C–C double bonds were isolated, indicating the loss of the steric effect (see ESI†). Subsequently, the scope of the CF₃-N-tosylhydrazones 2 substrate was investigated under the same catalytic conditions (Table 2-B). Various aromatic rings with alkyl-substituted CF₃-N-tosylhydrazones reacted efficiently with isoxazole 1a, yielding the construction of fluorinated 2-azadienes in moderate-to-good yields (3ab–3ad). Substituted CF₃-N-tosylhydrazones with electron-rich and electron-poor groups performed well, though the tested electron-poor substituted N-tosylhydrazone gave a lower yield (3ag, 31%) than electron-rich functionalities (3ae and 3af). Reactions with halogenic substitutions (–F, –Cl, and –Br) at different positions on the aryl ring proceeded smoothly under standard conditions, although with quite different yields (3ah–3ak). Furthermore, naphthyl and thienyl substrates afforded the corresponding azadiene products in 63% and 53% yields, respectively (3al–3am). Finally, methyl-substituted N-tosylhydrazone 2an also reacted smoothly and provided the desired product, albeit in a relatively low yield (3an, 45%).

Table 2 Isoxazole and CF₃-N-tosylhydrazone substrate scopes for copper-catalyzed ring opening^a,b

a Conditions: 1 (0.20 mmol), 2 (0.40 mmol), CuCl₂ (10 mol%), and K₂CO₃ (2.5 equiv.) were mixed in PhCF₃ (2.0 mL) under an argon atmosphere and stirred until the starting material 1 was consumed completely. b Isolated yields.

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Several control experiments were conducted to derive possible reaction mechanisms (Scheme 1). Initially, isoxazole 1a was deployed under the standard reaction conditions in the absence of trifluoromethyl N-tosylhydrazone 2a to produce carboxylic 2H-azirine 1a′ in 90% yield (Scheme 1A-1). This result prompted us to further study whether the 2H-azirine 1a′ is the key intermediate of the catalytic cycle. We found that the copper catalyst is essential to the ring contraction of isoxazole 1a to 2H-azirine 1a′ even without the base (Scheme 1A-2 and A-3). Notably, the reaction of 1a′ with 2a under standard reaction conditions generated corresponding CF₃-2-azadiene 3aa, albeit in a relatively low yield (48%). Based on these obtained results, a plausible mechanism is proposed taking a model reaction as an example. Initially, the isoxazole 1a ring contracts to 2H-azirine A, following previous mechanism-study results, with cleavage of one of the C–N bonds of A, further generating vinyl nitrene B. Conversely, the conversion of CF₃-N-tosylhydrazone 2a to fluoroalkyl carbene C under an external heating source was promoted by K₂CO₃, with carbene C then directly getting converted into carbenoid D with copper catalyst.²² We envisioned that there might be two possible pathways here. For path-I, coupling of the free nitrene of B with carbenoid D generates copper complex E, with this intermediate E releasing the copper catalyst and isomerizing to give the corresponding azadiene 3aa. In path-II, carbene complex D is directly attacked by the nitrogen lone pair of 2H-azirine A to provide copper counterion intermediate F,²³ with 3aa then obtained as a result of a C–N bond cleavage in the small ring.

Scheme 1 Control experiments and proposed pathways.

Notably, we were able to extend this method to a scale of 10 mmol for 1a in the standard catalytic system, here delivering the corresponding azadiene 3aa in 61% yield (2.03 g) (Scheme 2-I). Late-stage functionalization of fluorinated azadiene 3aa was then investigated. For instance, 3aa was easily brominated under mild conditions via reaction with N-bromo succinimide in dimethyl sulfoxide, and this reaction provided 4-bromo-2-aza-1,3-diene 4aa in 67% yield (Scheme 2-II).²⁴ Addition of the nucleophile methanol to the very active C–N double bond of 2-aza-1,3-diene 3aa provided 5aa in 72% yield under basic conditions (Scheme 2-III).²⁵ Conversely, the C–C double bond of 3aa smoothly to afford epoxide 6aa with retention of the C–N double bond; here, 6aa was afforded in only moderate yield (Scheme 2-IV).²⁶ Furthermore, by employing NaBH₄, the C–N double bond of azadiene 3aa was chemoselectively reduced to generate fluorinated enamine 7aa in 85% yield (Scheme 2-V).²⁷ These obtained results showed the potential for application of the designed strategy in industry and academic areas.

Scheme 2 Late-stage modifications of CF₃-2-azadienes.

Conclusions

A straightforward and efficient method for synthesizing CF₃-substituted 2-azadienes was described. The reaction transformation was concluded to proceed through the tandem cleavage of N–O/C–N bonds and formation of a C–N double bond in the presence of a copper catalyst with well-defined regio- and stereoselectivities. This unique strategy can be accomplished using an easy-handling procedure and mild catalytic system that has tolerance to diverse functionalities.

Author contributions

Y. Jiao and T. Wu contributed equally to this work. Y. Jiao, T. Wu and X. Zhang performed the experiments. Y. Jiang conceived and directed the project and wrote the manuscript. All authors discussed the results.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors gratefully acknowledge the funding received from the National Natural Science Foundation of China (21971112 and 22361010) and the Starting Funding of Research from Guizhou University.

References

1. (a) X. Zhu and S. Chiba, Copper-catalyzed Oxidative Carbon–Heteroatom Bond Formation: A Recent Update, Chem. Soc. Rev., 2016, 45, 4504–4523; (b) R. Blieck, M. Taillefer and F. Monnier, Metal-Catalyzed Intermolecular Hydrofunctionalization of Allenes: Easy Access to Allylic Structures via the Selective Formation of C–N, C–C, and C–O Bonds, Chem. Rev., 2020, 120, 13545–13598; (c) M.-Z. Lu, J. Goh, M. Maraswami, Z. Jia, J.-S. Tian and T.-P. Loh, Recent Advances in Alkenyl sp2 C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications, Chem. Rev., 2022, 122, 17479–17646.
2. (a) D. Zhu, L. Chen, H. Fan, Q. Yao and S. Zhu, Recent Progress on Donor and Donor–Donor Carbenes, Chem. Soc. Rev., 2020, 49, 908–950; (b) C. Wentrup, Carbenes and Nitrenes: Recent Developments in Fundamental Chemistry, Angew. Chem., Int. Ed., 2018, 57, 11508–11521; (c) Y.-C. Wang, X.-J. Lai, K. Huang, S. Yadav, G. Qiu, L. Zhang and H. Zhou, Unravelling Nitrene Chemistry from Acyclic Precursors: Recent Advances and Challenges, Org. Chem. Front., 2021, 8, 1677–1693.
3. (a) J. Rong, H. Li, R. Fu, W. Sun, T.-P. Loh and Y. Jiang, Cleavage and Reassembly C≡C Bonds of Ynones to Access Highly Functionalized Ketones, ACS Catal., 2020, 10, 3664–3669; (b) M.-Y. Huang and S.-F. Zhu, Catalytic Reactions for Enantioselective Transfers of Donor-Substituted Carbenes, Chem. Catal., 2022, 2, 3112–3139; (c) Z. K. Liu, Q. Q. Zhao, Y. Gao, Y. X. Hou and X. Q. Hu, Organic Azides: Versatile Synthons in Transition Metal–Catalyzed C(sp²)−H Amination/Annulation for N–Heterocycle Synthesis, Adv. Synth. Catal., 2021, 363, 411–424.
4. S. Dong, X. Liu and X. Feng, Asymmetric Catalytic Rearrangements with α-Diazocarbonyl Compounds, Acc. Chem. Res., 2022, 55, 415–428.
5. (a) M. Mato, A. Franchino, C. García-Morales and A. M. Echavarren, Gold-Catalyzed Synthesis of Small Rings, Chem. Rev., 2021, 121, 8613–8684; (b) J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin, D. Devarajan, D. H. Ess, L. Kürti and J. R. Falck, Direct Stereospecific Synthesis of Unprotected N-H and N-Me Aziridines from Olefins, Science, 2014, 343, 61–65; (c) A. Fanourakis, N. J. Hodson, A. R. Lit and R. J. Phipps, Substrate-Directed Enantioselective Aziridination of Alkenyl Alcohols Controlled by a Chiral Cation, J. Am. Chem. Soc., 2023, 145, 7516–7527.
6. (a) D. S. Davas, S. Bhardwaj, R. Sen, D. K. Gopalakrishnan and J. Vaitla, Synthesis of Olefins by Formal Carbene Coupling, Adv. Synth. Catal., 2022, 364, 3122–3142; (b) S. S. Kurup and S. Groysman, Catalytic Synthesis of Azoarenes via Metal-Mediated Nitrene Coupling, Dalton Trans., 2022, 51, 4577–4589.
7. (a) Y. Xia, Z. Liu, Q. Xiao, P. Qu, R. Ge, Y. Zhang and J. Wang, Rhodium(II)-Catalyzed Cyclization of Bis(N-tosylhydrazone)s: An Efficient Approach towards Polycyclic Aromatic Compounds, Angew. Chem., Int. Ed., 2012, 51, 5714–5717; (b) Q. Song, Y. Zhao, S. Liu, Y. Wu and Z. Liu, Stereoselective Synthesis of trans-Stilbenes through Silver-Catalyzed Self-Coupling of N-Triftosylhydrazones: An Experimental and Theoretical Study, Org. Lett., 2023, 25, 3461–3465.
8. (a) N. S. Y. Loy, A. Singh, X. Xu and C.-M. Park, Synthesis of Pyridines by Carbenoid-Mediated Ring Opening of 2H-Azirines, Angew. Chem., Int. Ed., 2013, 52, 2212–2216; (b) X.-P. Wu, Y. Su and P. Gu, Catalytic Enantioselective Desymmetrization of 1,3-Diazido-2-propanol via Intramolecular Interception of Alkyl Azides with Diazo(aryl)acetates, Org. Lett., 2014, 16, 5339–5341; (c) Z. Fang, Y. Gong, B. Liu, J. Zhang, X. Han, Z. Liu and Y. Ning, Rh-Catalyzed Coupling Reactions of Fluoroalkyl N-Sulfonylhydrazones with Azides Leading to α-Trifluoroethylated Imines, Org. Lett., 2022, 24, 8920–8924.
9. (a) X. Wang, Y. Xu, Y. Deng, Y. Zhou, J. Feng, G. Ji, Y. Zhang and J. Wang, Pd-Carbene Migratory Insertion: Application to the Synthesis of Trifluoromethylated Alkenes and Dienes, Chem. – Eur. J., 2014, 20, 961–965; (b) Z. Zhang, W. Yu, Q. Zhou, T. Li, Y. Zhang and J. Wang, Rh(I)-Catalyzed Reaction of Trifluoromethylketone N-Tosylhydrazones and Arylboronates, Chin. J. Chem., 2016, 34, 473–476; (c) X. Zhang, Z. Liu, X. Yang, Y. Dong, M. Virelli, G. Zanoni, E. A. Anderson and X. Bi, Use of Trifluoroacetaldehyde N-Tfsylhydrazone as a Trifluorodiazoethane Surrogate and Its Synthetic Applications, Nat. Commun., 2019, 10, 284; (d) X. Zhang, Y. Ning, Z. Liu, S. Li, G. Zanoni and X. Bi, Defluorinative Carboimination of Trifluoromethyl Ketones, ACS Catal., 2022, 12, 8802–8810; (e) X. Liang, P. Guo, W. Yang, M. Li, C. Jiang, W. Sun, T.-P. Loh and Y. Jiang, Stereoselective Synthesis of Trifluoromethyl-Substituted 2H-Furan-Amines from Enaminones, Chem. Commun., 2020, 56, 2043–2046; (f) X. Zhang, J. Zhang, J. Chen, B. Zhou, J. Zhang, S. Chen, J. Wu and Y. Jiang, Modular Synthesis of Fluorinated 2H-Thiophenes via, [4+1] Cyclization of Enaminothiones, Org. Biomol. Chem., 2023, 21, 3345–3349.
10. (a) P. Sivaguru and X. Bi, Fluoroalkyl N-Sulfonyl Hydrazones: An Efficient Reagent for the Synthesis of Fluoroalkylated Compounds, Sci. China: Chem., 2021, 64, 1614–1629; (b) Z. Liu, P. Sivaguru, G. Zanoni and X. Bi, N-Triftosylhydrazones: A New Chapter for Diazo-Based Carbene Chemistry, Acc. Chem. Res., 2022, 55, 1763–1781.
11. (a) J. Fu, G. Zanoni, E. A. Anderson and X. Bi, α-Substituted Vinyl Azides: an Emerging Functionalized Alkene, Chem. Soc. Rev., 2017, 46, 7208–7228; (b) B. Plietker and A. Röske, Recent Advances in Fe-Catalyzed C–H Aminations using Azides as Nitrene Precursors, Catal. Sci. Technol., 2019, 9, 4188–4197.
12. (a) Y. Gao, H. Li, Y. Zhao and X.-Q. Hu, Nitrene Transfer Reaction with Hydroxylamine Derivatives, Chem. Commun., 2023, 59, 1889–1906; (b) U. Todorović, R. M. Romero and L. Anthore-Dalion, Activation of N−O σ Bonds with Transition Metals: A Versatile Platform for Organic Synthesis and C−N Bonds Formation, Eur. J. Org. Chem., 2023, 26, e202300391.
13. (a) J. L. Roizen, M. E. Harvey and J. D. Bois, Metal-Catalyzed Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C-H Bonds, Acc. Chem. Res., 2012, 45, 911–922; (b) J. M. Alderson, J. R. Corbin and J. M. Schomaker, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts, Acc. Chem. Res., 2017, 50, 2147–2158.
14. (a) T. V. Nykaza, A. Ramirez, T. S. Harrison, M. R. Luzung and A. T. Radosevich, Biphilic Organophosphorus-Catalyzed Intramolecular C_sp2−H Amination: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations, J. Am. Chem. Soc., 2018, 140, 3103–3113; (b) S. Suárez-Pantiga, R. Hernández-Ruiz, C. Virumbrales, M. R. Pedrosa and R. Sanz, Reductive Molybdenum-Catalyzed Direct Amination of Boronic Acids with Nitro Compounds, Angew. Chem., Int. Ed., 2019, 58, 2129–2133.
15. (a) Y. F. Wang and S. Chiba, Mn(III)-Mediated Reactions of Cyclopropanols with Vinyl Azides: Synthesis of Pyridine and 2-Azabicyclo[3.3.1]non-2-en-1-ol Derivatives, J. Am. Chem. Soc., 2009, 131, 12570–12572; (b) Y. F. Wang, K. K. Toh, E. P. J. Ng and S. Chiba, Mn(III)-Mediated Formal [3+3]-Annulation of Vinyl Azides and Cyclopropanols: A Divergent Synthesis of Azaheterocycles, J. Am. Chem. Soc., 2011, 133, 6411–6421; (c) Y.-F. Wang, K. K. Toh, J.-Y. Lee and S. Chiba, Synthesis of Isoquinolines from α-Aryl Vinyl Azides and Internal Alkynes by Rh-Cu Bimetallic Cooperation, Angew. Chem., Int. Ed., 2011, 50, 5927–5931; (d) Y.-F. Wang, G. H. Lonca and S. Chiba, PhI(OAc)₂-M ediated Radical Trifluoromethylation of Vinyl Azides with Me₃SiCF₃, Angew. Chem., Int. Ed., 2014, 53, 1067–1071; (e) F.-L. Zhang, Y.-F. Wang, G. H. Lonca, X. Zhu and S. Chiba, Amide Synthesis by Nucleophilic Attack of Vinyl Azides, Angew. Chem., Int. Ed., 2014, 53, 4390–4394; (f) F. Chen, T. Shen, Y. X. Cui and N. Jiao, 2,4- vs 3,4-Disubsituted Pyrrole Synthesis Switched by Copper and Nickel Catalysts, Org. Lett., 2012, 14, 4926–4929.
16. F. Gholami, F. Yousefnejad, B. Larijani and M. Mahdavi, Vinyl Aides in Organic Synthesis: An Overview, RSC Adv., 2023, 13, 990–1018.
17. (a) Y. Jiang, W. C. Chan and C.-M. Park, Expedient Synthesis of Highly Substituted Pyrroles via Tandem Rearrangement of α-Diazo Oxime Ethers, J. Am. Chem. Soc., 2012, 134, 4104–4107; (b) Y. Jiang and C.-M. Park, A Catalyst-Controlled Selective Synthesis of Pyridines and Pyrroles, Chem. Sci., 2014, 5, 2347–2351; (c) Y. Jiang, C.-M. Park and T.-P. Loh, Transition-Metal-Free Synthesis of Substituted Pyridines via Ring Expansion of 2-Allyl-2H-azirines, Org. Lett., 2014, 16, 3432–3435; (d) Y. Ge, W. Sun, B. Pei, J. Ding, Y. Jiang and T.-P. Loh, Hoveyda–Grubbs II Catalyst: A Useful Catalyst for One-Pot Visible-Light-Promoted Ring Contraction and Olefin Metathesis Reactions, Org. Lett., 2018, 20, 2774–2777; (e) Y. Ge, W. Sun, Y. Chen, Y. Huang, Z. Liu, Y. Jiang and T.-P. Loh, Reactions of 5-Aminoisoxazoles with α-Diazocarbonyl Compounds: Wolff Rearrangement vs N–H Insertion, J. Org. Chem., 2019, 84, 2676–2688; (f) Y. Chen, W. Yang, J. Wu, W. Sun, T.-P. Loh and Y. Jiang, 2H-Azirines as Potential Bifunctional Chemical Linkers of Cysteine Residues in Bioconjugate Technology, Org. Lett., 2020, 22, 2038–2043.
18. (a) F. Hu and M. Szostak, Recent Developments in the Synthesis and Reactivity of Isoxazoles: Metal Catalysis and Beyond, Adv. Synth. Catal., 2015, 357, 2583–2614; (b) S. Madhavan, S. K. Keshri and M. Kapur, Transition Metal–Mediated Functionalization of Isoxazoles: A Review, Asian J. Org. Chem., 2021, 10, 3127–3165.
19. (a) K. Li, X. Shao, L. Tseng and S. J. Malcolmson, 2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Reductive Couplings with Ketones, J. Am. Chem. Soc., 2018, 140, 598–601; (b) P. E. Daniel, C. I. Onyeagusi, A. A. Ribeiro, K. Li and S. J. Malcolmson, Palladium-Catalyzed Synthesis of α-Trifluoromethyl Benzylic Amines via Fluoroarylation of gem-Difluoro-2-azadienes Enabled by Phosphine-Catalyzed Formation of an Azaallyl–Silver Intermediate, ACS Catal., 2019, 9, 205–210; (c) X. Shao and S. J. Malcolmson, Catalytic Enantio- and Diastereoselective Cyclopropanation of 2-Azadienes for the Synthesis of Aminocyclopropanes Bearing Quaternary Carbon Stereogenic Centers, Org. Lett., 2019, 21, 7380–7385; (d) J.-C. M. Monbaliu, K. G. R. Masschelein and C. V. Stevens, Electron-Deficient 1- and 2-Azabuta-1,3-Dienes: a Comprehensive Survey of Their Synthesis and Reactivity, Chem. Soc. Rev., 2011, 40, 4708–4739; (e) G. Masson, C. Lalli, M. Benohoud and G. Dagousset, Catalytic Enantioselective [4+2]-Cycloaddition: a Strategy to Access Aza-Hexacycles, Chem. Soc. Rev., 2013, 42, 902–923.
20. (a) A. Caballero, A. Espinosa, A. Tarraga and P. Molina, Ferrocene-Based Small Molecules for Dual-Channel Sensing of Heavy- and Transition-Metal Cations, J. Org. Chem., 2008, 73, 5489–5497; (b) R. Martínez, A. Espinosa, A. Tárraga and P. Molina, A New Bis(pyrenyl)azadiene-Based Probe for the Colorimetric and Fluorescent Sensing of Cu(II) and Hg(II), Tetrahedron, 2010, 66, 3662–3667.
21. (a) R. F. Heck, Palladium-Catalyzed Reactions of Organic Halides with Olefins, Acc. Chem. Res., 1979, 12, 146–151; (b) P. Knochel and R. D. Singer, Preparation and Reactions of Polyfunctional Organozinc Reagents in Organic-Synthesis, Chem. Rev., 1993, 93, 2117–2188; (c) N. Miyaura and A. Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds, Chem. Rev., 1995, 95, 2457–2483.
22. (a) M. Ni, J. Zhang, X. Liang, Y. Jiang and T.-P. Loh, Directed C–C Bond Ceavage of a Cyclopropane Intermediate Generated from N-Tosylhydrazones and Stable Enaminones: Expedient Synthesis of Functionalized 1,4-Ketoaldehydes, Chem. Commun., 2017, 53, 12286–12289; (b) J. Huo, K. Zhong, Y. Xue, M. Lyu, Y. Ping, Z. Liu, Y. Lan and J. Wang, Palladium-Catalyzed Enantioselective Carbene Insertion into Carbon–Silicon Bonds of Silacyclobutanes, J. Am. Chem. Soc., 2021, 143, 12968–12973.
23. N. S. Y. Loy, A. Singh, X. Xu and C.-M. Park, Synthesis of Pyridines by Carbenoid-Mediated Ring Opening of 2H-Azirines, Angew. Chem., Int. Ed., 2013, 52, 2212–2216.
24. I. Galve, R. Ondoño, C. de Rocafiguera, R. P. de la Bellacasa, X. Batllori, C. Puigjaner, M. Font-Bardia, O. Vallcorba, J. Teixidó and J. I. Borrell, A Captured Room Temperature Stable Wheland Intermediate as a Key Structure for the Orthogonal Decoration of 4-Amino-Pyrido[2,3-d]Pyrimidin-7(8H)-Ones, Org. Biomol. Chem., 2020, 18, 9810–9815.
25. M. Ikeda, T. Matsuzawa, T. Morita, T. Hosoya and S. Yoshida, Synthesis of Diverse Aromatic Ketones through C-F Cleavage of Trifluoromethyl Group, Chem. – Eur. J., 2020, 26, 12333–12337.
26. B. Solaja, J. Huguet, M. Karpf and A. S. Dreiding, The Synthesis of (±)-Isoptychanolide by Application of the α-Alkynone Cyclisation, Tetrahedron, 1987, 43, 4875–4886.
27. H. Suzuki, S. Yoshioka, A. Igesaka, H. Nishioka and Y. Takeuchi, Palladium-Catalyzed Hydrogenation with Use of Ionic Liquid bis(2-Hydroxyethyl)Ammonium Formate [BHEA][HCO₂] as a Solvent and Hydrogen Source, Tetrahedron, 2013, 69, 6399–6403.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2246278. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo01537h

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