Development of Nitrolactonization Mediated by Iron(III) Nitrate Nonahydrate

Abstract

The nitrolactonization of alkenyl carboxylic acids mediated by Fe(NO₃)₃·9H₂O has been developed. Nitrolactones were obtained in up to 93% yield by treatment of alkenyl carboxylic acids with Fe(NO₃)₃·9H₂O. Mechanistic studies disclosed that the reaction proceeded through a radical intermediate generated from addition of NO₂ to alkenyl carboxylic acids.

Introduction

Nitro compounds are useful synthons in synthetic organic chemistry due to their availability for various transformations. The strong electron-withdrawing property of the nitro group plays an important role in C–C bond formation reactions^1,2) including the nitro–aldol reaction (Henry reaction),^3–5) Michael reaction,^6–11) and alkylation.^12,13) Nitrones and nitrile oxides generated from nitro compounds undergo 1,3-dipole cycloaddition reaction to give various heterocycles.^14–16) The nitro group can be converted into a carbonyl or amino group through the Nef reaction^17,18) or reduction, respectively.¹⁹⁾ For these reasons, nitro compounds are heavily used as versatile starting materials in the synthesis of natural products and drugs.^20–25) Nitration mediated by iron(III) nitrate nonahydrate (Fe(NO₃)₃·9H₂O) has been recently reported.^26–35) The use of Fe(NO₃)₃·9H₂O has attracted attention as a source of nitrogen dioxide in organic synthesis due to its properties as a readily available reagent of low toxicity and cost. It has been suggested that these nitrations proceed via a radical intermediate derived by addition of nitrogen dioxide generated from Fe(NO₃)₃·9H₂O with heating.³⁶⁾ We envisioned the novel development of a nitrolactonization of styrene derivative 1 mediated by Fe(NO₃)₃·9H₂O (Chart 1). Because nitrolactone 2 could lead to 1,2-aminoalcohol and amino acid derivatives bearing a tetrasubstituted carbon center, the development of a new nitrolactonization reaction leading to substituted nitrolactones would be useful not only in natural product synthesis but in medicinal chemistry.

Chart 1. Nitrolactonization Mediated by Fe(NO₃)₃·9H₂O

Precursor 3a for nitrolactonization was prepared from benzene by Friedel–Crafts acylation with succinic anhydride followed by a Wittig reaction of the resultant ketone 4a (Chart 2).

Chart 2. Synthesis of Precursor 3a

Nitrolactonization of carboxylic acid 3a was investigated according to the reported method of generating NO₂ from Fe(NO₃)₃·9H₂O³⁷⁾ (Table 1). Treatment of 3a with 0.5 equivalent (equiv.) of Fe(NO₃)₃·9H₂O in 1,2-dichlorobenzene at 130 °C for 4 h afforded nitrolactone 5a, hydroxylactone 6a, and lactone 7a in 48, 3, and 7% yields, respectively (entry 1). The nitration regioselectively took place at the olefinic moiety of 3a to produce 5a, with the product structure confirmed by X-ray crystallographic analysis.³⁸⁾ Hydroxylactone 6a was envisioned to be produced via a nitrite lactone intermediate due to the ambident property of NO₂ while lactone 7a was likely produced via proto-lactonization mediated by HNO₃ that was generated from NO₂ gas and water.³⁹⁾ The effect of the metal nitrate was investigated by use of copper(II) nitrate, zinc nitrate, and silver nitrate in the reaction (entries 2–4). These metal nitrates afforded nitrolactone 5 in lower yield when compared to the reaction with Fe(NO₃)₃ (entry 1 vs. entries 2–4). Reducing or increasing the number of equivalents of Fe(NO₃)₃ resulted in diminished yields (entry 1 vs. entries 5 and 6). The differences in the yields of products involved in the number of equivalent of Fe(NO₃)₃ would attribute the concentration of NO₂ generated for Fe(NO₃)₃. Lower equivalent of Fe(NO₃)₃ would not be enough to undergo NO₂ addition reaction but lead to decomposition of 5a probably due to the equilibrium mixture between NO₂ and its various reactive isomers of N₂O₄ (entry 5).^40–43) Higher equivalent of Fe(NO₃)₃ would generate a high concentration of HNO₃, which lead to proto-lactonization rather than radical addition of NO₂ (entry 6). To investigate the assumption that the heating-up time and reaction temperature would affect the reaction progress and yield, the reaction mixture was quickly heated (entries 7–9). When the reaction was conducted in a pre-heated oil bath at 130 °C, nitrolactone 5a was produced in an improved yield of 58% and the reaction time was shortened (entry 1 vs. entry 7). Addition of KHCO₃ as a base to suppress the formation of byproduct 7a did not result in an improved yield of 5a (entry 8). Addition of proton-sponge^® resulted in a complex product mixture (entry 9).

Table 1. Optimization of Reaction Conditions^a)

Entry	Metal nitrate	X	Time (h)	Yield (%)
				5a	6a	7a
1	Fe(NO3)3·9H2O	0.5	4	48	3	7
2	Cu(NO3)2·3H2O	0.75	5	36	12	4
3	Zn(NO3)2·6H2O	0.75	3	8	8	30
4	AgNO3	1.5	3	3	4	0
5	Fe(NO3)3·9H2O	0.34	4	7	4	5
6	Fe(NO3)3·9H2O	0.67	4.5	24	3	49
7b)	Fe(NO3)3·9H2O	0.5	1.5	58	5	13
8b,c)	Fe(NO3)3·9H2O	0.5	2.5	54	approx. 10d)	7
9b,e)	Fe(NO3)3·9H2O	0.5	24	0	0	0

a) A stirring mixture of metal nitrate and 3 in 1,2-dichlorobenzen was heated gradually from room temperature (r.t.) to 130 °C and after temperature reached at 130 °C, the reaction was run for the indicated time. b) The reaction was performed in pre-heated oil bath (130 °C). c) 0.3 equiv. of KHCO₃ was added. d) A small amount of 4-phenyl-4-oxobutanoic acid was contained. e) 1.0 equiv. of proton-sponge^® was added.

The effect of substitution at the phenyl group of starting material 3 was examined (Table 2). Treatment of 3b with Fe(NO₃)₃·9H₂O in 1,2-dichlorobenzene at 130 °C afforded nitrolactone 5b and lactone 7b in 12 and 69% yields, respectively, without production of hydroxylactone. The yield of 7b was higher than that of 5b because the electron-donating effect of the methoxy group prompted a protonation reaction instead of the radical addition of nitrogen dioxide (entry 1). Substituents bearing electron-withdrawing groups such as NO₂ and CN at phenyl group resulted in low yields of 5c and 5d due to complication in reaction (entries 2 and 3).

Table 2. Effects of Substituent at Phenyl Group

Entry	Starting material	R	Time (h)	Products	Yield (%)
					5	7
1	3b	OMe	3	5b, 7b	12	69
2	3c	NO2	2	5c	16	0
3	3d	CN	4	5d	26	0

The nitrolactonization of benzoic acid derivatives 8a–d was investigated to determine whether yields would improve due to acceleration of the cyclization rate and stabilization of the radical intermediate (vide infra) (Table 3). The reaction of 8a for 22 h proceeded smoothly to give 9a⁴⁴⁾ as a sole product in 93% yield. Nitrolactonization of compounds 8b and 8c bearing electron-donating substituents at the aromatic ring produced not only 9b (65% yield) and 9c (89% yield), respectively, but also 10b (30% yield) and 10c (11% yield), respectively, as a result of addition of nitrogen dioxide and the competing formation of a stable cation at the double benzylic position. Substitution of a bromo group at the aromatic ring, which can be converted into various functional groups, resulted in a reduced yield of nitrolactone 9d (67%) but lactone 10d was not observed.

Table 3. Nitrolactonization of Benzoic Acid Derivatives 8

A plausible mechanism is shown in Chart 3. Nitrogen dioxide generated from Fe(NO₃)₃·9H₂O by pyrolysis would react with 3a at nitrogen atom to lead to radical intermediate A. Oxidation of A, which might be mediated by Fe(NO₃)₃ and/or HNO₃, would give carbocation B, which would undergo cyclization to form 5a. This radical mechanism is supported by the fact that nitrolactonization of 8a in the presence of 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger reduced the yield of 9a (12%) (Table 3, entry 1 vs. Chart 4) and recovered 8a in 16% yield. Isolation of 8a and 9a was possible although other products could be unidentified because of complication in the reaction. Through a similar process leading to production of 5a, hydroxylactone 6a would be obtained through nitrite radical intermediates C, carbocation D, and nitrite E, sequentially. It was assumed that cleavage of the O–NO bond of E took place in the reaction media or by addition of water during the workup stage. The ambident property of NO₂ might produce nitrite intermediate C. It had been reported not only that partial pressure of oxygen influenced the production of nitrite adducts in the reaction of isobutylene and N₂O₄ which has been regarded as an equilibrium mixture with NO₂,^40–43,45) but also that oxidative cleavage of a tetrasubstituted olefin catalyzed by Fe(NO₃)₃ would proceed via a dinitrite intermediate in the presence of molecular oxygen.³⁷⁾ We speculated that production of 6a might be related to the amount of dissolved oxygen in the reaction media, however the detailed effect of the dissolved oxygen on the production of 6a was unclear. Lactone 7a was obtained via carbocation F by catalysis of nitric acid generated from H₂O and NO₂ in the reaction media.

Chart 3. Plausible Mechanism

Chart 4. Effect of BHT for Nitrolactonization

The nitrolactonization of carboxylic acids mediated by Fe(NO₃)₃·9H₂O was developed. Mechanistic studies disclosed that the reaction proceeded via a radical intermediate derived from addition of NO₂, which was generated by pyrolysis of Fe(NO₃)₃·9H₂O, at the olefin moiety. These results demonstrate the utility of Fe(NO₃)₃·9H₂O as a source of nitrogen dioxide and could lead to the development of new reactions mediated by Fe(NO₃)₃·9H₂O.

Experimental

General

¹H-NMR were measured in CDCl₃ or dimethyl sulfoxide (DMSO)-d₆ solution and referenced from tetramethylsilane (TMS) (0.00 ppm) using JEOL JNM ECA-600 (600 MHz) or JEOL JNM ECA-400 (400 MHz) spectrophotometer, unless otherwise noted. ¹³C-NMR were measured in CDCl₃ solution and referenced to CDCl₃ (77.0 ppm), DMSO-d₆ ((CD₃)₃SO) (39.5 ppm) or CD₃OD (49.0 ppm) using JEOL JNM ECA-600 (150 MHz) or JEOL JNM ECX-400 (100 MHz) spectrophotometer, unless otherwise noted. Chemical shifts are reported in ppm. When peak multiplicities are reported, the following abbreviations are used: s, singlet; d, doublet; t, triplet, q, quartet; m, multiplet; br, broadened. IR spectra were recorded on Horiba IR-710 spectrometer. Mass spectra were obtained on JEOL JMS-T100TD. Flash column chromatography was performed on Silica Gel (SiliaFlash^® F60). TLC was performed on precoated plates (0.25 mm, silica gel Merck Kieselgel 60F₂₄₅), and compounds were visualized with UV light and p-anisaldehyde stain or phosphomolybdic acid stain. Melting points were measured with Yanaco MICRO MELTING POINTAPPARATUS. 1,2-Dichlorobenzene was purchased from TOKYO CHMICAL INDUSTRY CO., LTD. (Japan) and used without any purifications. Fe(NO₃)₃·9H₂O was purchased from FUJIFILM Wako Pure Chemical Corporation (Japan) and used without any purifications.

Compounds 3a,b⁴⁶⁾3c,⁴⁷⁾3d,⁴⁸⁾ and, 8a–d⁴⁹⁾ were prepared according to the literatures and identified with ¹H-NMR by comparison with the reported ones.

General Procedure 1: Optimization of Reaction Conditions (Table 1)

A mixture of 3a (47.0 mg, 0.27 mmol) and metal nitrate in 1,2-dichlorobenzene (2.7 mL) was stirred at 130 °C. After being stirred for the indicated time in Table 1, the reaction was quenched by addition of sat. aq. NaHCO₃ and the resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 8/2 to 7/3) to give 5a, 6a, and 7a, respectively.

Entry 1

According to the general procedure 1, the reaction was performed with Fe(NO₃)₃·9H₂O (54.0 mg, 0.13 mmol) for 4 h to give 5a (28.6 mg, 48%), 6a (1.7 mg, 3%), and 7a (3.5 mg, 7%), respectively.

Entry 2

According to the general procedure 1, the reaction was performed with Cu(NO₃)₂·3H₂O (48.3 mg, 0.2 mmol) for 5 h to give 5a (21.0 mg, 36%), 6a (6.4 mg, 12%), and 7a (1.7 mg, 4%), respectively.

Entry 3

According to the general procedure 1, the reaction was performed with Zn(NO₃)₂·6H₂O (59.5 mg, 0.2 mmol) for 3 h to give 5a (4.6 mg, 8%), 6a (3.9 mg, 8%), and 7a (14.2 mg, 30%), respectively.

Entry 4

According to the general procedure 1, the reaction was performed with AgNO₃ (68.0 mg, 0.4 mmol) for 3 h to give 5a (1.6 mg, 3%), 6a (1.9 mg, 4%), and recovered 3a (1.2 mg, 3%), respectively.

Entry 5

According to the general procedure 1, the reaction was performed with Fe(NO₃)₃·9H₂O (36.7 mg, 0.09 mmol) for 4 h to give 5a (4.3 mg, 7%), 6a (2.1 mg, 4%), and 7a (2.3 mg, 5%), respectively.

Entry 6

According to the general procedure 1, the reaction was performed with Fe(NO₃)₃·9H₂O (72.0 mg, 0.18 mmol) for 4.5 h to give 5a (14.4 mg, 24%), 6a (1.5 mg, 3%), and 7a (23.2 mg, 49%), respectively.

Entry 7

A mixture of 3a (44.0 mg, 0.25 mmol) and Fe(NO₃)₃·9H₂O (50.5 mg, 0.13 mmol) in 1,2-dichlorobenzene (2.5 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 1.5 h at same temperature, the mixture was cooled to r.t. and quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 9/1 to 3/2) to give 5a (31.8 mg, 58%), 6a (2.6 mg, 5%), and 7a (5.6 mg, 13%), respectively.

Entry 8

A mixture of 3a (44.0 mg, 0.25 mmol), Fe(NO₃)₃·9H₂O (50.5 mg, 0.13 mmol), and KHCO₃ (7.5 mg, 0.075 mmol) in 1,2-dichlorobenzene (2.5 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 2.5 h at same temperature, the mixture was cooled to r.t. and quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 9/1 to 3/2) to give 5a (29.6 mg, 54%), 6a (4.8 mg, a small amount of 4-phenyl-4-oxobutanoic acid was contaminated, approx. 10%), and 7a (3.2 mg, 7%), respectively.

5-Nitromethyl-5-phenyloxolan-2-one (5a)

White solid; mp: 95.0–95.5 °C; IR (CHCl₃) cm⁻¹: 1790, 1560; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.47–7.38 (5H, m), 4.81 (1H, d, J = 12.6 Hz), 4.75 (1H, d, J = 12.6 Hz), 3.00–2.91 (1H, m), 2.75–2.66 (2H, m), 2.58–2.49 (1H, m); ¹³C-NMR (CDCl₃, 150 MHz) δ: 174.7, 138.7, 129.1, 124.6, 84.6, 81.9, 31.8, 27.8; ¹³C-NMR (CD₃OD, 150 MHz) δ: 177.5, 141.0, 129.9, 129.7, 125.9, 86.6, 82.9, 33.6, 28.5; high resolution (HR)MS (DART) m/z Calcd for C₁₁H₁₂NO₄ [(M + H)⁺]: 222.07663. Found 222.07629.

5-Hydroxymethyl-5-phenyloxolan-2-one (6a)⁵⁰⁾

White solid; mp: 108.5–109.5 °C; IR (CHCl₃) cm⁻¹: 3953, 1716, 1686; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.40–7.34 (5H, m), 3.88 (1H, dd, J = 5.2, 12.4 Hz), 3.73 (1H, dd, J = 8.4, 12.4 Hz), 2.84–2.70 (2H, m), 2.57–2.49 (1H, m), 2.43–2.39 (1H, m), 1.91 (1H, dd, J = 5.2, 8.4 Hz); MS (DART) m/z: 193 [(M + H)⁺]. The spectral data were identified with the reported ones.

5-Methyl-5-phenyloxolan-3-one (7a)⁵¹⁾

Yellow oil; IR (CHCl₃) cm⁻¹: 1764, 1683; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.38–7.29 (5H, m), 2.64–2.41 (4H, m), 1.73 (3H, s); MS (DART) m/z: 177 [(M + H)⁺]. The spectral data were identified with the reported ones.

Nitrolactonization of 3b

A mixture of 3b (51.6 mg, 0.25 mmol) and Fe(NO₃)₃·9H₂O (50.5 mg, 0.13 mmol) in 1,2-dichlorobenzene (2.5 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 3 h at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 8/1 to 6/4) to give 5b (7.8 mg, 12%) and 7b (35.7 mg, 69%), respectively.

5-(4′-Methoxyphenyl)-5-nitromethyloxolan-2-one (5b)

Pale yellow solid; mp: 130.0–131.0 °C; IR (CHCl₃) cm⁻¹: 1790, 1558; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.33 (2H, d, J = 9.0 Hz), 6.94 (2H, d, J = 9.0 Hz), 4.78 (1H, d, J = 12.4 Hz), 4.71 (1H, d, J = 12.4 Hz), 3.83 (3H, s), 2.92–2.87 (1H, m), 2.73–2.64 (2H, m), 2.58–2.51 (1H, m); HRMS (DART) m/z Calcd for C₁₂H₁₇N₂O₅ [(M + NH₄)⁺]: 269.11375. Found 269.11193.

5-(4′-Methoxyphenyl)-5-methyloxolan-2-one (7b)⁵²⁾

Pale yellow oil; IR (CHCl₃) cm⁻¹: 1770, 1513, 1249; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.30 (2H, d, J = 8.8 Hz), 6.90 (2H, d, J = 8.8 Hz), 3.81 (3H, s), 2.63–2.37 (4H, m), 1.70 (3H, s). The spectral data were identified with the reported ones.

Nitrolactonization of 3c

A mixture of 3c (52.0 mg, 0.24 mmol) and Fe(NO₃)₃·9H₂O (48.5 mg, 0.12 mmol) in 1,2-dichlorobenzene (2.4 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 2 h at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 5/1 to 6/4) to give 5-(4′-nitrophenyl)-5-nitromethyloxolan-2-one (5c) (10.1 mg, 16%) as pale yellow needles; mp: 141.0–142.0 °C (recrystallized from AcOEt/hexane); IR (KBr) cm⁻¹: 1795, 1731, 1606, 1556, 1378; ¹H-NMR (DMSO-d₆, 600 MHz) δ: 8.29 (2H, d, J = 9.0 Hz), 7.75 (2H, d, J = 9.0 Hz), 5.52 (1H, d, J = 14.4 Hz), 5.39 (1H, d, J = 14.4 Hz), 2.80 (1H, ddd, J = 6.6, 9.6, 17.4 Hz), 2.71 (1H, ddd, J = 6.6, 9.6, 13.8 Hz), 2.55 (1H, ddd, J = 6.0, 10.2, 17.4 Hz), 2.39–2.35 (1H, m); ¹³C-NMR (DMSO-d₆, 150 MHz) δ: 175.3, 147.6, 147.3, 126.3, 123.7, 84.3, 81.4, 32.9, 27.2; HRMS (DART) m/z Calcd for C₁₁H₁₁N₂O₆ [(M + H)⁺]: 267.06171. Found 267.06153.

Nitrolactonization of 3d

A mixture of 3d (41.5 mg, 0.21 mmol) and Fe(NO₃)₃·9H₂O (41.6 mg, 0.11 mmol) in 1,2-dichlorobenzene (2.1 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 4 h at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 6/4 to 1/1) to give 5-(4′-cyanophenyl)-5-nitromethyloxolan-2-one (5d) (13.3 mg, 26%) as pale yellow solid; mp: 174.5–175.0 °C; IR (neat) cm⁻¹: 2231, 1788, 1631, 1612, 1556; ¹H-NMR (methanol-d₄, 400 MHz) δ: 7.81 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 5.20 (1H, d, J = 13.6 Hz), 5.14 (1H, d, J = 13.6 Hz), 2.88–2.70 (2H, m), 2.61–2.51 (2H, m); ¹³C-NMR (DMSO-d₆, 150 MHz) δ: 175.4, 145.6, 132.6, 125.8, 118.4, 111.1, 84.3, 81.3, 32.8, 27.1; HRMS (DART) m/z Calcd for C₁₂H₁₄N₃O₄ [(M + NH₄)⁺]: 264.09843. Found 264.09788.

Nitrolactonization of 8a

A mixture of 8a (56.0 mg, 0.25 mmol) and Fe(NO₃)₃·9H₂O (50.5 mg, 0.13 mmol) in 1,2-dichlorobenzene (2.5 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 22 h at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 9/1 to 3/1) to give 3-(nitromethyl)-3-phenylisobenzofuran-1(3H)-one (9a)⁴⁴⁾ (62.8 mg, 93%) as a white solid; mp: 128.5–130.0 °C; IR (CHCl₃) cm⁻¹: 1782, 1562; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.96–7.40 (9H, m), 5.26 (1H, d, J = 12.8 Hz), 5.17 (1H, d, J = 12.8 Hz); ¹³C-NMR (CDCl₃, 150 MHz) δ: 168.1, 147.5, 136.0, 134.7, 130.5, 129.6, 129.3, 126.5, 125.7, 125.1, 122.9, 85.5, 80.2; HRMS (DART) m/z Calcd for C₁₅H₁₂NO₄ [(M + H)⁺]: 270.07663. Found 270.07407.

Nitrolactonization of 8b

A mixture of 8b (35.6 mg, 0.14 mmol) and Fe(NO₃)₃·9H₂O (28.3 mg, 0.07 mmol) in 1,2-dichlorobenzene (1.4 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 30 min at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 9/1 to 7/3) to give 3-nitromethyl-3-(4′-methoxypheyl)isobenzofuran-1(3H)-one (9b) (26.9 mg, 65%) and 3-methyl-3-(4′-methoxyphenyl)isobenzofuran-1(3H)-one (10b) (10.5 mg, 30%), respectively.

3-Nitromethyl-3-(4′-methoxyphenyl)isobenzofuran-1(3H)-one (9b)

White solid; mp: 49.0–50.0 °C; IR (CHCl₃) cm⁻¹: 1780, 1560; ¹H-NMR (CDCl₃, 400 MH) δ: 7.96–7.60 (4H, m), 7.45 (2H, d, J = 9.2 Hz), 6.92 (2H, d, J = 9.2 Hz), 5.23 (1H, d, J = 13.0 Hz), 5.14 (1H, d, J = 13.0 Hz), 3.80 (3H, s); ¹³C-NMR (CDCl₃, 150 MHz) δ: 168.2, 160.3, 147.6, 134.6, 130.9, 127.7, 126.7, 126.3, 125.7, 123.0, 114.5, 85.5, 80.2, 55.3; HRMS (DART) m/z Calcd for C₁₆H₁₄NO₅ [(M + H)⁺]: 300.08720. Found 300.08665.

3-Methyl-3-(4′-methoxyphenyl)isobenzofuran-1(3H)-one (10b)⁴⁹⁾

Pale yellow oil; IR (CHCl₃) cm⁻¹: 1759, 1514, 1255; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.91 (1H, d, J = 8.0 Hz), 7.66 (1H, t, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.42 (1H, d, J = 8.0 Hz), 7.33 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 3.79 (3H, s), 2.03 (3H, s); ¹³C-NMR (CDCl₃, 150 MHz) δ: 170.0, 159.5, 154.4, 134.2, 132.5, 129.0, 126.6, 125.8, 125.2, 122.0, 113.9, 87.6, 55.3, 27.1; HRMS (DART) m/z Calcd for C₁₆H₁₅O₃ [(M + H)⁺]: 255.10212. Found 255.10299. The spectral data were identified with the reported ones.

Nitrolactonization of 8c

A mixture of 8c (59.6 mg, 0.25 mmol) and Fe(NO₃)₃·9H₂O (50.5 mg, 0.13 mmol) in 1,2-dichlorobenzene (2.5 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 30 min at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The mixture was filtered through a pad of Celite and the filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was purified through silica gel column chromatography (hexane/AcOEt = 9/1 to 7/3) to give 3-nitromethyl-3-(p-tolyl)isobenzofuran-1(3H)-one (9c) (63.0 mg, 89%) and 3-methyl-3-(p-tolyl)isobenzofuran-1(3H)-one (10c) (7.0 mg, 11%), respectively.

3-Nitromethyl-3-(p-tolyl)isobenzofuran-1(3H)-one (9c)

White solid; mp: 99.0–100.5 °C; IR (CHCl₃) cm⁻¹: 1780, 1560; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.94 (1H, d, J = 7.6 Hz), 7.78–7.74 (1H, m), 7.72 (1H, d, J = 7.6 Hz), 7.63–7.59 (1H, m), 7.43 (2H, d, J = 8.2 Hz), 7.23 (2H, d, J = 8.2 Hz), 5.24 (1H, d, J = 13.0 Hz), 5.16 (1H, d, J = 13.0 Hz), 2.35 (3H, s); ¹³C-NMR (CDCl₃, 150 MHz) δ: 168.2, 147.7, 139.6, 134.6, 133.0, 130.3, 129.9, 126.3, 125.6, 124.9, 122.9, 85.5, 80.1, 21.0; HRMS (DART) m/z Calcd for C₁₆H₁₄NO₄ [(M + H)⁺]: 284.09228. Found 284.09152.

3-Methyl-3-(p-tolyl)isobenzofuran-1(3H)-one (10c)

Pale yellow oil; IR (CHCl₃) cm⁻¹: 1759, 1514; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.90 (1H, d, J = 7.6 Hz), 7.67–7.63 (1H, m), 7.53–7.49 (1H, m), 7.44 (1H, d, J = 7.6 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.16 (2H, d, J = 7.8 Hz), 2.33 (3H, s), 2.03 (3H, s); ¹³C-NMR (CDCl₃, 150 MHz) δ: 170.0, 154.4, 138.2, 137.7, 134.2, 129.3, 129.0, 125.8, 125.08, 125.06, 122.0, 87.6, 27.2, 21.0; HRMS (DART) m/z Calcd for C₁₆H₁₅O₂ [(M + H)⁺]: 239.10720. Found 239.10637.

Nitrolactonization of 8d

A mixture of 8d (33.2 mg, 0.11 mmol) and Fe(NO₃)₃·9H₂O (22.1 mg, 0.06 mmol) in 1,2-dichlorobenzene (1.1 mL) was lowered into pre-heated oil bath (130 °C). After being stirred for 30 min at same temperature, the mixture was cooled into r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite and the filtrate was extracted with CH₂Cl₂. The extracts were washed with brine, and dried over Na₂SO₄, filtered, and concentrated. The residual oil was purified through silica gel column chromatography (hexane/AcOEt = 9/1 to 7/3) to give 3-(4′-bromophenyl)-3-nitromethylisobenzofuran-1(3H)-one (9d) as white solid; mp: 104.0–104.5 °C; IR (CHCl₃) cm⁻¹: 1784, 1558; ¹H-NMR (CDCl₃, 400 MHz) δ: 7.96 (1H, d, J = 7.6 Hz), 7.80–7.76 (1H, m), 7.70 (1H, d, J = 7.6 Hz), 7.66–7.62 (1H, m), 7.57 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz), 5.22 (1H, d, J = 13.2 Hz), 5.12 (1H, d, J = 13.2 Hz); ¹³C-NMR (CDCl₃, 150 MHz) δ: 167.8, 147.1, 135.1, 134.9, 132.5, 130.7, 126.8, 126.7, 125.5, 124.0, 122.7, 84.9, 80.0; HRMS (DART) m/z Calcd for C₁₅H₁₄BrN₂O₄ [(M + NH₄)⁺]: 365.01369. Found 365.01524.

Experiment for Chart 4

Di-tert-butylhydroxytoluene (BHT) (132.2 mg, 0.6 mmol) was added to a mixture of 8a (44.9 mg, 0.2 mmol) and Fe(NO₃)₃·9H₂O (40.4 mg, 0.1 mmol) in 1,2-dichlorobenzene (2.0 mL). The mixture was lowered into pre-heated oil bath (130 °C). After being stirred for 19 h at same temperature, the mixture was cooled to r.t. and the reaction was quenched by addition of sat. aq. NaHCO₃. The resulting mixture was filtered through a pad of Celite. The filtrate was acidified the 4N HCl and extracted with CH₂Cl₂. The extracts were washed with water, brine, and dried over Na₂SO₄, filtered, and concentrated. The residue was chromatographed on silica gel (hexane/AcOEt = 9/1 to 8/2) to give a mixture of 9a (12%) and 8a (16%), respectively. The yields of 9a and 8a were determined by qNMR using 1,4-dinitrobenzene as an internal standard.

Acknowledgments

This research was supported by JSPS KAKENHI Grant Number JP17K08208.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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