Fe(NO₃)₃·9H₂O-mediated visible-light photocatalysis for the nitration of cyclobutanols: access to functionalized nitrocyclobutenes

Abstract

A straightforward method for the synthesis of nitrocyclobutene derivatives from cyclobutanols with Fe(NO₃)₃·9H₂O has been developed via a visible-light photocatalytic radical addition reaction. The reaction utilizes Fe(NO₃)₃·9H₂O as the nitro source and RFTA as the photocatalyst, showing good functional group tolerance and furnishing the desired products in moderate to excellent yields. Preliminary mechanistic studies suggested that the nitro radical was involved in the reaction process.

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Introduction

Cyclobutenes, common motifs in both natural products and pharmaceutical molecules, possess high chemical reactivity originating from the inherent ring strain (Fig. 1).¹ Attributed to their high chemical reactivity originating from the inherent ring strain, cyclobutenes undergo various transformations, especially ring-opening and ring-expansion reactions, providing unique strategies to synthesize organic molecules with complex structures.² The double bonds of cyclobutenes can also be selectively functionalized to afford cyclobutane derivatives.³ While methods for synthesizing the cyclobutene core are well-established (Scheme 1a–c),^4–9 strategies for their direct functionalization, particularly via C–H or C–C bond activation, remain limited.

Fig. 1 Structures of important cyclobutene-based drugs.

Scheme 1 Strategy for synthesis of cyclobutene.

The introduction of nitro groups into organic frameworks is a transformation of paramount importance, as nitro groups serve as versatile precursors to amines, amides, and other nitrogen-containing compounds.¹⁰ A protocol for the nitration of cyclobutenes has not been reported. Recently, Zhou et al. reported a visible-light-induced nitration of arenes using Fe(NO₃)₃·9H₂O and RFTA (Scheme 1e).¹¹ Inspired by this work and our ongoing interest in the functionalization of cycloalkanols, we herein report a visible-light-induced nitration of cyclobutanols. This transformation is distinct from arene C–H functionalization and involves a sequence of dehydration, radical addition, and ring-opening to directly access valuable nitrocyclobutene derivatives from readily available cyclobutanols (Scheme 1f).

Results and discussion

We initiated our study by employing 1-phenylcyclobutan-1-ol (1a) and Fe(NO₃)₃·9H₂O as model substrates. The optimal conditions were obtained to furnish product 2a in 76% yield, after a comprehensive optimization of reaction conditions by screening solvents, nitro sources, and photocatalysts (Table 1, entry 1). The structure of 2a was unambiguously confirmed by X-ray crystallography (CCDC 2478060). To achieve consecutive nitration, several polar solvents including DMSO, MeCN and nonpolar solvents such as DCE, THF, and 1,4-dioxane were all inferior to DMF (Table 1, entry 2). Next, different nitro sources such as Cu(NO₃)₂·3H₂O, AgNO₃, Mn(NO₃)₂·4H₂O, and NaNO₂ were tested, but Fe(NO₃)₃·9H₂O gave the best result with good yield (Table 1, entries 3 and 4). Replacing Fe(NO₃)₃·9H₂O with TBN was not effective in this reaction (Table 1, entry 5). Various photocatalysts, including metal-containing Ru/Ir-tripyridines, organic dyes such as fluorescein, and 4-CzIPN salt, were screened but showed no reactivity (Table 1, entry 6). To investigate the role of molecular O₂ or N₂, the model reaction was conducted under an O₂ or N₂ atmosphere. The yield of 2a under these conditions (71% or 68%) was comparable to that obtained in air (76%), indicating that O₂ is not essential for the reaction outcome (Table 1, entry 7). A control experiment was conducted in darkness, leading to the absence of the desired product 2a (Table 1, entry 8).

Table 1 Optimization of reaction conditions^a

Entry	Variation from standard conditions	Yield^b (%)
a Reaction conditions: 1 (0.30 mmol, 1.0 equiv.), Fe(NO3)3·9H2O (0.60 mmol, 2.0 equiv.), RFTA (5 mol%), DMF (3 mL), 450–455 nm, 60–70 °C, 24 h, and air. b NMR yields using m-dinitrobenzene as the internal standard reference.
1	Standard conditions	76
2	DMSO, MeCN, DCE, THF, 1,4-dioxane instead of DMF	52, 17, 9, 0, 0
3	Cu(NO3)2·3H2O, AgNO3 and Mn(NO3)2·4H2O instead of Fe(NO3)3·9H2O	48, 21, 35
4	NaNO2 instead of Fe(NO3)3·9H2O	60
5	TBN instead of Fe(NO3)3·9H2O	Trace
6	[Ir(dFppy)2(dtbbpy)]PF6, Ru(phen)3(PF6)2, fluorescein, 4-CzIPN instead of RFTA	0, 0, 0, 0
7	O2, N2 instead of air	71, 68
8	Dark	Trace

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With the optimal conditions in hand, the scope of this cascade oxidative nitration of a range of cyclobutanols was investigated, as illustrated in Scheme 2. The scope of cyclobutanols with an aryl ring was evaluated. Cyclobutanols substituted with electron-donating groups of methyl at the ortho-, meta-, and para-positions of the aromatic ring (R¹) showed excellent reactivity and provided the nitration products 2b–2d in 68–75% yields. Steric and electronic factors also influenced the efficiency, as evidenced by the lower yield of ortho-substituted substrate 2b compared to its para-counterpart. Meanwhile, the results demonstrated that the reaction was sensitive to the steric effect at the ortho-position, and product 2b was obtained in only 68% yield. Cyclobutanols containing an aromatic moiety bearing either electron-donating substituents (Et, iPr, tBu, Ph, OMe, OTMS, OBn, and NMe₂) or electron-withdrawing groups (NO₂, Cl, Br, and CN) at the para-position were all converted to the corresponding products 2e–2p in 53–75% yields. Generally, the cyclobutanols with electron-donating groups on the aryl substituents provided yields higher than those of electron-withdrawing cyclobutanols (2a–2p), consistent with the electrophilic nature of the nitro radical. Disubstituted and trisubstituted substrates bearing methyl groups provided products 2q–2s in 64–70% yields. 2-Naphthyl and 9-anthryl-substituted cyclobutanols were also viable in this transformation to give 2t–2v in 46–54% yields, demonstrating the method's utility for complex scaffolds. The reaction also demonstrates excellent compatibility with heterocycles such as furan, thiophene, benzofuran, benzothiophene, dibenzofuran and dibenzothiophene, all of which were obtained in satisfactory yields (2w–2ab).

Scheme 2 Substrate scope of various cyclobutanols. Reaction conditions: 1 (0.30 mmol, 1.0 equiv.), Fe(NO₃)₃·9H₂O (0.60 mmol, 2.0 equiv.), RFTA (5 mol%), DMF (3 mL), 450–455 nm, 60–70 °C, 24 h, and air.

Alkenylated cyclobutanol gave 2ac in 63% yield. It is worth mentioning that the alkene group remained stable during the formation of 2ac. The alkyl substituents were subjected to the reaction to afford nitrocyclobutenes 2ad–2ag, respectively, in a comparable efficiency. It is noteworthy that alkyl-substituted cyclobutanols generally afforded moderate yields, which may be attributed to the lower stability of the corresponding alkyl radicals and potential competitive β-scission pathways. Notably, yield variability was observed for sterically crowded or alkyl-substituted substrates. For example, 3,3-disubstituted cyclobutanol afforded 2ai in only 19% yield (vs. 54% for monosubstituted 2ah and 43% for 2ai), which is attributed to the significant steric congestion around the reactive center, likely impeding the formation or reactivity of the key radical intermediate. 2aj was synthesized and showed good reactivity without interference from the isolated alkene, confirming the chemoselectivity of the nitration process.

To shed light on the mechanism of this reaction, a series of several control experiments were conducted. The reaction was nearly completely inhibited by the addition of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). A TEMPO adduct derived from the nitro radical was detected by HRMS, which provides supporting evidence for the involvement of a nitro radical species in the mechanism (Scheme 3a). Further studies disclosed that compound 3 was obtained in 42% yield when the reaction was performed under the standard reaction conditions for 2 h (Scheme 3b). Then, compound 3 was also employed as the substrate, and the corresponding product 2a was afforded in 81% yield under the optimized conditions (Scheme 3c). Based on the above results, compound 3 should be the intermediate in this reaction.

Scheme 3 Control experiments.

Based on these experimental results and previously reported studies,¹² a possible mechanism is proposed in Scheme 4. Firstly, 1-phenylcyclobutanol 1a undergoes Fe-catalyzed thermal dehydration to form cyclobutene intermediate A. Subsequently, upon photoexcitation, RFTA* undergoes single-electron transfer (SET) oxidation of intermediate A, generating radical cation species B alongside the reduced photocatalyst radical anion RFTA˙⁻. The RFTA˙⁻ species then mediates N–O bond homolysis in the ferric nitrate complex through a second SET event, regenerating the ground-state photocatalyst while releasing a nitro radical (˙NO₂). Radical recombination between radical cation B and the ˙NO₂ radical yields nitrated cyclobutyl intermediate D. Finally, deprotonation of D by the base present in the system affords the final nitrocyclobutene product 2a.

Scheme 4 Proposed mechanism for the photocatalytic nitration of cyclobutanols.

To demonstrate the synthetic utility of ring formation, we attempted a set of chemoselective transformations (Scheme 5). Nitrocyclobutene of 2a gave (2-nitrocyclobutyl)benzene 4 in 76% yield. Selective amination of 2a by using Pd/C afforded 2-phenylcyclobut-1-en-1-amine 5. Ozonization of 2a selectively gave 4-oxo-4-phenylbutanamide 6.

Scheme 5 Derivatization of 2a.

Conclusions

In summary, we have developed a novel and efficient protocol for the synthesis of nitrocyclobutenes via a photocatalytic nitration reaction of cyclobutanols with Fe(NO₃)₃·9H₂O as the nitro source. The broad substrate scope and tolerance of various functional groups have been demonstrated. Mechanistic studies reveal that the reaction is more likely to undergo excitation of RFTA to generate a reactive triplet excited state, facilitating single electron transfer (SET) processes that lead to the formation of nitro radicals. Ongoing studies in our laboratory are dedicated to further synthetic applications of this transformation.

Author contributions

Conceptualisation: Can Yang; methodology: Dongfang Jiang and Can Yang; investigation: Xinying Man; formal analysis: Xin Li; writing – original draft: Zhenjie Qi; writing – review & editing: Haifei Wang; funding acquisition: Dongfang Jiang; resources: Yunlin Song; supervision: Haifei Wang.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: synthetic details, experimental methods, and characterisation data (including copies of NMR spectra). See DOI: https://doi.org/10.1039/d5ob01627d.

CCDC 2478060 contains the supplementary crystallographic data for this paper.¹³

Acknowledgements

This research was funded by the Natural Science Foundation of Hunan Province (2023JJ60492) and the National Natural Science Foundation of China (No. 82203235) with generous financial support.

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