Visible-Light-Promoted Synthesis of Vinyloxaziridines from Conjugated Carbonyls

Abstract

We report the first visible-light-promoted synthesis of vinyloxaziridines from simple conjugated nitrones. We have found that vinyl nitrones formed by the condensation reaction between conjugated carbonyls and hydroxylamines undergo visible-light-promoted energy-transfer isomerization to the respective vinyloxaziridines in very high yields and selectivities. The reaction scope expands to a large array of substitution patterns, and evidence indicates that the proposed energy-transfer pathway is the predominant mechanism for this transformation.

Oxaziridines comprise a class of versatile chemical building blocks whose characteristic feature is the presence of N and O atoms within a strained three-membered ring.[1] Oxaziridines are generally used in synthesis as either N- or O-transfer reagents, for example in oxidations and aminations of alkenes, arenes, amines, sulfides, phosphines, and alkoxides.[2] In the past decade, the chemistry of oxaziridines has been significantly expanded to include transition-metal-mediated rearrangements,[3] dipolar cycloadditions,[4] and oxyaminations.[5] Therefore, due to the large synthetic value of oxaziridines, the continuous development of better methods for their synthesis is of fundamental interest in the field of organic chemistry. Since their discovery,[6] several efforts to synthesize oxaziridines under photochemical reaction conditions have found little success.[7] Tanaka determined that nitrone photocyclization involves a singlet state, whereas the photochemically induced cis–trans nitrone isomerization involves a triplet state.[8] Despite this early discovery, this approach for the synthesis of oxaziridines was never fully exploited due to its low yields and poor generality for photocyclizations.[9] Instead, the synthesis of oxaziridines has relied on the oxidation of substituted imines with a variety of reagents (Figure [1]).[10] Nitrones are well known as synthetic templates for cycloaddition reactions.[11] Conjugated nitrones are also powerful chromophores; consequently, they have drawn special attention as spin-trapping reagents.[12] They are also known to have neuroprotective properties and they are used in the treatment of inflammatory and neurodegenerative diseases.[13]

The photoirradiation of nitrones can be primarily summarized in terms of two important observations: the cis–trans isomerization reaction of nitrones proceeds under thermal conditions or through triplet excited states in the presence of photosensitizers, and their normal photoexcitation involves singlet excited states that subsequently form oxaziridines and other photoproducts.[14] The other noticeable feature of the nitrone photoexcitation is the varying stability of the oxaziridine photoproduct, and it has been found that N-alkyl substituents increase the stability of oxaziridines.[15] It has also been reported that the photochemical nitrone–oxaziridine conversion involves biradicaloid conical intersection geometries resembling a three-centered molecular orbital pathway.[16] Thus, a hypothetical visible-light-promoted pathway would have similar features without the detrimental consequences of high-energy photochemical reaction conditions.

The Moura-Letts laboratory focuses on developing novel methods for the synthesis of complex nitrogen-containing heterocycles.[17] Recently, we discovered that alkenyl nitrones undergo visible-light, redox-neutral, intra- and intermolecular photocatalytic cyclizations to provide isoxazolidines in high yields and with high stereoselectivities.[17a] [b] However, in the absence of a suitable dipolarophile, such nitrones are poised to undergo alternative visible-light-promoted transformations.

Visible-light can be employed to access excited states that possess a reactivity that is inherently different from that of the corresponding ground-state molecules, thereby providing access to otherwise unprecedented transformations.[18] We envisioned a visible-light-promoted cycloisomerization for the synthesis of vinyloxaziridines from conjugated nitrones.

Based on our efforts toward a better understanding of the selectivity of nitrone cycloadditions, we discovered that upon reacting benzaldehyde and benzylhydroxylamine hydrochloride with the intention of forming N-benzyl(phenyl)nitrone, the nitrone intermediate underwent a very slow conversion into the corresponding N-benzyloxaziridine in 12% yield during 18 hours near a windowsill. Analysis of the reaction products indicated complete selectivity toward the oxaziridine, without any traces of other photoadducts. A survey of the literature revealed not a single report on the visible-light-promoted photocyclization of nitrones, vinylnitrones, or other dipoles.

We therefore decided to focus on the optimization of this transformation and we quickly discovered that the nitrone had to be isolated to obtain synthetically useful conversions (Table [1]). Thus, the photocyclization of N-benzyl(phenyl)nitrone using a white LED in the presence or absence of [Ru(bpy)₃Cl₂] (bpy = 2,2′-bipyridine) as a photocatalyst provided the corresponding oxaziridine in yields of 42 and 38%, respectively (Table [1], entries 2 and 3). Further exposure of N-benzyl(phenyl)nitrone to a white LED in other solvents provided evidence that the best yields were obtained in benzene (entries 4–7). Attempts to further optimize the reaction conversion by manipulating the concentration failed (entries 8 and 9). This proved that N-benzyl(phenyl)nitrones are not ideal substrates for the visible-light-mediated formation of oxaziridines. We then turned our attention to N-benzyl(cinnamyl)nitrone, and we found that the additional conjugation permitted the isolation of the corresponding vinyloxaziridine in 96% yield on white LED irradiation. As with N-benzyl(phenyl)nitrone, a catalytic amount of Ru(bpy)₃Cl₂ provided the product in a lower yield (entry 14). Further concentration manipulation provided further evidence that 0.05 M was the optimal concentration (entries 15 and 16).

Table 1 Reaction Optimization

Entry	R1	Conditions	Solvent	Concn. (M)	Yielda (%)
1b	Ph	visible lightc	benzene	0.05	12
2	Ph	visible lightd	benzene	0.05	48
3	Ph	Ru(bpy)3Cl2 d,e	MeCN	0.05	38
4	Ph	visible lightd	MeCN	0.05	40
5	Ph	visible lightd	toluene	0.05	44
6	Ph	visible lightd	CH2Cl2	0.05	20
7	Ph	Ru(bpy)3Cl2 d,f	MeCN	0.05	40
8	Ph	visible lightd	benzene	0.01	28
9	Ph	visible lightd	benzene	0.025	20
10	cinnamyl	visible lightd	benzene	0.05	96
11b	cinnamyl	visible lightd	benzene	0.05	28
12	cinnamyl	visible lightd	MeCN	0.05	75
13	cinnamyl	visible lightd	CH2Cl2	0.05	35
14	cinnamyl	Ru(bpy)3Cl2 d,e	MeCN	0.05	82
15	cinnamyl	visible lightd	benzene	0.01	80
16	cinnamyl	visible lightd	benzene	0.025	64

^a Isolated yield.

^b The nitrone intermediate was isolated prior to photocyclization.

^c By a windowsill, 18 h.

^d White LED.

^e 5 mol%.

^f 10 mol%.

Because of the high conversion and undetectable photodecomposition, our next step focused on assessing the scope of the transformation across multiple diversification points (Table [2]). We found that nitrones derived from benzaldehydes did not undergo highly productive cycloisomerizations (Table [2], entries 1–3). The electronic and steric effects of functional groups around the cinnamyl ring were assessed to provide a better understanding of the reaction scope. Substituted cinnamaldehydes and enals proved ideal in condensing with alkylhydroxylamines to provide the required nitrones.[19] N-Benzyl(cinnamyl)nitrones with a 4-bromo, 4-fluoro, 4-nitro, or 2-nitro substituent provided the corresponding vinyloxaziridines 2d–h in very high yields (entries 5–8). N-benzyl-(4-methoxycinnamyl)- and -(2-methoxycinnamyl)nitrones also provided the corresponding vinyloxaziridines 2i and 2j in high yields (entries 9 and 10). Another substitution pattern around the cinnamyl aromatic ring also provided the desired vinyloxaziridine 2k in high yield (entry 11). Therefore, changing the electronic nature of the cinnamyl ring did not diminish the reaction efficiency. Further exploration of the reaction scope led to the discovery that the heterocyclic vinyl nitrone 1l underwent an equally high-yielding conversion into the respective vinyloxaziridine 2l (entry 12).

Table 2 Reaction Scope^a

Entry	Nitrone	Productb	Yieldc (%)
1	1a	2a	44
2	1b	2b	44
3	1c	2c	54
4	1d	2d	98
5	1e	2e	93
6	1f	2f	84
7	1g	2g	92
8	1h	2h	91
9	1i	2i	97
10	1j	2j	96
11	1k	2k	95
12	1l	2l	93

^a Reaction conditions: nitrone 1 (1 mmol), benzene (0.05 M), white LED irradiation, rt, 22 h.

^b Purified by standard silica gel chromatography.

^c Isolated yield.

We next assessed the efficiency of the visible-light-promoted process with deactivated (alkylvinyl)nitrones (Table [3]). Substrates that do not possess additional conjugation like the cinnamyl-derived substrates in Table [2] can suffer from slow cycloisomerization rates; consequently, studying (alkylvinyl)nitrones was of great significance. The (2-propylvinyl) nitrone 1m and the (2-heptylvinyl) nitrone 1p provided the resulting vinyloxaziridines 2m and 2p in yields of 79 and 75%, respectively (Table [3], entries 1 and 4), whereas the analogous 2-(non-1-enyl)vinyl and 2-(prop-1-enyl)vinyl nitrones 1n and 1o provided the heterocycles 2n and 2o, respectively, in better yields of 82 and 84% (entries 2 and 3). Diversification at the N-alkyl position showed similar success, as N-isopropyl, N-cyclohexyl, N-tert-butyl, and N-methyl nitrones provided the desired oxaziridines 2q–t in similar high yields and selectivities (entries 5–8). Efforts to enhance the green properties of this transformation led to the discovery that nitrones 1d and 1q reacted in toluene to provide the corresponding vinyl oxaziridines in equally high yields (98 and 90%). Nitrones with N-bound electron-withdrawing groups displayed very low conversions under the chosen reaction conditions.

Table 3 Reaction Scope^a

Entry	Nitrone	Productb	Yieldc (%)
1	1m	2m	79
2	1n	2n	82
3	1o	2o	84
4	1p	2p	75
5	1q	2q	91
6	1r	2r	92
7	1s	2s	91
8	1t	2t	95

^a Reaction conditions: Nitrone (1 mmol), benzene (0.05 M), white LED, 22 h.

^b Purified by standard silica gel chromatography.

^c Isolated yield.

The encouraging results from the study on the reaction scope shifted our focus toward a study of the reaction mechanism. Nitrones derived from aromatic aldehydes are good spin-trapping agents and are therefore suitable candidates for photooxidation pathways.[12] Moreover, aldonitrones with electron-donating groups (proposed substrates) are reported to undergo less-demanding oxidation pathways.[20]

We discovered that the reaction was completely inhibited by the presence of one equivalent of TEMPO as a radical scavenger. Moreover, product formation was observed only during periods of irradiation by light, indicating that a radical-chain-propagation mechanism was present. On the basis of these results, we propose that the reaction is promoted by the slow excitation of the substrate by visible light to form its singlet state, which then relaxes to an excited triplet state. The inherent stability of the triplet state permits an outer-sphere single-electron-transfer or an energy-transfer process, leading to rapid cyclization and subsequent relaxation to the ground state to provide the observed vinyl oxaziridine (Figure [2]).

In conclusion, we have developed the first reported visible-light-induced cycloisomerization of vinylnitrones to vinyloxaziridines.[21] The reaction proceeds in high yields for a wide variety of substrates with multiple diversification points under very mild conditions. Additionally, the reaction appears to be highly tolerant of a wide range of substitution patterns around the aromatic ring and the pendent alkenyl group. A visible-light photosensitized mechanism is proposed, and our ongoing efforts will focus on further understanding these types of photosensitized transformations, in addition to further studying other visible-light-promoted reactions for the synthesis of complex N-containing heterocycles.

Conflict of Interest

The authors declare no conflict of interest.

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• 21 General protocol for synthesis of vinyloxaziridines from vinylnitrones: A 50 mL round-bottomed flask equipped with a magnetic stirrer was charged with benzene (20 mL) and the appropriate vinyl nitrone (1 mmol, 1 equiv). The mixture was exposed to a white LED, and the reaction was monitored by TLC. The resulting mixture was purified by chromatography (silica gel). 2-Benzyl-3-[(E)-2-phenylvinyl]oxaziridine (2d): Prepared from nitrone 1d (0.1 mmol) by the general protocol and purified by automated flash chromatography [silica gel (10 g cartridge), heptanes–EtOAc (20:1 to 1:1, 14 mL/min, 12 min)] as a clear oil; yield: 23 mg (98%); TLC: R_f 0.58 (heptanes–EtOAc, 3:1). IR (thin film) 3104, 3041, 2992, 1654, 1520, 1498, 1464, 1281, 1201 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.32 (m, 10 H), 7.01 (d, J = 16.0 Hz, 1 H), 5.98 (dd, J = 16.0, 7.1 Hz, 1 H), 4.40 (d, J = 7.1 Hz, 1 H), 4.06 (d, J = 8.0 Hz, 1 H), 3.90 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.5, 135.3, 135.2, 128.9, 128.8, 128.7, 128.6, 127.9, 126.9, 124.2, 80.9, 65.5. ESI-MS: m/z (%): (pos.) 238.1 ([M + H]⁺, 100); (neg) 236.1 ([M – H]^–, 100). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆NO: 238.30945; found: 238.30968. Absolute difference: 0.96 ppm.

Corresponding Author

Publication History

Received: 31 May 2023

Accepted after revision: 14 August 2023

Accepted Manuscript online:
14 August 2023

Article published online:
28 September 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1a Williamson KS, Michaelis DJ, Yoon TP. Chem. Rev. 2014; 114: 8016
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• 21 General protocol for synthesis of vinyloxaziridines from vinylnitrones: A 50 mL round-bottomed flask equipped with a magnetic stirrer was charged with benzene (20 mL) and the appropriate vinyl nitrone (1 mmol, 1 equiv). The mixture was exposed to a white LED, and the reaction was monitored by TLC. The resulting mixture was purified by chromatography (silica gel). 2-Benzyl-3-[(E)-2-phenylvinyl]oxaziridine (2d): Prepared from nitrone 1d (0.1 mmol) by the general protocol and purified by automated flash chromatography [silica gel (10 g cartridge), heptanes–EtOAc (20:1 to 1:1, 14 mL/min, 12 min)] as a clear oil; yield: 23 mg (98%); TLC: R_f 0.58 (heptanes–EtOAc, 3:1). IR (thin film) 3104, 3041, 2992, 1654, 1520, 1498, 1464, 1281, 1201 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.32 (m, 10 H), 7.01 (d, J = 16.0 Hz, 1 H), 5.98 (dd, J = 16.0, 7.1 Hz, 1 H), 4.40 (d, J = 7.1 Hz, 1 H), 4.06 (d, J = 8.0 Hz, 1 H), 3.90 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.5, 135.3, 135.2, 128.9, 128.8, 128.7, 128.6, 127.9, 126.9, 124.2, 80.9, 65.5. ESI-MS: m/z (%): (pos.) 238.1 ([M + H]⁺, 100); (neg) 236.1 ([M – H]^–, 100). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆NO: 238.30945; found: 238.30968. Absolute difference: 0.96 ppm.

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