Highly Efficient Synthesis of 3,3-Disubstituted Oxindoles through Direct Oxidative Alkylarylation of N-Arylacrylamides with Simple Alkanes

Abstract

A direct oxidative alkylarylation reaction of N-arylacrylamides with simple alkanes for the synthesis of 3,3-disubstituted oxindoles under metal-free conditions was demonstrated. By using PhI(OAc)₂ [(diacetoxy)iodobenzene] as an oxidant, a series of 3,3-disubstituted oxindoles bearing different aryl or alkyl substituents were generated in moderate to excellent chemical yields via a radical-initiated alkylation/cyclization process. The reported method features good functional group tolerance and wide substrate range, and provides an effective method for the preparation of various alkyl substituted 3,3-disubstituted oxindoles.

Key words

oxindoles - alkylarylation - N-arylacrylamide - PhI(OAc)₂ - metal-free

The 3,3-disubstituted oxindoles are an important class of privileged core structures that are found widely in numerous pharmaceutical molecules and biologically active compounds with significant pharmacological properties including anticancer, antimicrobial as well as antidiabetic effects (Figure [1]).[1] Owing to these fascinating biological activities, a series of synthetic approaches for the construction of 3,3-oxindole derivatives have been established in the past decades.[2] Among the reported methods, the direct use of N-arylacrylamides as radical acceptors in radical-initiated addition/cyclization cascade reactions for rapid access to 3,3-disubstituted oxindole compounds has recently garnered significant research interest.[3]

Figure 1 Representative natural products and bioactive compounds containing the 3,3-oxindole moiety

Radical cascade reactions have emerged as a powerful and versatile tool with which to prepare a large variety of functional molecules, due to their simplicity and efficiency.[4] Regarding the construction of oxindoles with C3 quaternary stereocenters by intercepting alkyl radicals with N-arylacrylamides, a variety of 3,3-functionalized oxindoles have been achieved through transition-metal-catalyzed or metal-free oxidative difunctionalization/annulation approaches with alkenes.[5] By employing different radical precursors, such as alkyl halides,[6] carboxylic acids,[7] aliphatic aldehydes,[8] Hantzsch ester derivatives,[9] 1,3-dicarbonyl compounds,[10] peroxides,[11] alkyl boric acids,[12] and isocyanides,[13] many functional groups could be installed into oxindole frameworks, accompanied by a significant enrichment of a library of 3,3-disubstituted oxindole derivatives. In these reactions, the general pathway includes (i) generation of a carbon-centered radical from the hydrocarbons of prefunctionalized substrates; (ii) selective radical addition to the C−C double bond in N-arylacrylamides; (iii) intramolecular radical cyclization; and (iv) rearomatization.[14]

Although this research field has been growing rapidly in the past years, the straightforward alkylarylation of N-aryl­acrylamides with simple alkanes without any prefunctional groups to generate 3,3-disubstituted oxindoles is still rare. To our knowledge, there is only one example, reported by the Liu group[15] in 2014, through copper-catalyzed alkylarylation of N-methyl-N-phenylmethacrylamide with alkanes, to produce various alkyl-substituted oxindoles. In this reaction, Cu₂O was used as the catalyst and dicumylperoxide (DCP) was utilized as the oxidant. High chemical yields and good selectivities were realized under metal catalysis of cuprous oxide. An environmentally benign and efficient synthetic process for the direct alkylation of N-arylacrylamide with simple alkanes under metal-free conditions remains extremely desirable. Herein, we present a direct cascade oxidative alkylarylation of N-arylacrylamide with simple alkanes in the presence of PhI(OAc)₂ to access 3,3-disubstituted oxindoles under metal-free conditions.

We started our investigation by reacting N-methyl-N-phenylmethacrylamide 1a with cyclohexane 2a as model substrates to optimize reaction conditions (Table [1]). To our delight, 3,3-disubstituted oxindole 3a was produced in 44% yield when the reaction was performed in THF with PhI(OAc)₂ as the oxidant (entry 1). We were pleased to find that yield reached 60% when cyclohexane 2a was used directly as solvent (entry 2). With an increase of the temperature to 120 °C, the yield of target product 3a increased to 90% (entries 2–6). Target product 3,3-disubstituted oxindole 3a was produced in 38% yield when the reaction was performed for 12 h (entry 7). Reactions conducted with oxidants other than PhI(OAc)₂, such as oxone, IBX, DDQ, MnO₂ and TBHP, failed to promote the reaction (entries 8–12). Moreover, this annulation/cyclization cascade reaction was highly affected by the base used; other bases including inorganic and organic bases did not show better results (entries 13–19). The use of NaHCO₃ as base proved to be the best for the production of the target product 3a in high isolated yield (entry 6). Changing the amount of oxidant PhI(OAc)₂ from 3.0 to 2.0 equiv led to a decreased yield of 3a to 78% (entry 20). Therefore, the optimal conditions were established as: PhI(OAc)₂ (3.0 equiv), NaHCO₃ (3.0 equiv), with a reaction temperature of 120 °C.

Table 1 Screening of the Reaction Conditions^a

Entry	Solvent	Temp. (°C)	Oxidant	Base	t (h)	Yield of 3a (%)b
1c	THF	80	PhI(OAc)2	NaHCO3	36	44
2	cyclohexane	80	PhI(OAc)2	NaHCO3	36	60
3	cyclohexane	90	PhI(OAc)2	NaHCO3	36	63
4	cyclohexane	100	PhI(OAc)2	NaHCO3	36	72
5	cyclohexane	110	PhI(OAc)2	NaHCO3	36	78
6	cyclohexane	120	PhI(OAc)2	NaHCO3	36	90
7	cyclohexane	120	PhI(OAc)2	NaHCO3	12	38
8	cyclohexane	120	oxone	NaHCO3	36	<5
9	cyclohexane	120	IBX	NaHCO3	36	<5
10	cyclohexane	120	DDQ	NaHCO3	36	<5
11	cyclohexane	120	MnO2	NaHCO3	36	<5
12	cyclohexane	120	TBHP	NaHCO3	36	<5
13	cyclohexane	120	PhI(OAc)2	Na2CO3	36	45
14	cyclohexane	120	PhI(OAc)2	K2CO3	36	22
15	cyclohexane	120	PhI(OAc)2	Cs2CO3	12	14
16	cyclohexane	120	PhI(OAc)2	NaOH	36	25
17	cyclohexane	120	PhI(OAc)2	KOH	24	30
18	cyclohexane	120	PhI(OAc)2	NaH	36	<5
19	cyclohexane	120	PhI(OAc)2	t-BuOK	36	<5
20d	cyclohexane	120	PhI(OAc)2	NaHCO3	36	78

^a Reaction conditions: all reactions were carried out with 1a (0.40 mmol), base (1.2 mmol), oxidant (1.2 mmol), in cyclohexane (4.0 mL) for the specified reaction time.

^b Isolated yield.

^c THF (4.0 mL) was used in the reaction.

^d PhI(OAc)₂ (2.0 equiv) was examined in the reaction.

Under the optimized reaction conditions, we explored the scope of the reaction of cyclohexane with N-arylacrylamides 1. As shown in Scheme [1], substrates with a halogen atom or electron-donating substituents on the phenyl moiety of N-arylacrylamide 1 all yielded the desired products 3a–r with excellent regioselectivities. Importantly, the tert-butyl group in the phenyl ring of N-arylacrylamide 1 afforded the corresponding product 3k with 99% yield. 3,3-Disubstituted oxindole 3m, with a CN substituent in the phenyl ring, was produced in 83% yield. However, stronger electron-withdrawing substituents such as NO₂ and CF₃ gave the target products 3l and 3n in lower yields. Substituents presenting in the ortho-, meta-, or para- position of the aromatic ring of the N-methyl-N-phenylmethacrylamide 1a, afforded products 3o–r in good yields of 79–89%. In addition, it was found that both 3s and 3s′ were generated and they could be easily isolated in 31 and 37% yield, respectively, by using column chromatography on silica gel when the reaction was carried out between meta-chlorine substituted N-arylacrylamide and 2a. Furthermore, switching the phenyl ring of N-methyl-N-arylacrylamide 1 to naphthalene led to the formation of product 3t in moderate yield.

Scheme 1 Scope of the reaction with N-arylacrylamides. Reagents and conditions: 1 (0.4 mmol), NaHCO₃ (1.2 mmol), PhI(OAc)₂ (1.2 mmol), cyclohexane (4.0 mL), 120 °C.

In further studies, the alkylarylation of N-methyl-N-phenylmethacrylamide 1a with different alkanes to produce 3,3-disubstituted oxindoles 3 was also explored (Scheme [2]). It was found that cyclopentane afforded the corresponding oxindole 3u in 80% yield, while the use of toluene as substrate generated the product of 3v in moderate yield. Moreover, substrates of 1 with N-ethyl and N-benzyl groups were also well tolerated in this cascade alkylation annulation reaction, furnishing the desired oxindole derivatives 3w and 3x accordingly.

Scheme 2 Scope of the reaction with alkanes. Reagents and conditions: 1 (0.4 mmol), NaHCO₃ (1.2 mmol), PhI(OAc)₂ (1.2 mmol), 2 (4.0 mL), 120 °C, 36 h.

To further demonstrate the practicality of our method, the reaction of 1a and 2a was conducted on a gram scale (Scheme [3]). As shown in Scheme [3], when N-methyl-N-phenylmethacrylamide 1a (5.8 mmol, 1.0163 g) was reacted for 36 h with cyclohexane 2a (58 mL) under the optimized reaction conditions, the target product 3,3-disubstituted oxindole 3a was produced in 72% yield. The reaction proceeded smoothly for 48 h to afford the target product of 3a in 83% yield at the gram scale (1.2425 g) without significant decrease of reactivity.

Scheme 3 Gram-scale reaction of 1a with 2a

Based on the experimental results and on previous studies, a plausible mechanism for the direct oxidative alkylation reaction between N-arylacrylamide and simple alkanes is outlined in Figure [2]. Initially, PhI(OAc)₂ generates an acetoxy radical and an iodanyl radical under heating. Subsequently, hydrogen abstraction from cyclohexane 2a by the acetoxy radical would afford a cyclohexyl radical A, which could add to N-methyl-N-phenylmethacrylamide 1a to generate radical intermediate B. Further intramolecular cyclization of radical B with the N-phenyl ring generates intermediate C, which then transfers an electron to the iodanyl radical to produce cation D. Further deprotonation by the iodanyl anion finally gives the alkylated product 3a.

Figure 2 Proposed reaction mechanism

In conclusion, the present work demonstrates the direct oxidative alkylarylation reaction of N-arylacrylamides with simple alkanes in the presence of (diacetoxy)iodobenzene (PhI(OAc)₂) as an oxidant. Particularly, the approach affords an effective method for the synthesis of 3,3-disubstituted oxindoles under metal-free conditions. We believe that this direct oxidative alkylarylation will promote further efforts toward wide exploration and applications of oxindole derivatives.

All the reagents and solvents were obtained from commercial sources and were used without further purification unless otherwise stated. The starting compounds 1 were prepared according to reported methods.[16]

Melting points of solid products were measured with a Shanghai YDWG WRS-2A instrument. ¹H, ¹³C and ¹⁹F NMR spectra were recorded with AMX500 (500 MHz) or AMX400 (400 MHz) spectrometers. Chemical shifts are reported in parts per million (ppm), and the residual solvent peak was used as an internal reference: proton (chloroform δ = 7.26), carbon (chloroform δ = 77.0). Multiplicity is indicated as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet). Coupling constants are reported in Hertz (Hz). High-resolution mass (ESI) spectra were obtained with a Finnigan/ MAT 95XL-T spectrometer. Flash chromatographic separations were performed on Merck 60 (0.040–0.063 mm) mesh silica gel.

Synthesis of 3; General Procedure

To a solution of 1 (0.4 mmol) and alkane 2 (4 mL) were sequentially added the oxidant PhI(OAc)₂ (1.2 mmol, 386.5 mg) and NaHCO₃ (1.2 mmol, 100.8 mg) at room temperature. The reaction mixture was stirred at 120 °C for 24–48 h in a sealed pressure tube. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated NaCl solution (1 mL). The organic layer was dried on Na₂SO₄ and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 20:1 to 10:1) to afford pure product 3.

3-(Cyclohexylmethyl)-1,3-dimethylindolin-2-one (3a)

Yield: 92.6 mg (90%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.22 (m, 1 H), 7.16 (d, J = 7.1 Hz, 1 H), 7.06 (t, J = 7.4 Hz, 1 H), 6.85 (d, J = 7.7 Hz, 1 H), 3.22 (s, 3 H), 1.94 (dd, J = 14.1, 6.8 Hz, 1 H), 1.73 (dd, J = 14.0, 5.3 Hz, 1 H), 1.55–1.44 (m, 3 H), 1.36 (d, J = 13.5 Hz, 1 H), 1.32 (s, 3 H), 1.22 (d, J = 12.9 Hz, 1 H), 1.05–0.92 (m, 4 H), 0.88–0.71 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.1, 143.1, 134.4, 127.5, 122.7, 122.3, 107.9, 47.8, 45.4, 34.7, 34.5, 33.6, 26.2, 26.1, 26.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₄NO: 258.1852; found: 258.1855.

3-(Cyclohexylmethyl)-5-fluoro-1,3-dimethylindolin-2-one (3b)

Yield: 82.6 mg (75%); white solid; mp 36.0–38.9 °C.

¹H NMR (500 MHz, CDCl₃): δ = 6.99–6.84 (m, 2 H), 6.79–6.69 (m, 1 H), 3.24–3.14 (m, 3 H), 1.96–1.88 (m, 1 H), 1.72–1.65 (m, 1 H), 1.54–1.43 (m, 3 H), 1.30 (dd, J = 11.5, 9.2 Hz, 4 H), 1.20 (d, J = 11.3 Hz, 1 H), 1.03–0.88 (m, 4 H), 0.85–0.71 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.7, 160.2, 158.3 (d, J = 241 Hz), 139.0, 136.2 (d, J = 6.0 Hz), 113.7 (d, J = 23.4 Hz), 113.6, 111.0, 110.7 (d, J = 24.4 Hz), 108.3 (d, J = 8.2 Hz), 48.3, 45.3, 34.7, 34.4, 33.4, 26.3, 26.0.

¹⁹F NMR (471 MHz, CDCl₃): δ = –119.9 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃FNO: 276.1758; found: 276.1752.

5-Chloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3c)

Yield: 103.6 mg (89%); white solid; mp 73.0–74.8 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.29–7.19 (m, 1 H), 7.14 (d, J = 4.0 Hz, 1 H), 6.83–6.69 (m, 1 H), 3.21 (d, J = 5.9 Hz, 3 H), 1.94 (dd, J = 13.8, 6.9 Hz, 1 H), 1.75–1.67 (m, 1 H), 1.50 (d, J = 6.3 Hz, 3 H), 1.31 (d, J = 5.9 Hz, 4 H), 1.27–1.20 (m, 1 H), 1.05–0.92 (m, 4 H), 0.88–0.75 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃) δ 180.6, 141.7, 136.2, 127.8, 127.5, 123.2, 108.9, 48.1, 45.3, 34.7, 34.4, 33.4, 26.3, 26.2, 26.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃ClNO: 292.1463; found: 292.1458.

5-Bromo-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3d)

Yield: 88.5 mg (66%); yellow solid; mp 51.0–52.8 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.32 (dd, J = 8.2, 1.9 Hz, 1 H), 7.19 (d, J = 2.3 Hz, 1 H), 6.74–6.60 (m, 1 H), 3.13 (d, J = 5.0 Hz, 3 H), 1.86 (dd, J = 14.1, 7.3 Hz, 1 H), 1.63 (dd, J = 14.1, 5.2 Hz, 1 H), 1.62–1.56 (m, 1 H), 1.49–1.38 (m, 3 H), 1.23 (s, 3 H), 1.18 (d, J = 8.0 Hz, 1 H), 0.96–0.83 (m, 4 H), 0.79–0.67 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.5, 141.1, 135.5, 129.4, 125.0, 114.1, 109.4, 47.0, 44.3, 33.7, 33.4, 32.4, 25.3, 25.2, 25.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃BrNO: 336.0958; found: 336.0964.

3-(Cyclohexylmethyl)-5-iodo-1,3-dimethylindolin-2-one (3e)

Yield: 119.5 mg (78%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.49 (dd, J = 8.1, 1.7 Hz, 1 H), 7.37 (d, J = 1.6 Hz, 1 H), 6.57 (d, J = 8.2 Hz, 1 H), 3.12 (s, 3 H), 1.85 (dd, J = 14.1, 7.2 Hz, 1 H), 1.62 (dd, J = 14.1, 5.3 Hz, 1 H), 1.54–1.43 (m, 3 H), 1.25 (d, J = 9.7 Hz, 1 H), 1.22 (s, 3 H), 1.16 (d, J = 12.8 Hz, 1 H), 0.98–0.83 (m, 4 H), 0.86–0.74 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃) δ 180.1, 142.8, 135.9, 135.4, 131.5, 110.0, 85.1, 47.9, 45.3, 34.7, 34.4, 33.4, 26.3, 26.2, 26.1, 26.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃INO: 384.0819; found: 384.0823.

7-Chloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3f)

Yield: 74.5 mg (64%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.17 (dd, J = 8.1, 1.0 Hz, 1 H), 7.04 (dd, J = 7.3, 1.1 Hz, 1 H), 6.95 (dd, J = 8.0, 7.5 Hz, 1 H), 3.58 (s, 3 H), 1.94 (dd, J = 14.1, 7.0 Hz, 1 H), 1.70 (dd, J = 14.1, 5.2 Hz, 1 H), 1.56–1.45 (m, 3 H), 1.35 (d, J = 12.5 Hz, 1 H), 1.31 (d, J = 8.2 Hz, 3 H), 1.22 (d, J = 12.8 Hz, 1 H), 1.05–0.96 (m, 3 H), 0.95–0.71 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.2, 139.0, 137.2, 129.8, 123.1, 121.2, 115.3, 47.6, 45.6, 34.6, 34.4, 33.4, 31.3, 29.5, 26.5, 26.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃ClNO: 292.1463; found: 292.1465.

7-Bromo-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3g)

Yield: 113.9 mg (85%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.26 (dd, J = 8.2, 0.9 Hz, 1 H), 6.98 (dd, J = 7.3, 1.0 Hz, 1 H), 6.84–6.77 (m, 1 H), 3.51 (s, 3 H), 1.85 (dd, J = 14.1, 7.0 Hz, 1 H), 1.61 (dd, J = 14.1, 5.2 Hz, 1 H), 1.48–1.37 (m, 3 H), 1.29–1.24 (m, 1 H), 1.21 (d, J = 5.9 Hz, 3 H), 1.16–1.10 (m, 1 H), 0.95–0.81 (m, 4 H), 0.77–0.62 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.4, 140.4, 137.6, 133.2, 123.5, 121.8, 102.3, 47.6, 45.6, 34.6, 34.5, 33.4, 29.7, 26.6, 26.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃BrNO: 336.0958; found: 336.0960.

3-(Cyclohexylmethyl)-1,3,7-trimethylindolin-2-one (3h)

Yield: 82.4 mg (76%); white solid; mp 54.6–56.8 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.02–6.83 (m, 3 H), 3.48 (s, 3 H), 2.58 (s, 3 H), 1.90 (dd, J = 14.0, 7.0 Hz, 1 H), 1.68 (dd, J = 14.0, 5.2 Hz, 1 H), 1.57–1.46 (m, 3 H), 1.35 (d, J = 12.7 Hz, 1 H), 1.27 (s, 3 H), 1.24–1.18 (m, 1 H), 1.03–0.89 (m, 4 H), 0.86–0.70 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.9, 140.9, 135.1, 131.2, 122.2, 120.7, 119.5, 47.1, 45.7, 34.6, 34.5, 33.5, 29.5, 26.6, 26.1, 26.0, 19.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₆NO: 272.2009; found: 272.2011.

3-(Cyclohexylmethyl)-1,3,5-trimethylindolin-2-one (3i)

Yield: 74.8 mg (69%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.04 (d, J = 7.8 Hz, 1 H), 6.96 (s, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 3.18 (s, 3 H), 2.34 (s, 3 H), 1.90 (dd, J = 14.0, 7.1 Hz, 1 H), 1.69 (dd, J = 14.0, 5.2 Hz, 1 H), 1.53–1.44 (m, 3 H), 1.34 (d, J = 12.0 Hz, 1 H), 1.28 (s, 3 H), 1.21 (d, J = 12.7 Hz, 1 H), 1.02–0.90 (m, 4 H), 0.86–0.72 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.1, 140.7, 134.5, 131.8, 127.7, 123.5, 107.6, 47.9, 45.4, 34.7, 34.5, 33.5, 26.3, 26.2, 26.1, 21.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₆NO: 272.2009; found: 272.2003.

3-(Cyclohexylmethyl)-5-methoxy-1,3-dimethylindolin-2-one (3j)

Yield: 85.0 mg (74%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 6.81–6.74 (m, 2 H), 6.75–6.69 (m, 1 H), 3.80 (s, 3 H), 3.18 (s, 3 H), 1.91 (dd, J = 14.1, 7.1 Hz, 1 H), 1.68 (dd, J = 14.1, 5.3 Hz, 1 H), 1.54–1.43 (m, 3 H), 1.33 (d, J = 12.9 Hz, 1 H), 1.28 (d, J = 7.8 Hz, 3 H), 1.24–1.19 (m, 1 H), 1.02–0.89 (m, 4 H), 0.86 –0.70 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.8, 155.9, 136.7, 135.9, 111.4, 110.5, 108.1, 55.8, 48.3, 45.4, 34.7, 34.4, 33.5, 26.3, 26.1, 26.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₆NO₂: 288.1958; found: 288.1953.

5-(tert-Butyl)-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3k)

Yield: 124.0 mg (99%); colorless oil.

¹H NMR (500 MHz, CDCl₃) δ 7.27 (dd, J = 8.2, 1.9 Hz, 1 H), 7.19 (d, J = 1.9 Hz, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 3.20 (s, 3 H), 1.89 (dd, J = 14.0, 6.3 Hz, 1 H), 1.74–1.70 (m, 1 H), 1.55–1.44 (m, 3 H), 1.40–1.36 (m, 1 H), 1.32 (s, 9 H), 1.32 (s, 3 H), 1.20–1.16 (m, 1 H), 1.03–0.91 (m, 4 H), 0.85–0.68 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.3, 145.5, 140.8, 134.1, 123.3, 120.1, 107.2, 48.1, 45.4, 34.7, 34.5, 34.4, 33.8, 31.6, 26.2, 26.1, 26.0, 25.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₃₂NO: 314.2478; found: 314.2479.

3-(Cyclohexylmethyl)-1,3-dimethyl-5-nitroindolin-2-one (3l)

Yield: 59.2 mg (49%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 8.26 (dd, J = 8.6, 2.2 Hz, 1 H), 8.05 (d, J = 2.2 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 3.28 (s, 3 H), 1.99 (dd, J = 14.2, 7.1 Hz, 1 H), 1.82–1.78 (m, 1 H), 1.71 (s, 1 H), 1.36 (s, 3 H), 1.26–1.18 (m, 4 H), 0.94–0.88 (m, 4 H), 0.86–0.72 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.1, 148.8, 143.4, 135.3, 125.1, 118.9, 107.5, 48.0, 45.2, 34.8, 34.4, 33.4, 26.6, 26.0, 25.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃N₂O₃: 303.1703; found: 303.1698.

3-(Cyclohexylmethyl)-1,3-dimethyl-2-oxoindoline-5-carbonitrile (3m)

Yield: 93.7 mg (83%); yellow solid; mp 112.0–114.8 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.48 (d, J = 8.1 Hz, 1 H), 7.32 (s, 1 H), 6.85 (d, J = 8.1 Hz, 1 H), 3.13 (s, 3 H), 1.82 (dd, J = 14.2, 7.1 Hz, 1 H), 1.64 (dd, J = 14.2, 5.2 Hz, 1 H), 1.40–1.31 (m, 3 H), 1.20 (s, 3 H), 1.10 (dd, J = 25.3, 12.8 Hz, 2 H), 0.89–0.75 (m, 4 H), 0.66 (dd, J = 25.3, 12.8 Hz, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.5, 146.0, 135.5, 133.0, 126.0, 119.3, 108.5, 105.3, 47.6, 45.1, 34.6, 34.3, 33.3, 26.4, 26.0, 25.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₃N₂O: 283.1805; found: 283.1801.

3-(Cyclohexylmethyl)-1,3-dimethyl-5-(trifluoromethyl)indolin-2-one (3n)

Yield: 63.7 mg (49%); yellow oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.46 (d, J = 8.1 Hz, 1 H), 7.31 (s, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 3.16 (s, 3 H), 1.87 (dd, J = 14.2, 6.9 Hz, 1 H), 1.68 (dd, J = 14.2, 5.3 Hz, 1 H), 1.45–1.35 (m, 3 H), 1.25 (s, 3 H), 1.16 (t, J = 15.7 Hz, 1 H), 1.13–1.08 (m, 1 H), 0.94–0.81 (m, 4 H), 0.78–0.64 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.9, 145.1, 135.0, 125.4 (q, J = 3.8 Hz), 124.5 (q, J = 32.8 Hz), 124.4 (q, J = 272.2 Hz), 123.4, 119.6 (q, J = 3.6 Hz), 107.6, 47.8, 45.2, 34.7, 34.3, 33.5, 29.6, 26.2, 26.1, 25.7.

¹⁹F NMR (471 MHz, CDCl₃): δ = –62.7 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₃F₃NO: 326.1726; found: 326.1720.

3-(Cyclohexylmethyl)-7-fluoro-1,3-dimethyl-4-(trifluoromethyl)indolin-2-one (3o)

Yield: 116.7 mg (85%); yellow solid; mp 61.0–63.6 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.22 (dd, J = 9.0, 4.2 Hz, 1 H), 7.06 (d, J = 10.1 Hz, 1 H), 3.38 (d, J = 3.7 Hz, 3 H), 1.97–1.92 (m, 1 H), 1.87 (dd, J = 14.2, 6.8 Hz, 1 H), 1.40 (d, J = 23.9 Hz, 3 H), 1.33 (s, 3 H), 1.15 (dd, J = 20.0, 8.3 Hz, 2 H), 0.96–0.80 (m, 3 H), 0.79–0.66 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 179.4, 148.6 (d, J = 249.5 Hz), 133.72, 130.8 (d, J = 8.8 Hz), 122.7 (q, J = 273.4 Hz), 122.3 (d, J = 2.5 Hz), 122.0 (d, J = 5.0 Hz), 120.3 (q, J = 6.3 Hz), 115.2 (d, J = 21.0 Hz), 49.0, 43.9, 34.1, 32.9, 27.9, 27.8, 25.0, 24.4.

¹⁹F NMR (471 MHz, DMSO): δ = –60.8 (s), –110.6 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₂F₄NO: 344.1632; found: 344.1636.

4,7-Dichloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3p)

Yield: 102.7 mg (79%); white solid; mp 96.8–97.9 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.16 (dd, J = 8.7, 2.1 Hz, 1 H), 6.93 (dd, J = 8.7, 3.0 Hz, 1 H), 3.61 (d, J = 3.3 Hz, 3 H), 2.32–2.22 (m, 1 H), 1.91 (dd, J = 14.1, 7.1 Hz, 1 H), 1.59–1.55 (m, 3 H), 1.51 (s, 1 H), 1.45 (s, 3 H), 1.38–1.31 (m, 1 H), 1.28–1.22 (m, 1 H), 1.04 (dd, J = 18.5, 8.1 Hz, 2 H), 0.93–0.79 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 176.1, 135.9, 128.0, 126.3, 124.7, 119.4, 109.3, 44.6, 38.0, 30.4, 29.1, 28.3, 24.9, 21.3, 18.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₂Cl₂NO: 326.1073; found: 326.1078.

3-(Cyclohexylmethyl)-1,3,4,7-tetramethylindolin-2-one (3q)

Yield: 92.4 mg (81%); white solid; mp 179.1–181.9 °C.

¹H NMR (500 MHz, CDCl₃): δ = 6.83 (d, J = 7.8 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 3.44 (s, 3 H), 2.50 (s, 3 H), 2.26 (s, 3 H), 1.91 (d, J = 5.5 Hz, 2 H), 1.49–1.39 (m, 3 H), 1.30 (s, 3 H), 1.27–1.19 (m, 2 H), 1.00–0.86 (m, 3 H), 0.84–0.73 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 182.1, 141.0, 131.8, 131.5, 131.1, 134.8, 117.0, 48.0, 43.8, 35.0, 34.1, 33.0, 29.7, 26.1, 26.0, 24.2, 19.1, 18.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₈NO: 286.2165; found: 286.2162.

3-(Cyclohexylmethyl)-1,3-dimethyl-4,6-bis(trifluoromethyl)indolin-2-one (3r)

Yield: 140.0 mg (89%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.55 (s, 1 H), 7.23 (s, 1 H), 3.27 (s, 3 H), 2.04–1.94 (m, 2 H), 1.45 (d, J = 10.6 Hz, 3 H), 1.39 (s, 3 H), 1.22–1.17 (m, 1 H), 1.12 (d, J = 9.1 Hz, 1 H), 0.98–0.90 (m, 2 H), 0.86–0.71 (m, 4 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.2, 145.8, 135.2, 131.0 (q, J = 32.8 Hz), 127.5 (q, J = 32.8 Hz), 123.2 (q, J = 273.4 Hz), 123.1 (q, J = 274.7 Hz), 117.5 (d, J = 15.0 Hz), 117.8 (q, J = 6.3 Hz), 107.9 (q, J = 2.5 Hz), 49.7, 44.6, 35.1, 33.9, 32.9, 26.6, 26.0, 25.9, 25.1.

¹⁹F NMR (471 MHz, DMSO): δ = –58.8 (s), –61.4 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₂F₆NO: 394.1601; found: 394.1601.

6-Chloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3s)

Yield: 36.1 mg (31%); white solid; mp 76.0–77.8 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.07–7.02 (m, 2 H), 6.84 (d, J = 1.7 Hz, 1 H), 3.20 (s, 3 H), 1.92 (dd, J = 14.1, 7.0 Hz, 1 H), 1.70 (dd, J = 14.1, 5.2 Hz, 1 H), 1.55–1.46 (m, 3 H), 1.33 (d, J = 3.9 Hz, 1 H), 1.29 (s, 3 H), 1.25–1.19 (m, 1 H), 1.02–0.89 (m, 4 H), 0.85–0.72 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.0, 144.3, 133.2, 132.8, 123.6, 122.1, 108.7, 47.6, 45.3, 34.7, 34.5, 33.5, 26.3, 26.1, 26.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃ClNO: 292.1463; found: 292.1465.

4-Chloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (3s′)

Yield: 43.1 mg (37%); white solid; mp 59.0–60.8 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.21 (t, J = 8.0 Hz, 1 H), 6.99 (dd, J = 8.2, 0.5 Hz, 1 H), 6.75 (d, J = 7.7 Hz, 1 H), 3.21 (s, 3 H), 2.24 (dd, J = 14.1, 4.4 Hz, 1 H), 1.89 (dd, J = 14.1, 7.1 Hz, 1 H), 1.50 (d, J = 11.1 Hz, 2 H), 1.45 (dd, J = 3.9, 2.2 Hz, 1 H), 1.43 (s, 3 H), 1.30 (dd, J = 8.9, 5.5 Hz, 1 H), 1.26–1.21 (m, 1 H), 1.05–0.95 (m, 2 H), 0.95–0.75 (m, 4 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.6, 144.9, 130.8, 130.3, 128.8, 123.5, 106.5, 49.5, 42.8, 35.2, 33.8, 33.1, 26.5, 26.1, 26.0, 23.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃ClNO: 292.1463; found: 292.1467.

3-(Cyclohexylmethyl)-1,3-dimethyl-1,3-dihydro-2H-benzo[f]indol-2-one (3t)

Yield: 92.2 mg (75%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.71 (dd, J = 8.1, 0.7 Hz, 1 H), 7.55–7.49 (m, 2 H), 7.45–7.38 (m, 2 H), 6.97–6.91 (m, 1 H), 3.53 (s, 3 H), 2.41 (dd, J = 14.0, 7.8 Hz, 1 H), 1.88 (dd, J = 14.0, 5.0 Hz, 1 H), 1.62 (s, 3 H), 1.46–1.39 (m, 3 H), 1.35–1.29 (m, 1 H), 1.23–1.16 (m, 1 H), 1.13–0.34 (m, 1 H), 0.99–0.93 (m, 1 H), 0.93–0.87 (m, 1 H), 0.87–0.82 (m, 2 H), 0.81–0.73 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 173.9, 138.5, 136.9, 133.4, 126.9, 126.3, 125.7, 123.1, 122.4, 119.6, 108.1, 50.9, 46.5, 34.8, 34.5, 33.5, 32.9, 29.6, 26.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₆NO: 308.2009; found: 308.2006.

3-(Cyclopentylmethyl)-1,3-dimethylindolin-2-one (3u)

Yield: 77.8 mg (80%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.26 (d, J = 1.2 Hz, 1 H), 7.20–7.14 (m, 1 H), 7.06 (d, J = 0.7 Hz, 1 H), 6.84 (d, J = 7.7 Hz, 1 H), 3.22 (s, 3 H), 2.06 (dd, J = 13.7, 7.3 Hz, 1 H), 1.89 (dd, J = 13.7, 6.1 Hz, 1 H), 1.48–1.38 (m, 3 H), 1.34 (s, 3 H), 1.28 (s, 1 H), 1.29–1.21 (m, 3 H), 1.06–0.96 (m, 1 H), 0.85–0.78 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.1, 143.3, 134.4, 127.6, 122.7, 122.3, 107.9, 48.5, 44.5, 37.2, 33.8, 32.7, 26.2, 25.3, 24.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₂NO: 244.1696; found: 244.1690.

1,3-Dimethyl-3-phenethylindolin-2-one (3v)

Yield: 60.5 mg (57%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.29 (m, 1 H), 7.26–7.18 (m, 3 H), 7.17–7.07 (m, 2 H), 7.07–6.99 (m, 2 H), 6.85 (dd, J = 12.8, 7.8 Hz, 1 H), 3.21 (d, J = 3.2 Hz, 3 H), 2.38–2.16 (m, 2 H), 2.19–2.06 (m, 1 H), 2.06–1.96 (m, 1 H), 1.44–1.36 (m, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.2, 143.5, 141.4, 133.7, 128.3, 128.3, 125.9, 122.6, 122.5, 108.1, 107.9, 48.4, 40.3, 31.0, 26.2, 24.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₀NO: 251.1383; found: 251.1383.

3-(Cyclohexylmethyl)-1-ethyl-3-methylindolin-2-one (3w)

Yield: 46.6 mg (43%); colorless oil.

¹H NMR (500 MHz, CDCl₃): δ = 7.29–7.24 (m, 1 H), 7.18 (dd, J = 7.3, 0.7 Hz, 1 H), 7.07 (dd, J = 7.5, 0.7 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 3.90 (dd, J = 14.2, 7.2 Hz, 1 H), 3.69 (dd, J = 14.1, 7.1 Hz, 1 H), 1.95 (dd, J = 14.0, 6.8 Hz, 1 H), 1.73 (dd, J = 13.9, 5.2 Hz, 1 H), 1.56–1.51 (m, 1 H), 1.53–1.39 (m, 3 H), 1.32 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.20–1.16 (m, 1 H), 1.04–0.90 (m, 4 H), 0.90–0.80 (m, 1 H), 0.80–0.69 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 180.6, 142.2, 134.8, 127.4, 122.9, 122.1, 108.1, 47.7, 45.5, 34.8, 34.4, 34.3, 33.7, 26.1, 26.0, 12.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₆NO: 272.2009; found: 272.2002.

1-Benzyl-3-(cyclohexylmethyl)-3-methylindolin-2-one (3x)

Yield: 87.9 mg (66%); white solid; mp 75.2–76.9 °C.

¹H NMR (500 MHz, CDCl₃): δ = 7.33 (d, J = 4.3 Hz, 4 H), 7.29 (s, 1 H), 7.18 (dd, J = 9.0, 4.2 Hz, 2 H), 7.05 (d, J = 7.3 Hz, 1 H), 6.76 (d, J = 7.7 Hz, 1 H), 5.07 (d, J = 15.6 Hz, 1 H), 4.83 (d, J = 15.6 Hz, 1 H), 2.01 (dd, J = 14.0, 6.3 Hz, 1 H), 1.78 (dd, J = 14.0, 5.8 Hz, 1 H), 1.54–1.44 (m, 4 H), 1.39 (s, 3 H), 1.17 (dd, J = 12.9, 1.6 Hz, 1 H), 1.05–0.92 (m, 4 H), 0.90–0.82 (m, 1 H), 0.79–0.68 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃): δ = 181.0, 142.2, 136.2, 134.6, 128.7, 127.5, 127.4, 123.6, 122.8, 122.3, 109.1, 47.9, 45.5, 43.7, 34.8, 34.4, 34.0, 26.6, 26.2, 26.1, 26.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₈NO: 334.2166; found: 334.2165.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 26 January 2023

Accepted after revision: 20 April 2023

Article published online:
08 May 2023