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Synthesis 2020; 52(18): 2689-2697
DOI: 10.1055/s-0040-1707147
paper
© Georg Thieme Verlag Stuttgart · New York

P(OEt)3-Mediated Formal S–H Insertion: Reductive Couplings of Isatins with Thiols to Generate 3-Sulfenylated Oxindoles

Tiao Huang
a   Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, Hainan Province, P. R. of China   Email: wmsh@hainnu.edu.cn
,
Li Liu
a   Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, Hainan Province, P. R. of China   Email: wmsh@hainnu.edu.cn
,
Qinghe Wang
a   Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, Hainan Province, P. R. of China   Email: wmsh@hainnu.edu.cn
,
Dulin Kong∗
b   School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, Hainan Province, P. R. of China   Email: kongdulin@126.com
,
Mingshu Wu  ∗
a   Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry & Chemical Engineering, Hainan Normal University, Haikou 571158, Hainan Province, P. R. of China   Email: wmsh@hainnu.edu.cn
› Author Affiliations

This work was supported by Natural Science Foundation of Hainan Province (2019RC215) and Graduate Innovative Research Project of Hainan Normal University (Hsyx2018-25).
Further Information

Publication History

Received: 14 April 2020

Accepted after revision: 20 May 2020

Publication Date:
10 June 2020 (online)

 
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Abstract

A new P(OEt)3-mediated formal S–H bond-insertion reaction of isatins into thiols for the synthesis of valuable 3-sulfenylation oxindoles has been developed. This approach takes advantage of the unique reactivity of Kukhtin–Ramirez adducts to allow direct reductive S–H functionalization with commercially available and bench-stable starting materials.


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Key words

triethyl phosphite - S–H bond insertion - carbenoids - 3-sulfenylation oxindoles - isatins

The construction of carbon–heteroatom (C–X) bonds is essential in organic synthesis and many efficient methods have been developed for the formation of such bonds.[1] For organosulfur compounds, which represent an important class of pharmaceutical and biological compounds, C–S bond-formation constitutes a very important reaction.[2] In particular, oxindoles bearing a sulfur atom at the carbon stereocenter have been found to have anticancer,[3] antifungal,[4] or antitubercular activities (Figure [1]).[5] Therefore, research on the construction of a C–S bond at the carbon stereocenter of oxindoles has great significance.

Zoom Image
Figure 1 Selected natural products and bioactive oxindoles featuring a sulfur atom

Owing to the importance and usefulness of 3-sulfur substituted oxindoles, considerable effort has been devoted to developing various approaches to the synthesis of such oxindoles. Classical approaches include the SN1-type reaction of thiols with 3-substituted oxindoles bearing halo, hydroxyl or alkoxyl groups with the assistance of a base and an acid or a catalyst-free heterolytic cleavage (Scheme [1a])[6] and the direct sulfenylation of 3-substituted oxindoles with various sulfenylation reagents such as N-(benzyl­thio)phthalimide, N-(benzylthio)succinimide, N-(benzyl­thio)-1,2,4-triazole and N-(benzylthio)imidazole under transition-metal or metal-free catalyzed conditions (Scheme [1b]).[7] In addition, Xu’s group recently reported that 3-sulfenyl oxindoles could be synthesized by direct iron-catalyzed cross-dehydrogenative coupling between indoline-2-ones with thiols, employing air as the oxidant (Scheme [1b]).[8] Other representative methods for the synthesis of 3-sulfenyl oxindoles that involve Rh(II)-catalyzed thia-Sommelet–Hauser-type rearrangement between diazooxindoles and sulfenamides or disulfides have also been developed (Scheme [1c,d]).[9] Although these impressive advances have been made in this area, new strategies and methods to construct these scaffolds are still highly desirable and challenging.

Zoom Image
Scheme 1 Development for the C–S bond formation reactions

Transition-metal-catalyzed insertion of carbenes or carbenoids, generated in situ from diazo compounds, into heteroatom–hydrogen (X–H, X = N, O, S, Si, etc.) bonds for the construction of C–X bonds has achieved great success in the past decade.[10] This diazo decomposition insertion is a very powerful organic transformation, but preparation, isolation, and storage of these α-diazocompounds is problematic due in large part to their instability and hazardous nature. In view of the above cases, as an alternative carbene synthetic equivalent, Kukhtin–Ramirez adducts are generated from α-keto carbonyl derivatives and trivalent phosphorus reagents, which, by analogy to α-diazo ester resonance contributions, could serve as a synthetic equivalent to a carbenoid.[11] Thus, this class of readily accessible and stable compounds could be utilized to directly provide carbene-like reactivity for X–H bond insertion, while obviating the intermediacy of unstable α-diazo compounds. Recently, this elegant X–H insertion protocol has been reported for phenolic O–H, carboxylic O–H and amino N–H direct functionalization of α-keto esters, which lead to α-functionalized ester products.[12] However, the corresponding insertion reaction of Kukhtin–Ramirez adducts as formal carbene equivalents into S–H bonds has remained unexploited so far. On the basis of this unique reactivity pattern of Kukhtin–Ramirez adducts, we envisioned that a formal S–H bond-insertion reaction would be feasible by treating the Kukhtin–Ramirez adduct with α-dicarbonyl compounds and S–H bond-containing substrates. We herein report a P(OEt)3-mediated formal S–H bond insertion of isatins into thiols, leading to a facile synthesis of 3-sulfonated oxindoles.

Table 1 Optimization of the Reaction Conditionsa

Entry

PR3 (equiv)

Solvent

Temp (°C)

Yield (%)b

 1

PPh3 (1)

CHCl3

r.t.

n.r.

 2

P(OPh)3 (1)

CHCl3

r.t.

n.r.

 3

PBu3 (1)

CHCl3

r.t.

50

 4

P(NMe2)3 (1)

CHCl3

r.t.

70

 5

P(OMe)3 (1)

CHCl3

r.t.

40

 6

P(OEt)3 (1)

CHCl3

r.t.

80

 7

P(OEt)3 (1.5)

CHCl3

r.t.

86

 8

P(OEt)3 (1.7)

CHCl3

r.t.

86

 9

P(OEt)3 (1.5)

CH2Cl2

r.t.

78

10

P(OEt)3 (1.5)

CH3CN

r.t.

74

11

P(OEt)3 (1.5)

DMF

r.t.

72

12

P(OEt)3 (1.5)

THF

r.t.

77

13

P(OEt)3 (1.5)

toluene

r.t.

50

14

P(OEt)3 (1.5)

CHCl3

 0

72

15

P(OEt)3 (1.5)

CHCl3

40

77

a Reaction conditions (unless otherwise noted): 1a (0.1 mmol), 2a (0.12 mmol), solvent (1.0 mL) for 4 h.

b Isolated yield.

We initially attempted to apply the S–H bond-insertion protocol by treatment of N-benzyl isatin 1a with 4-methylbenzenethiol 2a mediated by trivalent phosphorus reagents (P(R)3) as oxygen-atom acceptors under the conditions listed in Table [1]. At the outset, when a stoichiometric amount of PPh3 and P(OPh)3 was added, respectively, no reaction was observed between 1a and 2a (entries 1 and 2). To our delight, performing the reaction using PBu3, P(NMe2)3 or P(OMe)3 all led to the desired product 3a, albeit with low or moderate yields (entries 3–5). Notably, the yield of the desired product 3a was upgraded to 80% when a stoichiometric amount of P(OEt)3 was used, and increasing the P(OEt)3 loading from 1 to 1.5 equiv relative to 1a, the yield was improved to 86% and further increasing the loading to 1.7 equiv of 1a led to the same result (entry 8). Among the trivalent phosphorus reagents examined, only P(OEt)3 was effective. The reaction temperature was then varied in an attempt to improve the yields: lowering the temperature to 0 °C gave 72% of 3a (entry 14), whereas rising the temperature to 40 °C provided product 3a in 77% yield (entry 15). Subsequently, other solvents were also tested for this reaction, including THF, CH3CN, toluene, DMF and CH2Cl2, but they did not give satisfactory results (entries 9–13); thus CHCl3 proved to be the most suitable solvent. Considering all of the active parameters, the optimal reaction conditions were chosen as summarized in Table [1], entry 7.

Once the optimization studies were concluded, we focused our attention on investigating the substrate scope and generality of this reaction. In general, a range of substituted thiols and isatins were all smoothly converted into the corresponding 3-sulfenylated oxindoles 3a–z in good to excellent yields (70–89%; Scheme [2]).

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Scheme 2 Substrates scope of the insertion reaction of isatins 1 into thiols 2. Reagents and conditions: 1 (0.5 mmol), 2 (0.6 mmol), P(OEt)3 (0.75 mmol, 1.5 equiv), CHCl3 (2.0 mL), r.t., 4 h. Isolated yields are given.

Regardless of the electronic nature of the substituted groups (electron-donating MeO or electron-withdrawing F) on the phenyl ring moiety, the desired products 3a–z were obtained in good yields (90–89%). The bis-substituted thiophenols afforded slightly lower yields (Scheme [2], 3zc, 78%) than those of other counterparts. The position of the substitution on the aryl ring of the thiol did not affect the efficiency of the reaction. Similarly, isatins 1 substituted at different positions (1 and 4–7) with a wide range of substituents (F, Cl, Br, MeO, Me, Et and Bn) were also examined and afforded 3 in high yields (70–89%). Unfortunately, the reaction of isatin bearing strongly electron-withdrawing nitro or trifluoromethyl groups at the 4- or 5-positions, gave complex mixtures, and the pure product could not be obtained. In addition, it was disappointing that N-unprotected isatins (R2 = H) did not participate in the reaction to furnish the desired product 3.

To further extend the substrate scope of the reaction, naphthalene-1-thiol was also studied, and delivered the desired product 4a in 70% yield (Scheme [3]). When aliphatic thiols, such as cyclopentanethiol and 3-methylbutane-2-thiol were used in the reaction, the corresponding 3-sulfenylated oxindoles 4b and 4c were obtained in 51–54% yields. Heterocyclic thiols such as benzothiazole-2-thiol, pyrimidine-2-thiol, 2-methylfuran-3-thiol, and 5-phenyl-1,3,4-oxadiazole-2-thiol were also well suited for the S–H bond-insertion reaction under the optimized reaction conditions and furnished the sulfenylation products 4d–g in moderate yields of 60–68%.

Zoom Image
Scheme 3 Substrates scope of the reaction with heterocyclic thiols, aliphatic thiols and naphthalene-1-thiol 2′. Reagents and conditions: 1 (0.5 mmol), 2′ (0.6 mmol), P(OEt)3 (0.75 mmol, 1.5 equiv), CHCl3 (1.5 mL), r.t., 4 h. Isolated yields are given.

The structures of all products 3 and 4 were assigned based on 1H, 13C NMR and HRMS analysis, and by diagnosis of singlets at δ = 5.23–4.25 in their 1H NMR spectra, which were attributed to reductive couplings at the C3 carbonyl groups of the isatins. In particular, the product 4b gave a quite complex NMR spectrum because of substantial peak doubling. It seemed likely that rotamers of 4b exist in solution as a result of hindered rotation of the C–S bond, giving rise to a 1:1 mixture of two diastereomers. The relative configuration of 3q was unequivocally assigned by X-ray diffraction (Scheme [2]; CCDC 1912827,[13] see the Supporting Information), and those of other products 3 and 4 were assigned by analogy.

Based on the experimental observations reported in this study, we propose a probable mechanism for the P(OEt)3-mediated S–H bond-insertion reaction by analogy with other formal reductive X–H insertion reactions (Scheme [4]).[12] [14] The reaction starts with the generation of the Kukhtin–Ramirez adduct I in situ from addition of P(OEt)3 to isatins, which would experience stabilization as oxyphosphonium enolate resonance structure II or 1,3-dipolar intermediate III. Subsequent S–H functionalization could evolve along two mechanistic pathways (A and B). The Kukhtin–Ramirez adduct I triggers loss of triethyl phosphate to give a free carbene intermediate IV, subsequent capture of which by S–H bond insertion would lead to product 3. Alternatively, Kukhtin–Ramirez adducts I–III may be intercepted by proton transfer from the thiol pronucleophile (S–H) to give ethyloxyphosphonium intermediate III′, which could then undergo nucleophilic displacement to furnish product 3 along with the release of the triethyl phosphate by-product.

Zoom Image
Scheme 4 Proposed mechanism

In summary, we have described a new P(OEt)3-mediated formal S–H bond-insertion reaction of isatins into thiols for the synthesis of valuable 3-sulfenylation oxindoles from commercially available and bench-stable starting materials. This metal-free S–H bond-insertion protocol allows rapid construction of 3-sulfur substituted oxindoles from isatins under mild conditions in a single step, which is different from the existing methodologies that require the use of prefunctionalized substrates or unstable diazo compounds. Therefore, readily available starting materials, mild reaction conditions, inexpensive metal-free catalysts and practical processes make this reaction a valuable addition to the synthetic chemistry toolbox.

The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF254. All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded with a Bruker Avance III (1H: 400 MHz, 13C: 100 MHz,19F NMR: 377 MHz), chemical shifts (δ) are expressed in ppm, and J values are given in Hz. CDCl3 were used as solvents. High-resolution mass spectra (HRMS) were recorded with an LCMS-IT-TOF. All chemicals and solvents were used as received without further purification unless otherwise stated. Column chromatography was performed on silica gel (200–300 mesh).


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Compounds 3; General Procedure

A 10-mL round-bottomed flask was charged with isatin 1 (0.5 mmol), thiophenol 2 (0.6 mmol), and CHCl3 (2 mL). Then the reaction mixture was stirred at r.t. for 5 minutes, and triethyl phosphite (1.5 equiv relative­ to 1, 0.75 mmol, 124.5 mg) was added. The formation of the product was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo and the residue was purified by column chromatography (silica gel, EtOAc PE = 1:6) to afford the desired products 3.


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Compounds 4; General Procedure

The experimental procedure was similar to the above process and used to obtain the desired products 4.


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1-Benzyl-3-(p-tolylthio)indolin-2-one (3a)

Yield: 148.5 mg (86%); white solid; mp 94–95 °C.

1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.3 Hz, 1 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.21–7.12 (m, 3 H), 7.11–6.99 (m, 2 H), 6.96–6.87 (m, 4 H), 6.47 (d, J = 7.6 Hz, 1 H), 4.92 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.56 (s, 1 H, CH, CH b ), 4.54 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.1, 143.2, 139.1, 135.3, 135.1 (2C), 129.6 (2C), 128.9, 128.6 (2C), 127.4, 127.1 (2C), 126.8, 126.4, 125.3, 122.8, 109.3, 49.6, 44.0, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C22H20NOS: 346.1260; found: 346.1256.


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1-Ethyl-3-(p-tolylthio)indolin-2-one (3b)

Yield: 117.6 mg (83%); yellow solid; mp 97–98 °C.

1H NMR (400 MHz, CDCl3): δ = 7.31 (dd, J = 7.3, 1.4 Hz, 1 H), 7.15–7.07 (m, 3 H), 6.95 (t, J = 7.6 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 2 H), 6.54 (d, J = 7.9 Hz, 1 H), 4.34 (s, 1 H, CH, CH b ), 3.57 (dq, J = 14.5, 7.3 Hz, 1 H), 3.35 (dq, J = 14.3, 7.2 Hz, 1 H), 2.14 (s, 3 H), 0.85 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.7, 143.1, 138.9, 134.9 (2C), 129.3 (2C), 128.9, 126.8, 125.4, 122.5, 108.1 (2C), 49.4, 34.7, 21.1, 12.1.

HRMS (ESI): m/z [M + Na]+ calcd for C17H17NaNOS: 306.0923; found: 306.0977.


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1-Benzyl-5-methyl-3-(p-tolylthio)indolin-2-one (3c)

Yield: 147.4 mg (82%); white solid; mp 126–127 °C.

1H NMR (400 MHz, CDCl3): δ = 7.29–7.16 (m, 6 H), 6.99–6.89 (m, 5 H), 6.38 (d, J = 7.9 Hz, 1 H), 4.92 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.55 (s, 1 H, CH, CH b ), 4.54 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 2.31 (d, J = 7.3 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 174.1, 140.7, 139.0, 135.4, 135.0 (2C), 132.3, 129.6 (2C), 129.2, 128.6 (2C), 127.4, 127.1 (3C), 126.4, 126.0, 109.0, 49.7, 44.0, 21.3, 21.1.

HRMS (ESI): m/z [M + H]+ calcd for C23H22NOS: 360.1417; found: 360.1423.


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1-Benzyl-3-((4-methoxyphenyl)thio)-5-methylindolin-2-one (3d)

Yield: 150.2 mg (80%); white solid; mp 148–149 °C.

1H NMR (400 MHz, CDCl3): δ = 7.31–7.23 (m, 3 H), 7.18–7.12 (m, 3 H), 6.92–6.87 (m, 1 H), 6.83–6.79 (m, 2 H), 6.69–6.64 (m, 2 H), 6.34 (d, J = 7.9 Hz, 1 H), 4.93 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.47 (s, 1 H, CH, CH b ), 4.46 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 3.73 (s, 3 H), 2.32 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.0, 160.6, 140.8, 137.3 (2C), 135.3, 132.3, 129.1, 128.5 (2C), 127.3, 126.9 (2C), 126.5, 126.0, 120.7, 114.3 (2C), 109.0, 55.2, 50.1, 43.9, 21.1.

HRMS (ESI): m/z [M + H]+ calcd for C23H22NO2S: 376.1366; found: 376.1379.


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1-Benzyl-3-((4-fluorophenyl)thio)-5-methylindolin-2-one (3e)

Yield: 161.7 mg (89%); yellow solid; mp 116–117 °C.

1H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 3 H), 7.22–7.17 (m, 3 H), 6.94–6.78 (m, 5 H), 6.40 (d, J = 8.0 Hz, 1 H), 4.89 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 4.51 (s, 1 H, CH, CH b ), 4.50 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 2.32 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.8, 163.5 (d, J F–C = 249.2 Hz), 140.8, 137.4, 137.3, 135.3, 132.5, 129.4, 128.6 (2C), 127.5, 127.0 (2C), 126.0, 125.5, 125.4, 116.0, 115.8, 109.0, 49.7 (d, J = 1.4 Hz), 44.0, 21.1.

19F NMR (377 MHz, CDCl3): δ = –111.52 (s).

HRMS (ESI): m/z [M + K]+ calcd for C22H18FKNOS: 402.0725; found: 402.0797.


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1-Ethyl-5-methyl-3-(p-tolylthio)indolin-2-one (3f)

Yield: 121.9 mg (82%); white solid; mp 123–124 °C.

1H NMR (400 MHz, CDCl3): δ = 7.14–7.08 (m, 3 H), 6.94–6.80 (m, 3 H), 6.42 (dd, J = 7.9, 2.6 Hz, 1 H), 4.29 (s, 1 H, CH, CH b ), 3.59–3.49 (m, 1 H, Bn, CH a ), 3.36–3.26 (m, 1 H, Bn, CH a ), 2.23 (d, J = 2.5 Hz, 3 H), 2.13 (d, J = 2.7 Hz, 3 H), 0.87–0.78 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.6, 140.7, 138.8, 134.7 (2C), 132.0, 129.3 (2C), 129.1, 127.1, 126.7, 126.1, 107.9, 49.4, 34.7, 21.1, 21.0, 12.1.

HRMS (ESI): m/z [M + K]+ calcd for C18H19KNOS: 336.0819; found: 336.0815.


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1-Ethyl-3-((4-methoxyphenyl)thio)-5-methylindolin-2-one (3g)

Yield: 126.9 mg (81%); yellow solid; mp: 102–103 °C.

1H NMR (400 MHz, CDCl3): δ = 7.17–7.11 (m, 3 H), 6.92 (d, J = 7.9 Hz, 1 H), 6.57 (d, J = 8.5 Hz, 2 H), 6.42 (d, J = 8.0 Hz, 1 H), 4.25 (s, 1 H, CH, CH b ), 3.62 (s, 3 H), 3.54 (dq, J = 14.6, 7.3 Hz, 1 H, Bn, CH a ), 3.31 (dq, J = 14.1, 7.2 Hz, 1 H, Bn, CH a ), 2.26 (s, 3 H), 0.83 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.6, 160.5, 140.7, 137.0 (2C), 132.0, 129.1, 126.8, 126.2, 120.7, 114.0 (2C), 107.8, 55.2, 49.8, 34.6, 21.1, 12.2.

HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2S: 314.1209; found: 314.1220.


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1-Ethyl-3-((4-fluorophenyl)thio)-5-methylindolin-2-one (3h)

Yield: 125.1 mg (83%); white solid; mp 102–103 °C.

1H NMR (400 MHz, CDl3): δ = 7.30–7.25 (m, 3 H), 7.02 (dd, J = 7.9, 1.7 Hz, 1 H), 6.82 (t, J = 8.6 Hz, 2 H), 6.53 (d, J = 7.9 Hz, 1 H), 4.39 (s, 1 H, CH, CH b ), 3.63 (dq, J = 14.4, 7.2 Hz, 1 H, Bn, CH a ), 3.41 (dq, J = 14.3, 7.2 Hz, 1 H, Bn, CH a ), 2.35 (s, 3 H), 0.93 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.4, 163.3 (d, J F–C = 249.3 Hz), 140.7, 137.2, 137.1, 132.1, 129.3, 126.3, 126.1, 125.5, 115.7, 115.4, 107.9, 49.5 (d, J = 1.5 Hz), 34.7, 21.0, 12.2.

19F NMR (377 MHz, CDCl3): δ = –111.97 (s).

HRMS (ESI): m/z [M + Na]+ calcd for C17H16FNaNOS: 324.0829; found: 324.0836.


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1-Benzyl-5-ethyl-3-(p-tolylthio)indolin-2-one (3i)

Yield: 140.1 mg (75%); gray solid; mp 80–81 °C.

1H NMR (400 MHz, CDCl3): δ = 7.30–7.25 (m, 3 H), 7.22–7.14 (m, 3 H), 7.00–6.90 (m, 5 H), 6.40 (d, J = 7.9 Hz, 1 H), 4.92 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 4.56 (s, 1 H, CH, CH b ), 4.55 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 2.61 (q, J = 7.6 Hz, 2 H), 2.30 (s, 3 H), 1.21 (t, J = 7.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.2, 141.0, 139.0, 135.5, 135.0 (2C), 129.6 (2C), 128.5 (2C), 128.1, 127.4, 127.1, 127.0 (2C), 126.4, 124.9 (2C), 109.0, 49.7, 44.0, 28.6, 21.3, 16.0.

HRMS (ESI): m/z [M + H]+ calcd for C24H24NOS: 374.1573; found: 374.1580.


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1-Benzyl-5-ethyl-3-((4-methoxyphenyl)thio)indolin-2-one (3j)

Yield: 151.9 mg (78%); grey solid; mp 122–123 °C.

1H NMR (400 MHz, CDCl3): δ = 7.34–7.14 (m, 6 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.86–6.79 (m, 2 H), 6.65 (d, J = 8.7 Hz, 2 H), 6.37 (d, J = 8.0 Hz, 1 H), 4.93 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.50 (s, 1 H, CH, CH b ), 4.49 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 3.73 (s, 3 H), 2.61 (q, J = 7.6 Hz, 2 H), 1.21 (t, J = 7.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.1, 160.6, 141.0, 138.9, 137.4 (2C), 135.4, 128.5 (2C), 128.0, 127.4, 127.0 (2C), 126.5, 124.9, 120.6, 114.3 (2C), 109.0, 55.2, 50.1, 43.9, 28.6, 16.1.

HRMS (ESI): m/z [M + H]+ calcd for C24H24NO2S: 390.1522; found: 390.1530.


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1-Benzyl-5-ethyl-3-((4-fluorophenyl)thio)indolin-2-one (3k)

Yield: 154.8 mg (82%); yellow solid; mp 99–100 °C.

1H NMR (400 MHz, CDCl3): δ = 7.36–7.26 (m, 3 H), 7.21–7.15 (m, 3 H), 6.96–6.86 (m, 3 H), 6.79 (t, J = 8.5 Hz, 2 H), 6.42 (d, J = 7.9 Hz, 1 H), 4.88 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 4.52 (s, 1 H, CH, CH b ), 4.51 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 2.61 (q, J = 7.6 Hz, 2 H), 1.21 (t, J = 7.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.9, 163.5 (d, J F–C = 249.4 Hz), 141.0, 139.1, 137.4 (d, J = 8.4 Hz), 135.4, 128.6 (2C), 128.3, 127.5, 127.1 (2C), 126.0, 125.5, 125.4, 124.9, 116.0, 115.8, 109.1, 49.8, 44.0, 28.6, 16.1.

19F NMR (377 MHz, CDCl3): δ = –111.47 (s).

HRMS (ESI): m/z [M + H]+ calcd for C23H21FNOS: 387.1322; found: 378.1320.


#

1-Benzyl-5-methoxy-3-(p-tolylthio)indolin-2-one (3l)

Yield: 159.6 mg (85%); yellow solid; mp 138–139 °C.

1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 7.9 Hz, 2 H), 7.23–7.15 (m, 3 H), 7.07 (d, J = 2.6 Hz, 1 H), 6.98 (d, J = 7.8 Hz, 2 H), 6.92–6.86 (m, 2 H), 6.64 (dd, J = 8.5, 2.6 Hz, 1 H), 6.37 (d, J = 8.5 Hz, 1 H), 4.92 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.56–4.51 (m, 2 H, Bn and CH), 3.77 (s, 3 H), 2.30 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.8, 156.1, 139.1, 136.6, 135.3 (2C), 135.1, 129.6 (2C), 128.6 (2C), 127.7, 127.4, 127.0 (2C), 126.8, 113.8, 112.1, 109.7, 55.9, 50.0, 44.1, 21.3.

HRMS (ESI): m/z [M + K]+ calcd for C23H21KNOS: 414.0925; found: 414.0920.


#

1-Benzyl-5-chloro-3-(p-tolylthio)indolin-2-one (3m)

Yield: 153.8 mg (81%); grey solid; mp 141–142 °C.

1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 1 H), 7.28–7.17 (m, 5 H), 7.07–6.96 (m, 3 H), 6.90–6.83 (m, 2 H), 6.38 (dd, J = 8.3, 2.0 Hz, 1 H), 4.91 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.54 (s, 1 H, CH, CH b ), 4.53 (d, J = 15.6 Hz, 1 H, Bn, CH a ), 2.30 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.6, 141.6, 139.4, 135.3 (2C), 134.8, 129.8 (2C), 128.8, 128.7 (2C), 128.3, 128.1, 127.6, 127.0 (2C), 126.2, 125.7, 110.2, 49.5, 44.1, 21.3.

HRMS (ESI): m/z [M + Na]+ calcd for C22H17ClNaNOS: 402.0690; found: 402.0671.


#

1-Benzyl-5-chloro-3-((4-methoxyphenyl)thio)indolin-2-one (3n)

Yield: 138.6 mg (70%); white solid; mp 149–150 °C.

1H NMR (400 MHz, CDCl3): δ = 7.37–7.36 (m, 1 H), 7.17 (d, J = 8.3 Hz, 2 H), 7.14–7.03 (m, 3 H), 7.01–6.95 (m, 1 H), 6.72–6.67 (m, 2 H), 6.59 (d, J = 8.5 Hz, 2 H), 6.26 (d, J = 8.3 Hz, 1 H), 4.85 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 4.40 (s, 1 H, CH, CH b ), 4.39 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 3.66 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.5, 160.9, 141.7, 137.6 (2C), 134.7, 128.8, 128.6 (2C), 128.4, 128.1, 127.6, 126.9 (2C), 125.6, 119.9, 114.5 (2C), 110.2, 55.3, 49.9, 44.0.

HRMS (ESI): m/z [M + H]+ calcd for C22H19ClNO2S: 396.0820; found: 396.0805.


#

1-Benzyl-5-chloro-3-((4-fluorophenyl)thio)indolin-2-one (3o)

Yield: 142.0 mg (74%); white solid; mp 110–111 °C.

1H NMR (400 MHz, CDCl3): δ = 7.31–7.18 (m, 5 H), 7.09–6.97 (m, 2 H), 6.94–6.86 (m, 2 H), 6.81–6.72 (m, 1 H), 6.37 (d, J = 7.5 Hz, 1 H), 4.76 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 4.61–4.40 (m, 2 H, Bn + CH).

13C NMR (100 MHz, CDCl3): δ = 173.3, 163.7 (d, J F–C = 250.1 Hz), 144.7, 138.1, 138.0, 134.9, 131.7, 130.3, 128.7 (2C), 127.8, 127.1 (2C), 124.6 (d, J = 3.4 Hz), 123.5, 123.2, 116.0, 115.8, 107.6, 49.7 (d, J = 1.6 Hz), 44.2.

19F NMR (377 MHz, CDCl3): δ = –110.86 (s).

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClFNOS: 384.0620; found: 384.0627.


#

1-Benzyl-4-bromo-3-(p-tolylthio)indolin-2-one (3p)

Yield: 169.7 mg (80%); yellow solid; mp 108–109 °C.

1H NMR (400 MHz, CDCl3): δ = 7.21–7.13 (m, 6 H), 6.97–6.84 (m, 5 H), 6.35 (d, J = 7.8 Hz, 1 H), 4.76 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.49 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.41 (s, 1 H, CH, CH b ), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.5, 144.8, 139.5, 135.8 (2C), 134.9, 130.3, 129.6 (2C), 128.7 (2C), 127.6, 127.1 (2C), 126.4, 125.9, 125.4, 120.4, 108.1, 51.2, 44.1, 21.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H18BrNOS: 424.0365; found: 424.0335.


#

1-Benzyl-4-chloro-3-(p-tolylthio)indolin-2-one (3q)

Yield: 148.2 mg (78%); yellow solid; mp 114–115 °C.

1H NMR (400 MHz, CDCl3): δ = 7.14–7.04 (m, 5 H), 6.96–6.86 (m, 2 H), 6.78 (dd, J = 13.6, 7.2 Hz, 4 H), 6.22 (d, J = 7.2 Hz, 1 H), 4.68 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.42–4.39 (m, 2 H, Bn + CH), 2.16 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.6, 144.7, 139.5, 135.8 (2C), 134.9, 131.6, 130.1, 129.6 (2C), 128.7 (2C), 127.6, 127.1 (2C), 125.9, 123.5, 123.4, 107.6, 49.7, 44.2, 21.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H19ClNOS: 380.0870; found: 380.0878.


#

1-Benzyl-4-chloro-3-((4-fluorophenyl)thio)indolin-2-one (3r)

Yield: 142.0 mg (74%); white solid; mp 102–103 °C.

1H NMR (400 MHz, CDCl3): δ = 7.47 (dd, J = 2.1, 1.1 Hz, 1 H), 7.37–7.29 (m, 2 H), 7.26–7.17 (m, 3 H), 7.14–7.06 (m, 1 H), 6.95–6.76 (m, 4 H), 6.41 (d, J = 8.3 Hz, 1 H), 4.90 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.53 (s, 1 H, CH b ), 4.52 (d, J = 15.8 Hz, 1 H, Bn, CH a ).

13C NMR (100 MHz, CDCl3): δ = 173.3, 162.7 (d, J F–C = 250.0 Hz), 141.6, 137.7, 137.7, 134.7, 129.0, 128.7 (2C), 128.3, 127.9, 127.7, 127.0 (2C), 125.7, 124.7, 116.2, 116.0, 110.2, 49.6, 44.1.

19F NMR (377 MHz, CDCl3): δ = –110.81 (s).

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClFNOS: 384.0620; found: 384.0627.


#

4-Chloro-1-ethyl-3-(p-tolylthio)indolin-2-one (3s)

Yield: 166.0 mg (73%); yellow solid; mp 128–129 °C.

1H NMR (400 MHz, CDCl3): δ = 7.07–6.99 (m, 3 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.79 (d, J = 7.9 Hz, 2 H), 6.37 (d, J = 7.8 Hz, 1 H), 4.25 (s, 1 H, CH, CH b ), 3.50 (dq, J = 14.5, 7.3 Hz, 1 H, Bn, CH a ), 3.21 (dq, J = 14.3, 7.2 Hz, 1 H, Bn, CH a ), 2.12 (s, 3 H), 0.75 (t, J = 7.3 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.9, 144.6, 139.5, 135.7 (2C), 131.5, 130.1, 129.2 (2C), 125.5, 123.8, 123.0, 106.4, 49.4, 34.8, 21.1, 12.0.

HRMS (ESI): m/z [M + H]+ calcd for C17H17ClNOS: 318.0741; found: 318.0736.


#

4-Chloro-1-ethyl-3-((4-methoxyphenyl)thio)indolin-2-one (3t)

Yield: 123.5 mg (74%); white solid; mp 148–149 °C.

1H NMR (400 MHz, CDCl3): δ = 7.11–7.03 (m, 3 H), 6.94 (dd, J = 8.2, 0.8 Hz, 1 H), 6.56–6.51 (m, 2 H), 6.38 (d, J = 7.7 Hz, 1 H), 4.26 (s, 1 H, CH, CH b ), 3.62 (s, 3 H), 3.50 (dq, J = 14.5, 7.3 Hz, 1 H, Bn, CH a ), 3.25 (dq, J = 14.3, 7.2 Hz, 1 H, Bn, CH a ), 0.80 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.1, 160.8, 144.6, 137.7 (2C), 131.6, 130.0, 123.9, 123.0, 119.5, 113.9 (2C), 106.4, 55.3, 49.7, 34.8, 12.1.

HRMS (ESI): m/z [M + Na]+ calcd for C17H16ClNaNO2S: 356.0482; found: 356.0471.


#

4-Chloro-1-ethyl-3-((4-fluorophenyl)thio)indolin-2-one (3u)

Yield: 123.9 mg (77%); yellow solid; mp 116–117 °C.

1H NMR (400 MHz, CDCl3): δ = 7.27–7.17 (m, 3 H), 7.04 (d, J = 8.2 Hz, 1 H), 6.86–6.75 (m, 2 H), 6.49 (d, J = 7.8 Hz, 1 H), 4.40 (s, 1 H, CH, CH b ), 3.60 (dq, J = 14.5, 7.2 Hz, 1 H, Bn, CH a ), 3.38 (dq, J = 14.2, 7.2 Hz, 1 H, Bn, CH a ), 0.91 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.8, 163.6 (d, J F–C = 250.3 Hz), 144.5, 138.1 (d, J = 8.4 Hz), 131.7, 130.3, 124.3, 123.4, 123.2, 115.7, 115.5, 106.4, 49.4, 34.9, 12.1.

19F NMR (377 MHz, CDCl3): δ = –111.05 (s).

HRMS (ESI): m/z [M + Na]+ calcd for C16H13ClFNaNOS: 344.0283; found: 344.0279.


#

1-Benzyl-6-bromo-3-(p-tolylthio)indolin-2-one (3v)

Yield: 165.5 mg (78%); yellow solid; mp 118–119 °C.

1H NMR (400 MHz, CDCl3): δ = 7.22–7.08 (m, 7 H), 6.89 (d, J = 7.9 Hz, 2 H), 6.80 (dd, J = 7.4, 2.0 Hz, 2 H), 6.55 (d, J = 1.7 Hz, 1 H), 4.81 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 4.54–4.37 (m, 2 H, Bn + CH), 2.22 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.9, 144.4, 139.4, 135.2 (2C), 134.7, 129.8 (2C), 128.7 (2C), 127.6, 127.0 (2C), 126.5, 126.3, 125.7, 125.5, 122.4, 112.5, 49.2, 44.0, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C22H19ClNOS: 424.0365; found: 424.0362.


#

1-Benzyl-6-bromo-3-((4-methoxyphenyl)thio)indolin-2-one (3w)

Yield: 167.3 mg (76%); white solid; mp 143–144 °C.

1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 7.9 Hz, 1 H), 7.25–7.17 (m, 6 H), 6.83–6.78 (m, 2 H), 6.70–6.65 (m, 2 H), 6.60 (d, J = 1.8 Hz, 1 H), 4.91 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 4.47 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.44 (s, 1 H, CH, CH b ), 3.74 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.8, 160.8, 144.4, 137.5 (2C), 134.6, 128.7 (2C), 127.6, 126.9 (2C), 126.5, 125.7, 125.6, 122.3, 119.9, 114.5 (2C), 112.5, 55.3, 49.6, 44.0.

HRMS (ESI): m/z [M + H]+ calcd for C22H19BrNO2S: 440.0314; found: 440.0318.


#

6-Bromo-1-ethyl-3-(p-tolylthio)indolin-2-one (3x)

Yield: 135.7 mg (75%); white solid; mp 104–105 °C.

1H NMR (400 MHz, CDCl3): δ = 7.27 (s, 1 H), 7.19 (d, J = 7.9 Hz, 3 H), 6.97 (d, J = 7.9 Hz, 2 H), 6.78 (d, J = 1.7 Hz, 1 H), 4.38 (s, 1 H, CH, CH b ), 3.65 (dq, J = 14.5, 7.3 Hz, 1 H, Bn, CH a ), 3.41 (dq, J = 14.3, 7.2 Hz, 1 H, Bn, CH a ), 2.26 (s, 3 H), 0.94 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.5, 144.4, 139.3, 135.0 (2C), 129.5 (2C), 126.6, 126.2, 125.8, 125.3, 122.4, 111.5, 49.0, 34.9, 21.2, 12.0.

HRMS (ESI): m/z [M + H]+ calcd for C17H17BrOS: 362.0209; found: 362.0210.


#

1-Benzyl-7-fluoro-3-(p-tolylthio)indolin-2-one (3y)

Yield: 143.6 mg (79%); white solid; mp 130–131 °C.

1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.1 Hz, 2 H), 7.21–7.15 (m, 4 H), 6.97 (d, J = 7.9 Hz, 2 H), 6.89–6.85 (m, 2 H), 6.79 (td, J = 8.9, 2.7 Hz, 1 H), 6.37 (dd, J = 8.6, 4.1 Hz, 1 H), 4.92 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 4.54 (s, 1 H, CH, CH b ), 4.53 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 2.30 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.8, 159.2 (d, J F–C = 241.1 Hz), 139.4, 139.0 (d, J = 2.0 Hz), 135.3, 135.0, 129.7 (2C), 128.6 (2C), 128.2, 128.2, 127.5, 127.0 (2C), 126.2, 115.2 (d, J = 23.5 Hz), 113.2 (d, J = 25.2 Hz), 109.8 (d, J = 8.0 Hz), 49.8 (d, J = 1.9 Hz), 44.1, 21.3.

19F NMR (377 MHz, CDCl3): δ = –119.97 (s).

HRMS (ESI): m/z [M + H]+ calcd for C22H29FNOS: 364.1166; found: 364.1155.


#

1-Benzyl-7-fluoro-3-((4-methoxyphenyl)thio)indolin-2-one (3z)

Yield: 138.5 mg (73%); white solid; mp 99–100 °C.

1H NMR (400 MHz, CDCl3): δ = 7.29–7.16 (m, 7 H), 7.00–6.93 (m, 3 H), 6.67–6.60 (m, 2 H), 4.99 (d, J = 15.5 Hz, 1 H, Bn, CH a ), 4.75 (d, J = 15.4 Hz, 1 H, Bn, CH a ), 4.50 (s, 1 H, CH, CH b ), 3.73 (d, J = 1.7 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 173.8, 160.7, 147.1 (d, J F–C = 244.8 Hz), 137.3 (2C), 136.5, 129.9 (d, J = 8.9 Hz), 129.5 (d, J = 3.2 Hz), 128.4 (2C), 127.3, 127.2, 123.3, 121.3 (d, J = 3.3 Hz), 120.0, 117.0, 116.8, 114.4 (2C), 55.2, 50.1 (d, J = 2.2 Hz), 45.4 (d, J = 4.7 Hz).

19F NMR (377 MHz, CDCl3): δ = –134.04 (s).

HRMS (ESI): m/z [M + H]+ calcd forC22H19FNO2S: 380.1115; found: 380.1113.


#

1-Benzyl-3-((3-bromophenyl)thio)indolin-2-one (3za)

Yield: 172.3 mg (84%); white solid; mp 112–113 °C.

1H NMR (400 MHz, CDCl3): δ = 7.45 (t, J = 1.8 Hz, 1 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.26 (dt, J = 8.1, 1.4 Hz, 1 H), 7.21 (dt, J = 7.9, 1.3 Hz, 1 H), 7.16–7.09 (m, 3 H), 7.04 (t, J = 7.6 Hz, 1 H), 6.98–6.87 (m, 4 H), 6.47 (d, J = 7.8 Hz, 1 H), 4.78 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 4.54 (s, 1 H, CH, CH b ), 4.53 (d, J = 15.7 Hz, 1 H, Bn, CH a ).

13C NMR (100 MHz, CDCl3): δ = 174.0, 143.2, 136.4, 135.3, 133.3, 132.6, 131.7, 130.1, 129.3, 128.8 (2C), 127.6, 127.1 (2C), 125.6, 125.4, 123.0, 122.4, 109.4, 49.1, 44.1.

HRMS (ESI): m/z [M + H]+ calcd for C21H17BrNOS: 410.0209; found: 410.0218.


#

1-Benzyl-3-((2-methoxyphenyl)thio)indolin-2-one (3zb)

Yield: 139.2 mg (77%); red oil.

1H NMR (400 MHz, CDCl3): δ = 7.51 (dd, J = 7.6, 1.7 Hz, 1 H), 7.30–7.23 (m, 5 H), 7.19–7.15 (m, 2 H), 7.12 (t, J = 7.8 Hz, 1 H), 6.96 (td, J = 7.6, 1.0 Hz, 1 H), 6.87–6.81 (m, 2 H), 6.61 (d, J = 7.8 Hz, 1 H), 4.90 (s, 1 H, CH, CH b ), 4.89 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 4.79 (d, J = 15.7 Hz, 1 H, Bn, CH a ), 3.78 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.5, 159.4, 143.1, 135.6, 135.5, 130.2, 128.8, 128.7 (2C), 127.6, 127.3 (2C), 126.2, 125.4, 122.5, 120.9, 119.9, 110.9, 109.1, 55.7, 46.7, 43.9.

HRMS (ESI): m/z [M + H]+ calcd for C22H20NO2S: 362.1209; found: 362.1215.


#

1-Benzyl-3-((2,4-dimethylphenyl)thio)indolin-2-one (3zc)

Yield: 140.2 mg (78%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.38–7.32 (m, 1 H), 7.26–7.18 (m, 4 H), 7.13–7.12 (m, 1 H), 7.06 (d, J = 7.7 Hz, 1 H), 7.04–6.97 (m, 4 H), 6.55 (d, J = 7.7 Hz, 1 H), 4.95 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.67 (s, 1 H, CH, CH b ), 4.64 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 2.40 (s, 3 H), 2.12 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.4, 143.2, 138.4, 135.9, 135.4, 135.4, 130.5, 130.3, 129.6, 129.0, 128.7 (2C), 127.5, 127.0 (2C), 126.5, 125.4, 122.7, 109.2, 48.7, 44.0, 20.7, 20.6.

HRMS (ESI): m/z [M + H]+ calcd forC23H22NOS: 360.1417; found: 360.1411.


#

1-Benzyl-3-(naphthalen-1-ylthio)indolin-2-one (4a)

Yield: 133.5 mg (70%); white solid; mp 107–108 °C.

1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 1.8 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.44 (d, J = 8.6 Hz, 1 H), 7.39–7.34 (m, 2 H), 7.30–7.27 (m, 1 H), 7.23 (dd, J = 8.5, 1.8 Hz, 1 H), 6.97–6.90 (m, 3 H), 6.72 (t, J = 7.7 Hz, 2 H), 6.60 (d, J = 7.1 Hz, 2 H), 6.39–6.26 (m, 1 H), 4.80 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.57 (s, 1 H, CH, CH b ), 4.36 (d, J = 15.8 Hz, 1 H, Bn, CH a ).

13C NMR (100 MHz, CDCl3): δ = 174.1, 143.2, 135.1, 134.4, 134.3, 133.5, 133.1, 131.2, 129.1, 128.5 (2C), 128.3, 128.0, 127.7, 127.4, 126.9, 126.8 (2C), 126.5, 126.3, 125.4, 122.9, 109.4, 49.5, 44.0.

HRMS (ESI): m/z [M + H]+ calcd forC25H20NOS: 382.1260; found: 382.1289.


#

1-Benzyl-3-((3-methylbutan-2-yl)thio)indolin-2-one (4b)

Yield: 83.0 mg (51%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.37 (dd, J = 7.1, 3.8 Hz, 2 H), 7.34–7.25 (m, 10 H), 7.18 (t, J = 7.7 Hz, 2 H), 7.03 (t, J = 7.5 Hz, 2 H), 6.73 (s, 1 H), 6.72 (s, 1 H), 4.97–4.93 (m, 2 H, CH24b ), 4.88–4.84 (m, 2 H, CH2 4b′ ), 4.42 (s, 1 H, CH 4b ), 4.41 (s, 1 H, CH 4b′ ), 3.30–3.19 (m, 2 H, CH), 2.04–1.93 (m, 1 H, CH 4b ), 1.88–1.75 (m, 1 H, CH 4b′ ), 1.36 (s, 2 H, CH24b ), 1.34 (s, 2 H, CH2 4b′ ), 1.14 (d, J = 7.1 Hz, 2 H, CH24b ), 1.02 (d, J = 6.8 Hz, 2 H, CH2 4b′ ), 0.96 (d, J = 7.0 Hz, 4 H, 2CH2 4b′ ), 0.93 (d, J = 6.6 Hz, 4 H, 2CH24b ).

13C NMR (100 MHz, CDCl3): δ (4b selected peaks) = 176.0, 143.1, 135.8, 128.8 (3C), 127.7, 127.4 (2C), 126.3, 125.2, 122.8, 109.2, 45.2, 43.9, 43.3, 33.1, 19.5, 18.9, 17.6.

13C NMR (100 MHz, CDCl3): δ (4b′ selected peaks) = 175.9, 143.0, 135.7, 128.7 (3C), 127.7, 127.4 (2C), 126.5, 125.1, 122.7, 109.1, 45.7, 44.4, 44.0, 32.7, 19.8, 18.3, 17.0.

HRMS (ESI): m/z [M + H]+ calcd for C20H24NOS: 326.1573; found: 326.1578.


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1-Benzyl-3-(cyclopentylthio)indolin-2-one (4c)

Yield: 87.3 mg (54%); yellow oil.

1H NMR (400 MHz, CDl3): δ = 7.30 (d, J = 7.4 Hz, 1 H), 7.26–7.15 (m, 5 H), 7.10 (t, J = 7.6 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 4.87 (d, J = 15.6 Hz, 1 H, Bn, CH a ), 4.80 (d, J = 15.6 Hz, 1 H, Bn, CH a ), 4.33 (s, 1 H, CH, CH b ), 3.38–3.35 (m, 1 H), 2.02–1.86 (m, 1 H), 1.80–1.52 (m, 4 H), 1.52–1.37 (m, 2 H), 1.38–1.23 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 175.8, 143.0, 135.7, 128.8 (3C), 127.7, 127.5 (2C), 126.5, 125.2, 122.8, 109.2, 45.2, 44.0, 42.4, 34.5, 33.5, 25.0, 24.8.

HRMS (ESI): m/z [M + H]+ calcd for C20H22NOS: 324.1417; found: 324.1416.


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1-Benzyl-3-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)indolin-2-one (4d)

Yield: 131.8 mg (66%); red oil.

1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.6 Hz, 2 H), 7.53–7.32 (m, 5 H), 7.27–7.07 (m, 5 H), 6.95 (t, J = 7.7 Hz, 1 H), 6.66 (d, J = 7.9 Hz, 1 H), 5.24 (s, 1 H, CH, CH b ), 4.90 (d, J = 15.3 Hz, 1 H, Bn, CH a ), 4.83 (d, J = 15.6 Hz, 1 H, Bn, CH a ).

13C NMR (100 MHz, CDCl3): δ = 172.7, 166.5, 161.2, 143.5, 135.2, 131.9, 130.0, 129.1 (2C), 128.9 (2C), 127.9, 127.4 (2C), 126.8 (2C), 126.4, 125.2, 124.2, 123.4, 109.8, 46.6, 44.6.

HRMS (ESI): m/z [M + H]+ calcd for C23H18N3O2S: 400.1114; found: 400.1120.


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1-Benzyl-3-((2-methylfuran-3-yl)thio)indolin-2-one (4e)

Yield: 109.0 mg (65%); white solid; mp 123–124 °C.

1H NMR (400 MHz, CDCl3): δ = 7.39 (dd, J = 7.4, 1.4 Hz, 1 H), 7.20–7.11 (m, 3 H), 7.08–7.01 (m, 1 H), 7.00–6.94 (m, 2 H), 6.88–6.83 (m, 2 H), 6.44 (d, J = 7.8 Hz, 1 H), 5.78 (d, J = 1.7 Hz, 1 H), 4.88 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 4.49 (d, J = 15.8 Hz, 1 H, Bn, CH a ), 4.28 (s, 1 H, CH, CH b ), 2.09 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 174.3, 158.1, 143.4, 140.2, 135.3, 128.9, 128.7 (2C), 127.4, 126.8 (2C), 126.8, 125.3, 122.7, 115.7, 109.1, 105.4, 49.0, 43.9, 11.8.

HRMS (ESI): m/z [M + H]+ calcd for C20H18NO2S: 336.1053; found: 336.1100.


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1-Benzyl-3-(pyrimidin-2-ylthio)indolin-2-one (4f)

Yield: 100.0 mg (60%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 4.9 Hz, 2 H), 7.36–7.28 (m, 3 H), 7.27–7.18 (m, 3 H), 7.11 (t, J = 7.8 Hz, 1 H), 6.91 (t, J = 7.2 Hz, 1 H), 6.85 (t, J = 4.9 Hz, 1 H), 6.70 (d, J = 7.8 Hz, 1 H), 5.31 (s, 1 H, CH, CH b ), 4.96 (d, J = 15.9 Hz, 1 H, Bn, CH a ), 4.83 (d, J = 15.8 Hz, 1 H, Bn, CH a ).

13C NMR (100 MHz, CDCl3): δ = 173.2, 169.1, 156.3 (2C), 142.7, 134.8, 127.8, 127.7 (2C), 126.8, 126.7 (2C), 125.1, 123.4, 121.7, 116.1, 108.0, 44.7, 43.4.

HRMS (ESI): m/z [M + H]+ calcd for C19H16N3OS: 334.1009; found: 334.1032.


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3-(Benzo[d]oxazol-2-ylthio)-4-chloro-1-ethylindolin-2-one (4g)

Yield: 117.2 mg (68%); yellow solid; mp 137–138 °C.

1H NMR (400 MHz, CDCl3): δ = 7.50–7.46 (m, 1 H), 7.39–7.36 (m, 1 H), 7.28–7.21 (m, 3 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.80 (d, J = 7.9 Hz, 1 H), 5.23 (s, 1 H, CH, CH b ), 3.92 (dq, J = 14.4, 7.2 Hz, 1 H, Bn, CH a ), 3.73 (dq, J = 14.3, 7.2 Hz, 1 H, Bn, CH a ), 1.34 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.0, 161.1, 152.0, 145.4, 141.7, 132.0, 130.9, 124.4, 124.3, 123.6, 121.5, 118.8, 110.0, 107.0, 46.1, 35.7, 12.2.

HRMS (ESI): m/z [M + H]+ calcd for C17H14ClN2O2S: 345.0459; found: 345.0453.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707147. Included are experimental details, characterization of new compounds, crystallographic data, and NMR spectra (PDF).
  • Supporting Information


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Figure 1 Selected natural products and bioactive oxindoles featuring a sulfur atom
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Scheme 1 Development for the C–S bond formation reactions
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Scheme 2 Substrates scope of the insertion reaction of isatins 1 into thiols 2. Reagents and conditions: 1 (0.5 mmol), 2 (0.6 mmol), P(OEt)3 (0.75 mmol, 1.5 equiv), CHCl3 (2.0 mL), r.t., 4 h. Isolated yields are given.
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Scheme 3 Substrates scope of the reaction with heterocyclic thiols, aliphatic thiols and naphthalene-1-thiol 2′. Reagents and conditions: 1 (0.5 mmol), 2′ (0.6 mmol), P(OEt)3 (0.75 mmol, 1.5 equiv), CHCl3 (1.5 mL), r.t., 4 h. Isolated yields are given.
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Scheme 4 Proposed mechanism