Diastereoselective synthesis of cyclopentene spiro-rhodanines containing three contiguous stereocenters via phosphine-catalyzed [3 + 2] cycloaddition or one-pot sequential [3 + 2]/[3 + 2] cycloaddition

Abstract

Two different diastereoselective phosphine-catalyzed cascade reactions to form cyclopentene spiro-rhodanine scaffolds are described. In the first approach, alkynoate derivatives and 5-arylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one react in the presence of PBu₃ through a [3 + 2] cycloaddition to afford 5-spiro-cyclopentene-rhodanines in high yields (up to 99%) and with excellent diastereoselectivities [20 : 1 diastereomeric ratio (dr)]. In the second approach, the sequential [3 + 2]/[3 + 2] annulation reaction of ethyl 5-phenylpent-2-ynoate, substituted arylethylpropiolates, amines, and carbon disulfide with phosphine catalysis produces the corresponding monospirocyclic rhodanine products in good yields (up to 92%) and with excellent diastereoselectivities (up to 20 : 1 dr).

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Introduction

Spirocyclic compounds are structural motifs frequently found in a large number of natural or synthetic products displaying interesting biological properties.¹ Accordingly, the search for developing concise approaches to asymmetrically synthesize spirocyclic molecules, which feature the intriguing combination of two perpendicular rings connected through one tetrasubstituted stereogenic center, has attracted much attention among synthetic and medicinal chemists.² Some of these approaches have focused on the stereoselective integration of five-membered multiheterocyclic rings into spirocyclic scaffolds.³ Recently, 2-thioxo-1,3-thiazolidin-4-one (rhodanine) derivative epalrestat, thiazolidine-2,4-dione derivatives, glitazones (Avandia, Rezulin, and Actos) and the thiohydantoin derivative (TH2) have been introduced to clinical use for treatment of diabetic complications, type II diabetes, mellitus and epilepsy, respectively (Fig. 1).⁴ Among the thiazolidinone derivatives, rhodamine is one of the most promising molecules in the drug discovery process.

Fig. 1 Representative examples of biologically active thiazolidinones and thiohydantoin derivatives.

In 2013, Ye and co-workers described a new synthetic route to cyclohexene-fused spiro-rhodanines by exploiting aminocatalyzed asymmetric Diels–Alder cycloaddition of 2,4-dienals and rhodanine derivatives with high yields and excellent diastereo- and enantioselectivities (Scheme 1a).⁵ Narayanan also reported the regio- and stereocontrolled synthesis of dispiropyrrolidine derivatives of thiazolidinedione and rhodanine through [3 + 2] cycloaddition reactions (Scheme 1b).⁶

Scheme 1 Previous and proposed work.

In contrast to the few examples of asymmetric catalytic synthesis of cyclohexene-fused spiro-rhodanines, the construction of cyclopentene-fused spiro-rhodanines has not been reported to the best of our knowledge. Recently, a nucleophilic-phosphine-catalyzed annulation of electron-deficient alkenes and alkynes has emerged as a powerful tool for the construction of various biologically active carbocycles and heterocycles.⁷ Typically, they have been used in phosphine-catalyzed [2 + 3] cycloaddition,⁸ [2 + 4] cycloaddition,⁹ [3 + 2]/[3 + 2] annulation¹⁰ and [4 + 2]/[4 + 2] annulation.¹¹ Encouraged by these elegant studies as well as our recently successes in preparing diverse spiroheterocyclic compounds,¹² we wish to report the production of cyclopentene-fused spiro-rhodanine derivatives through phosphine-catalyzed [3 + 2] cycloaddition (Scheme 1c) or a one-pot four-component sequential [3 + 2]/[3 + 2] annulation reaction (Scheme 1d).

Results and discussion

In the initial studies, the reaction of ethyl 5-phenylpent-2-ynoate 1a¹³ with 5-phenylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one 2a¹⁴ was performed in toluene at room temperature in the presence of 20 mol% catalyst. We first examined the reaction by utilizing 1a (0.15 mmol, 1.5 equiv.) and 2a (0.10 mmol) as the substrates and triphenylphosphine (PPh₃) (20 mol%) as the catalyst. No product was obtained after 12 h, and 1a was completely recovered (Table 1, entry 1). We assumed that the lack of reaction was due to steric hindrance and the weak nucleophilic ability of the phosphine. Therefore, triphenylphosphine (PPh₃) was changed to more strongly nucleophilic phosphines, including methyl(diphenyl)phosphine (PPh₂Me), tributylphosphine (PBu₃), and various of bisphosphines such as 1,3-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), and 1,3-bis(diphenylphosphino)butane (DPPB) as nucleophilic catalysts (Table 1, entries 2–6). Among several phosphine catalysts tested, PBu₃ emerged as the preferred catalyst in terms of the yield and diastereoselectivity. With tributylphosphine (PBu₃) as the catalyst, the desired cycloaddition product cyclopentene 5-spiro-rhodanine 3a was obtained in 87% yield with excellent diastereoselectivity (dr: >20 : 1) (Table 1, entry 3).

Table 1 Optimization of the [3 + 2] cycloaddition reaction conditions^a

Entry	Catalyst	Solvent	Time (h)	dr^b	Yield^c (%)
a Unless otherwise specified, all reactions were carried out using ethyl 5-phenylpent-2-ynoate 1a (0.15 mmol, 1.5 equiv.) and 5-phenylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one 2a (0.10 mmol) in 1 mL solvent with 20 mol% of catalyst at room temperature.b Diastereomeric ratio (dr) values were determined by ^1H NMR of crude products.c Yield of isolated product of 3a after column chromatography.d MTBE = methyl tert-butyl ether.e 10 mol% of catalyst was used.
1	PPh3	Toluene	12	—	—
2	PPh2Me	Toluene	12	>20 : 1	53
3	PBu3	Toluene	12	>20 : 1	87
4	DPPE	Toluene	12	>20 : 1	67
5	DPPP	Toluene	12	>20 : 1	62
6	DPPB	Toluene	12	>20 : 1	65
7	PBu3	DCM	12	>20 : 1	78
8	PBu3	THF	12	>20 : 1	75
9	PBu3	CHCl3	12	>20 : 1	64
10	PBu3	MeCN	12	>20 : 1	61
11	PBu3	MTBE^d	12	>20 : 1	39
12	PBu3	Toluene	24	>20 : 1	95
13^e	PBu3	Toluene	24	>20 : 1	78

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With PBu₃ chosen as the catalyst, other parameters for the reaction conditions were further examined. A solvent screening was subsequently performed, and toluene was identified to be the best solvent for the reaction, whereas other solvent such as DCM, THF, CHCl₃, MeCN, and methyl tert-butyl ether (MTBE), could readily afford the desired product 3a in inferior yields (Table 1, entries 7–11). Further studies suggested that prolong reaction time favoured this reaction, when the reaction time extended to 24 h, the reaction yield increased to 95% (Table 1, entry 12). The loading of catalysts has some influences on the yield. Lower yield was observed when the catalyst loading was decreased to 10 mol% (Table 1, entry 13). It should be noted that the cycloaddition reaction is completely regioselective and highly diastereoselective (only one isomer was detected in all reactions). Thus, the optimal reaction conditions for this transformation were determined to be ethyl 5-phenylpent-2-ynoate (1a; 0.15 mmol), 5-phenylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one (2a; 0.10 mmol), and PBu₃ (20 mol%) as catalyst in toluene (1 mL) as a solvent at room temperature.

Using these optimized reaction conditions, we then examined the scope and limitations of the PBu₃-catalyzed [3 + 2] cycloaddition reaction between alkynoate derivatives 1 and 5-arylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one 2, and the results are shown in Table 2. Significant structural variation in compound 2 could be carried out. Aryl units containing electron-donating or electron-withdrawing substitutents in different position were readily tolerated, thus giving preferentially the corresponding cyclopentene 5-spiro-rhodanines 3 in moderate to good yields with excellent diastereoselectivities (Table 2, entries 1–17). Notably, the electronic properties of the substituent on 2 have a certain influence on this reaction, and electron-donating substituents resulted in moderate yields (Table 2, entries 10–17).

Table 2 Scope of the reaction^a

Entry	Product	R^1	R^2	dr^b	Yield^c (%)
a Reaction conditions: ethyl 5-arylpent-2-ynoate 1 (0.15 mmol), 5-arylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one 2 (0.10 mmol), in 1 mL of toluene at room temperature in the presence of 20 mol% of PBu3.b Diastereomeric ratio (dr) values were determined by ^1H NMR of crude products.c Isolated yield after silica gel chromatography of 3.
1	3a	Bn	C6H5 (2a)	>20 : 1	95
2	3b	Bn	2-Br-C6H4 (2b)	>20 : 1	92
3	3c	Bn	3-NO2-C6H4 (2c)	>20 : 1	96
4	3d	Bn	3-CF3-C6H4 (2d)	>20 : 1	98
5	3e	Bn	2-Cl-C6H4 (2e)	>20 : 1	95
6	3f	Bn	2,4-(Cl)2-C6H3 (2f)	>20 : 1	99
7	3g	Bn	4-Br-C6H4 (2g)	>20 : 1	96
8	3h	Bn	4-Cl-C6H4 (2h)	>20 : 1	95
9	3i	Bn	4-F-C6H4 (2i)	>20 : 1	93
10	3j	Bn	4-MeO-C6H4 (2j)	>20 : 1	79
11	3k	Bn	4-^iPr-C6H4 (2k)	>20 : 1	87
12	3l	Bn	3-Me-C6H4 (2l)	>20 : 1	85
13	3m	Bn	4-Me-C6H4 (2m)	>20 : 1	87
14	3n	Bn	4-N,N-(Me)2-C6H4 (2n)	>20 : 1	82
15	3o	Bn	2-Me-C6H4 (2o)	>20 : 1	89
16	3p	Bn	3,4-(Me)2-C6H3 (2p)	>20 : 1	86
17	3q	Bn	2-MeO-C6H4 (2q)	>20 : 1	84
18	3r	Bn	1-Naphthyl (2r)	>20 : 1	87
19	3s	Bn	2-Thienyl (2s)	>20 : 1	99
20	3t	Ph	C6H5 (2a)	6 : 1	91
21	3u	Ph	2-Br-C6H4 (2b)	8 : 1	93
22	3v	Ph	4-^iPr-C6H4 (2k)	6 : 1	81

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We were delighted to find that the 5-arylidene rhodanine derivatives 2r and 2s, bearing naphthyl and thienyl groups, respectively, underwent smooth sequential annulations with 1a, to give the corresponding products (i.e., 3r and 3s) in good yields with excellent diastereoselectivities (Table 2, entries 18 and 19). It appears that the benzyl group in the alkynoates 1 is critical for achieving a high diastereoselectivity. When ethyl-4-phenylbut-2-ynoate 1b was employed as the substrate the reaction proceeded in high yields, but with poor diastereoselectivities (Table 2, entries 20–22). The diastereomeric ratio of product was determined by ¹H NMR spectroscopy of the crude product. In order to determine the structure of the products, a single crystal X-ray diffraction study of 3l was performed.¹⁵ The molecular structure of 3l is shown in Fig. 2, and the structure showed that the relative configuration of the product was assigned as erythro.

Fig. 2 X-ray crystal structure of 3l.

Encouraged by these results, we envisioned that the cycloaddition reaction could proceed by multi-component coupling reactions (MCCRs) in one pot. MCCRs are useful tool to synthesize complex molecular architectures.¹⁶ Owing to their exceptional synthetic efficiency and high atom economy, the design of MCCRs for the synthesis of diverse biologically active compounds, have gained great attention in organic synthesis.¹⁷ These advantages of MCCRs prompted us to design synthesis of cyclopentene 5-spiro-rhodanine derivatives via phosphine-catalyzed one-pot sequential [3 + 2]/[3 + 2] cycloaddition. First, we found optimized conditions by studying a model reaction between ethyl 5-phenylpent-2-ynoate 1a (0.15 mmol), phenylethylpropiolate 4a (0.10 mmol),¹⁸ benzylamine 5a (0.22 mmol), and carbon disulfide 6 (0.11 mmol) with 20 mol% of phosphine catalyst in 1.0 mL of toluene at room temperature. In the absence of catalyst, the reaction did not proceed even after a prolonged reaction time (Table 3, entry 1). Gratifyingly, the optimized conditions were simple, in which 20 mol% PBu₃ at room temperature in toluene as solvent were required for the formation of the four-component coupling product 7a in 85% yield with excellent diastereoselectivity (dr: >20 : 1) (Table 3, entry 2). Other phosphine and bisphosphine catalysts, such as PPh₂Me, PPh₂Et, DPPP, and DPPB, also gave the desired product 7a in similar yields (Table 3, entries 3–6). A low product yield was obtained when the reaction was performed with 10 mol% of PBu₃ (Table 3, entry 7).

Table 3 Optimization of the [3 + 2]/[3 + 2] cycloaddition reaction conditions^a

Entry	Catalyst	Solvent	dr^b	Yield^c (%)
a Reaction conditions: ethyl 5-phenylpent-2-ynoate 1a (0.15 mmol), phenylethylpropiolate 4a (0.10 mmol), benzylamine 5a (0.22 mmol), carbon disulfide 6 (0.11 mmol) in 1 mL of solvent at room temperature in the presence of 20 mol% of catalyst.b Diastereomeric ratio (dr) values were determined by ^1H NMR of crude products.c Isolated yield after silica gel chromatography of 7.d 10 mol% of catalyst was used.
1	—	Toluene	—	—
2	PBu3	Toluene	>20 : 1	85
3	PPh2Me	Toluene	>20 : 1	46
4	PPh2Et	Toluene	>20 : 1	42
5	DPPP	Toluene	>20 : 1	55
6	DPPB	Toluene	>20 : 1	62
7^d	PBu3	Toluene	>20 : 1	52
8	PBu3	DCM	>20 : 1	63
9	PBu3	THF	>20 : 1	68
10	PBu3	MeCN	>20 : 1	64

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We then examined the effect of the solvent on the yield and diastereoselectivity. Compared with DCM, THF, and MeCN, the use of toluene as a solvent gave a better yield and diastereoselectivity (Table 3, entries 8–10). Thus, the optimal reaction conditions for this transformation were determined to be ethylalkynoate 1a (0.15 mmol), phenylethylpropiolate 4a (0.10 mmol), benzylamine 5a (0.22 mmol), carbon disulfide 6 (0.11 mmol), and PBu₃ (20 mol%) as a catalyst in toluene (1 mL) as a solvent at room temperature.

Having determined the optimal conditions, we investigated the scope of the one-pot four-component protocol for the reaction of ethyl 5-phenylpent-2-ynoate 1a, substituted arylethylpropiolates 4a–d, and amines 5a–c, with carbon disulfide 6 as presented in Table 4. Substituted arylethylpropiolates 4 containing electron-donating or electron-withdrawing groups at the para position of the benzene ring reacted smoothly to give 7a–e in moderate to good yields with excellent diastereoselectivities (Table 4, entries 1–5). We next examined various aliphatic amines using phenylethylpropiolate 4a, and carbon disulfide 6 as the reaction partners. Aliphatic amines 5b–c smoothly participated in the [3 + 2]/[3 + 2] cycloaddition to afford the corresponding products 7 in moderate yields with excellent diastereoselectivities (Table 4, entries 2–7). The aromatic ring of arylethylpropiolates 4 bearing an electron-donating or -withdrawing group were all compatible, had little influence on the reaction outcome and resulted in the formation of the corresponding products 7 in good to excellent yields (74–92%) (Table 4, entries 2–5).

Table 4 Scope of the reaction^a

Entry	Product	R^3	R^4	dr^b	Yield^c (%)
a Reaction conditions: ethyl 5-phenylpent-2-ynoate 1a (0.15 mmol), arylethylpropiolate 4 (0.10 mmol), amine 5 (0.22 mmol), carbon disulfide 6 (0.11 mmol) in 1 mL of solvent at room temperature in the presence of 20 mol% of catalyst.b Diastereomeric ratio (dr) values were determined by ^1H NMR of crude products.c Isolated yield after silica gel chromatography of 7.
1	7a	H (4a)	Bn (5a)	>20 : 1	85
2	7b	4-Me (4b)	^nPr (5b)	>20 : 1	79
3	7c	4-Me (4b)	^nBu (5c)	>20 : 1	76
4	7d	4 Et (4c)	^nBu (5c)	>20 : 1	74
5	7e	4 F (4d)	^nPr (5b)	6 : 1	92
6	7f	H (4a)	^nPr (5b)	>20 : 1	89
7	7g	H (4a)	^nBu (5c)	>20 : 1	87

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A mechanism for this one-pot sequential [3 + 2]/[3 + 2] annulation cycloaddition is proposed on the basis of previous literature reports,^10a,19 and is shown in Scheme 2. The first cycle involves the nucleophilic attack of the phosphine on phenylethylpropiolate 4a to yield the phosphonium salt A (zwitterionic intermediate). The process is continued by the addition of RNH₂ to CS₂ and subsequent undergoes α addition to intermediate A to give the intermediate B.

Scheme 2 Proposed reaction mechanism.

Followed by a hydrogen shift to get the intermediate B′ by a reverse equilibrium, which undergoes another intramolecular nucleophilic addition to give intermediate C. Proton transfer and subsequent β-elimination of the catalyst phosphine leads to the formation of the corresponding adduct 2.

In the second cycle, the nucleophilic attack of the regenerated catalyst PBu₃ on ethyl alkynoate 1a to give monozwitterion D, which can isomerize to intermediate E. Intermediate E is assumed to undergo δ-addition to the carbon–carbon double bond of substrate 2 to product intermediate F, which further undergoes an intramolecular cyclization to furnish the phosphorane G. Charge migration followed by tributyl phosphine elimination of intermediate G produces the final product 7. The reaction rate and diastereoselective product distribution of 7 is attributed to the steric hindrance effects and electronic repulsions between benzyl group and tributyl-phosphonium.

Conclusions

In conclusion, we have developed an efficient method for the diastereoselective synthesis of 5-spiro-cyclopentene-rhodanine skeletons through phosphine-catalyzed [3 + 2] cycloaddition of alkynoate derivatives 1 with 5-arylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one 2. As an extension, we also developed a phosphine-catalyzed one-pot four-component sequential [3 + 2]/[3 + 2] cycloaddition reaction of ethyl 5-phenylpent-2-ynoate, substituted arylethylpropiolates, amines, with carbon disulfide. The two protocols proceeded well under mild conditions to furnish a series of 5-spiro-cyclopentene-rhodanines containing three contiguous stereocenters, including one spiro quateruary chiral center in excellent diastereoselectivities (only one isomer), and good to excellent yields. Further investigations on the mechanism and synthetic application of this new approach to complex molecule synthesis are currently underway in our laboratory and will be reported in due course.

Experimental

General section

All reactions were performed under N₂ atmosphere in oven-dried glassware with magnetic stirring. Solvents were dried and distilled prior to use according to the standard methods. Unless otherwise indicated, all materials were obtained from commercial sources, and used as purchased without dehydration. Flash column chromatography was performed on silica gel (particle size 10–40 μm, Ocean Chemical Factory of Qingdao, China). Nitrogen gas (99.999%) was purchased from Boc Gas Inc. ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra were recorded in CDCl₃ at Bruker 400 MHz spectrometers, TMS served as internal standard (δ = 0 ppm) for ¹H NMR and ¹³C NMR. HR-MS were recorded on APEXII and ZAB-HS spectrometer.

Experimental section

General procedure for formal [3 + 2] cycloaddition reaction for products 3. Under a nitrogen atmosphere, to a mixture of 5-arylidene-3-(tert-butyl)-2-thioxothiazolidin-4-one 2 (0.1 mmol, 1.0 equiv.), and Bu₃P (4.1 mg, 0.02 mmol, 20 mmol%) was added toluene (1 mL) via a syringe and allowed to stir for 5 min at room temperature. Ethyl alkynoate 1 (0.15 mmol, 1.5 equiv.) was added and the reaction was allowed to stir for 24 h at room temperature. The reaction was monitored by TLC spectroscopy. After the reaction was completed, the reaction mixture was directly purified by flash column chromatograph (eluted with 20 : 1 petroleum ether/EtOAc) to afford the product 3.
Ethyl 9-benzyl-3-(tert-butyl)-4-oxo-6-phenyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3a). Yellow oil (45.6 mg, 95% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.34–7.26 (m, 5H), 7.22 (d, J = 6.8 Hz, 3H), 7.01 (dd, J = 7.4, 1.9 Hz, 2H), 6.77 (t, J = 2.3 Hz, 1H), 4.76 (t, J = 2.1 Hz, 1H), 4.12–3.95 (m, 2H), 3.95–3.85 (m, 1H), 2.99 (dd, J = 13.8, 8.3 Hz, 1H), 2.90 (dd, J = 13.8, 8.3 Hz, 1H), 1.61 (s, 9H), 1.05 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.5, 179.0, 163.7, 144.4, 137.6, 136.8, 135.8, 129.2, 128.8, 128.7, 128.3, 128.0, 126.8, 73.1, 65.1, 60.7, 60.3, 54.5, 38.0, 28.8, 13.9; HRMS (ESI): m/z calcd for C₂₇H₃₀NO₃S₂ [M + H]⁺ 480.1662, found 480.1664.
Ethyl 9-benzyl-6-(2-bromophenyl)-3-(tert-butyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3b). Yellow oil (51.4 mg, 92% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.36–7.26 (m, 3H), 7.26–7.19 (m, 3H), 7.16 (dd, J = 7.8, 1.6 Hz, 1H), 6.98 (dd, J = 7.7, 1.6 Hz, 1H), 6.85 (t, J = 2.3 Hz, 1H), 5.26 (d, J = 0.9 Hz, 1H), 4.11–3.93 (m, 2H), 3.83–3.71 (m, 1H), 3.08 (dd, J = 13.5, 6.8 Hz, 1H), 2.63 (dd, J = 13.5, 10.2 Hz, 1H), 1.76 (s, 9H), 1.03 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 201.0, 180.4, 163.1, 145.2, 138.3, 137.7, 135.4, 133.1, 129.4, 129.0, 128.9, 128.7, 127.6, 126.8, 126.7, 69.5, 65.4, 60.7, 58.4, 56.0, 39.4, 28.8, 13.9; HRMS (ESI): m/z calcd for C₂₇H₂₉BrNO₃S₂ [M + H]⁺ 558.0767, found 558.0765.
Ethyl 9-benzyl-3-(tert-butyl)-6-(3-nitrophenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3c). Yellow oil (50.4 mg, 96% yield); ¹H NMR (400 MHz, CDCl₃): δ 8.21–8.12 (m, 1H), 7.89 (t, J = 1.9 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.35–7.27 (m, 3H), 7.22 (d, J = 7.1 Hz, 3H), 6.87 (t, J = 2.3 Hz, 1H), 4.90 (t, J = 2.3 Hz, 1H), 4.08–3.97 (m, 2H), 2.99 (d, J = 8.6 Hz, 2H), 1.55 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.3, 178.4, 163.2, 147.9, 146.1, 138.8, 137.0, 135.1, 134.3, 129.2, 128.9, 126.9, 123.5, 123.1, 73.3, 65.6, 61.0, 60.2, 54.5, 37.5, 28.8, 14.0; HRMS (ESI): m/z calcd for C₂₇H₂₉N₂O₅S₂ [M + H]⁺: 525.1512, found 525.1511.
Ethyl 9-benzyl-3-(tert-butyl)-4-oxo-2-thioxo-6-(3-(trifluoromethyl)phenyl)-1-thia-3-azaspiro[4.4]-non-7-ene-7-carboxylate (3d). Yellow oil (53.7 mg, 98% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.33–7.26 (m, 3H), 7.24–7.14 (m, 4H), 6.82 (s, 1H), 4.85 (s, 1H), 4.08 (d, J = 7.1 Hz, 1H), 4.02 (dd, J = 7.1 Hz, 6.9 Hz, 2H), 2.97 (d, J = 8.2 Hz, 2H), 1.55 (s, 9H), 1.05 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.7, 178.6, 163.4, 145.4, 137.7, 137.2, 134.9, 132.4, 129.2, 128.8, 128.7, 126.9, 125.4, 124.9, 124.9, 60.8, 73.5, 65.4, 60.8, 60.4, 54.5, 37.6, 28.7, 13.9; ¹⁹F NMR (376 MHz, CDCl₃): δ −62.59; HRMS (ESI): m/z calcd for C₂₈H₂₉F₃NO₃S₂ [M + H]⁺: 548.1535, found 548.1535.
Ethyl 9-benzyl-3-(tert-butyl)-6-(2-chlorophenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3e). Yellow oil (48.8 mg, 95% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.40 (dd, J = 5.7, 3.6 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.22 (dd, J = 8.3, 4.7 Hz, 5H), 6.98 (dd, J = 5.8, 3.5 Hz, 1H), 6.85 (t, J = 2.1 Hz, 1H), 5.27 (s, 1H), 4.12–4.02 (m, 2H), 3.83 (dd, J = 12.1, 4.6 Hz, 1H), 3.06 (dd, J = 13.5, 7.1 Hz, 1H), 2.66 (dd, J = 13.5, 9.9 Hz, 1H), 1.74 (s, 9H), 1.03 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.8, 180.1, 163.2, 145.4, 137.7, 136.4, 135.3, 135.2, 129.8, 129.2, 129.0, 128.8, 128.8, 126.9, 126.8, 69.9, 65.3, 60.7, 56.0, 55.6, 39.1, 28.7, 13.9: HRMS (ESI): m/z calcd for C₂₇H₂₉ClNO₃S₂ [M + H]⁺: 514.1272, found 514.1268.
Ethyl 9-benzyl-3-(tert-butyl)-6-(2,4-dichlorophenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3f). Yellow oil (54.3 mg, 99% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 2.1 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.21 (dd, J = 13.5, 7.1 Hz, 4H), 6.87 (t, J = 5.5 Hz, 2H), 5.21 (s, 1H), 4.12–3.97 (m, 2H), 3.84 (dd, J = 8.2, 7.3 Hz, 1H), 3.05 (dd, J = 13.6, 7.2 Hz, 1H), 2.66 (dd, J = 13.5, 9.6 Hz, 1H), 1.72 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.3, 180.0, 163.0, 145.8, 137.5, 135.8, 135.1, 134.6, 134.3, 129.6, 129.6, 129.1, 128.9, 127.3, 126.9, 69.8, 65.5, 60.9, 55.7, 55.6, 39.0, 28.7, 14.0. HRMS (ESI): m/z calcd for C₂₇H₂₈Cl₂NO₃S₂ [M + H]⁺: 548.0882, found 548.0873.
Ethyl 9-benzyl-6-(4-bromophenyl)-3-(tert-butyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3g). Yellow oil (53.6 mg, 96% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 8.4 Hz, 2H), 7.35–7.27 (m, 2H), 7.21 (t, J = 6.7 Hz, 3H), 6.88 (d, J = 8.4 Hz, 2H), 6.78 (t, J = 2.3 Hz, 1H), 4.73 (s, 1H), 4.10–4.05 (m, 2H), 3.92–3.87 (ddd, J = 21.3, 12.2, 5.1 Hz, 1H), 3.00–2.86 (ddd, J = 21.3, 4.9 Hz, 2H), 1.59 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.9, 178.8, 163.4, 144.9, 137.3, 136.0, 135.3, 131.5, 130.4, 129.2, 128.8, 126.8, 122.0, 72.9, 65.2, 60.8, 59.7, 54.6, 37.9, 28.8, 14.0; HRMS (ESI): m/z calcd for C₂₇H₂₉BrNO₃S₂ [M + H]⁺: 558.0767, found 558.0757.
Ethyl 9-benzyl-3-(tert-butyl)-6-(4-chlorophenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3h). Yellow oil (48.8 mg, 95% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.28 (dd, J = 10.2, 4.7 Hz, 3H), 7.25 (s, 1H), 7.20 (t, J = 6.4 Hz, 3H), 6.93 (d, J = 8.4 Hz, 2H), 6.77 (t, J = 2.3 Hz, 1H), 4.73 (t, J = 2.1 Hz, 1H), 4.13–3.95 (m, 2H), 3.90 (tt, J = 13.8, 2.0 Hz, 1H), 2.99–2.85 (ddd, J = 33.1, 13.8, 8.3 Hz, 2H), 1.58 (d, J = 7.6 Hz, 9H), 1.07 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.9, 178.9, 163.4, 144.8, 137.4, 135.5, 135.3, 133.9, 130.1, 129.1, 128.8, 128.5, 126.8, 73.0, 65.2, 60.8, 59.7, 54.6, 37.9, 28.8, 14.0; HRMS (ESI): m/z calcd for C₂₇H₂₉ClNO₃S₂ [M + H]⁺: 514.1272, found 514.1266.
Ethyl 9-benzyl-3-(tert-butyl)-6-(4-fluorophenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3i). Yellow oil (46.3 mg, 93% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.55 (dd, J = 12.8, 6.1 Hz, 2H), 7.48 (d, J = 6.8 Hz, 3H), 7.25 (d, J = 6.6 Hz, 4H), 7.04 (d, J = 1.4 Hz, 1H), 5.02 (s, 1H), 4.41–4.24 (m, 2H), 4.18 (t, J = 7.7 Hz, 1H), 3.31–3.06 (m, 2H), 1.86 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.1, 178.9, 163.5, 144.6, 137.4, 135.5, 130.4, 130.4, 129.2, 128.8, 126.8, 115.3, 115.1, 73.3, 65.2, 60.7, 59.7, 54.4, 37.9, 28.8, 14.0; ¹⁹F NMR (376 MHz, CDCl₃): δ −113.87; HRMS (ESI): m/z calcd for C₂₇H₂₉FNO₃S₂ [M + H]⁺: 498.1567, found 498.1565.
Ethyl 9-benzyl-3-(tert-butyl)-6-(4-methoxyphenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3j). Yellow oil (40.3 mg, 79% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.28 (d, J = 6.6 Hz, 2H), 7.22 (s, 3H), 6.93 (d, J = 7.3 Hz, 2H), 6.82 (d, J = 7.8 Hz, 2H), 6.74 (s, 1H), 4.70 (s, 1H), 4.12–3.99 (m, 2H), 3.86 (s, 1H), 3.78 (s, 3H), 2.93 (dt, J = 13.4 Hz, 2H), 1.62 (s, 9H), 1.08 (t, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.5, 178.1, 162.7, 158.2, 143.0, 136.6, 134.9, 128.8, 128.1, 128.0, 127.7, 125.7, 112.6, 72.3, 64.0, 59.6, 58.5, 54.2, 53.3, 37.1, 27.8, 13.0; HRMS (ESI): m/z calcd for C₂₈H₃₂NO₄S₂ [M + H]⁺: 510.1767, found 510.1760.
Ethyl 9-benzyl-3-(tert-butyl)-6-(4-isopropylphenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3k). Yellow oil (45.4 mg, 87% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.30 (t, J = 7.2 Hz, 2H), 7.22 (d, J = 7.2 Hz, 3H), 7.13 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.75 (s, 1H), 4.71 (s, 1H), 4.16–3.94 (m, 2H), 3.84 (t, J = 8.0 Hz, 1H), 2.99 (dd, J = 8.0 Hz, 1H), 2.93–2.79 (m, 2H), 1.62 (s, 9H), 1.22 (s, 3H), 1.20 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.6, 179.0, 163.7, 148.6, 144.0, 137.7, 136.0, 134.1, 129.1, 128.7, 128.7, 126.7, 126.3, 73.1, 64.9, 60.6, 59.8, 54.4, 38.2, 33.7, 28.7, 23.9, 13.9; HRMS (ESI): m/z calcd for C₃₀H₃₆NO₃S₂ [M + H]⁺: 522.2131, found 522.2130.
Ethyl 9-benzyl-3-(tert-butyl)-4-oxo-2-thioxo-6-(m-tolyl)-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3l). Yellow oil (41.9 mg, 85% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.29 (dd, J = 9.5, 5.5 Hz, 2H), 7.24–7.14 (m, 4H), 7.06 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 6.3 Hz, 2H), 6.74 (t, J = 2.2 Hz, 1H), 4.73 (d, J = 1.9 Hz, 1H), 4.17–3.97 (m, 2H), 3.94–3.85 (m, 1H), 2.94 (dd, J = 13.8, 8.3 Hz, 2H), 2.30 (s, 3H), 1.61 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.7, 179.1, 163.8, 144.1, 137.7, 137.6, 136.8, 135.9, 129.4, 129.2, 128.8, 128.2, 126.7, 125.8, 73.1, 65.0, 60.7, 60.3, 54.5, 38.0, 28.8, 21.5, 14.0; HRMS (ESI): m/z calcd for C₂₈H₃₂NO₃S₂ [M + H]⁺: 494.1818, found 494.1823.
Ethyl 9-benzyl-3-(tert-butyl)-4-oxo-2-thioxo-6-(p-tolyl)-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3m). Yellow oil (42.9 mg, 87% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.28 (d, J = 7.1 Hz, 2H), 7.22 (d, J = 6.1 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H), 6.89 (d, J = 7.9 Hz, 2H), 6.74 (d, J = 2.1 Hz, 1H), 4.71 (s, 1H), 4.15–3.97 (m, 2H), 3.86 (dd, J = 11.4, 5.0 Hz, 1H), 2.98 (dd, J = 13.6, 8.2 Hz, 1H), 2.87 (dd, J = 13.7, 8.5 Hz, 1H), 2.31 (s, 3H), 1.62 (s, 9H), 1.07 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.6, 179.2, 163.7, 144.0, 137.7, 135.9, 134.0, 129.2, 129.1, 128.8, 128.6, 126.7, 73.0, 65.0, 60.7, 59.9, 54.5, 38.2, 28.8, 21.2, 14.0; HRMS (ESI): m/z calcd for C₂₈H₃₂NO₃S₂ [M + H]⁺: 494.1818, found 494.1820.
Ethyl 9-benzyl-3-(tert-butyl)-6-(4-(dimethylamino)phenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro-[4.4]-non-7-ene-7-carboxylate (3n). Yellow oil (42.9 mg, 82% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.33–7.27 (m, 2H), 7.25–7.19 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.71 (t, J = 2.2 Hz, 1H), 6.62 (d, J = 8.6 Hz, 2H), 4.63 (s, 1H), 4.12–3.97 (m, 2H), 3.78 (t, J = 8.3 Hz, 1H), 2.99 (dd, J = 13.6, 7.7 Hz, 1H), 2.92 (d, J = 10.1 Hz, 6H), 2.82 (dd, J = 13.6, 9.0 Hz, 1H), 1.65 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.8, 179.4, 157.0, 150.1, 143.4, 137.9, 136.4, 129.4, 129.1, 128.8, 126.7, 124.8, 112.1, 73.3, 64.8, 60.6, 59.3, 54.3, 40.5, 38.5, 28.8, 14.0; HRMS (ESI): m/z calcd for C₂₉H₃₅N₂O₃S₂ [M + H]⁺: 523.2084, found 523.2090.
Ethyl 9-benzyl-3-(tert-butyl)-4-oxo-2-thioxo-6-(o-tolyl)-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3o). Yellow oil (43.9 mg, 89% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.33 (t, J = 7.3 Hz, 2H), 7.21 (dd, J = 8.5, 4.3 Hz, 6H), 6.99–6.90 (m, 1H), 6.83–6.71 (m, 1H), 4.98 (d, J = 1.1 Hz, 1H), 4.12–3.91 (m, 2H), 3.83–3.47 (m, 1H), 3.06 (dd, J = 13.4, 6.6 Hz, 1H), 2.69 (dd, J = 13.4, 10.4 Hz, 1H), 2.30 (s, 3H), 1.74 (s, 9H), 1.03 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.7, 180.4, 163.4, 143.6, 138.0, 137.1, 137.1, 136.5, 130.8, 129.0, 128.9, 127.9, 126.9, 126.8, 126.3, 70.0, 65.0, 60.6, 55.9, 54.4, 39.4, 28.8, 20.1, 13.9; HRMS (ESI): m/z calcd for C₂₈H₃₂NO₃S₂ [M + H]⁺: 494.1818, found 494.1819.
Ethyl 9-benzyl-3-(tert-butyl)-6-(3,4-dimethylphenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3p). Yellow oil (43.7 mg, 86% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.29 (d, J = 7.0 Hz, 2H), 7.22 (d, J = 6.9 Hz, 3H), 7.04 (d, J = 7.6 Hz, 1H), 6.81–6.63 (m, 3H), 4.69 (s, 1H), 4.00–4.10 (m, 2H), 3.85 (t, J = 8.1 Hz, 1H), 2.99 (dd, J = 13.6, 8.1 Hz, 1H), 2.87 (dd, J = 13.6, 8.7 Hz, 1H), 2.21 (s, 6H), 1.63 (s, 9H), 1.09 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.8, 179.2, 163.8, 143.7, 137.7, 136.3, 136.3, 136.0, 134.4, 129.9, 129.6, 129.1, 128.8, 126.7, 126.0, 72.9, 64.9, 60.6, 59.8, 54.6, 38.2, 28.8, 19.9, 19.6, 14.0; HRMS (ESI): m/z calcd for C₂₉H₃₄NO₃S₂ [M + H]⁺: 508.1975, found 508.1981.
Ethyl 9-benzyl-3-(tert-butyl)-6-(2-methoxyphenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3q). Yellow oil (42.8 mg, 84% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.43–7.26 (m, 3H), 7.21 (t, J = 7.4 Hz, 4H), 6.91 (d, J = 3.8 Hz, 2H), 6.80 (s, 1H), 5.14 (s, 1H), 4.09–3.99 (m, 2H), 3.79 (s, 3H), 3.72 (s, 1H), 3.00 (dd, J = 13.1, 6.4 Hz, 1H), 2.66–2.48 (m, 1H), 1.77 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 201.5, 180.3, 163.6, 157.5, 145.1, 138.0, 135.1, 129.2, 129.0, 128.8, 127.7, 126.9, 126.7, 120.4, 110.6, 69.9, 64.8, 60.6, 55.7, 54.7, 52.4, 39.1, 28.9, 14.0; HRMS (ESI): m/z calcd for C₂₈H₃₂NO₄S₂ [M + H]⁺: 510.1767, found 510.1771.
Ethyl 9-benzyl-3-(tert-butyl)-6-(naphthalen-1-yl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3r). Yellow oil (46.1 mg, 87% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.97–7.89 (m, 1H), 7.84 (dd, J = 5.9, 3.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.52–7.44 (m, 2H), 7.44–7.39 (m, 1H), 7.33–7.27 (m, 2H), 7.23 (d, J = 8.0 Hz, 3H), 7.16–7.12 (m, 1H), 6.85 (t, J = 2.3 Hz, 1H), 5.68 (s, 1H), 4.06–3.94 (m, 2H), 3.94–3.73 (m, 1H), 3.02 (dd, J = 13.7, 7.8 Hz, 1H), 2.87 (dd, J = 13.7, 8.9 Hz, 1H), 1.57 (s, 9H), 0.92 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.9, 180.2, 163.7, 144.2, 137.7, 136.3, 134.4, 133.9, 132.2, 129.3, 129.1, 128.8, 128.7, 126.8, 126.6, 126.0, 125.8, 125.0, 122.8, 72.2, 65.2, 60.6, 55.9, 54.4, 38.5, 28.6, 13.9; HRMS (ESI): m/z calcd for C₃₁H₃₂NO₃S₂ [M + H]⁺: 530.1818, found 530.1818.
Ethyl 9-benzyl-3-(tert-butyl)-4-oxo-6-(thiophen-2-yl)-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3s). Yellow oil (48.1 mg, 99% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.31 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 8.6 Hz, 4H), 6.97 (t, J = 3.5 Hz, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 4.95 (s, 1H), 4.18–4.04 (m, 2H), 3.74 (t, J = 8.3 Hz, 1H), 3.06 (dd, J = 13.4, 7.5 Hz, 1H), 2.91–2.81 (m, 1H), 1.68 (s, 9H), 1.12 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.3, 179.0, 163.3, 144.0, 140.9, 137.7, 136.0, 129.1, 128.8, 127.4, 127.1, 126.8, 125.4, 71.9, 65.0, 60.8, 54.5, 54.4, 39.1, 28.8, 14.0; HRMS (ESI): m/z calcd for C₂₅H₂₈NO₃S₃ [M + H]⁺: 486.1226, found 486.1224.
Ethyl 3-(tert-butyl)-4-oxo-6,9-diphenyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3t). Yellow oil (42.4 mg, 91% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.34 (d, J = 7.0 Hz, 2H), 7.27 (d, J = 7.0 Hz, 3H), 7.23 (s, 1H), 7.17–6.97 (m, 5H), 4.93 (s, 1H), 4.86 (s, 1H), 4.15–4.03 (m, 2H), 1.78 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.2, 179.6, 163.6, 143.0, 137.5, 137.4, 137.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 127.9, 126.9, 74.8, 65.0, 60.8, 59.6, 58.8, 29.0, 13.9; HRMS (ESI): m/z calcd for C₂₆H₂₈NO₃S₂ [M + H]⁺: 466.1505, found 466.1502.
Ethyl 6-(2-bromophenyl)-3-(tert-butyl)-4-oxo-9-phenyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3u). Yellow oil (50.6 mg, 93% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 14.5, 8.6 Hz, 4H), 7.13–6.99 (m, 5H), 5.45 (s, 1H), 4.73 (s, 1H), 4.17–4.00 (m, 2H), 1.86 (s, 9H), 1.07 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 201.2, 181.1, 163.1, 143.2, 138.6, 137.5, 133.1, 129.3, 129.0, 128.9, 128.8, 128.6, 128.4, 127.5, 126.4, 71.5, 65.4, 61.6, 60.8, 58.2, 29.0, 13.9; HRMS (ESI): m/z calcd for C₂₆H₂₇BrNO₃S₂ [M + H]⁺: 544.0610, found 544.0646.
Ethyl 3-(tert-butyl)-6-(4-isopropylphenyl)-4-oxo-9-phenyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (3v). Yellow oil (41.1 mg, 81% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.33 (ddd, J = 15.1, 14.1, 9.1 Hz, 4H), 7.14 (ddd, J = 15.0, 8.0, 3.3 Hz, 4H), 7.07–6.88 (m, 2H), 4.89 (t, J = 2.2 Hz, 1H), 4.83 (t, J = 2.1 Hz, 1H), 4.26–3.95 (m, 2H), 2.87 (dd, J = 14.0, 7.0 Hz, 1H), 1.89–1.39 (m, 9H), 1.22 (ddd, J = 7.6, 7.0, 1.1 Hz, 6H), 1.08 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 200.4, 179.6, 163.6, 148.5, 142.5, 137.7, 137.3, 134.7, 128.9, 128.8, 128.6, 128.3, 127.6, 127.0, 126.4, 74.7, 65.0, 60.7, 59.2, 58.7, 33.8, 28.9, 23.9, 13.9; HRMS (ESI): m/z calcd for C₂₉H₃₄NO₃S₂ [M + H]⁺: 508.1975, found 508.1982.

General procedure for one-pot sequential [3 + 2]/[3 + 2] cycloaddition for products 7. A mixture of amine 5 (0.22 mmol, 2.2 equiv.) and carbon disulfide 6 (0.11 mmol, 1.1 equiv.) in dry toluene (1.0 mL) was stirred at room temperature for about 3 h. PBu₃ (4.1 mg, 0.02 mmol, 20 mmol%) and phenylethylpropiolate 4 (0.1 mmol, 1 equiv.) were added to the mixture under N₂. After stirring for 6 h at room temperature, ethyl 5-phenylpent-2-ynoate 1a (30.3 mg, 0.15 mmol, 1.5 equiv.) was added slowly and the mixture was stirred 15 hours at room temperature. The reaction was monitored by TLC spectroscopy. After the reaction was completed, the reaction mixture was directly purified by flash column chromatograph (eluted with 20 : 1 petroleum ether/EtOAc) to afford the product 7.
Ethyl 3,9-dibenzyl-4-oxo-6-phenyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7a). Yellow oil (43.6 mg, 85% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.26 (d, J = 3.2 Hz, 5H), 7.18 (dd, J = 12.7, 6.4 Hz, 6H), 7.11 (d, J = 7.3 Hz, 2H), 6.76 (dd, J = 13.7, 4.5 Hz, 3H), 4.88 (d, J = 14.6 Hz, 2H), 4.47 (d, J = 14.3 Hz, 1H), 4.14–4.05 (m, 1H), 4.04–3.95 (m, 2H), 3.08 (dd, J = 13.8, 7.2 Hz, 1H), 2.99–2.86 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 198.7, 177.8, 163.8, 144.1, 136.8, 136.2, 136.1, 134.7, 129.1, 128.6, 128.5, 128.4, 128.3, 127.9, 126.9, 76.1, 60.8, 60.7, 55.6, 47.2, 37.1, 13.9; HRMS (ESI): m/z calcd for C₃₀H₂₈NO₃S₂ [M + H]⁺: 514.1505, found 514.1514.
Ethyl 9-benzyl-4-oxo-3-propyl-2-thioxo-6-(p-tolyl)-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7b). Yellow oil (37.9 mg, 79% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.23 (d, J = 7.0 Hz, 2H), 7.17 (d, J = 7.5 Hz, 3H), 7.03 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 7.9 Hz, 2H), 6.76 (d, J = 2.1 Hz, 1H), 4.95 (d, J = 41.2 Hz, 1H), 4.17–4.02 (m, 2H), 4.01–3.94 (m, 1H), 3.57 (ddd, J = 13.1, 9.1, 6.1 Hz, 1H), 3.45–3.30 (m, 1H), 3.05 (dd, J = 13.9, 7.4 Hz, 1H), 2.95 (dd, J = 13.9, 9.5 Hz, 1H), 2.28 (s, 3H), 1.44–1.32 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.2, 178.1, 163.8, 144.0, 137.6, 137.0, 136.4, 133.3, 129.0, 129.0, 128.6, 128.3, 126.8, 76.0, 60.7, 60.6, 55.5, 45.9, 37.3, 21.2, 20.2, 14.0, 11.1; HRMS (ESI): m/z calcd for C₂₇H₃₀NO₃S₂ [M + H]⁺: 480.1662, found 480.1665.
Ethyl 9-benzyl-3-butyl-4-oxo-2-thioxo-6-(p-tolyl)-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7c). Yellow oil (37.5 mg, 76% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.23 (d, J = 7.0 Hz, 2H), 7.19–7.12 (m, 3H), 7.03 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 2.3 Hz, 1H), 4.88 (t, J = 2.4 Hz, 1H), 4.15–4.01 (m, 2H), 3.98 (ddd, J = 9.5, 6.3, 2.6 Hz, 1H), 3.61 (ddd, J = 13.2, 9.0, 5.9 Hz, 1H), 3.49–3.37 (m, 1H), 3.04 (dd, J = 13.9, 7.4 Hz, 1H), 2.94 (dd, J = 13.9, 9.5 Hz, 1H), 2.28 (s, 3H), 1.35–1.26 (m, 2H), 1.23–1.13 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.1, 178.0, 163.8, 144.0, 137.6, 137.0, 136.4, 133.3, 129.0, 129.0, 128.6, 128.4, 126.8, 75.9, 60.7, 60.6, 55.5, 44.3, 37.3, 28.8, 21.2, 19.9, 14.0, 13.7; HRMS (ESI): m/z calcd for C₂₈H₃₂NO₃S₂ [M + H]⁺: 494.1818, found 494.1823.
Ethyl 9-benzyl-3-butyl-6-(4-ethylphenyl)-4-oxo-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7d). Yellow oil (37.5 mg, 74% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.23 (s, 1H), 7.17 (dd, J = 5.0, 2.5 Hz, 4H), 7.04 (t, J = 8.9 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.76 (t, J = 2.3 Hz, 1H), 4.91 (dd, J = 18.3, 16.0 Hz, 1H), 4.18 (dd, J = 14.3, 7.2 Hz, 1H), 4.07–3.96 (m, 2H), 3.62 (ddd, J = 13.1, 8.9, 6.0 Hz, 1H), 3.51–3.32 (m, 2H), 3.05 (dd, J = 13.9, 7.4 Hz, 1H), 2.99–2.89 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.25 (d, J = 7.1 Hz, 2H), 1.17 (d, J = 7.6 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H), 0.92–0.82 (m, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.1, 178.0, 163.8, 144.0, 137.0, 133.5, 129.0, 128.6, 128.5, 128.3, 127.7, 126.8, 126.3, 76.0, 60.7, 60.6, 55.5, 49.5, 44.2, 37.3, 28.8, 19.9, 15.3, 13.9, 13.7; HRMS (ESI): m/z calcd for C₂₉H₃₄NO₃S₂ [M + H]⁺: 508.1975, found 508.1976.
Ethyl 9-benzyl-6-(4-fluorophenyl)-4-oxo-3-propyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7e). Yellow oil (44.4 mg, 92% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.26 (d, J = 7.0 Hz, 2H), 7.19 (t, J = 6.1 Hz, 3H), 6.99–6.89 (m, 4H), 6.82 (t, J = 2.4 Hz, 1H), 4.94 (t, J = 2.6 Hz, 1H), 4.18–4.10 (m, 1H), 4.05 (ddd, J = 16.8, 9.6, 6.7 Hz, 2H), 3.56 (ddd, J = 13.0, 9.2, 6.1 Hz, 1H), 3.36 (ddd, J = 13.0, 9.2, 6.0 Hz, 1H), 3.11 (dd, J = 14.0, 7.0 Hz, 1H), 2.97 (dd, J = 14.0, 9.8 Hz, 1H), 1.40–1.31 (m, 2H), 1.10 (t, J = 7.1 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 198.5, 177.7, 163.5, 144.6, 136.7, 136.0, 130.3, 130.2, 129.0, 128.6, 126.9, 115.3, 115.1, 76.2, 60.8, 60.2, 55.3, 45.9, 37.0, 20.2, 13.9, 11.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.86; HRMS (ESI): m/z calcd for C₂₆H₂₇FNO₃S₂ [M + H]⁺: 484.1411, found 484.1408.
Ethyl 9-benzyl-4-oxo-6-phenyl-3-propyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7f). Yellow oil (41.4 mg, 89% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.25–7.20 (m, 5H), 7.19–7.12 (m, 3H), 6.91 (dd, J = 6.7, 2.8 Hz, 2H), 6.81–6.75 (m, 1H), 4.93 (t, J = 2.6 Hz, 1H), 4.09 (dd, J = 10.8, 7.1 Hz, 1H), 4.05–3.96 (m, 2H), 3.55 (ddd, J = 13.0, 9.2, 6.1 Hz, 1H), 3.44–3.30 (m, 1H), 3.07 (dd, J = 14.0, 7.3 Hz, 1H), 2.94 (dd, J = 13.9, 9.6 Hz, 1H), 1.44–1.30 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 199.0, 177.9, 163.8, 144.3, 136.9, 136.3, 129.0, 128.6, 128.5, 128.3, 128.0, 126.8, 76.0, 61.0, 60.7, 55.5, 45.9, 37.2, 20.2, 13.9, 11.1; HRMS (ESI): m/z calcd for C₂₆H₂₈NO₃S₂ [M + H]⁺: 466.1505, found 466.1514.
Ethyl 9-benzyl-3-butyl-4-oxo-6-phenyl-2-thioxo-1-thia-3-azaspiro[4.4]non-7-ene-7-carboxylate (7g). Yellow oil (41.7 mg, 87% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.24 (dd, J = 8.5, 5.0 Hz, 5H), 7.17 (d, J = 6.5 Hz, 3H), 6.92 (dd, J = 6.5, 2.8 Hz, 2H), 6.79 (t, J = 2.3 Hz, 1H), 4.93 (s, 1H), 4.22–4.10 (m, 1H), 4.07–3.94 (m, 2H), 3.60 (ddd, J = 13.3, 9.0, 5.8 Hz, 1H), 3.48–3.38 (m, 1H), 3.07 (dd, J = 14.0, 7.2 Hz, 1H), 2.92 (ddd, J = 15.9, 13.5, 7.8 Hz, 2H), 1.47–1.28 (m, 2H), 1.23–1.14 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 198.9, 177.9, 163.8, 144.2, 136.9, 136.3, 129.0, 128.6, 128.5, 128.3, 128.2, 128.0, 126.8, 126.3, 75.8, 61.0, 60.7, 55.4, 44.3, 37.2, 28.8, 19.9, 13.9, 13.6; HRMS (ESI): m/z calcd for C₂₇H₃₀NO₃S₂ [M + H]⁺: 480.1662, found 480.1667.

Acknowledgements

We thank the National Natural Science Foundation of China (21072102), the Committee of Science and Technology of Tianjin (15JCYBJC20700) and State Key Laboratory of Elemento-Organic Chemistry in Nankai University for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General information, experimental procedures, characterized data and copies of ¹H and ¹³C NMR spectra for products. CCDC 1494917. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra23399f

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