Enantioselective sulfonylation using sodium hydrogen sulfite, 4-substituted Hantzsch esters and 1-(arylethynyl)naphthalen-2-ols

Abstract

Synthesis of sulfonyl-containing axially chiral styrenes through a catalytic asymmetric three-component reaction of 4-substituted Hantzsch esters, NaHSO₃ (sodium hydrogen sulfite), and 1-(arylethynyl)naphthalen-2-ols in the presence of a photocatalyst under visible light irradiation is reported. This transformation proceeds through a radical process under mild conditions, leading to axially chiral (S,E)-1-(1-(alkylsulfonyl)-2-arylvinyl)naphthalen-2-ols in good yields with excellent enantioselectivities. During the reaction process, excellent regioselectivity and chemoselectivity were observed as well. Notably, sodium hydrogen sulfite is used as the sulfur dioxide surrogate in this organocatalytic enantioselective radical sulfonylation under photoinduced conditions.

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Significant progress has been achieved in the generation of sulfonyl compounds with the insertion of sulfur dioxide.^1,2 In such transformations, sulfur dioxide surrogates including DABCO·(SO₂)₂ and inorganic sulfites have been used widely, which show remarkable advantages namely easy availability and operational simplicity. Over the past decade, we have focused on radical reactions for the preparation of sulfonyl compounds from sulfur dioxide surrogates.³ The key intermediate of a sulfonyl radical can be formed via a combination of an alkyl/alkenyl radical with sulfur dioxide. Although various strategies with regard to the radical reaction of sulfur dioxide have been developed, asymmetric radical reactions for the enantioselective synthesis of sulfonyl compounds from sulfur dioxide are rare. The first example of asymmetric sulfonylation from sulfur dioxide was reported by Han, Pan and coworkers (Scheme 1, eqn (a)),⁴ who developed a reaction of an unsaturated carboxylic acid, aryldiazonium tetrafluoroborate, and DABCO·(SO₂)₂. However, the yields and enantioselectivities were low to moderate and were not satisfactory. A reaction of MBH acetate, 4-substituted Hantzsch ester and NaHSO₃ (sodium hydrogen sulfite) catalyzed by a chiral tertiary amine by using Mes-Acr⁺ as the photocatalyst under visible light irradiation was described, although the corresponding chiral allylic sulfone was afforded in 43% yield with 33% ee.⁵ Subsequently, Gong and co-workers demonstrated a photoinduced asymmetric sulfonyl radical addition to α,β-unsaturated carbonyl compounds under chiral nickel catalysis (Scheme 1, eqn (b)).⁶ The sulfonyl radical was generated in situ from a reaction of the C(sp³)–H precursor and DABCO·(SO₂)₂. Lian and coworkers disclosed the synthesis of chiral β-sulfonyl nitriles via a copper-catalyzed four-component enantioselective arylsulfonylcyanation of vinylarenes with a bench-stable SO₂ surrogate (SOgen) (Scheme 1, eqn (c)).⁷ Very recently, we developed a photoinduced asymmetric radical approach to access sulfonyl-containing axially chiral styrenes through a three-component reaction of potassium alkyltrifluoroborates, potassium metabisulfite and 1-(arylethynyl)naphthalen-2-ols (Scheme 1, eqn (d)).⁸ Later, the synthesis of chiral β-sulfonyl carbonyl compounds through an organocatalytic enantioselective radical reaction of potassium alkyltrifluoroborates, DABCO·(SO₂)₂ and α,β-unsaturated carbonyl compounds under photoinduced conditions was achieved (Scheme 1, eqn (d)).⁹

Scheme 1 Synthesis of chiral sulfonyl compounds.

In the past few years, the development of methods for the generation of axially chiral alkenes has attracted continuous interest due to their great potential in the development of chiral ligands, catalysts and functional materials.¹⁰ Compared with the well-established atropisomeric aryl-dihydronaphthyl skeleton,¹¹ the catalytic asymmetric synthesis of axially chiral styrenes with non-cyclic alkenes is less explored due to the challenges of a low rotational barrier and a more flexible framework.¹² In 2017, Tan and co-workers reported a seminal work on the atroposelective construction of axially chiral styrenes through an organocatalytic asymmetric nucleophilic addition to alkynals.¹³ Later, several strategies were successively developed to access axially chiral styrenes including our work related to asymmetric radical reactions (Scheme 1, eqn (d)).^8,14 Encouraged by the recent advances in sulfur dioxide insertion chemistry with inorganic sulfites via a radical process, we envisioned that axially chiral styrenes would also be accessible through a photoinduced asymmetric radical sulfonylation using inorganic sulfite as the sulfur dioxide surrogate and 4-substituted Hantzsch ester as the radical precursor (Scheme 2). We conceived that 1-(arylethynyl)naphthalen-2-ol 1 would be an ideal choice as the substrate, which would convert to the allene intermediate Int-I ^8,13 in the presence of a chiral organocatalyst. Meanwhile, a radical formed in situ from the 4-substituted Hantzsch ester 2 under suitable conditions would be trapped by sulfur dioxide, giving rise to a sulfonyl radical. Subsequently, the sulfonyl radical would react with the allene intermediate Int-I, producing a radical intermediate. After reductive single electron transfer and protonation, sulfonyl-containing axially chiral styrene 3 would be formed. During the transformation, chirality could be introduced via a coordination of a substrate with a chiral organocatalyst. Herein, we report the synthesis of sulfonyl-containing axially chiral styrenes through a catalytic asymmetric three-component reaction of 4-substituted Hantzsch esters, NaHSO₃ (sodium hydrogen sulfite), and 1-(arylethynyl)naphthalen-2-ols in the presence of a photocatalyst under visible light irradiation. This transformation proceeds through a radical process under mild conditions, leading to axially chiral (S,E)-1-(1-(alkylsulfonyl)-2-arylvinyl)naphthalen-2-ols in good yields with excellent enantioselectivity and regioselectivity. Notably, sodium hydrogen sulfite is used as the sulfur dioxide surrogate in this asymmetric reaction.

Scheme 2 Generation of axially chiral styrenes from inorganic sulphite and 4-substituted Hantzsch ester.

Recently, we demonstrated that 4-substituted Hantzsch esters were excellent radical precursors in the sulfonylation process with sulfur dioxide under visible light irradiation in the presence of a photocatalyst.¹⁵ Inspired by these results, we commenced our study by using 1-(phenylethynyl)naphthalen-2-ol 1a and 4-cyclohexyl Hantzsch ester 2a as the model substrates with inorganic sulfite as the sulfur dioxide surrogate to explore the optimal reaction conditions (Table 1). At the outset, potassium metabisulfite was employed in the reaction by using compound A as the organocatalyst and Mes-Acr⁺ClO₄⁻ as the photocatalyst in PhCF₃ at 20 °C under visible light irradiation (Table 1, entry 1). However, no reaction occurred under these conditions. Interestingly, the desired product 3a was afforded in 21% yield and 99% ee when sodium metabisulfite was used instead (Table 1, entry 2). Further investigation showed that the result was dramatically improved when sodium hydrogen sulfite was utilized as the source of sulfur dioxide (80% yield, 99% ee, Table 1, entry 3). Encouraged by this result, we then examined the reaction with other bifunctional organocatalysts B–D (Table 1, entries 4–6). However, no better result was obtained. Other solvents including CH₂Cl₂, MeCN, 1,4-dioxane, THF and CHCl₃ were screened subsequently (Table 1, entries 7–11). Remarkably, excellent enantioselectivities were observed in all cases, although the yields were not satisfactory. No reaction took place for control experiments without light irradiation or photocatalysts. A similar result was achieved when DABCO·(SO2)2 was used as a replacement for sodium hydrogen sulfite (Table 1, entry 12). Considering the easy availability and cost, using sodium hydrogen sulfite as the source of sulfur dioxide would be ideal for reaction development.

Table 1 Initial studies on the reaction of 1-(phenylethynyl)naphthalen-2-ol 1a, 4-substituted Hantzsch ester 2a and sodium hydrogen sulfite

Entry	“SO2”	Cat.* (mol%)	Solvent	Yield^a (%)	ee^b (%)
Reaction conditions: 1-(phenylethynyl)naphthalen-2-ol 1a (0.2 mmol), 4-substituted Hantzsch ester 2a (0.4 mmol), NaHSO3 (0.4 mmol), Mes-Acr^+ClO4^− (5 mol%), Cat.* (10 mol%), solvent (2.0 mL), blue LEDs, 48 h.a Isolated yield based on 1-(phenylethynyl)naphthalen-2-ol 1a.b Determined by HPLC analysis on a chiral stationary phase.
1	K2S2O5	A	PhCF3	n.r.	—
2	Na2S2O5	A	PhCF3	21	99
3	NaHSO3	A	PhCF3	80	99
4	NaHSO3	B	PhCF3	78	94
5	NaHSO3	C	PhCF3	76	96
6	NaHSO3	D	PhCF3	80	90
7	NaHSO3	A	CH2Cl2	79	96
8	NaHSO3	A	MeCN	43	96
9	NaHSO3	A	1,4-Dioxane	5	96
10	NaHSO3	A	THF	23	96
11	NaHSO3	A	CHCl3	76	98
12	DABCO·(SO2)2	A	PhCF3	83	98

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With the above-mentioned optimal conditions in hand, we then explored the substrate scope of this organocatalytic asymmetric three-component reaction of 1-(arylethynyl)naphthalen-2-ols 1, 4-substituted Hantzsch esters 2 and sodium hydrogen sulfite in the presence of a photocatalyst under visible light irradiation (Table 2). In general, the reaction proceeded efficiently with a wide range of substrates, leading to the corresponding products 3 in moderate to good yields with universally excellent enantioselectivities. For example, 1-(phenylethynyl)naphthalen-2-ol 1a reacted well with 4-substituted Hantzsch esters 2 and sodium hydrogen sulfite, giving rise to the desired products 3a–3d in 97–99% ee. Subsequently, diverse 1-(arylethynyl)naphthalen-2-ols 1 were examined in the reaction of 4-cyclopentyl Hantzsch ester and sodium hydrogen sulfite under the standard conditions. Various functional groups were compatible with satisfactory results. Changing the aryl group of R² to alkyl and heteroaryl groups had little effect on the outcome of enantioselectivities. The absolute configuration of the product was determined to compare with a previous report.⁸

Table 2 Scope exploration for the reaction of 1-alkynylnaphthalen-2-ols 1, 4-substituted Hantzsch esters 2 and NaHSO₃^a

a Isolated yield based on 1-(phenylethynyl)naphthalen-2-ols 1.

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To further evaluate the practicality of this method, the large-scale synthesis of axially chiral (S,E)-1-(1-(alkylsulfonyl)-2-arylvinyl)naphthalen-2-ol 3e was performed at the 2 mmol scale with 1-(phenylethynyl)naphthalen-2-ol 1a, 4-cyclopentyl Hantzsch ester 2b and sodium hydrogen sulfite in the presence of a photocatalyst under visible light irradiation. As shown in Scheme 3, the desired product 3e was obtained in 53% yield and 97% ee.

Scheme 3 Large-scale synthesis.

Next, several control experiments were carried out to elucidate the reaction pathway. No reaction took place without the addition of a chiral organocatalyst or photocatalyst. Additionally, the reaction failed to provide the desired product 5 (Scheme 4) when the hydroxyl group in 1-(phenylethynyl)naphthalen-2-ol 1a was protected as the acetyl group (OAc). This result showed that the hydroxyl group played a crucial role during the reaction process. Moreover, the transformation was completely hampered with the addition of 4.0 equiv. of the radical scavenger TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) under the standard conditions (Scheme 4). Consequently, the radical trapping adduct was detected by HRMS (high-resolution mass spectrometry). These preliminary results suggested that a radical process would be involved in this organocatalytic asymmetric reaction.

Scheme 4 Control experiments.

On the basis of the above experiment results and previous reports on organocatalytic asymmetric radical transformations,¹⁴ we proposed a plausible reaction pathway for this photoinduced enantioselective radical sulfonylation (Scheme 5). We reasoned that 1-(arylethynyl)naphthalen-2-ol 1 would be converted to allene Int-I with the assistance of the chiral organocatalyst. Meanwhile, an alkyl radical would be produced from the 4-substituted Hantzsch ester 2 through a single electron transfer by the photocatalyst under visible light irradiation, which would be trapped by sulfur dioxide, affording the alkylsulfonyl radical. Subsequently, the enantioselective addition of the alkylsulfonyl radical to allene Int-I would occur, giving rise to the radical intermediate Int-II. After a reductive single electron transfer with an excited photocatalyst, the anion intermediate Int-III would be produced, which would be isomerized to intermediate Int-IV. Further protonation of intermediate Int-IV would provide the corresponding product 3.

Scheme 5 Proposed mechanism.

In conclusion, we report an efficient strategy for the synthesis of sulfonyl-containing axially chiral styrenes through a catalytic asymmetric three-component reaction of 4-substituted Hantzsch esters, NaHSO₃ (sodium hydrogen sulfite), and 1-(arylethynyl)naphthalen-2-ols in the presence of a photocatalyst under visible light irradiation. This transformation proceeds through a radical process under mild conditions, leading to axially chiral (S,E)-1-(1-(alkylsulfonyl)-2-arylvinyl)naphthalen-2-ols in good yields with excellent enantioselectivities. During the reaction process, excellent regioselectivity and chemoselectivity are observed as well. Notably, sodium hydrogen sulfite is used as the sulfur dioxide surrogate in this organocatalytic enantioselective radical sulfonylation under photoinduced conditions.

Data availability

The data supporting this study are available within the article and the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no. 22171206), the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (no. 2019R01005), and the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (2020ZD04) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data, copies of ¹H and ¹³C NMR spectra. See DOI: https://doi.org/10.1039/d2qo01654k

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