Oxidative Annulation of Diphenylpropanamides via In Situ Hypervalent Iodine-Promoted Intramolecular C–N/C–O Bond Formation

Abstract

An aryl iodide catalyzed intramolecular oxidative transformation of diphenylpropanamide derivatives is described that can readily afford the C–N/C–O coupling products in a single step. The speed of the 1,3-aryl iodide migration process determines the diversity of target compound generation in this reaction. This straightforward approach can be performed with the use of inexpensive and readily available catalyst, transition-metal-free, mild conditions and good functional group tolerance.

Key words

catalytic - aryl iodide - C–N bond formation - C–O bond formation

Possessing properties of low toxicity, favourable safety profile and environmentally benign nature, hypervalent iodine reagents have been shown to be effective promoters of many organic transformations.[1] Since their catalytic utility was proposed in 2005,[2] chemists have focused on the use of catalytic systems in many reactions for the formation of C–C, C–N, C–O or C–X (X = halogen) bonds, such as dearomatization of phenol derivatives,[3] oxidation of alkenes[4] and α-functionalization of carbonyl compounds.[5] Among the various strategies developed to date, carbon–carbon double bonds, hydroxyl groups of phenol derivatives, and α-positions of ketone compounds have frequently emerged as activated positions in aryl iodide catalytic chemistry (Figure [1]). However, the N-alkoxyl group of amides as a highly active group has rarely been studied in aryl iodide chemistry.[6]

Metal-catalyzed C–N/C–O bond-coupling reactions have been successfully utilized widely in organic synthesis as powerful synthetic tools.[7] Recently, Wang and co-workers reported the first example of a Pd(II)-catalyzed amination of aryl C–H bonds of diphenylpropanamide derivatives to afford various oxindole frameworks (Scheme [1]).[8]

Figure 1 General activated groups in aryl iodide catalysis

Scheme 1 Approaches to intramolecular annulation of diphenyl­propanamides

An organocatalytic desymmetrization approach applied in C–H amination has many advantages. Based on previous work,[9] we have studied the construction of oxindole derivatives, mainly focused on those dialkyl-substituted at the α-position. We also found that a significant challenge in this reaction was when the starting materials had two aromatic rings that contained electron-donating or -withdrawing groups; in this case, in addition to C–N bond coupling products, C–O bond products also formed. In this work, we focussed on building C–O bond oxime molecules. Herein, we detail studies of the aryl iodide-catalyzed intramolecular oxidation of diphenylpropanamide derivatives.

Table 1 Optimization of the Reaction Conditions^a

Entry	2	Oxidant	Solvent	Yield (%)b (3a + 3a′)	Ratio (3a/3a′)c
1	2a	mCPBA	HFIP	64	2.0:1
2	2b	mCPBA	HFIP	57	3.0:1
3	2c	mCPBA	HFIP	82	2.0:1
4	2d	mCPBA	HFIP	72	1.7:1
5	2e	mCPBA	HFIP	41	1.5:1
6	2f	mCPBA	HFIP	54	2.1:1
7	2g	mCPBA	HFIP	47	2.0:1
8	2h	mCPBA	HFIP	77	1.6:1
9	2h	Selectfluor	HFIP	53	1.5:1
10	2h	H2O2	HFIP	trace	–
11	2h	MeCO3H	HFIP	<10	–
12	2h	TBHP	HFIP	trace	–
13	2h	mCPBA	TFE	72	2.0:1
14	2h	mCPBA	TFIP	70	2.0:1
15	2h	mCPBA	DCM	52	3.0:1
16	2h	mCPBA	EtOAc	<10	–
17	2h	mCPBA	toluene	<10	–
18	2h	mCPBA	MeCN	81	2.0:1
19	2h	mCPBA	THF	trace	–
20	2h	mCPBA	MeOH	17	2.0:1
21d	2h	mCPBA	HFIP	71	1.6:1
22e	2h	mCPBA	HFIP	62	1.8:1

^a Unless otherwise indicated, the reaction was carried out at 0.1 mmol scale of 1a, catalyzed by 2 (20 mol%) in solvent (1 mL) at room temperature for 8 h. The molar ratio of 1a/mCPBA was 1:1.3.

^b Isolated yield.

^c The ratio of 3a/3a′ was determined by ¹H NMR analysis.

^d Temperature of reaction was 0 °C.

^e Temperature of reaction was 50 °C.

Initially, the reaction of N-methoxy-2,2-di-p-tolylpropanamide (1a) catalyzed by 20 mol% of 2-iodotoluene (2a) with meta-chloroperoxybenzoic acid as the stoichiometric oxidant in hexafluoro-2-propanol at room temperature was employed to optimize reaction conditions. The desired C–N/C–O annulation products 3a and 3a′ were successfully obtained in a total of 64% yield in a 2:1 ratio, respectively (Table [1], entry 1). Subsequently, various catalysts 2b–e were screened in this transformation, which revealed that catalyst 2c, with a methyl group at the para-position of the benzene ring, delivered the highest reactivity, resulting in 82% combined yield of 3a and 3a′ (entries 2–5) with less C–O bond formation of oxime product (3a/3a′ = 2:1). Inspired by these results, different substituents at the para-position of the catalyst were applied to this reaction (entries 6–8). When 1-ethyl-4-iodobenzene (2f) and 4-iodo-1,1′-biphenyl (2g) were utilized as the catalysts, the yields decreased significantly to 54% and 47%, respectively (entries 6 and 7). In contrast, 1-(tert-butyl)-4-iodobenzene (2h) promoted the reaction effectively, with a yield of 77% and 1.6:1.0 ratio of 3a/3a′ (entry 8). To increase the yield of C–O bond-formation product, various conditions including oxidants and solvents were tested in this oxidative reaction (entries 9–20). Unfortunately, the results revealed that this proved ineffective for optimization of C–O bond formation. However, when acetonitrile was employed as the solvent, the combined yield of 3a and 3a′ increased to 81%, albeit with an unsatisfactory ratio of 3a/3a′ of 2:1 (entry 18).

Further attempts to improve the yield and the ratio of 3a/3a′ by changing temperature (entries 21 and 22), and additives also proved to be unfruitful.

Scheme 2 Aryl iodide catalyzed intramolecular oxidation of diphenylpropanamides: substrate scope.

Under the optimized conditions, a series of diphenylpropanamides 1 was explored to demonstrate the scope and generality of this transformation. As shown in Scheme [2, a] wide range of substrates was successfully employed, affording the corresponding C–N/C–O bond products in good combined yields. For example, 4-methyl substituted diphenylpropanamide 1a gave the corresponding lactam 3a in 47% yield accompanied by C–O bond oxime product 3a′ in 27% yield. Initially, we examined potential substituent effects on the benzene ring of diphenylpropanamides 1a–f. Ethyl-, n-butyl-, tert-butyl-, chloro- and multi-substituted reactants were employed in this transformation, and the results revealed that, whether the aryl ring possessed electron-donating or electron-withdrawing groups, the products of C−N bond formation 3a–f were preferentially generated in moderate yields. Unfortunately, the yield of oxime (3d′ and 3e′) decreased in line with the increase in steric hindrance on the aryl ring in this transformation. For instance, the use of a multi-substituted benzene ring significantly favoured the oxindole over the oxime (3e/3e′ = 10:1). Further exploration of the substrate scope focused on α-alkyl-substituted diphenylpropanamides 1g–h. The results showed that bulky steric alkyl groups at the α-position could improve the ratio of C–O bond formation (3h/3h′ = 1:1). Finally, we investigated the effect of substituents 1i–j on the terminal N-atom in this reaction. The reaction proceeded well with an isopropyl group as functional substituent, although lactam products 3i and 3j were generated in 39% and 37% yield, respectively, along with reduced levels of C–O coupling products (3i/3i′ = 2:1 and 3j/3j′ = 2:1).

Scheme 3 Proposed catalytic mechanism

We also monitored the progress of the reaction of 1a without mCPBA or aryl iodide catalyst 2h, but the reaction was highly inefficient under these conditions. Meanwhile, we utilized hypervalent iodine (PIDA) as a direct oxidant to mediate this transformation, which gave the corresponding products 3a and 3a′ in 50% and 24% yield, respectively (3a/3a′ = 2:1). Considering the various substrates in this oxidative transformation and a previous report,[10] a plausible mechanism is shown in Scheme [3]. Aryl iodide 2h is proposed to be oxidized to a hypervalent iodine(III) species by mCPBA. Subsequent coordination with the carbonyl group of 1 would enable a ligand exchange process to form an O-bonded hypervalent iodine intermediate Int-1. Subsequently, there are two possible pathways in this reaction: intramolecular 1,3-aryl iodide migration from oxygen to nitrogen atom would generate N-iodonium amide intermediate Int-2, and S_N2 type C–N bond formation between the carbon of the aryl ring and the amide nitrogen would yield the terminal lactam product 3. Alternatively, direct C–O bond formation between the carbon of the benzene ring and the nitrogen atom of the amide without 1,3-aryl iodide migration would afford oxime product 3′. Based on the experimental results, we found that the migration speed of aryl iodide was relatively rapid, leading to simultaneous generation of the (major) C–N coupling lactam and C–O coupling oxime.

In summary, we have developed the aryl iodide-catalyzed intramolecular oxidation of diphenylpropanamide derivatives to afford C–N and C–O bond coupling products in a simple step. This protocol illustrates that the speed of 1,3-aryl iodide migration is fast in this reaction, leading to preferential formation of the C–N bond coupling lactams rather than the desired oxime products. This strategy not only takes advantage of organocatalytic oxidation, simultaneously to construct oxindole and oxime architectures with potential bioactivity in one step, but also greatly enriches the research area of aryl iodide chemistry. Further design of novel reactants containing N-alkoxyl functional groups and application of this methodology are underway in our laboratory.

All commercially available compounds were used as provided without further purification. Solvents used in reactions were technical grade and dried only if indicated. Solvents for chromatography were technical grade and were distilled prior to use. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminium-backed plates (F-254 indicator). NMR spectra were recorded with a Bruker ARX 400 spectrometer and are reported in ppm (δ) downfield of TMS (δ = 0) in deuterated solvent as specified. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), or multiplet (m), with coupling constants (J) in hertz. Mass spectra were conducted with a Micromass Q-T instrument (ESI) and an Agilent Technologies 5973N (EI).

C−N/ C−O Bond Oxidative Coupling; General Procedure

To a reaction tube filled with reactant 1 (0.1 mmol) and aryl iodide 2 (20 mol%) was added mCPBA (1.3 equiv) and HFIP (1.0 mL). The resulting mixture was stirred at room temperature for 8 h, the reaction was quenched with aqueous saturated NaHCO₃, and the mixture was extracted with DCM (3 × 5 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the solvent was removed in vacuo. The residue was directly purified by preparative thin-layer chromatography to afford target products 3 and 3′.

1-Methoxy-3,6-dimethyl-3-(p-tolyl)indolin-2-one (3a)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 13.2 mg (47%); colourless viscous oil.

IR (neat): 2916, 2848, 1726, 1444, 1292, 1029, 809, 734, 699, 511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.22–7.16 (m, 2 H), 7.11 (d, J = 8.0 Hz, 2 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.94–6.88 (m, 2 H), 4.01 (s, 3 H), 2.42 (s, 3 H), 2.30 (s, 3 H), 1.76 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 138.5, 137.5, 136.1, 136.1, 128.3, 127.4, 125.4, 123.1, 122.8, 107.3, 62.4, 49.3, 22.5, 20.7, 19.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₀NO₂: 282.1494; found: 282.1485.

3,6-Dimethyl-3-(p-tolyl)benzofuran-2(3H)-one O-Methyl Oxime (3a′)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 7.7 mg (27%); colourless oil.

IR (neat): 2917, 2849, 1722, 1473, 1264, 1028, 810, 733, 701, 510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.16 (m, 2 H), 7.15–7.09 (m, 3 H), 6.98 (s, 1 H), 6.95 (d, J = 7.9 Hz, 1 H), 4.00 (s, 3 H), 2.33 (s, 3 H), 2.31 (s, 3 H), 1.77 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.1, 137.2, 137.1, 137.1, 133.0, 131.7, 129.4, 129.3, 128.5, 126.4, 125.1, 107.3, 63.4, 50.6, 23.3, 21.2, 21.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₀NO₂: 282.1494; found: 282.1486.

6-Ethyl-3-(4-ethylphenyl)-1-methoxy-3-methylindolin-2-one (3b)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 15.5 mg (50%); colourless viscous oil.

IR (neat): 2928, 2857, 1728, 1445, 1219, 1028, 819, 734, 700, 534 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.23 (d, J = 8.3 Hz, 2 H), 7.11 (dd, J = 13.5, 7.8 Hz, 3 H), 6.99–6.89 (m, 2 H), 4.02 (s, 3 H), 2.71 (q, J = 7.6 Hz, 2 H), 2.61 (q, J = 7.6 Hz, 2 H), 1.77 (s, 3 H), 1.29 (t, J = 7.6 Hz, 3 H), 1.20 (t, J = 7.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.5, 144.9, 143.4, 139.5, 137.4, 128.7, 128.1, 126.5, 124.2, 122.7, 107.1, 63.5, 50.4, 29.1, 28.4, 23.6, 15.6, 15.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₄NO₂: 310.1807; found: 310.1798.

6-Ethyl-3-(4-ethylphenyl)-3-methylbenzofuran-2(3H)-one O-Methyl Oxime (3b′)

IR (neat): 2926, 2839, 1729, 1438, 1242, 1031, 821, 729, 696, 528 cm^–1.

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 8.4 mg (27%); colourless viscous oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.19 (m, 2 H), 7.18–7.11 (m, 3 H), 7.02 (s, 1 H), 6.97 (d, J = 7.9 Hz, 1 H), 4.00 (s, 3 H), 2.62 (p, J = 7.6 Hz, 4 H), 1.78 (s, 3 H), 1.21 (td, J = 7.6, 6.2 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.2, 143.4, 139.6, 137.3, 137.3, 131.6, 128.1, 128.1, 127.3, 126.5, 124.0, 107.3, 63.4, 50.7, 28.7, 28.4, 23.5, 15.9, 15.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₄NO₂: 310.1807; found: 310.1815.

6-Butyl-3-(4-butylphenyl)-1-methoxy-3-methylindolin-2-one (3c)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 15.4 mg (42%); colourless viscous oil.

IR (neat): 2933, 2857, 1731, 1448, 1299, 1024, 811, 742, 699, 519 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.22 (d, J = 7.9 Hz, 2 H), 7.14–7.05 (m, 3 H), 6.99–6.78 (m, 2 H), 4.02 (s, 3 H), 2.67 (t, J = 7.8 Hz, 2 H), 2.56 (t, J = 7.8 Hz, 2 H), 1.77 (s, 3 H), 1.68–1.61 (m, 2 H), 1.60–1.51 (m, 2 H), 1.43–1.30 (m, 4 H), 0.96 (t, J = 7.4 Hz, 3 H), 0.91 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.5, 143.6, 142.0, 139.5, 137.4, 128.6, 128.6, 126.4, 124.2, 123.3, 107.6, 63.4, 50.4, 36.0, 35.2, 33.7, 33.5, 23.7, 22.5, 22.4, 14.0, 13.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₁NO₂ + Na: 388.2253; found: 388.2246.

6-Butyl-3-(4-butylphenyl)-3-methylbenzofuran-2(3H)-one O-Methyl Oxime (3c′)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 8.8 mg (24%); colourless oil.

IR (neat): 2931, 2852, 1727, 1446, 1294, 1022, 805, 744, 692, 515 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.20 (d, J = 8.3 Hz, 2 H), 7.16–7.08 (m, 3 H), 7.01 (s, 1 H), 6.96 (d, J = 7.9 Hz, 1 H), 4.00 (s, 3 H), 2.57 (q, J = 8.4 Hz, 4 H), 1.78 (s, 3 H), 1.61–1.53 (m, 4 H), 1.39–1.29 (m, 4 H), 0.91 (td, J = 7.3, 4.9 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.2, 142.1, 138.3, 137.3, 137.3, 131.5, 128.7, 127.9, 126.4, 124.5, 107.3, 63.4, 50.7, 35.5, 35.2, 34.0, 33.5, 23.6, 22.4, 22.4, 14.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₁NO₂ + Na: 388.2253; found: 388.2238.

6-(tert-Butyl)-3-(4-(tert-butyl)phenyl)-1-methoxy-3-methylindolin-2-one (3d)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 22.4 mg (61%); white solid; mp 156–157 °C.

IR (neat): 2931, 2854, 1728, 1440, 1288, 1030, 817, 739, 689, 510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.30 (m, 2 H), 7.28–7.23 (m, 2 H), 7.15–7.11 (m, 2 H), 7.07 (s, 1 H), 4.04 (s, 3 H), 1.78 (s, 3 H), 1.37 (s, 9 H), 1.28 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 151.0, 149.1, 138.2, 136.1, 127.3, 125.2, 124.5, 122.9, 119.1, 103.7, 62.4, 49.3, 34.1, 33.4, 30.4, 30.2, 22.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₁NO₂ + Na: 388.2253; found: 388.2245.

3-(3,4-Dimethylphenyl)-1-methoxy-3,5,6-trimethylindolin-2-one (3e)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 21.3 mg (69%); colourless viscous oil.

IR (neat): 2929, 2849, 1741, 1453, 1283, 1031, 828, 751, 705, 527 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.10–7.03 (m, 2 H), 7.02–6.96 (m, 1 H), 6.93 (s, 1 H), 6.86 (s, 1 H), 4.01 (s, 3 H), 2.32 (s, 3 H), 2.25–2.14 (m, 9 H), 1.75 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.4, 137.7, 137.3, 136.8, 136.6, 135.8, 131.3, 129.8, 129.1, 127.7, 125.5, 123.9, 108.8, 63.3, 50.4, 23.4, 20.2, 20.0, 19.6, 19.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₃NO₂ + Na: 332.1627; found: 332.1620.

6-Chloro-3-(4-chlorophenyl)-1-methoxy-3-methylindolin-2-one (3f)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 16.3 mg (51%); colourless viscous oil.

IR (neat): 2955, 2879, 1736, 1491, 1231, 1077, 959, 815, 744, 511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.27–7.22 (m, 2 H), 7.18 (d, J = 8.3 Hz, 2 H), 7.12–7.01 (m, 3 H), 3.98 (s, 3 H), 1.73 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.5, 139.6, 136.8, 133.5, 132.8, 127.9, 127.9, 126.9, 124.4, 122.4, 107.4, 62.7, 49.2, 22.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₃Cl₂NO₂ + Na: 344.0221; found: 344.0211.

6-Chloro-3-(4-chlorophenyl)-3-ethyl-1-methoxyindolin-2-one (3g)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 12.1 mg (36%); colourless viscous oil.

IR (neat): 2957, 2870, 1731, 1478, 1230, 1081, 961, 810, 743, 508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.25 (m, 4 H), 7.17–7.11 (m, 2 H), 7.09–7.06 (m, 1 H), 4.00 (s, 3 H), 2.47–2.35 (m, 1 H), 2.22–2.12 (m, 1 H), 0.72 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.8, 141.6, 137.4, 134.7, 133.9, 129.0, 128.4, 126.3, 126.1, 123.4, 108.5, 63.9, 55.4, 31.0, 9.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₅Cl₂NO₂ + Na: 358.0378; found: 358.0372.

6-Chloro-3-(4-chlorophenyl)-3-ethylbenzofuran-2(3H)-one O-Methyl Oxime (3g′)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 5.4 mg (16%); colourless viscous oil.

IR (neat): 2961, 2848, 1730, 1471, 1259, 1013, 947, 793, 738, 509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.35 (dd, J = 8.3, 2.0 Hz, 1 H), 7.31–7.26 (m, 4 H), 7.20–7.16 (m, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 4.00 (s, 3 H), 2.49–2.33 (m, 1 H), 2.27–2.10 (m, 1 H), 0.73 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.4, 139.0, 137.3, 134.0, 129.9, 129.1, 129.0, 128.8, 128.3, 125.4, 108.8, 63.8, 55.8, 30.9, 9.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₅Cl₂NO₂ + Na: 358.0378; found: 358.0386.

6-Chloro-3-(4-chlorophenyl)-3-isopentyl-1-methoxyindolin-2-one (3h)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 10.2 mg (27%); colourless viscous oil.

IR (neat): 2965, 2849, 1728, 1492, 1261, 1093, 1013, 811, 737, 506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.24 (m, 4 H), 7.16–7.12 (m, 2 H), 7.10–7.06 (m, 1 H), 3.98 (s, 3 H), 2.38 (dd, J = 13.9, 7.8 Hz, 1 H), 2.09 (dd, J = 13.9, 5.1 Hz, 1 H), 1.45–1.36 (m, 1 H), 0.77 (d, J = 6.6 Hz, 3 H), 0.71 (d, J = 6.7 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 141.6, 138.8, 134.7, 133.8, 128.9, 128.1, 126.7, 126.1, 123.2, 108.6, 63.8, 54.4, 46.5, 25.8, 24.4, 23.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₁Cl₂NO₂ + Na: 400.0847; found: 400.0851.

6-Chloro-3-(4-chlorophenyl)-3-isopentylbenzofuran-2(3H)-one O-Methyl Oxime (3h′)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 30:1).

Yield: 9.8 mg (26%); colourless viscous oil.

IR (neat): 2970, 2936, 1730, 1491, 1267, 1209, 1013, 812, 736, 505 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36 (dd, J = 8.3, 2.0 Hz, 1 H), 7.30–7.26 (m, 4 H), 7.23–7.19 (m, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 3.98 (s, 3 H), 2.39 (dd, J = 14.0, 7.9 Hz, 1 H), 2.09 (dd, J = 13.9, 5.2 Hz, 1 H), 1.49–1.38 (m, 1 H), 0.77 (d, J = 6.6 Hz, 3 H), 0.72 (d, J = 6.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 139.0, 138.7, 133.9, 129.7, 129.0, 128.9, 128.8, 128.0, 126.0, 109.0, 63.7, 54.8, 46.4, 25.8, 24.4, 23.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₁Cl₂NO₂ + Na: 400.0847; found: 400.0839.

1-Isopropoxy-3,6-dimethyl-3-(p-tolyl)indolin-2-one (3i)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 50:1).

Yield: 12.1 mg (39%); colourless viscous oil.

IR (neat): 2931, 2810, 1724, 1457, 1281, 1011, 817, 752, 703, 522 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.16 (m, 2 H), 7.14–7.08 (m, 3 H), 6.96 (s, 1 H), 6.92 (d, J = 7.9 Hz, 1 H), 4.66–4.56 (m, 1 H), 2.32 (s, 1 H), 2.30 (s, 3 H), 1.76 (s, 3 H), 1.35–1.31 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.3, 139.2, 137.6, 137.2, 132.8, 131.8, 129.5, 128.5, 126.6, 124.9, 108.0, 78.8, 50.7, 23.6, 21.3, 21.2, 21.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₃NO₂ + Na: 332.1627; found: 332.1633.

3,6-Dimethyl-3-(p-tolyl)benzofuran-2(3H)-one O-Isopropyl Oxime (3i′)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 50:1).

Yield: 6.2 mg (20%); colourless oil.

IR (neat): 2936, 2825, 1733, 1451, 1270, 1022, 822, 749, 700, 517 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.22–7.16 (m, 2 H), 7.12–7.08 (m, 2 H), 7.04 (d, J = 7.5 Hz, 1 H), 6.92–6.88 (m, 1 H), 6.85 (s, 1 H), 4.65–4.58 (m, 1 H), 2.41 (s, 3 H), 2.30 (s, 3 H), 1.76 (s, 3 H), 1.34 (s, 3 H), 1.33 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.7, 141.6, 138.5, 137.6, 137.1, 129.5, 129.4, 128.6, 126.5, 124.0, 123.8, 109.0, 78.8, 50.4, 23.8, 21.9, 21.2, 21.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₃NO₂ + Na: 332.1627; found: 332.1622.

6-Butyl-3-(4-butylphenyl)-1-isopropoxy-3-methylindolin-2-one (3j)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 50:1).

Yield: 14.5 mg (37%); colourless oil.

IR (neat): 2939, 2866, 1727, 1451, 1221, 1033, 822, 747, 693, 522 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.20 (d, J = 8.1 Hz, 2 H), 7.15–7.06 (m, 3 H), 7.01–6.97 (m, 1 H), 6.93 (d, J = 7.9 Hz, 1 H), 4.66–4.55 (m, 1 H), 2.63–2.51 (m, 4 H), 1.77 (s, 3 H), 1.61–1.52 (m, 4 H), 1.39–1.30 (m, 10 H), 0.95–0.87 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.4, 142.1, 139.4, 138.1, 137.8, 131.6, 128.8, 127.9, 126.6, 126.5, 124.3, 108.0, 78.8, 50.8, 35.6, 35.3, 34.1, 33.6, 23.7, 22.5, 21.2, 21.2, 14.1, 14.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₃₅NO₂ + Na: 416.2566; found: 416.2571.

6-Butyl-3-(4-butylphenyl)-3-methylbenzofuran-2(3H)-one O-Isopropyl Oxime (3j′)

Purification by preparative thin-layer chromatography (petroleum ether/EtOAc = 50:1).

Yield: 7.1 mg (18%); colourless oil.

IR (neat): 2936, 2849, 1721, 1452, 1218, 1036, 824, 749, 698, 518 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 8.2 Hz, 2 H), 7.12–7.04 (m, 3 H), 6.93–6.87 (m, 1 H), 6.86–6.82 (m, 1 H), 4.67–4.57 (m, 1 H), 2.65 (t, J = 7.8 Hz, 2 H), 2.55 (t, J = 7.8 Hz, 2 H), 1.76 (s, 3 H), 1.70–1.61 (m, 3 H), 1.60–1.50 (m, 3 H), 1.45–1.37 (m, 2 H), 1.36–1.34 (m, 3 H), 1.34–1.33 (m, 3 H), 0.95 (t, J = 7.3 Hz, 3 H), 0.90 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.7, 143.6, 142.1, 141.5, 137.8, 128.8, 128.8, 126.5, 124.0, 123.2, 108.3, 78.8, 50.5, 36.1, 35.3, 33.8, 33.6, 23.8, 22.6, 22.5, 21.2, 21.1, 14.1, 14.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₃₅NO₂ + Na: 416.2566; found: 416.2562.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We gratefully acknowledge Prof. Shuhua Li (Nanjing University) for calculations and discussions of mechanisms.

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Publication History

Received: 30 October 2021

Accepted after revision: 23 November 2021

Article published online:
21 December 2021