Visible-light-induced bifunctionalisation of (homo)propargylic amines with CO₂ and arylsulfinates

Abstract

An unprecedented carboxylative sulfonylation of (homo)propargyl amines with CO₂ and sodium arylsulfinates under visible light irradiation has been developed with high efficiency. This ruthenium-catalysed photochemical protocol offers broad substrate scope giving 2-oxazolidinones and 2-oxazinones bearing alkyl sulfones in good yields under ambient reaction conditions. An in situ double bond isomerisation occurs in tandem. A mechanistic rationale for these radical-initiated carboxylative cyclisations involving sulfinyl radicals is presented, supported by control and quenching experiments.

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Over the past century atmospheric CO₂ concentration has increased dramatically causing severe climate changes.¹ In this context, utilisation of CO₂ for the functionalisation of organic molecules has gained much attention.² The conversion of CO₂ typically requires high energy due to its thermodynamic stability and kinetic inertness.³ Nonetheless, various synthetic methods have been developed to transform CO₂ into valuable organic compounds.⁴ Among them, multicomponent carboxylative bifunctionalisation of propargyl amines with CO₂ and other functional groups represents a promising strategy for synthesising valuable functionalised heterocycles like 2-oxazolidines.⁵ 2-Oxazolidine and 2-oxazinone motifs are frequently found in various bio-active molecules and chiral auxiliaries.⁶

Generally, carboxylative bifunctionalisation of propargyl amines affords functionalized vinyloxazolidinones, but the analogous conversion of homopropargyl amines to synthesise larger ring vinyloxazinones is still an unsolved challenge (Scheme 1a).⁷ Literature reported carboxylative bifunctionalisations of propargyl amines are depicted in Scheme 1b(1–4), including the synthesis of aryl, phosphono, selenyl and amino oxazolidinones.^8–11 While all have potential advantages, the previous methods use high loadings of metal catalysts, oxidants and/or elevated temperatures and are limited to propargyl amines. Therefore, carboxylative bifunctionalisations of (homo)propargyl amines with other functional groups under mild conditions are highly sought after. Recently, visible light-promoted fixation of CO₂ has played a promising role in organic synthesis because of the demonstrated complex bond constructions under mild reaction conditions and the environmentally benign nature of visible light.¹² On the other hand sulfones are versatile building blocks in organic chemistry as they can be readily transformed into various useful functional groups.¹³ Furthermore, sulfones are frequently found in pharmaceuticals, agrochemicals and functional materials.¹⁴ Sulfur is found more often than fluorine in drug molecules and recently alkyl/vinyl sulfones have been found to act as radical precursors in synthetic organic chemistry.¹⁵ To the best of our knowledge, carboxylative sulfonylation of alkynyl amines to obtain sulfonylated oxazolidinones/oxazinones is unknown in the literature. Continuing our interest in photocatalysis and sulfonylation,¹⁶ herein we report an unprecedented double bond isomerised carboxylative sulfonylation of (homo)propargylamines with CO₂ for the synthesis of oxazolidinones and oxazinones under mild photochemical conditions (Scheme 1c).

Scheme 1 Background and context of this work.

We began our investigation with amine 1aa and sulfinate 2a as model substrates to optimise photochemical carboxylative bifunctionalisation, and the results are shown in Table 1. Initially, the visible light irradiation of 1aa (0.14 mmol), 2a (0.21 mmol) and iodine (0.14 mmol) with MTBD as a base (0.28 mmol) under a CO₂ balloon in DMF (2 mL) afforded 3a in 50% isolated yield (entry 1). We examined different organic and inorganic bases (Cs₂CO₃, DBU and DABCO) and photocatalysts (Eosin Y, 4-CzIPN and Ru(bpy)₃²⁺) (entries 2–8). After screening it was found that 2 mol% Ru(bpy)₃²⁺ and 2 equiv. of Cs₂CO₃ in DMSO under a CO₂ atmosphere for 14 h were the best reaction conditions, yielding 3a in 84% yield (entry 8). Decreasing the loading of the catalyst and reaction time was found to lower the yield (entries 9 and 10). We screened different solvents: DMA was found to be less efficient than DMSO (entry 11) and other solvents such as MeCN, EtOH and H₂O failed to afford 3a (entries 12–14). No product was observed in the absence of CO₂ (entry 15) or blue light irradiation (entry 16).

Table 1 Optimisation of reaction conditions^a

Entry	Solvent	Catalyst	Additive	Base	Time (h)	Yield 3a^b (%)
a Standard reaction conditions: 1aa (0.14 mmol), 2a (0.21 mmol), base (0.28 mmol), catalyst (2 mol%) and additive (0.14 mmol) in solvent (2 mL) was irradiated with a blue LED (456 nm, 40 W) under a CO2 atmosphere. Ru(II) = Ru(bpy)3Cl2·6H2O. b Isolated yields. c 1 mol% Ru(II). d Reaction mixture was irradiated under N2. e Without light.
1	DMF	—	I2	MTBD	14	50
2	DMF	—	I2	Cs2CO3	14	48
3	DMF	Eosin Y	I2	Cs2CO3	14	55
4	DMF	—	I2	DABCO	14	0
5	DMF	—	I2	DBU	14	0
6	DMF	4-CzIPN	—	Cs2CO3	14	15
7	DMF	Ru(II)	—	Cs2CO3	14	81
8	DMSO	Ru(II)	—	Cs2CO3	14	84
9^c	DMSO	Ru(II)	—	Cs2CO3	14	68
10	DMSO	Ru(II)	—	Cs2CO3	10	71
11	DMA	Ru(II)	—	Cs2CO3	14	51
12	MeCN	Ru(II)	—	Cs2CO3	14	0
13	EtOH	Ru(II)	—	Cs2CO3	14	0
14	H2O	Ru(II)	—	Cs2CO3	14	0
15^d	DMSO	Ru(II)	—	Cs2CO3	14	0
16^e	DMSO	Ru(II)	—	Cs2CO3	14	0

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Having found suitable reaction conditions, we examined the generality of this photochemical carboxylative bifunctionalisation reaction and the results are shown in Table 2. Various propargyl amines with different N-substituents 1 and sulfinate 2a smoothly underwent photochemical carboxylative sulfonylation and afforded the corresponding oxazolidinones (3a–3t) in moderate to good yields. We established the structures of these novel double bond isomerized sulfonylative oxazolidinones from an X-ray crystal structure of 3a (see ESI† for details). α-Methyl and ethyl-substituted bulky propargyl amines 1ab and 1ac were well tolerated in this photochemical protocol giving the corresponding compounds 3b and 3c in 68% and 65% yields, respectively. N-Phenethyl-tethered propargyl amine 1ad afforded oxazolidone 3d in 82% yield. Furthermore, N-benzyl motifs bearing methoxyl groups at o/m/p-positions underwent photochemical carboxylative bifunctionalisation with sulfinate 2a smoothly, affording the corresponding sulfonylated oxazolidinones 3e–3g in 66–79% yield. Propargyl amines with halogen-substituents on the benzyl ring such as 2-Cl, 4-Cl, 3-Br and 4-Br were also suitable for this bifunctionalisation reaction giving the corresponding compounds 3g–3k in 69–75% yields. N-Benzyl motifs bearing electron-withdrawing groups such as 4-CN, 4-COOMe and 3-CF₃ were well tolerated in this photochemical method giving compounds 3l–3o in good yields. Aromatic heterocyclic furan-3-ylmethyl and aliphatic cyclohexyl and propyl-substituted propargyl amines were also well tolerated in this protocol and afforded the corresponding oxalidones 3o–3q in 62–82% yield. In contrast, N-phenyl and N-tosyl substituted propargyl amines failed to produce the corresponding sulfonylated oxazolidinones 3r and 3s, presumably due to the poorer nucleophilicity of the amines. Notably, N-benzylbut-3-yn-2-amine 1at and N-benzyl-2-methylbut-3-yn-2-amine 1au afforded the corresponding products 3t and 3u in 57% yield and in trace amounts, respectively.

Table 2 Scope of the synthesis of sulfonylative vinyloxazolidinones^ab

a Reaction conditions: 1 (0.14 mmol), 2a (0.21 mmol) and Ru(bpy)₃Cl₂·6H₂O (2 mol%) in DMSO (2 mL) was irradiated with a blue LED (456 nm, 40 W) under a CO₂ atmosphere. b Isolated yields. c 1.4 mmol scale, 346 mg.

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Then we addressed the unsolved challenge of the synthesis of vinyloxazinones using N-substituted homopropargyl amines under our optimised conditions and the results are depicted in Table 3. To our delight, N-benzylbut-3-yn-1-amine 1ba smoothly reacted with sulfinate 2a under this protocol and gave the corresponding oxazinone compound 4a in 52% yield. We established the structure of the novel sulfonylated oxazinone from an X-ray crystal structure of 4a (see ESI† for details). To the best of our knowledge, this is the first report of carboxylative functionalization of homopropargyl amines for the synthesis of 6-membered rings. Homopropargyl amines with electron-donating groups (4-Me), halogen-substituents (2-Cl and 3-Br) and electron-withdrawing groups (4-CO₂Me and 3-CF₃) on the benzyl ring smoothly reacted in this photochemical carboxylative sulfonylation reaction and afforded the corresponding compounds 4b–4f in 39–50% yield. N-Cyclohexyl homopropargyl amine 1bg and N-benzylpent-4-yn-2-amine 1bh were also well tolerated, giving the corresponding products 4g and 4h in moderate yields. Finally, we screened the scope of sulfinates in this photochemical bifunctionalisation. Halogen (4-Cl and 4-F) bearing sulfinates and simple benzenesulfinate 1bi–1bj reacted smoothly under this protocol affording the corresponding compounds 4i–4j in 38–49% yield. In contrast, alkyl sulfinate 1bl failed to produce compound 4l under these photochemical conditions.

Table 3 Scope of the synthesis of sulfonylative vinyloxazinones^ab

a Reaction conditions: 1 (0.14 mmol), 2 (0.21 mmol) and Ru(bpy)₃Cl₂·6H₂O (2 mol%) in DMSO (2 mL) was irradiated with a blue LED (456 nm, 40 W) under a CO₂ atmosphere. b Isolated yields.

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To gain insights into the reaction mechanism we performed quenching and control experiments (Scheme 2a and b). Addition of the radical scavenger TEMPO under standard reaction conditions stopped the production of 3a and 4a (Scheme 2aa and ab). Addition of BHT also lowered the yield of 3a (Scheme 2ac). Thus, both reactions are proposed to proceed via a radical pathway. When 1aa was subjected to the standard conditions without 2a the reaction failed to produce the carboxylative cyclization product 5 and the starting material 1aa was recovered in 91% yield (Scheme 2ba). The cyclized product 5 was synthesized¹⁷ and subjected to the standard conditions without CO₂ but this failed to produce the product 3a (Scheme 2bb). Both these reaction outcomes suggest that the reaction is not proceeding via carboxylative cyclization intermediate 5. When the reaction mixture was quenched after 5 h and analysed by HRMS, target product 3a and intermediate 6 were observed (Scheme 2bc). When 1aa was subjected to the standard conditions without CO₂ the reaction failed to produce intermediate 6, implying that in the case of free amine sulfinate 2a failed to react with propargyl amine (Scheme 2bd).

Scheme 2 Mechanistic investigations.

Based on the above experiments and earlier literature,¹⁸ we propose the reaction pathway of carboxylative sulfonylation (Scheme 3). Initially, a Ru^II complex is excited by the absorption of blue light, which then oxidises sulfinate 2 to form sulfinyl radical A and Ru^I species. Propargyl amine 1 reacts with CO₂ and a base to form carbamate intermediate B.¹⁹ The addition of sulfinyl radical A to carbamate B produces vinyl radical intermediate C. Intermediate C then undergoes single electron transfer (SET) with Ru, followed by cyclization to afford cyclic intermediate D. Intermediate D might undergo SET with Ru^I followed by H⁺ addition to produce radical intermediate E and regenerate the Ru^II complex. The reaction of intermediate E in the presence of a base and photocatalyst can result in the loss of H⁺ affording the final product 3. Alternatively, intermediate D in the presence of a base could form anion F/G and the addition of H⁺ to the intermediate F/G affords the final product 3.²⁰

Scheme 3 Plausible mechanism.

In conclusion, we have demonstrated a sustainable carboxylative sulfonylation of propargylamines with CO₂ and sodium arylsulfinates under photochemical conditions. This photochemical bifunctionalisation afforded a broad substrate scope of sulfonylated 5- and 6-membered heterocycles, 2-oxazolidinones (18 examples) and 2-oxazinones (11 examples), with good to moderate yields. A plausible mechanism was supported by control and quenching experiments. We anticipate that this methodology will enable further applications of carboxylative bifunctionalisation, especially with respect to homopropargyl amine bifunctionalisation with CO₂, which was previously unknown in the literature.

M. B. R. thanks the Irish Research Council for a Postdoctoral Fellowship (GOIPD/2022/576). We thank Julia Bruno-Colmenárez of the UCD X-Ray Diffraction Laboratory for the crystal structure of 3a and 4a. We thank SFI (18/RI/5702) for MS infrastructure, and the A2P CDT which is supported by Science Foundation Ireland (SFI) and the Engineering and Physical Sciences Research Council (EPSRC) under Grant No. 18/EPSRC-CDT/3582 and BiOrbic, the Bioeconomy SFI Research Centre, which is funded by Ireland's European Structural and Investment Programmes, Science Foundation Ireland (16/RC/3889) and the European Regional Development Fund.

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, characterisation, X-ray data for 3a and 4a and copies of NMR spectra. CCDC 2287477 and 2287478. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3cc04160c

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