Palladium-Catalyzed Cycloisomerization of Carbamimidothioates

Abstract

A palladium-catalyzed cycloisomerization of carbamimidothioates with the formation of a quaternary carbon and a sulfide is described. The use of (IPr)Pd(allyl)Cl (CX21), K₃PO₄, and Me-C(OTBS)=NTBS in refluxing xylenes was optimal, and the methoxycarbonyl group was the most suitable substituent for the nitrogen atom of the carbamimidothioate. Phenyl and alkyl groups can be used as tethers for carbamimidothioates, and alkyl and aryl carbamimidothioates can undergo Pd-catalyzed cycloisomerization in high yields.

Reactions with an excellent atom economy must be developed to reduce environmental impacts. Isomerization reactions involving C–C bond formations that afford constitutional isomers are particularly useful as they do not generate byproducts; moreover, they render the isolation and purification process easy in both industrial- and laboratory-scale reactions. Cycloisomerizations that convert the degree of unsaturation of multiple bonds into cyclic constitutional isomers, along with C–C bond formation, have been reported.[1] Additionally, cycloisomerization through the successive reactions of single-bond cleavage, cyclization with C–C bond formation, and single-bond formation to afford constitutional isomers has been achieved.[2]

Here, we report a Pd-catalyzed cycloisomerization of carbamimidothioates. This cycloisomerization efficiently afforded constitutional isomers by forming a quaternary carbon and a C–S bond.

Transition-metal-catalyzed cascade reactions are important because they permit the formation of quaternary carbons and successive C–C bonds. It has been reported that the oxidative addition of aryl halides bearing a disubstituted terminal alkene, such as compound 1, in the presence of a Pd catalyst affords the σ-aryl Pd complex 2, which cyclizes to afford the σ-alkyl Pd complex 3 with the formation of a quaternary carbon. Further reaction with TIPSSPh [(i-Pr)₃SiSPh] and Cs₂CO₃ affords an alkyl phenyl sulfide 4 (Scheme [1]).[3] Additionally, a Pd-catalyzed thiocarbonylation proceeds in the presence of carbon monoxide.[4] Recently, further developments have been made in the above two reactions by using thioesters as thiolate sources instead of TIPSSPh.[5] These reactions are useful in synthetic chemistry because they permit the formation of quaternary carbons and the introduction of functional groups at adjacent positions.

A Pd-catalyzed coupling reaction of organoboron and tin compounds with imidothiocarbonate 5 has also been reported, along with its utilization for the synthesis of imides 6 (Scheme [2]).[6] In this reaction, the oxidative addition of compound 5 to the Pd catalyst affords the imidoyl palladium complex 7, which undergoes transmetalation with an organoboron or organotin compound, followed by reductive elimination and hydrolysis to form imides 6.

The reactions presented in Schemes 1 and 2 suggest that the oxidative addition reaction of compound 8 (Scheme [3]) in the presence of a Pd catalyst might afford the imidoyl Pd complex 9, which might undergo a cyclization and concomitant formation of a quaternary carbon; subsequently, a successive reductive elimination of the resulting σ-alkyl Pd complex 10 might afford 11. This reaction can also be viewed as a cycloisomerization reaction, because 11 is a constitutional isomer of 8. The scaffold of 11 is present in some bioactive natural products, including hexahydropyrrolo[2,3-b]indole and its dimeric alkaloids such as (–)-physoventine, (–)-physostigmine, and (+)-folicanthine (Figure [1]).

We therefore investigated the Pd-catalyzed cycloisomerization of carbamimidothioates. First, we examined the cycloisomerization of carbamimidothioate 13a, which was synthesized by the conversion of the known compound 12 into 13a by reaction with potassium isothiocyanate and methyl chloroformate, and subsequent S-arylation (Scheme [4]).

When the Pd-catalyzed cycloisomerization of 13a was examined using Pd(PPh₃)₄ (10 mol%) as the catalyst in toluene at 100 °C for 36 hours, compound 14a was obtained in 43% yield (Table [1], entry 1). The yield increased to 51% when (IPr)Pd(allyl)Cl (CX21)[7] was used as the catalyst (entry 2) and to 54% when both CX21 and K₂CO₃ (3 equiv) were used (entry 3). However, it decreased to 8% when CX21 and Cs₂CO₃ were used (entry 4). We therefore tested other additives, and a yield of 67% was obtained by using K₃PO₄ (entry 5). Evidently, the use of smaller amounts of K₃PO₄ decreased the yield (entries 6 and 7). To enhance the reaction, the solvent was changed to xylenes, and the reaction was conducted using CX21 and three equivalents of K₃PO₄ at the reflux temperature. Consequently, the reaction time was shortened to two hours and the yield increased to 94% (entry 8). It had been previously reported that the addition of MeC(OTMS)=NTMS (BSA) improves the yield of Pd-catalyzed reactions of organosulfur compounds.[3b] We therefore performed the reaction in the presence of BSA under the conditions of entry 8, and obtained compound 14a in 95% yield; however, consumption of the starting material 13a required five hours (entry 9). Because the addition of BSA was effective, other silylating reagents were also investigated. The reaction in the presence of MeC(OTBS)=NTBS (BTBSA) resulted in a faster (2 h) disappearance of 13a, and afforded 14a in 96% yield (entry 10).[8]

Table 1 Optimization of the Reaction Conditions for the Pd-Catalyzed Cycloisomerization of Compound 13a

Entry	Catalyst	Solvent	Additive(s) (equiv)	Yielda (%)
1	Pd(PPh3)4	tolueneb	–	43
2	CX21	tolueneb	–	51
3	CX21	tolueneb	K2CO3 (3.0)	54
4	CX21	tolueneb	Cs2CO3 (3.0)	8
5	CX21	tolueneb	K3PO4 (3.0)	67
6	CX21	tolueneb	K3PO4 (2.0)	59
7	CX21	tolueneb	K3PO4 (1.0)	57
8	CX21	xylenesc	K3PO4 (3.0)	94
9	CX21	xylenesd	K3PO4 (3.0) + BSA (2.0)	95
10	CX21	xylenesc	K3PO4 (3.0) + BTBSA (2.0)	96

^a Isolated yield.

^b 100 °C, 36 h.

^c Reflux, 2 h.

^d Reflux, 5 h.

We investigated the reaction of 13a (R¹ = Ph, R² = CO₂Me) to optimize the reaction conditions, as summarized in Table [1]. However, we were also interested in whether similar reactions of carbamimidothioates 13b–e bearing other substituents on the nitrogen atom would also proceed (Table [2]).

Table 2 Optimization of the Substituent on the Carbamimidothioate 13

Entry	R1	R2	Time (h)	Product	Yielda (%)
1	Ph	CO2Me	2	14a	96
2	Ph	Ph	36	14b	91
3	Ph	p-O2NC6H4 (14c)	3	14c	78
4	Ph	2-pyridyl	21	14d	83
5	Me	Me	24	14e	78

^a Isolated yield.

The optimized reaction conditions listed in Table [1], entry 10 [CX21 (10 mol%), K₃PO₄ (3.0 equiv), BTBSA (2.0 equiv), xylenes, reflux] were used for the reactions of 13b–e.[9] First, in the case of 13b (R¹ = R² = Ph), the desired product was obtained in 91% yield (Table [2], entry 2); however, the starting material 13b took 36 hours to disappear. The reaction of 13c, in which a p-nitrophenyl group was introduced as substituent R², afforded the desired product 14c in 78% yield within three hours (entry 3). The reaction of 13d, bearing a pyridyl group that could coordinate with the palladium atom of the imidoyl palladium intermediate, took 21 hours to afford the desired product 14d in 83% yield (entry 4). The preparation of 13f (R¹ = Ph; R² = Me)[10] was difficult; however, 13e (R¹ = R² = Me) was prepared and subjected to the reaction, affording 14e in 78% yield in a reaction that required 24 hours to complete. As described above, although the reactions of all the substrates 13a–e afforded the desired products, the reactions of substrates bearing an electron-withdrawing R² group (13a and 13c) proceeded more quickly, and the methoxycarbonyl group was found to be the optimal R² substituent of 13.

By using our optimized conditions, we studied the substrate scope by changing the substituent R³. The synthesized substrates and the reaction results are shown in Scheme [5]. When the substituent R³ was a tolyl group, products 14f–h were obtained yields of 89, 87, and 86%, respectively. When a 3,5-dimethylphenyl group was used, the yield of 14i was 84%, whereas with a mesityl (2,4,6-trimethylphenyl) group, the yield of 14j was 83%. When the R³ was an alkylphenyl group (14f–j), no significant changes were observed in the yields or reaction times. The formation of 14j required 60 hours; however, the reaction was probably slowed by steric hindrance from the bulky mesityl group.

When R³ was a phenyl group with an electron-donating methoxy group, 14k was obtained in 90% yield, whereas when R³ was a phenyl group with an electron-withdrawing nitro or trifluoromethyl group, 14l and 14m were obtained in yields of 71 and 85%, respectively. Therefore, compared with 14k, products 14l, and 14m were obtained in 24 and 12 hours, respectively, indicating that the reaction is faster when R³ is a phenyl group with an electron-donating substituent.

When the substituent R³ was a 2-thienyl or 1-naphthyl group, products 14n and 14o were both obtained in 90% yield, whereas when it was methyl group, product 14p was obtained in 76% yield, which increased to 96% when one equivalent of BTBSA was used. When the substituent R³ was benzyl, 14q was obtained in 60% yield; however, this increased to 95% when the reaction was conducted using BSA instead of BTBSA in refluxing toluene. Therefore, when the substituent R³ is alkyl, the reaction is completed in 0.5 hours and the yield is excellent. The above results suggest that the reaction is faster when R³ is electron donating.

To further explore the substrate scope, the reactions of aliphatic substrates were investigated (Scheme [6]). The substrates were prepared according to the procedure shown in Scheme [4]. Initial studies were conducted by using 15a bearing a 1-naphthyl group, which made the compound easier to handle and facilitated the ring-closing reaction by bringing the reaction points closer to one another, owing to steric bulkiness. When the reaction of 15a [11] was performed under the same conditions as those in Scheme [5], the desired cycloisomerization proceeded to afford 16a in 95% yield. As the reaction of 15a bearing a 1-naphthyl group proceeded satisfactorily, reactant 15b bearing a 4-methoxyphenyl group, which could be oxidatively deprotected by treatment with CAN or by other means, was subjected to the same reaction conditions, and the desired product 16b was obtained in 93% yield. The reaction of 15c (n = 1; R³ = Ph; R⁴ = p-MeOC₆H₄) also proceeded, giving 16c in 81% yield. Furthermore, the reaction of 15d (n = 1; R³ = Me; R⁴ = Me) with a methyl group on the nitrogen atom (which had little effect on bringing the reaction points closer due to steric bulkiness) afforded the desired product 16d in 89% yield. However, 16e and 16f, containing a six-membered ring, were not produced in this reaction.

In summary, we have developed a Pd-catalyzed cycloisomerization of carbamimidothioates, accompanied by the formation of quaternary carbon and sulfide moieties. The use of CX21, K₃PO₄, and BTBSA in refluxing xylenes was optimal, and the methoxycarbonyl group was the most suitable substituent for the nitrogen atom of the carbamimidothioate. Phenyl and alkyl groups can be used as tethers for carbamimidothioates, and alkyl and aryl carbamimidothioates can undergo Pd-catalyzed cycloisomerization in high yields. Further investigations on the substrate scope and related reactions are underway, and the results will be reported in subsequent papers.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

This work was the result of using research equipment (C1020, C1027, and C1028) shared with a MEXT Project for promoting public utilization of advanced research infrastructure (Program for supporting construction of core facilities); Grant Number: JPMXS0440500023.

• References and Notes


For selected papers, see:
• 1a Hosseyni S, Wojtas L, Li M, Shi X. J. Am. Chem. Soc. 2016; 138: 3994
  CrossrefPubMedSearch in Google Scholar
• 1b Aubert C, Fensterbank L, Garcia P, Malacria M, Simonneau A. Chem. Rev. 2011; 111: 1954
  CrossrefPubMedSearch in Google Scholar
• 1c Nolan SP. Acc. Chem. Res. 2011; 44: 91
  CrossrefPubMedSearch in Google Scholar
• 1d Michelet V, Toullec PY, Genêt J.-P. Angew. Chem. Int. Ed. 2008; 47: 4268
  CrossrefPubMedSearch in Google Scholar
• 1e Fürstner A, Davies PW. Angew. Chem. Int. Ed. 2007; 46: 3410
  CrossrefPubMedSearch in Google Scholar

Selected papers on Pd-catalyzed reactions; for carbothiolation, see:
• 2a Delcaillau T, Schmitt HL, Boehm P, Falk E, Morandi B. ACS Catal. 2022; 12: 6081
  CrossrefSearch in Google Scholar

Thioacylation:
• 2b Wu J, Xu W.-H, Lu H, Xu P.-F. Adv. Synth. Catal. 2021; 363: 3013
  CrossrefSearch in Google Scholar

Oxycyanation:
• 2c Koester DC, Kobayashi M, Werz DB, Nakao Y. J. Am. Chem. Soc. 2012; 134: 6544
  CrossrefPubMedSearch in Google Scholar

Selenocarbamoylation:
• 2d Toyofuku M, Murase E, Nagai H, Fujiwara S.-i, Shin-ike T, Kuniyasu H, Kambe N. Eur. J. Org. Chem. 2009; 3141
  Crossref

Carboiodination and Carbohalogenation:
• 2e Marchese AD, Durant AG, Reid CM, Jans C, Arora R, Lautens M. J. Am. Chem. Soc. 2022; 144: 20554
  CrossrefPubMedSearch in Google Scholar
• 2f Chen X, Zhao J, Dong M, Yang N, Wang J, Zhang Y, Liu K, Tong X. J. Am. Chem. Soc. 2021; 143: 1924
  CrossrefPubMedSearch in Google Scholar
• 2g Newman SG, Howell JK, Nicolaus N, Lautens M. J. Am. Chem. Soc. 2011; 133: 14916
  CrossrefPubMedSearch in Google Scholar
• 2h Liu H, Li C, Qiu D, Tong X. J. Am. Chem. Soc. 2011; 133: 6187
  CrossrefPubMedSearch in Google Scholar
• 2i Newman SG, Lautens M. J. Am. Chem. Soc. 2011; 133: 1778
  CrossrefPubMedSearch in Google Scholar

Cyanoamidation:
• 2j Kamisaki H, Yasui Y, Takemoto Y. Tetrahedron Lett. 2009; 50: 2589
  CrossrefSearch in Google Scholar
• 2k Yasui Y, Takeda H, Takemoto Y. Chem. Pharm. Bull. 2008; 56: 1567
  CrossrefPubMedSearch in Google Scholar
• 2l Yasui Y, Takemoto Y. Chem. Rec. 2008; 8: 386
  CrossrefPubMedSearch in Google Scholar
• 2m Kobayashi Y, Kamisaki H, Takeda H, Yasui Y, Yanada R, Takemoto Y. Tetrahedron 2007; 63: 2978
  CrossrefSearch in Google Scholar
• 2n Kobayashi Y, Kamisaki H, Yanada R, Takemoto Y. Org. Lett. 2006; 8: 2771
  CrossrefPubMedSearch in Google Scholar
• 3a Hosoya Y, Yasukochi H, Mizoguchi K, Nakada M. Heterocycles 2022; 104: 655
  CrossrefSearch in Google Scholar
• 3b Hosoya Y, Kobayashi I, Mizoguchi K, Nakada M. Org. Lett. 2019; 21: 8280
  CrossrefPubMedSearch in Google Scholar
• 4 Hosoya Y, Mizoguchi K, Yasukochi H, Nakada M. Synlett 2022; 33: 495
  Thieme ConnectSearch in Google Scholar
• 5 Ito R, Okura F, Nakada M. Synlett 2023; 34: 2319
  Thieme ConnectSearch in Google Scholar
• 6 Tomizawa T, Orimoto K, Niwa T, Nakada M. Org. Lett. 2012; 14: 6294
  CrossrefPubMedSearch in Google Scholar
• 7 Viciu MS, Germaneau RF, Navarro-Fernandez O, Stevens ED, Nolan SP. Organometallics 2002; 21: 5470
  CrossrefSearch in Google Scholar
• 8 Silylating reagents may accelerate the formation of Pd(0) species; for a related reference, see: Marion N, Navarro O, Mei J, Stevens ED, Scott NM, Nolan SP. J. Am. Chem. Soc. 2006; 128: 4101
  CrossrefPubMedSearch in Google Scholar
• 9 For the preparation of 13b–e, see the Supporting Information.
• 10 For the preparation of 13f–q, see the Supporting Information.
• 11 For the preparation of 15a–f, see the Supporting Information.
• 12 Methyl {1,3-Dimethyl-3-[(phenylsulfanyl)methyl]-1,3-dihydro-2H-indol-2-ylidene}carbamate (14a); Typical Procedure A 10 mL test tube was charged with 13a (20.0 mg, 0.059mmol), K₃PO₄ (37.4 mg, 0.176 mmol, 3.0 equiv), BTBSA (0.0394 mL, 0.118 mmol, 2.0 equiv), CX20 (3.4 mg, 0.00594 mmol, 10 mol%), and xylenes (5.9 mL). The mixture was degassed and refluxed for 2 h, then cooled to r.t. H₂O (2 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 2 mL). The combined organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography [silica gel, CH₂Cl₂ (one drop) + hexane–EtOAc (20:1 to 10:1)] to give a colorless oil; yield: 19.2 mg (96%); R_f = 0.41 (hexane–EtOAc, 2:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (dd, J = 7.3 Hz, 1 H), 7.10–7.20 (m, 6 H), 6.96 (dd, J = 7.8, 7.3 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 3.98 (d, J = 12.8 Hz, 1 H), 3.73 (s, 3 H), 3.51 (d, J = 12.8 Hz, 1 H), 3.28 (s, 3 H), 1.61 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 170.4, 161.6, 143.6, 136.1, 134.2, 130.9, 128.7, 128.5, 126.5, 122.8, 122.5, 108.3, 53.0, 52.4, 43.4, 28.6, 23.1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₀N₂NaO₂S: 363.1138; found: 363.1138.

Corresponding Author

Publication History

Received: 11 November 2023

Accepted after revision: 29 November 2023

Article published online:
30 January 2024

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• References and Notes


For selected papers, see:
• 1a Hosseyni S, Wojtas L, Li M, Shi X. J. Am. Chem. Soc. 2016; 138: 3994
  CrossrefPubMedSearch in Google Scholar
• 1b Aubert C, Fensterbank L, Garcia P, Malacria M, Simonneau A. Chem. Rev. 2011; 111: 1954
  CrossrefPubMedSearch in Google Scholar
• 1c Nolan SP. Acc. Chem. Res. 2011; 44: 91
  CrossrefPubMedSearch in Google Scholar
• 1d Michelet V, Toullec PY, Genêt J.-P. Angew. Chem. Int. Ed. 2008; 47: 4268
  CrossrefPubMedSearch in Google Scholar
• 1e Fürstner A, Davies PW. Angew. Chem. Int. Ed. 2007; 46: 3410
  CrossrefPubMedSearch in Google Scholar

Selected papers on Pd-catalyzed reactions; for carbothiolation, see:
• 2a Delcaillau T, Schmitt HL, Boehm P, Falk E, Morandi B. ACS Catal. 2022; 12: 6081
  CrossrefSearch in Google Scholar

Thioacylation:
• 2b Wu J, Xu W.-H, Lu H, Xu P.-F. Adv. Synth. Catal. 2021; 363: 3013
  CrossrefSearch in Google Scholar

Oxycyanation:
• 2c Koester DC, Kobayashi M, Werz DB, Nakao Y. J. Am. Chem. Soc. 2012; 134: 6544
  CrossrefPubMedSearch in Google Scholar

Selenocarbamoylation:
• 2d Toyofuku M, Murase E, Nagai H, Fujiwara S.-i, Shin-ike T, Kuniyasu H, Kambe N. Eur. J. Org. Chem. 2009; 3141
  Crossref

Carboiodination and Carbohalogenation:
• 2e Marchese AD, Durant AG, Reid CM, Jans C, Arora R, Lautens M. J. Am. Chem. Soc. 2022; 144: 20554
  CrossrefPubMedSearch in Google Scholar
• 2f Chen X, Zhao J, Dong M, Yang N, Wang J, Zhang Y, Liu K, Tong X. J. Am. Chem. Soc. 2021; 143: 1924
  CrossrefPubMedSearch in Google Scholar
• 2g Newman SG, Howell JK, Nicolaus N, Lautens M. J. Am. Chem. Soc. 2011; 133: 14916
  CrossrefPubMedSearch in Google Scholar
• 2h Liu H, Li C, Qiu D, Tong X. J. Am. Chem. Soc. 2011; 133: 6187
  CrossrefPubMedSearch in Google Scholar
• 2i Newman SG, Lautens M. J. Am. Chem. Soc. 2011; 133: 1778
  CrossrefPubMedSearch in Google Scholar

Cyanoamidation:
• 2j Kamisaki H, Yasui Y, Takemoto Y. Tetrahedron Lett. 2009; 50: 2589
  CrossrefSearch in Google Scholar
• 2k Yasui Y, Takeda H, Takemoto Y. Chem. Pharm. Bull. 2008; 56: 1567
  CrossrefPubMedSearch in Google Scholar
• 2l Yasui Y, Takemoto Y. Chem. Rec. 2008; 8: 386
  CrossrefPubMedSearch in Google Scholar
• 2m Kobayashi Y, Kamisaki H, Takeda H, Yasui Y, Yanada R, Takemoto Y. Tetrahedron 2007; 63: 2978
  CrossrefSearch in Google Scholar
• 2n Kobayashi Y, Kamisaki H, Yanada R, Takemoto Y. Org. Lett. 2006; 8: 2771
  CrossrefPubMedSearch in Google Scholar
• 3a Hosoya Y, Yasukochi H, Mizoguchi K, Nakada M. Heterocycles 2022; 104: 655
  CrossrefSearch in Google Scholar
• 3b Hosoya Y, Kobayashi I, Mizoguchi K, Nakada M. Org. Lett. 2019; 21: 8280
  CrossrefPubMedSearch in Google Scholar
• 4 Hosoya Y, Mizoguchi K, Yasukochi H, Nakada M. Synlett 2022; 33: 495
  Thieme ConnectSearch in Google Scholar
• 5 Ito R, Okura F, Nakada M. Synlett 2023; 34: 2319
  Thieme ConnectSearch in Google Scholar
• 6 Tomizawa T, Orimoto K, Niwa T, Nakada M. Org. Lett. 2012; 14: 6294
  CrossrefPubMedSearch in Google Scholar
• 7 Viciu MS, Germaneau RF, Navarro-Fernandez O, Stevens ED, Nolan SP. Organometallics 2002; 21: 5470
  CrossrefSearch in Google Scholar
• 8 Silylating reagents may accelerate the formation of Pd(0) species; for a related reference, see: Marion N, Navarro O, Mei J, Stevens ED, Scott NM, Nolan SP. J. Am. Chem. Soc. 2006; 128: 4101
  CrossrefPubMedSearch in Google Scholar
• 9 For the preparation of 13b–e, see the Supporting Information.
• 10 For the preparation of 13f–q, see the Supporting Information.
• 11 For the preparation of 15a–f, see the Supporting Information.
• 12 Methyl {1,3-Dimethyl-3-[(phenylsulfanyl)methyl]-1,3-dihydro-2H-indol-2-ylidene}carbamate (14a); Typical Procedure A 10 mL test tube was charged with 13a (20.0 mg, 0.059mmol), K₃PO₄ (37.4 mg, 0.176 mmol, 3.0 equiv), BTBSA (0.0394 mL, 0.118 mmol, 2.0 equiv), CX20 (3.4 mg, 0.00594 mmol, 10 mol%), and xylenes (5.9 mL). The mixture was degassed and refluxed for 2 h, then cooled to r.t. H₂O (2 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 2 mL). The combined organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography [silica gel, CH₂Cl₂ (one drop) + hexane–EtOAc (20:1 to 10:1)] to give a colorless oil; yield: 19.2 mg (96%); R_f = 0.41 (hexane–EtOAc, 2:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (dd, J = 7.3 Hz, 1 H), 7.10–7.20 (m, 6 H), 6.96 (dd, J = 7.8, 7.3 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 3.98 (d, J = 12.8 Hz, 1 H), 3.73 (s, 3 H), 3.51 (d, J = 12.8 Hz, 1 H), 3.28 (s, 3 H), 1.61 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 170.4, 161.6, 143.6, 136.1, 134.2, 130.9, 128.7, 128.5, 126.5, 122.8, 122.5, 108.3, 53.0, 52.4, 43.4, 28.6, 23.1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₀N₂NaO₂S: 363.1138; found: 363.1138.

• Supplementary Material