Ground-state dioxygen undergoes metal-free [3 + 2]-annulations with allenes and nitrosoarenes under ambient conditions

We report novel [3 + 2]-annulations among ground-state ³O₂ (1 bar), allenes, and nitrosoarenes at low temperatures, efficiently yielding dioxygen-containing oxacycles.

Abstract

The cycloadditions of molecular dioxygen with neutral π-bond motifs rely heavily on singlet-state ¹O₂, whereas ground state ³O₂ is chemically inactive. Here we report novel [3 + 2]-annulations among ground-state ³O₂ (1 bar), allenes, and nitrosoarenes at low temperatures, efficiently yielding dioxygen-containing oxacycles. With less hindered 1-arylallene derivatives, these dioxygen species undergo skeletal rearrangement to 3-hydroxy-1-ketonyl-2-imine oxides. These cycloadditions represent valuable one-pot O,N,O-trifunctionalizations of allenes. Our EPR experiments confirm the presence of 1,4-diradical intermediates from an allene/nitrosoarene mixture, which manifest the hidden diradical properties of nitrosoarenes.

Introduction

Cycloadditions of two or three π-bond molecules are powerful tools to access carbo- or heterocycles. Ground-state ³O₂ has low-lying LUMO orbitals, but its triplet state greatly reduces its chemical reactivity toward neutral molecules¹ unless a metal catalyst is present. The cycloadditions of ³O₂ dioxygen rely nearly exclusively on prior photo-activation to form singlet-state ¹O₂ (ref. 1) that reacts with dienes,² olefins³ or even arenes⁴ in [n + 2]-cycloadditions (n = 2 and 4, Scheme 1, eqn (1)). This photolytic process requires a sensitizer in a cold bath (–40 °C) over a protracted period (>12 h) because highly energetic ¹O₂ might produce byproducts from the oxygen-ene reactions⁵ and oxidative C C cleavages.⁶ In the case of allenes, singlet dioxygen afforded a complicated mixture of undesired compounds. ^7a,b

Scheme 1. Cycloadditions of unsaturated hydrocarbons with ¹O₂ and ³O₂.

As ground-state ³O₂ is a free π-molecule and is available everywhere; its metal-free [n + 2]-cycloadditions with commonly used unsaturated hydrocarbons would provide a clean and cheap synthesis of valuable 1,n-diols, although there is no literature precedence. As far as we are aware, only 1,4-diradical precursors such as o-benzocyclobutanes,⁸ 1,2,6,7-octatetraenes,⁹ 2,3-dimethylenebicyclo[2.2.0]hexane¹⁰ and other 1,4-diazo species¹¹ reacted with ground-state ³O₂ in thermal [4 + 2]-cycloadditions; these precursors are too uncommon to show general utility. We recently achieved metal-catalyzed annulations of N-hydroxy allenylamines with nitrosoarenes via a single radical process.^7d In search of a breakthrough in dioxygen chemistry, we developed facile [3 + 2]-cycloadditions among nitrosoarenes, allenes and ground-state ³O₂ to efficiently afford N-(1,2-dioxolan-4-ylidene)aniline oxides (eqn (2)). Particularly notable are the ambient conditions: –15 to 0 °C, ³O₂ (1 bar), no light, no catalyst and no additive. Importantly, these facile spin-forbidden dioxygen annulations reveal a new role of nitrosoarenes as effective diradical precursors that is synthetically significant in nitroso chemistry.¹² In the context of nitroso/alkene and nitroso/alkyne reactions,¹³ theoretical calculations by Houk ^12e,f suggested the intermediacy of the diradical species, but these transient species could not be trapped with dioxygen or other small molecules.

2-Amino-1,3-diols are present in numerous natural products with diverse biological activity (Fig. 1).¹⁴ Catalytic O,N,O-trifunctionalization of allenes is a new appealing tool to assess these motifs, as noted by the work of Schomaker, who reported Rh-catalyzed intramolecular cyclizations of homoallenylsulfamate esters via a two-step sequence.^15a In contrast, our one-pot intermolecular O,N,O-functionalizations employ common and cheap nitrosoarenes, allenes and oxygen.

Fig. 1. O,N,O-Trifunctionalizations of allenes and selected natural products.

Results and discussion

Table 1 presents the optimized yields of a O,N,O-trifunctionalized molecule 3a from a mixture of allene 1a, nitrosobenzene 2a (n equiv.) and O₂ (1 bar). When 1.5 equiv. of nitrosobenzene 2a was used in cold THF (–15 °C), the yield was 43% (entry 1). The yield of 3a increased to 63% with nitrosobenzene in three fold proportions (entry 2). In other solvents, the yields of 3a were 50% in toluene, 54% in CH₃CN, and 58% in DCM (entries 3–5). The yield of 3a decreased substantially to 10% in THF at 25 °C (entry 6). The reaction under N₂ failed to yield the desired product 3a in a traceable amount (entry 7).¹⁶ Compound 3a assumes an E-configuration with its hydroxyl cis to the nitrone oxygen to form a hydrogen bond. This structure was inferred from X-ray diffraction measurements of its relative 3b ¹⁷ (Table 2 entry 1).

Table 1. Optimization of reaction conditions.

Entry	Solvent a	Gas	n	T (°C)	t (h)	Yield b (%)
1	THF	O2	1.5	–15	2	43
2	THF	O2	3	–15	2	63
3	Toluene	O2	3	–15	2	50
4	MeCN	O2	3	–15	2	54
5	DCM	O2	3	–15	2	58
6	THF	O2	3	25	2	10
7	THF	N2	3	–15	10	—

^a[1a] = 0.1 M.

^bProduct yields are reported after purification using a silica column.

Table 2. O,N,O-Trifunctionalizations of allenes with O₂ and ArNO ^{a , b} .

^a[1] = 0.1 M.

^bProduct yields are reported after purification using a silica column.

To assess the reaction scope, we applied these optimized conditions to additional mono- and 1,3-disubstituted allenes 1b–1g; Table 2 summarizes the results. For phenylallene 1a, its corresponding reactions with 4-methyl-, 4-methoxy- and 3,5-dimethylphenylnitroso species afforded 3-hydroxy-1-ketonyl-2-imine oxides 3b–3d in 54–68% yields (entries 1–3). Varied arylallenes 1b–1e (Ar = 4-MeC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄ and 3-thienyl) yielded desired compounds 3e–3h in satisfactory yields (50–74%, entries 4–6). 3-Substituted phenylallenes 1f and 1g (R = n-Bu and Ph) were also effective substrates for these cycloadditions (entries 8–10).

Notably, the reaction of sterically hindered 3-cyclohexyl-1-phenylallene 1i with 4-methoxyphenylnitroso 2c and O₂ (1 bar) afforded dioxygen-containing oxacycle 4a together with desired product 3l; the yields were 45% and 28%, respectively. Species 4a assumes an anti-configuration (dr > 20 : 1) according to its ¹H NOE spectra; this new compound was efficiently converted to compound 3l in hot THF (eqn (3)), via a Kornblum–DeLaMare rearrangement.²²

3

The kinetic stability of dioxygen-containing oxacycle 4a is enhanced with a suitable steric environment. We further tested the reactions on various 1-aryl-1-methylallenes 1j–1m with 4-methoxyphenylnitroso 2c and O₂ (1 bar) in THF (0 °C), generating dioxygen-containing compounds 4b–4e (Ar = 4-RC₆H₄, R = H, Me, MeO, Br) in satisfactory yields (Table 3, entries 1–4). The molecular structure of compound 4b was confirmed by its X-ray diffraction pattern.¹⁷ Various 1-aryl-3,3-dimethylallenes 1n–1q (Ar = 4-RC₆H₄, R = H, Me, MeO, Br), electron-rich nitrosoarenes and O₂ were also amenable to such cycloadditions, yielding desired compounds 4f–4m in satisfactory yields (60–72%, entries 5–12) except 4k in only 38% yield. This dioxygen cycloaddition was applicable to cyclohexylidene-derived phenylallene 1r, affording compound 4n in 66% yield (entry 13). Compounds 4 serve as the first examples of the cycloadditions of ground-state ³O₂ with unsaturated hydrocarbons at low temperatures.

Table 3. [3 + 2]-Cycloadditions among O₂, allenes and nitrosoarenes ^{a , b} .

^a[1] = 0.1 M.

^bProduct yields are reported after purification using a silica column.

An electron-deficient nitrosoarene is an inapplicable substrate, as shown by eqn (4). Under O₂, the reaction of trisubstituted allene 1p with 4-chlorophenylnitroso species 2f in cold THF (0 °C) afforded nitroso-containing cycloadduct 5a in 53% yield; the dioxygen-containing product, ca. 5%, was unstable for isolation (eqn (4)). In contrast, the same allene 1p could deliver dioxygen-containing species 4j and 4k using electron-rich nitrosoarenes under the same conditions (entries 9–10, Table 3).

4

5

Under nitrogen, trisubstituted allene 1p reacted with 4-methylphenylnitroso 2b in cold THF to form nitroso-containing cycloadduct 5b in 60% yield (eqn (5)). The stereochemistry and its E-configuration of this new compound was confirmed by its X-ray diffraction pattern.¹⁷ Such a new reaction represents a new and useful O,N,N-functionalization of allenes. A preliminary survey of the reaction scope is summarized in Table 4. We tested the reactions on 1,3-di- and 1,1,3-trisubstituted allenes 1g and 1t that reacted with nitroso-arenes (R = H, Cl, CO₂Et) to afford nitroso-containing cycloadducts 5c–5g in reasonable yields (58–83%). Furthermore, the anti-configuration of compound 5c was determined by X-ray diffraction.¹⁷

Table 4. [3 + 2]-Cycloadditions among allenes and nitrosoarenes under N₂ ^{a , b} .

^a[1] = 0.1 M.

^bProduct yields are reported after purification using a silica column.

Dioxygen-containing heterocycles 4 are readily reduced with Pd/C, H₂ (1 atm) in MeOH (23 °C)¹⁸ to cleave their O–O bonds, satisfactorily yielding desired 1,3-dihydroxy-2-imine oxides 6. These reductions highlight the utility of molecular oxygen to afford 1,3-dihydroxy-2-amino derivatives. Several instances of affording tertiary 1,3-alcohol derivatives are illustrated in eqn (6) and (7); their chemical yields exceed 65%. Under these reductions, the valuable nitrone functionalities of these acyclic 1,3-diols remain intact as indicated by their HRMS and ¹³C-NMR spectra.

6

7

The facile cycloadditions among allenes, nitrones and ground-state O₂ are very astonishing because an intersystem crossing (ISC) must be involved for one key intermediate. To investigate the mechanism, we examined the reaction of 1-phenyl-3-cyclopropylallene 1s with 4-methylphenylnitroso species 2b under O₂, yielding compound 3m in 71% yield; this transformation did not induce cyclopropane cleavage because of the stability of the phenylallylic radical A (eqn (8)).¹⁹ We thus exclude the intermediacy of the dicarbon radical A′, although analogous carbon radicals were postulated for the o-quinodimethine species.⁸ We isolated compound 7 in 13% yield from the reaction of 1-phenylallene 1a with PhNO (1.2 equiv.) and TEMPO (2 equiv.) under N₂, indicating the formation of diradical intermediates (eqn (9)). We employed EPR to characterize the diradical species from a mixture of 3,3-dimethyl-1-phenylallene 1n and nitrosobenzene 2a in THF at 0 °C (0.5 h). Fig. 2 (top) shows the EPR signal of the diradical species; the intensity of this signal remains unchanged for 5 h under N₂. The simulation analysis was performed using the EasySpin program.²⁰ The satisfactory fit was achieved with a two-component simulation (bottom). The abundant component (70%) corresponds to nitrogen-centered diradicals (g = 2.00616, a _N = 10.7 G and 3.0 G).²¹ The minor component corresponds to a monoradical nitroxide with a _N = 10.7 G. Notably, when recorded at T < 130 K, the spectrum exhibits a well-known nitroxide rigid-limit lineshape in accordance with the above simulation result; the coupling of unpaired electrons with the nitrogen center is evident.

8

9

Fig. 2. Observed and simulated EPR spectra.

Scheme 2 depicts a plausible mechanism to rationalize the remarkable facility of such dioxygen annulations. We postulate that allene 1 reacts initially with nitrosobenzene to form 1,4-diradical species A, which is likely to be a major component, as detected in the EPR spectra; its nitroxy and allylic radicals are expected to couple with nitrogen in two magnitudes, i.e. a _N = 10.7 G and 3.0 G respectively.²¹ The capture of molecular dioxygen ³O₂ by 1,4-diradical species A forms peroxy diradical B in a triplet state, as the two radical centers of species B are remote from each other, rendering an intersystem crossing (ISC) feasible. After a change of spin state, singlet-state diradical B′ is expected to form primary 1,2-oxaziridine diradical C through a 3-exo-trig cyclization that is more feasible than an alternative 5-endo-trig cyclization.²³ A final radical–radical coupling of resulting species C forms precursor D, and ultimately yields desired 1,2-dioxolanes 4. This proposed path rationalizes the formation of compound 7 from the TEMPO experiment (eqn (9)) well. The trapping of the 1,4-biradical generates single radical species F that undergoes a rapid 3-exo-trig cyclization to form benzylic radical G. A second trapping of this species with the TEMPO radical is expected to yield species I that is prone to hydrolysis on a silica column to yield observed product 7.

Scheme 2. A plausible mechanism.

Conclusions

Prior to this work, singlet state oxygen ¹O₂ failed to react with allenes to give useful oxygenated products.⁷ This study reports the first examples of metal-free [3 + 2]-cycloadditions among allenes, nitrosoarenes and ground-state ³O₂ (1 bar) at low temperatures, efficiently yielding dioxygen-containing oxacycles.²⁴ With less hindered 1-arylallene derivatives, the resulting oxacycles undergo skeletal rearrangement to 3-hydroxy-1-ketonyl-2-imine oxides. These transformations highlight a cheap, efficient and clean synthesis of 1,3-dihydroxy-2-amino derivatives. Our experimental data indicate that an initial attack of a nitrosoarene at an allene generates a diradical species that is detectable with EPR. We envisage that the concept of nitrosoarenes as diradical precursors will inspire new synthetic concepts.