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Article

Rhodium(III)-Catalyzed [4+2] Annulation via C-H Activation: Synthesis of Multi-Substituted Naphthalenone Sulfoxonium Ylides

by
Xiaohan Song
1,2,
Xu Han
1,2,
Rui Zhang
1,2,
Hong Liu
1,2,* and
Jiang Wang
1,2,*
1
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(10), 1884; https://doi.org/10.3390/molecules24101884
Submission received: 28 April 2019 / Revised: 14 May 2019 / Accepted: 14 May 2019 / Published: 16 May 2019
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Abstract

:
A convenient Rh(III)-catalyzed C-H activation and cascade [4+2] annulation for the synthesis of naphthalenone sulfoxonium ylides has been developed. This method features perfect regioselectivity, mild and redox-neutral reaction conditions, and broad substrate tolerance with good to excellent yields. Preliminary mechanistic experiments were conducted and a plausible reaction mechanism was proposed. The new type naphthalenone sulfoxonium ylides could be further transformed into multi-substituted naphthols, which demonstrates the practical utility of this methodology.

Graphical Abstract

1. Introduction

Substituted naphthols have been characterized as crucial organic motifs and are embedded in various pharmaceuticals and natural products such as rifampicin [1,2,3], gossypol [4,5,6], dioncophylline A [7,8,9], propranolol [10,11,12,13], and naftopidil [14,15,16] (Figure 1). As a result, the development of efficient methods to synthesize multi-substituted naphthols is important [17,18,19,20]. Over the past few years, transition-metal-catalyzed C–H activation has been demonstrated to be a convenient strategy to establish aromatic and heteroaromatic skeletons [21,22,23,24]. Nevertheless, the synthetic approach for multi-substituted naphthols is scarcely reported [25,26,27,28,29]. For example, it can be synthesized by the Rh(III)-catalyzed cross-coupling of benzoylates with diphenylacetylene (Scheme 1a) [25,26,27]. Recently, Li and co-workers have demonstrated a strategy using phosphonium ylides and diazo compounds to access naphthol derivatives [29]. Thus, development of an efficient, straightforward route to the naphthol framework is highly desired.
Recently, sulfoxonium ylides have been identified as a precursor of carbenoid in the transition-metal-catalyzed reactions [30,31,32]. Being successfully applied to the multi-kilogram synthesis of drug intermediates via Ir(I)-catalyzed reactions in industry [33,34] sulfoxonium ylides have also been widely investigated in the Rh(III)- [35,36,37,38,39,40,41,42,43,44], Co(III)- [45], or Ru(II)-catalyzed [46,47] C-H bond functionalization. However, the application of sulfoxonium ylides is severely limited by its substrate scope because the C1 position substitution in the ylide center is only H. To overcome such limitations, Bayer and co-workers reported the synthesis of bis-substituted sulfoxonium ylides via rhodium-catalyzed coupling of iodonium ylides with sulfoxides (Scheme 1b) [48]. Burtoloso et al. described another strategy to access α-aryl-β-keto sulfoxonium ylides using aryne [49]. Furthermore, Aïssa et al. developed a palladium-catalyzed C−H cross-coupling of α-ester sulfoxonium ylides with aryl halide to afford the (hetero)aryl-substituted sulfoxonium ylides, which expanded the scope of the substitution in the ylide center [50]. However, the synthetic approach for cyclic sulfoxonium ylides remains unexplored.
A seminal work reported by Li and co-workers revealed that sulfoxonium ylides could serve as weak directing-groups to participate in C-H activation [27,51]. Inspired by the previous work, we report a Rh(III)-catalyzed C-H activation and [4+2] annulation to afford the naphthalenone sulfoxonium ylides and its synthetic utility is further demonstrated through simple reactions to access multi-substituted naphthols. It is worth mentioning that, during our submission, Fan’s group also reported a very similar approach to the synthesis of naphthalenone sulfoxoniums [52].

2. Results and Discussion

We initiated our studies with model substrates sulfoxonium ylide 1a and diazo compound 2a to investigate the optimal reaction conditions (Table 1). Initially, transition-metal catalysts (Ru(II), Co(III), Ir(III), and Rh(III)), which could potentially trigger the cross-coupling of 1a with 2a, were screened to demonstrate the feasibility of this method (entries 1–4). To our delight, the target molecule naphthalenone sulfoxonium ylide 3aa could be obtained in a moderate yield of 65% in the presence of [Cp*RhCl2]2 and AgSbF6 under air condition at r.t. for 12 h. Several typical additives, including PivOH, CsOAc, Zn(OTf)2, Cu(OAc)2, and Zn(OAc)2, were subsequently explored (entries 5–9), and Zn(OAc)2 exhibited the best additive for this annulation, because a more powerful catalyst Cp*Rh(OAc) could be formed after adding Zn(OAc)2 [42], while CsOAc and Zn(OTf)2 could not afford compound 3aa at all. Subsequent Ag salt screening revealed that replacement of AgSbF6 by AgNTf2 decreased the yield (entry 10). Encouraged by these results, we further screened the solvent and found that TFE, MeOH, and MeCN reduced the reaction conversion (entries 11–13). The optimal results could be achieved when sulfoxonium ylide (1a, 0.2 mmol) and diazo compounds (2a, 0.44 mmol) were treated with the catalytic system of [Cp*RhCl2]2 (5 mol%), AgSbF6 (30 mol%), and Zn(OAc)2 (30 mol%) in DCE at room temperature for 12 h.
With the optimal reaction conditions in hand, we started to explore the generality and scope of sulfoxonium ylides (1a–1j) by performing the annulation with diazo compound 2a (Scheme 2). It was found that this reaction could tolerate various substrates with both electron-donating and electron-withdrawing substituents in the sulfoxonium ylides system, and afforded the corresponding naphthalenone sulfoxonium ylides in good to excellent yields (3aa–3da, 44–96%). Generally, sulfoxonium ylides with electron-donating substituents gave higher yields compared with electron-withdrawing substituents. To further investigate the effect of substituted group of the sulfoxonium yield, several moieties were independently introduced at the para-position of the phenyl ring while the ortho-position was blocked by chlorine. As a result, the naphthalenone sulfoxonium ylides were obtained in good to excellent yields (3ea–3ia, 78–96%). Introducing substituents at the meta-position resulted in excellent yields (3ja–3la, 84–94%). It is worth noting that using ortho-non-substituted benzoyl sulfoxonium ylides (1m–1p) with 2a, the dialkylated product could be obtained in good yields (3ma–3pa, 59–76%).
Next, in order to expand the utility of this reaction, we investigated the scope and generality of the diazo compounds (Scheme 3). Diazo compounds with the electron-donating and halogen groups at the para-position of its phenyl ring (R2) resulted in good to excellent yields of corresponding products (3ab–3ad and 3af, 79–95%), while electron-withdrawing group led to poor yield (3ae, 53%). The structure of product 3ac was confirmed by X-ray crystallography (CCDC 1899265). It should be mentioned that the substituents of diazo compounds at the different positions of its phenyl ring (R2) did not alter the reaction efficiency, provided the desired products in high yields (3ag–3aj, 77%–84%). Moreover, when R2 was replaced by methyl or cyclopropyl the yields are 91% and 72%, respectively (3ak and 3al), which indicated that increasing of the steric hindrance of R2 group decreased the yield of this reaction. At the same time, R3 groups with the large steric hindrance were well tolerated in this reaction (3am and 3an, 89% and 61%).
To further assess synthetic utility of the reaction, a gram-scale reaction between 1a and 2a has been performed, and the product 3aa was isolated with a 79% yield (Scheme 4a). Moreover, as a versatile structural motif, the synthetic application of the naphthalenone sulfoxonium ylides has been investigated. Naphthalenone sulfoxonium ylide 3ak was transformed to the tetra-substituted α-naphthol 5ak, of which the skeleton was embedded in rifampicin [1,2,3], via Ir(II)-catalyzed amination in a moderate yield of 45% (Scheme 4b) [49]. In addition, compound 3ak was reduced to sulfoxide 6ak in a good yield of 65%, which could be used to synthesize the FabH inhibitor [51,53], (Scheme 4c).
To obtain more insight into the mechanism of this annulation, a series of experiments were performed (Scheme 5). First, a hydrogen−deuterium exchange experiment of 1a was carried out using CD3OD under the standard conditions (Scheme 5a). Compound 1a underwent slight H/D exchange in the presence of the Rh(III) catalyst, indicating the reversibility of the C(aryl)−H bond cleavage. To further probe the C-H activation process, the kinetic isotopic effect (KIE) studies with separate kinetic experiments were performed to gain insights into the rate-determining step for this cross-coupling reaction (Scheme 5b). The KIE was determined by performing intermolecular competition experiments using an equimolar mixture of 1a and 1a-d7 in the couplings with 2k under standard conditions. The KIE value was 2.8, which was observed on the basis of the 1H NMR analysis (see supplementary materials), indicating that the C–H activation was involved in the turnover-limiting step.
Based on these preliminary mechanistic investigations, a plausible reaction mechanism for the formation of naphthalenone sulfoxonium ylide 3aa is proposed in Scheme 6. Initially, oxygen coordination of 1a is followed by cyclometalation to deliver a five-membered rhodacyclic intermediate A. Then, the nucleophilic C(aryl)−Rh species further attacks the diazo compound 2a to generate Rh(III) carbene species B with the loss of N2. The resulting species B further undergoes carbene migratory insertion to furnish another six-membered rhodacyclic intermediate C. Protonolysis of the Rh−C bond by HX releases the key intermediate D with the regeneration of the active Rh(III) catalyst. Finally, intermediate D undergoes a sequential aldol condensation to form the desired product 3aa.

3. Materials and Methods

3.1. General Information

The reagents (chemicals) were purchased from commercial sources, and used without further purification. Analytical thin layer chromatography (TLC) was HSGF 254 (0.15–0.2 mm thickness). All products were characterized by their NMR and MS spectra. The 1H- (500 MHz) and 13C-NMR (125 MHz) spectra were recorded in deuterochloroform (CDCl3) on Bruker Avance III spectrometer (Billerica, MA, USA). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m). Low-resolution mass spectra (LRMS) were measured on Agilent 1260 Infinity II (Palo Alto, CA, USA). High-resolution mass spectra (HRMS) were measured on Agilent 1290-6545 UHPLC-QTOF respectively (Palo Alto, CA, USA).

3.2. Experimental Part Method

3.2.1. General Procedure for the Preparation of Sulfoxonium Ylides 1a–1p

Sulfoxonium ylides 1a–1p were prepared according to the reported procedures [28]. To a stirred solution of potassiumtert-butoxide (3.3 equiv.) in THF was added trimethylsulfoxonium iodide (3.0 equiv.) at room temperature. The resulting mixture is refluxed for 2 h. Then reaction mixture was cooled to 0 °C, followed by the addition of acyl chlorides (1.0 equiv.) in THF. The reaction was allowed to reach room temperature and stirred for 3 h. Next, the solvent was evaporated, and water and ethylacetate were added to the resulting slurry. The layers were separated and the aqueous layer was washed with ethyl acetate and the organic layers were combined. The organic solution was dried over anhydrous sodium sulphate (Na2SO4), filtered over a sintered funnel, and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using DCM/MeOH (95:5) to afford the corresponding sulfoxonium ylides 1a–1p.

3.2.2. General Procedure for the Preparation of α-Diazocarbonyl Compounds 2a–2n

The α-diazocarbonyl compounds 2a–2n were prepared according to the reported procedures [29]. To a solution of β-ketoester or β-diketone (1.0 equiv.) and N-(4-azidosulfonylphenyl)acetamide (1.2 equiv.) in CH3CN at 0 °C was added DBU (1.2 equiv.). The resulting solution was stirred at 0 °C for 3 h and slowly brought to room temperature. Upon completion, as indicated by thin layer chromatography (TLC), the reaction was quenched with water, extracted with ethyl acetate, and dried over anhydrous Na2SO4. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography using n-hexane/EtOAc (92:8) to afford corresponding α-diazocarbonyl compounds 2a–2n.

3.2.3. General Procedures for the Products 3aa–3la, 3ab–3an (Compound 3aa as the Example)

A tube was charged with [Cp*RhCl2] 2 (6.0 mg, 5 mol%), AgSbF6 (14 mg, 20 mol%), Zn(OAc)2 (14 mg, 30 mol%), sulfoxonium ylide (1a, 0.2 mmol), α-diazocarbonyl compound (2a, 0.24 mmol), and DCE (3 mL). The reaction mixture was stirred at room temperature for 12 h under air condition. After that, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using DCM/MeOH (98:2) to afford the product 3aa as a light yellow solid.

3.2.4. General Procedures for the Products 3ma–3pa (Compound 3ma as the Example)

A tube was charged with [Cp*RhCl2] 2 (6.0 mg, 5 mol%), AgSbF6 (14 mg, 20 mol%), Zn(OAc)2 (14 mg, 30 mol%), sulfoxonium ylide (1m, 0.2 mmol), α-diazocarbonyl compound (2a, 0.44 mmol), and DCE (3 mL). The reaction mixture was stirred at 60 °C for 4 h under air condition. After that, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using DCM/MeOH (98:2) to afford the product 3ma as a light yellow solid.

3.2.5. Gram-Scale Synthesis of Compound 3aa

A round bottomed flask was charged with [Cp*RhCl2]2 (147 mg, 238 μmol), AgSbF6 (327 mg, 951 μmol), Zn(OAc)2 (262 mg, 1.43 mmol), sulfoxonium ylide (1a, 4.76 mmol), α-diazocarbonyl compound (2a, 1.25 g, 5.71 mmol). Dichloroethane (35 mL) was then added to the reaction mixture and stirring was turned on. The reaction mixture was stirred at r.t. for 12 h under air condition. After that, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using DCM/MeOH (99:1) to afford the product 3aa (1.45 g, 79%, light yellow solid).

3.2.6. Synthesis of Compound 5ak

To a 15 mL microwave glass tube containing a magnetic stirrer and fitted with a Teflon cap, sulfoxonium ylide 3ak (64 mg, 1.0 equiv.), p-methoxyaniline 4 (24 mg, 2.0 equiv.), [Ir(COD)Cl]2 (3 mg, 2.5 mol%), and toluene (1 mL) were added. The mixture was stirred for 1 h at 150 °C under microwave irradiation. Then, the organic solvent was removed in a rotary evaporator and the crude product purified by flash chromatography (petroleum ether: ethyl acetate = 10:1).

3.2.7. Synthesis of Compound 6ak

A mixture of 3ak (64 mg, 1 equiv.) and NaH (60%, dispersion in paraffin liquid) (28 mg, 0.7 mmol, 3.5 equiv.) was added to a Schlenk tube equipped with a stir bar. Dry THF (1.0 mL) was added and the mixture was stirred at 80 °C for 24 h under Ar atmosphere. Then, the organic solvent was removed in a rotary evaporator and the crude product was purified by flash chromatography (petroleum ether: ethyl acetate = 10:1).

3.2.8. Mechanistic Studies

A tube was charged with [Cp*RhCl2] 2 (6.0 mg, 5 mol%), AgSbF6 (14 mg, 20 mol%), Zn(OAc)2 (14 mg, 30 mol%), sulfoxonium ylide (1a, 0.2 mmol), CD3OD (72 mg, 10 equiv.), and DCE (3 mL). The reaction mixture was stirred at r.t. for 12 h under air condition. After that, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using DCM/MeOH (96:4) to afford the product, which was characterized by 1H NMR spectroscopy. 1H NMR analysis of 1a revealed 47% deuteration at the 6-position of phenyl ring and 8% deuteration at the α-position of the carbonyl.
Two tubes were charged with [Cp*RhCl2]2 (6.0 mg, 5 mol%), AgSbF6 (14 mg, 20 mol%), Zn(OAc)2 (14 mg, 30 mol%), sulfoxonium ylide (1a or 1a–d7, 0.2 mmol), α-diazocarbonyl compounds (2k, 0.24 mmol) and DCE (3 mL). The reaction mixture was stirred at r.t. for 2 h under air condition. After that, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using DCM/MeOH (99:1) to afford the product. The KIE value was determined to be kH/kD = 2.8 on the basis of 1H NMR analysis.

3.3. Product Characterization

Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3aa): light yellow solid; m.p.:182–184 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 8.3, 7.1 Hz, 1H), 7.38–7.31 (m, 5H), 7.17 (d, J = 7.1, 1H), 3.92 (q, J = 7.1 Hz, 2H), 3.77 (s, 6H), 2.99 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 176.1, 169.3, 139.5, 137.3, 136.9, 135.9, 130.2, 129.2, 128.8, 128.6, 127.4, 127.2, 123.1, 118.4, 98.3, 60.8, 44.2, 24.4, 13.7. LRMS (ESI): 381.4 [M − H]+. HRMS (ESI) calculated for C21H20O4S [M − H]+: 381.1166; found: 381.1177.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ba): light yellow solid; m.p.: 225–226 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.57 (dd, J = 6.4, 3.1 Hz, 1H), 7.41–7.37 (m, 3H), 7.35–7.31 (m, 3H), 7.31–7.26 (m, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.79 (s, 6H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 172.7, 168.3, 138.1, 136.7, 135.7, 132.6, 129.9, 128.6, 128.2, 127.2, 126.8, 125.6, 123.7, 117.4, 99.1, 60.5, 43.9, 13.1. LRMS (ESI): 403.3 [M − H]+. HRMS (ESI) calculated for C21H19ClO4S [M − H]+: 403.0765; found: 403.0774.
Ethyl 5-bromo-3-(dimethyl(oxo)-λ6-sulfanylidene)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ca): light yellow solid; m.p.: 203-204 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.42–7.23 (m, 6H), 3.89 (q, J = 7.1 Hz, 2H), 3.76 (s, 6H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 172.9, 168.7, 138.5, 137.1, 136.3, 132.5, 130.6, 129.1, 127.6, 127.2, 126.6, 124.8, 120.2, 117.7, 99.2, 61.0, 44.2, 13.6. LRMS (ESI): 447.2 [M − H]+. HRMS (ESI) calculated for C21H19BrO4S [M − H]+: 447.0260; found: 447.0254.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-4-oxo-2-phenyl-5-(trifluoromethyl)-3,4-dihydronaphthalene-1-carboxylate (3da): light yellow solid; m.p.: 228-230 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.41–7.30 (m, 5H), 3.98–3.85 (q, J = 7.2 Hz, 2H), 3.79 (s, 6H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) δ 172.0, 168.8, 139.2, 136.4, 136.2, 129.6, 129.3, 129.0, 127.7 (q, JC–F = 31.0 Hz), 127.7, 127.3, 125.2 (q, JC–F = 8.2 Hz), 124.5 (JC–F = 271.0 Hz), 117.4, 100.2, 61.0, 43.8, 13.6. 19F NMR (470 MHz, Chloroform-d) δ -56.9. LRMS (ESI): 459.2 [M − H]+. HRMS (ESI) calculated for C22H19F3O4S [M + Na]+: 459.0848; found: 459.0857.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-7-methyl-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ea): light yellow solid; m.p.: 212–214 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.42–7.27 (m, 6H), δ 7.24 (d, J = 1.6 Hz, 1H). 3.89 (q, J = 7.1 Hz, 2H), 3.75 (s, 6H), 2.40 (s, 3H), 0.86 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 173.0, 168.9, 141.0, 138.6, 137.1, 136.4, 132.8, 130.2, 129.1, 127.6, 127.2, 124.0, 123.7, 117.6, 99.0, 61.0, 44.4, 21.5, 13.6. LRMS (ESI): 417.4 [M − H]+. HRMS (ESI) calculated for C22H21ClO4S [M − H]+: 417.0922; found: 417.0927.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-7-fluoro-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3fa): light yellow solid; m.p.: 208–210 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.37–7.32 (m, 3H), 7.30–7.24 (m, 3H), 7.17 (dd, J = 8.3, 2.5 Hz, 1H), 3.87 (q, J = 7.1 Hz, 2H), 3.77 (s, 6H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 172.2, 167.9, 161.8 (d, JC–F = 251.6 Hz), 139.8, 137.9 (d, JC–F = 10.4 Hz), 135.6, 134.7 (d, JC–F = 11.8 Hz), 128.4, 127.3, 126.8, 122.6, 117.0 (d, JC–F = 26.3 Hz), 116.8 (d, JC–F = 3.7 Hz), 108.5 (d, JC–F = 22.2 Hz), 99.3, 60.7, 43.9, 13.1. 19F NMR (470 MHz, Chloroform-d) δ −108.2. LRMS (ESI): 421.2 [M − H]+. HRMS (ESI) calculated for C21H18FClO4S [M − H]+: 421.0676; found: 421.0671.
Ethyl 5,7-dichloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ga): light yellow solid; m.p.: 215–217 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 1.9 Hz, 1H), 7.37–7.31 (m, 4H), 7.29–7.25 (m, 3H), 3.87 (q, J = 7.1 Hz, 2H), 3.75 (s, 6H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 172.6, 168.3, 140.2, 137.7, 136.0, 135.9, 134.3, 129.0, 128.4, 127.8, 127.3, 124.4, 123.3, 116.8, 100.4, 61.2, 44.2, 13.6. LRMS (ESI): 437.2 [M − H]+. HRMS (ESI) calculated for C21H18Cl2O4S [M − H]+: 437.0382; found: 437.0376.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-7-methoxy-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ha): light yellow solid; m.p.: 217–218 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.35–7.25 (m, 5H), 7.03 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 3.86 (q, J = 7.1 Hz, 2H), 3.83(s, 3H), 3.72 (s, 6H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, Chloroform-d) δ 172.7, 168.8, 160.1, 139.5, 138.3, 136.4, 134.3, 128.9, 127.5, 127.1, 120.5, 118.1, 117.1, 105.1, 98.4, 60.8, 55.4, 44.3, 13.5. LRMS (ESI): 433.3 [M − H]+. HRMS (ESI) calculated for C22H21ClO5S [M − H]+: 433.0871; found: 433.0874.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-4-oxo-2-phenyl-7-(trifluoro-methyl)-3,4-dihydronaphthalene-1-carboxylate (3ia): light yellow solid; m.p.: 212–214 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.37 (dd, J = 4.9, 2.3 Hz, 3H), 7.32–7.25 (m, 2H), 3.91 (q, J = 7.0 Hz, 2H), 3.79 (s, 6H), 0.88 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 172.4, 168.1, 140.5, 136.9, 135.7, 134.4, 131.8 (q, J = 33.1 Hz), 128.9, 128.2 (q, J = 274.7 Hz) 127.9, 127.6, 127.3, 124.1 (q, J = 3.3 Hz), 121.3 (q, J = 4.3 Hz), 117.5, 101.7, 61.3, 44.1, 13.5. 19F NMR (470 MHz, Chloroform-d) δ −63.1. LRMS (ESI): 471.3 [M − H]+. HRMS (ESI) calculated for C22H18ClF3O4S [M − H]+: 471.0639; found: 471.0644.
Ethyl 6-bromo-5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ja): light yellow solid; m.p.: 232–234 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.38–7.34 (m, 3H), 7.32–7.29 (m, 2H), 3.89 (q, J = 7.1 Hz, 2H), 3.79 (s, 6H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 172.3, 168.4, 139.4, 136.0, 134.7, 132.5, 129.0, 127.8, 127.6, 127.3, 124.8, 122.7, 117.4, 100.7, 61.1, 44.3, 13.6. LRMS (ESI): 480.8 [M − H]+. HRMS (ESI) calculated for C21H19BrClO4S [M − H]+: 480.9870; found: 480.9866.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-6-methyl-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ka): light yellow solid; m.p.: 230–232 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.38–7.29 (m, 5H), 3.93–3.87 (q, J = 7.1 Hz 2H), 3.79 (s, 6H), 2.52 (s, 3H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 173.3, 168.9, 137.7, 136.4, 135.4, 135.1, 133.0, 132.3, 129.1, 127.5, 127.2, 126.3, 123.3, 117.7, 99.7, 60.9, 44.5, 21.1, 13.6. LRMS (ESI): 416.9 [M − H]+.HRMS (ESI) calculated for C22H22ClO4S [M − H]+: 417.0922; found: 417.0922.
Ethyl 5-chloro-3-(dimethyl(oxo)-λ6-sulfanylidene)-8-methoxy-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3la): light yellow solid; m.p.: 225–227 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.35–7.26 (m, 6H), 6.90 (d, J = 8.5 Hz, 1H), 3.82 (q, 2H), 3.81 (s, 3H), 3.73 (s, 6H), 0.96 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, Chloroform-d) δ 172.4, 169.3, 153.7, 138.1, 135.3, 129.8, 128.5, 128.2, 127.5, 127.1, 126.9, 124.6, 114.6, 111.7, 100.5, 60.5, 56.7, 44.0, 13.9. LRMS (ESI): 432.9 [M − H]+. HRMS (ESI) calculated for C22H22ClO5S [M − H]+: 433.0871; found: 433.0882.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3ma): light yellow solid; m.p.: 88–90 °C; 1H NMR (400 MHz, Chloroform-d) δ 8.08–8.00 (m, 2H), 7.95 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.55–7.30 (m, 9H), 7.17 (d, J = 7.3 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.91 (q, J = 7.2 Hz, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 195.4, 175.0, 170.4, 169.0, 137.6, 136.7, 136.6, 136.1, 133.8, 132.9, 130.2, 129.3, 129.2, 129.0, 128.5, 127.6, 127.2, 126.9, 125.3, 118.4, 99.5, 61.2, 60.9, 58.5, 44.0, 43.9, 14.2, 13.7. LRMS (ESI): 559.3 [M − H]+, HRMS (ESI) calculated for C32H31O7S [M − H]+: 559.1785; found: 559.1793.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-7-methoxy-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3na): light yellow solid; m.p.: 95–97 °C; 1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 7.4 Hz, 2H), 7.92 (s, 1H), 7.55–7.48 (m, 1H), 7.45–7.31 (m, 7H), 7.02 (d, J = 2.5 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.89 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, Chloroform-d) δ 195.2, 174.7, 170.2, 169.2, 160.4, 138.6, 138.0, 136.8, 136.6, 135.8, 132.9, 129.2, 129.1, 129.0, 128.5, 127.6, 127.3, 121.5, 118.0, 117.9, 105.6, 98.2, 61.3, 60.9, 58.4, 55.2, 44.4, 44.2, 14.3, 13.7. LRMS (ESI): 589.0 [M − H]+. HRMS (ESI) calculated for C33H33O8S [M − H]+: 589.1891; found: 589.1870.
Ethyl 7-(tert-butyl)-3-(dimethyl(oxo)-l6-sulfanylidene)-5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3oa): light yellow solid; m.p.: 110–112 °C; 1H NMR (400 MHz, Chloroform-d) δ 8.05–7.98 (m, 2H), 7.93 (s, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42-7.30 (m, 7H), 7.20 (d, J = 1.8 Hz, 1H), 4.28 (qd, J = 7.1, 3.3 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.69 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.24 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 195.8, 174.9, 170.4, 169.1, 152.9, 137.4, 136.9, 136.7, 135.9, 133.3, 132.6, 129.3, 129.2, 129.0, 128.4, 127.6, 127.3, 126.8, 120.9, 118.7, 98.7, 61.1, 60.8, 58.7, 44.3, 44.1, 35.0, 30.8, 14.3, 13.8. LRMS (ESI): 615.0 [M − H]+. HRMS (ESI) calculated for C36H39O7S [M − H]+: 615.2411; found: 615.2396.
Ethyl 7-bromo-3-(dimethyl(oxo)-l6-sulfanylidene)-5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-4-oxo-2-phenyl-3,4-dihydronaphthalene-1-carboxylate (3pa): light yellow solid; m.p.: 113–115 °C; 1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 7.7 Hz, 2H), 7.88–7.77 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 3H), 7.41–7.30 (m, 5H), 4.28 (q, J = 7.1 Hz, 2H), 3.91 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.66 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 194.5, 174.6, 169.8, 168.5, 139.0, 137.3, 136.7, 136.2, 135.8, 133.0, 130.3, 129.2, 129.1, 128.9, 128.6, 127.8, 127.7, 127.3, 125.5, 125.1. 117.5. 100.0, 61.5, 61.1, 58.1, 44.1, 14.2, 13.6. LRMS (ESI): 636.8 [M − H]+. HRMS (ESI) calculated for C32H30BrO7S [M − H]+: 637.0890; found: 637.0903.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ab): light yellow solid; m.p.: 217–218 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.47 (dd, J = 8.5, 1H), 7.42 (dd, J = 8.3, 7.1 Hz, 1H), 7.31-7.26 (m, 2H), 7.16 (d, J = 7.0, 1H), 7.07–7.01 (m, 1H), 3.95 (q, J = 7.1 Hz, 2H), 3.75 (s, 6H), 2.97 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 175.6, 168.7, 161.8 (d, J C–F = 246.3 Hz), 139.1, 135.6, 135.3, 132.1 (d, J C–F = 3.5 Hz), 130.4 (d, J C–F = 8.0 Hz), 129.8, 128.4, 128.3, 122.6, 118.4, 113.7 (J C–F = 21.5 Hz), 97.6, 60.4, 43.9, 23.9, 13.3. 19F NMR (470 MHz, Chloroform-d) δ −144.6. LRMS (ESI): 401.2 [M − H]+. HRMS (ESI) calculated for C22H21FO4S [M − H]+: 401.1223; found: 401.1226.
Ethyl 2-(4-chlorophenyl)-3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ac): light yellow solid; m.p.: 199–201°C; 1H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 7.0 Hz, 1H), 3.93 (q, J = 7.1 Hz, 2H), 3.69 (s, 6H), 2.94 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 176.0, 169.1, 139.6, 135.9, 135.8, 135.3, 133.4, 130.6, 130.3, 128.8, 127.4, 123.1, 118.7, 98.0, 60.9, 44.2, 24.3, 13.7. LRMS (ESI): 417.2 [M − H]+. HRMS (ESI) calculated for C22H21ClO4S [M − H]+: 417.0922; found: 417.0927.
Ethyl 2-(4-bromophenyl)-3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ad): light yellow solid, 88 mg, yield: 95%. m.p.: 217–219 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.49–7.44 (m, 3H), 7.39 (t, J = 7.6 Hz, 1H), 7.19–7.08 (m, 3H), 3.92 (q, J = 7.1 Hz, 2H), 3.67 (s, 6H), 2.94 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 175.9, 169.0, 139.6, 135.9, 135.8, 135.8, 130.9, 130.3, 128.9, 123.1, 121.6, 118.5, 98.0, 60.9, 44.2, 24.4, 13.7. LRMS (ESI): 459.2 [M − H]+. HRMS (ESI) calculated for C22H21BrO4S [M − H]+: 459.0271; found: 459.0263.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-2-(4-(trifluoromethyl)ph-enyl)-3,4-dihydronaphthalene-1-carboxylate (3ae): light yellow solid; m.p.: 202–204 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 3H), 7.19 (d, J = 7.0 Hz, 1H), 3.91 (q, J = 7.1 Hz, 2H), 3.75 (s, 6H), 2.98 (s, 3H), 0.87 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 176.1, 168.9, 140.8, 139.7, 135.8, 135.7, 130.4, 129.7, 129.3 (q, JC–F = 92.4 Hz), 129.0, 124.2 (q, JC–F = 270.3 Hz), 124.0 (q, JC-F = 8.2 Hz), 123.2, 118.6, 97.6, 60.9, 44.2, 24.4, 13.5. 19F NMR (470 MHz, Chloroform-d) δ −62.4. LRMS (ESI): 451.2 [M − H]+. HRMS (ESI) calculated for C23H21F3O4S [M − H]+: 451.1185; found: 451.1184.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2-(4-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3af): light yellow solid, 78 mg, yield: 95%. m.p.: 152–154 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.50–7.46 (m, 1H), 7.42 (dd, J = 8.3, 7.1 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.15 (dt, J = 7.1, 1.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 6H), 2.98 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) δ 176.1, 169.4, 158.9, 139.5, 136.9, 135.8, 130.2, 130.1, 128.9, 128.7, 128.5, 122.9, 118.8, 112.6, 98.3, 60.8, 55.2, 44.3, 24.4, 13.8. LRMS (ESI): 413.3 [M − H]+, HRMS (ESI) calculated for C23H24O5S [M − H]+: 413.1417; found: 413.1420.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2-(3-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ag): light yellow solid; m.p.: 80–82 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.3, 7.1 Hz, 1H), 7.30–7.21 (m, 1H), 7.14 (d, J = 7.1 Hz, 1H), 6.94–6.85 (m, 3H), 3.95 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.70 (d, J = 2.6 Hz, 6H), 2.97 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 176.1, 169.3, 158.6, 139.5, 138.2, 137.0, 135.8, 130.2, 128.8, 128.1, 123.0, 122.0, 118.1, 115.3, 112.8, 98.3, 60.8, 55.2, 44.2, 24.4, 13.7. LRMS (ESI): 413.3 [M − H]+, HRMS (ESI) calculated for C19H24O4S [M − H]+: 413.1417; found: 413.1427.
Ethyl 2-(3-bromophenyl)-3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ah) light yellow solid; m.p.: 90–92 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.49–7.43 (m, 3H), 7.43–7.37 (m, 1H), 7.25–7.16 (m, 1H), 7.16–7.11 (m, 1H), 3.94 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.69 (s, 3H), 2.94 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 175.5, 168.5, 139.1, 138.4, 135.3, 135.1, 131.7, 129.9, 129.8, 128.5, 128.2, 127.6, 122.7, 120.7, 118.1, 97.4, 60.5, 43.8, 43.7, 23.9, 13.3. HRMS (ESI) calculated for C22H21BrO4S [M − H]+: 461.0417; found: 461.0427.
Ethyl 2-(2-chlorophenyl)-3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ai): light yellow solid; m.p.: 86–88 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.54 (d, J = 8.1 Hz, 1H), 7.44–7.34 (m, 2H), 7.32–7.21 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 3.96–3.82 (m, 2H), 3.81 (s, 3H), 3.71 (s, 3H), 2.97 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 175.2, 168.4, 139.1, 135.7, 135.4, 134.0, 133.9, 130.2, 129.6, 128.7, 128.5, 127.8, 125.5, 123.0, 117.5, 96.7, 60.3, 43.5, 41.6, 24.0, 13.2. HRMS (ESI) calculated for C22H21BrO4S [M − H]+: 417.0922; found: 417.0931.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2-(2-methoxyphenyl)-5-methyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3aj): light yellow solid; m.p.: 210–212 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.59–7.54 (m, 1H), 7.38 (dd, J = 8.3, 7.2 Hz, 1H), 7.33 (td, J = 7.9, 1.8 Hz, 1H), 7.21 (dd, J = 7.4, 1.7 Hz, 1H), 7.13 (dt, J = 7.2, 1.1 Hz, 1H), 6.96 (td, J = 7.4, 1.1 Hz, 1H), 6.87 (dd, J = 8.3, 1.0 Hz, 1H), 3.97–3.83 (m, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 2.98 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 174.8, 168.9, 157.0, 138.9, 135.8, 133.8, 129.3, 129.3, 128.7, 128.4, 128.0, 125.9, 122.7, 119.8, 117.5, 109.4, 97.9, 60.1, 55.2, 43.4, 41.3, 24.0, 13.2. LRMS (ESI): 413.3 [M − H]+. HRMS (ESI) calculated for C23H24O5S [M − H]+: 413.1417; found: 413.1421.
Ethyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2,5-dimethyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3ak): light yellow solid; m.p.: 146–148 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.37–7.32 (m, 1H), 7.28 (d, J = 6.2 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.80 (s, 6H), 2.90 (s, 3H), 2.43 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 175.6, 170.1, 138.8, 135.8, 132.6, 129.4, 127.6, 127.5, 117.4, 98.1, 60.7, 44.2, 23.8, 16.3, 13.8. LRMS (ESI): 321.2 [M − H]+. HRMS (ESI) calculated for C17H20O4S [M − H]+: 321.1155; found: 321.1157.
Ethyl 2-cyclopropyl-3-(dimethyl(oxo)-λ6-sulfanylidene)-5-methyl-4-oxo-3,4-dihy-dronaphthalene-1-carboxylate (3al): light yellow solid; m.p.: 180–182 °C; 1H NMR (500 MHz, Chloroform-d) δ 7.47 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.4, 7.2 Hz, 1H), 7.07 (dt, J = 7.1, 1.2 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.81 (d, J = 2.4 Hz, 6H), 2.89 (s, 3H), 2.25 (tt, J = 8.6, 5.9 Hz, 1H), 1.41 (t, J = 7.2 Hz, 2H), 0.93 (dd, J = 8.4, 1.7 Hz, 2H), 0.64 (dd, J = 5.9, 1.7 Hz, 2H). 13C NMR (125 MHz, Chloroform-d) δ 175.6, 170.0, 139.2, 138.7, 135.7, 129.2, 128.1, 127.9, 122.1, 118.2, 99.7, 60.6, 44.0, 23.9, 13.86, 13.72, 8.3. LRMS (ESI): 331.4 [M − H]+. HRMS (ESI) calculated for C19H24O4S [M − H]+: 331.1010; found: 331.1011.
Isopropyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2,5-dimethyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3am): light yellow solid; m.p.: 148–150 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.35 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 5.35 (hept, J = 5.7 Hz, 1H), 3.79 (s, 6H), 2.89 (s, 3H), 2.44 (s, 3H), 1.40 (d, J = 6.3 Hz, 6H). 13C NMR (125 MHz, Chloroform-d) δ 176.3, 170.1, 139.3, 136.3, 132.8, 129.8, 128.2, 127.9, 122.3, 118.0, 98.3, 68.7, 44.6, 24.3, 21.9, 16.6. LRMS (ESI): 335.3 [M − H]+. HRMS (ESI) calculated for C18H22O4S [M − H]+: 335.1312; found: 335.1308.
Tert-butyl 3-(dimethyl(oxo)-λ6-sulfanylidene)-2,5-dimethyl-4-oxo-3,4-dihydronaphthalene-1-carboxylate (3an): light yellow solid; m.p.: 152–154 °C; 1H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 4.1 Hz, 2H), 7.05 (s, 1H), 3.80 (s, 6H), 2.88 (s, 3H), 2.45 (s, 3H), 1.63 (s, 9H). 13C NMR (125 MHz, Chloroform-d) δ 176.0, 169.9, 139.3, 136.4, 132.1, 129.8, 128.1, 127.9, 122.3, 119.4, 98.2, 81.7, 44.7, 28.3, 24.3, 16.5. LRMS (ESI): 349.3 [M − H]+. LRMS (ESI): 349.4 [M − H]+, HRMS (ESI) calculated for C19H24O4S [M − H]+: 349.1468; found: 349.1472.
Ethyl 4-hydroxy-3-((4-methoxyphenyl)amino)-2,5-dimethyl-1-naphthoate (5ak): green oil, 33 mg, yield: 35%. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.6, 6.9 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 6.96 (s, 1H), 6.74 (d, J = 8.9 Hz, 2H), 6.45 (d, J = 8.9 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.63 (s, 3H), 2.88 (s, 3H), 2.11 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.8, 154.0, 152.3, 141.6, 135.7, 133.3, 130.6, 127.8, 126.9, 123.7, 123.4, 122.6, 122.3, 115.0, 114.9, 61.3, 55.7, 25.2, 16.0, 14.5. LRMS (ESI): 364.4 [M − H]+, HRMS (ESI) calculated for C22H23NO4 [M – H]+: 364.1154; found: 364.1157.
Ethyl 4-hydroxy-2,5-dimethyl-3-(methylsulfinyl)-1-naphthoate (6ak): white solid, 40 mg, yield: 65%. m.p.: 128–130 °C. 1H NMR (500 MHz, Chloroform-d) δ 12.33 (s, 1H), 7.53–7.48 (m, 1H), 7.43 (dd, J = 8.5, 7.0 Hz, 1H), 7.23 (dt, J = 7.0, 1.1 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.05 (s, 3H), 2.96 (s, 3H), 2.37 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, Chloroform-d) δ 169.5, 162.9, 137.5, 133.9, 129.0, 129.0, 128.0, 124.5, 124.2, 114.5, 61.6, 39.4, 25.1, 16.0, 14.3. LRMS (ESI): 306.5 [M − H]+, HRMS (ESI) calculated for C16H18O4S [M − H]+: 308.0853; found: 308.0854.

4. Conclusions

In summary, we developed a novel method to access naphthalenone sulfoxonium ylides via Rh(III)-catalyzed C-H activation and [4+2] annulation of sulfoxonium ylides with diazo compounds. High regioselectivity, mild and redox-neutral reaction conditions, and wide substrate tolerance make this protocol efficient to prepare various naphthalenone sulfoxonium ylides. Moreover, the new type of naphthalenone sulfoxonium ylides could be further transformed into multi-substituted naphthols smoothly, which may find important applications in the synthesis of natural products and biologically-active molecules.

Supplementary Materials

The Supplementary Materials are available online.

Author Contributions

Conceptualization: X.S.; experiments and analyses: X.S., X.H., and R.Z; writing—original draft preparation: X.S.; writing—review and editing: J.W. and H.L.

Accession Codes

CCDC 1899265 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Funding

This research was funded by the National Natural Science Foundation of China (nos. 21632008, 21672231, 21877118, and 81620108027) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040107 and XDA12040201) for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Not available.
Molecules 24 01884 g001 550
Figure 1. Representative compounds with a 1-naphthol moiety.
Figure 1. Representative compounds with a 1-naphthol moiety.
Molecules 24 01884 g001
Molecules 24 01884 sch001 550
Scheme 1. (a) Reports of approaches to substituted naphthol; (b) Recent advances in the synthesis of bis-substituted sulfoxonium ylide.
Scheme 1. (a) Reports of approaches to substituted naphthol; (b) Recent advances in the synthesis of bis-substituted sulfoxonium ylide.
Molecules 24 01884 sch001
Molecules 24 01884 sch002 550
Scheme 2. Scope of sulfoxonium ylides a, b. a Reaction conditions: 1 (0.2 mmol), 2a (0.22 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), and Zn(OAc)2 (30 mol%) in DCE (2 mL) at r.t. for 12 h under air condition. b Yield of the isolated product. c Reaction conditions: sulfoxonium ylide 1 (0.2 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), and Zn(OAc)2 (30 mol%) in DCE (2 mL) at 60 °C for 4 h under air condition.
Scheme 2. Scope of sulfoxonium ylides a, b. a Reaction conditions: 1 (0.2 mmol), 2a (0.22 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), and Zn(OAc)2 (30 mol%) in DCE (2 mL) at r.t. for 12 h under air condition. b Yield of the isolated product. c Reaction conditions: sulfoxonium ylide 1 (0.2 mmol), diazo compound 2a (0.44 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), and Zn(OAc)2 (30 mol%) in DCE (2 mL) at 60 °C for 4 h under air condition.
Molecules 24 01884 sch002
Molecules 24 01884 sch003 550
Scheme 3. Scope of diazo compounds a,b. a Reaction conditions: sulfoxonium ylide 1a (0.2 mmol), diazo compounds 2 (0.22 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), and Zn(OAc)2 (30 mol%) in DCE (2 mL) at r.t. for 12 h under air condition. b Yield of the isolated product. c Determined by single X-ray crystal structure analysis.
Scheme 3. Scope of diazo compounds a,b. a Reaction conditions: sulfoxonium ylide 1a (0.2 mmol), diazo compounds 2 (0.22 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), and Zn(OAc)2 (30 mol%) in DCE (2 mL) at r.t. for 12 h under air condition. b Yield of the isolated product. c Determined by single X-ray crystal structure analysis.
Molecules 24 01884 sch003
Molecules 24 01884 sch004 550
Scheme 4. (a) Gram-scale synthesis of compound 3aa; (b) Synthetic applications of 3ak.
Scheme 4. (a) Gram-scale synthesis of compound 3aa; (b) Synthetic applications of 3ak.
Molecules 24 01884 sch004
Molecules 24 01884 sch005 550
Scheme 5. (a) H/D exchange experiment of 1a; (b) KIE experiment.
Scheme 5. (a) H/D exchange experiment of 1a; (b) KIE experiment.
Molecules 24 01884 sch005
Molecules 24 01884 sch006 550
Scheme 6. Proposed reaction mechanism.
Scheme 6. Proposed reaction mechanism.
Molecules 24 01884 sch006
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 24 01884 i001
EntryCatalystAdditiveAg SaltSolventYield b
1[RuCl2(p-cymene)]2-AgSbF6DCE dN.R. f
2Cp*C°COI2-AgSbF6DCEN.R.
3[Cp*IrCl2]2 c-AgSbF6DCEN.R.
4[Cp*RhCl2]2-AgSbF6DCE65%
5[Cp*RhCl2]2PivOHAgSbF6DCE77%
6[Cp*RhCl2]2CsOAcAgSbF6DCEN.R.
7[Cp*RhCl2]2Zn(OTf)2AgSbF6DCEN.R.
8[Cp*RhCl2]2Cu(OAc)2AgSbF6DCE65%
9[Cp*RhCl2]2Zn(OAc)2AgSbF6DCE95% (90% g)
10[Cp*RhCl2]2Zn(OAc)2AgSbF6DCE48%
11[Cp*RhCl2]2Zn(OAc)2AgSbF6TFE e85%
12[Cp*RhCl2]2Zn(OAc)2AgSbF6MeOH14%
13[Cp*RhCl2]2Zn(OAc)2AgSbF6MeCNtrace
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (5 mol%), Ag salt (20 mol%), additive (30 mol%), in solvent (3 mL), tube for 12 h at room temperature. b Yield determined by 1H NMR. c Cp* = 1,2,3,4,5-pentamethylcyclopenta-1,3-diene. d DCE = dichloroethane. e TFE = trifluoroethanol. f N.R. = No reaction. g Yield of the isolated product.

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Song, X.; Han, X.; Zhang, R.; Liu, H.; Wang, J. Rhodium(III)-Catalyzed [4+2] Annulation via C-H Activation: Synthesis of Multi-Substituted Naphthalenone Sulfoxonium Ylides. Molecules 2019, 24, 1884. https://doi.org/10.3390/molecules24101884

AMA Style

Song X, Han X, Zhang R, Liu H, Wang J. Rhodium(III)-Catalyzed [4+2] Annulation via C-H Activation: Synthesis of Multi-Substituted Naphthalenone Sulfoxonium Ylides. Molecules. 2019; 24(10):1884. https://doi.org/10.3390/molecules24101884

Chicago/Turabian Style

Song, Xiaohan, Xu Han, Rui Zhang, Hong Liu, and Jiang Wang. 2019. "Rhodium(III)-Catalyzed [4+2] Annulation via C-H Activation: Synthesis of Multi-Substituted Naphthalenone Sulfoxonium Ylides" Molecules 24, no. 10: 1884. https://doi.org/10.3390/molecules24101884

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