2-(2,5-Dimethoxyphenoxy)isoindoline-1,3-dione

Abstract

In this work, the direct C-H functionalization reaction of 1,4-dimethoxybenzene with N-hydroxyphthalimide has been disclosed. A previously unknown product of the C-O coupling of 1,4-dimethoxybenzene and N-hydroxyphthalimide was obtained. The reaction proceeded under mild conditions, in which a commercially available manganese-based oxidizing agent was used for generation of a phthalimide-N-oxyl radical. The obtained compound is a promising valuable precursor of O-aryl hydroxylamine.

1. Introduction

The development of new approaches regarding the construction of C-C and C-heteroatom bonds is an urgent task in modern organic chemistry. One of the most versatile and efficient ways to create a new bond is cross-dehydrogenative coupling [1,2]. In contrast to other types of coupling reactions, this method does not require prefuctionalization of the starting compounds. This feature allows one to perform such processes with high atomic efficiency. A particularly noticeable and actively developing trend in organic chemistry is the functionalization of C(sp²)-H bonds in (hetero)arenes [3,4].

The use of N-hydroxy compounds as the O-component for cross-dehydrogenative C-O coupling has proven to be the most efficient and universal way to obtain hydroxylamine derivatives, [5] which are valuable building blocks in modern organic and medical chemistry [6,7]. N-hydroxyphthalimide (NHPI) is currently one of the most popular N-hydroxy compounds used in various oxidative processes [8,9]. The ability of the phthalimide-N-oxyl (PINO) radical, which is generated from NHPI, to act as a mediator of hydrogen atom abstraction is well known, [10] but the preparative chemistry of this radical remains less studied. A number of processes are known in which the resulting PINO radical enters into reactions of C-H functionalization [11,12] or selective difunctionalization of multiple bonds [13,14,15,16]. However, direct C-H functionalization of aromatic systems with NHPI remains poorly studied and is represented by a single work [17]. Recently, we discovered a process in which the PINO radical formed from NHPI selectively reacts with electron-rich arenes to form a C-O coupling product.

2. Results and Discussion

1,4-Dimethoxybenzene 1 was tested in an oxyamination reaction with NHPI 2 (Scheme 1). We began our investigation with oxidative coupling under the action of Mn(OAc)₃, a trustworthy oxidant for NHPI, [18,19] in MeCN (

Table 1. Optimization of the reaction conditions.

Entry	Oxidant (mol per mol of 2)	Solvent	Yield 3, % a
1	Mn(OAc)3·2H2O (2.0)	MeCN	n.d.
2	Mn(OAc)3·2H2O (2.0)	AcOH	n.d.
3	Mn(OAc)3·2H2O (2.0)	MeOH	n.d.
4	Mn(OAc)3·2H2O (2.0)	TFE	14
5	Mn(OAc)3·2H2O (2.0)	HFIP	74 (71)
6	Mn(acac)3 (2.0)	HFIP	65
7	(NH4)2Ce(NO3)6 (2.0)	HFIP	n.d.
8	PhI(OAc)2 (1.0)	HFIP	54
9 b	Mn(OAc)3·2H2O (2.0)	HFIP	n.d.

^a NMR yields; isolated yield in parentheses. ^b TEMPO (2 mol per mol of 1) was added.

, Entry 1), and we observed no formation of product 3. The reaction did not proceed in other polar protic solvents—AcOH and MeOH (Table 1, Entries 2 and 3, respectively). Finally, we decided to use fluorinated alcohol as the solvent (trifluoroethanol (TFE), Table 1, Entry 4), and we were able to obtain 3 in a low yield of 14%. Then, we tested other fluorinated alcohols and changed the solvent to hexafluoroisopropanol (HFIP) (Table 1, Entry 5), which raised the yield of 3 to 74% determined by NMR. After solvent optimization, a number of oxidants usually used for the oxidation of NHPI 2 [20,21] were tested (Table 1, Entries 6–8). Cerium(IV) ammonium nitrate was not efficient in this process (Table 1, Entry 7). Mn(acac)₃ and PhI(OAc)₂ promoted this transformation, but yields of 3 were lower than in the case of Mn(OAc)₃ (Table 1, Entries 6 and 8 vs. Entry 5). In the presence of TEMPO (Table 1, entry 9), no formation of product 3 was observed, which indicates the radical nature of the process.

Finally, we performed oxyamination of 1,4-dimetoxybenzene 1 with N-hydroxyphthalimide 2 in HFIP with Mn(OAc)₃ as the oxidant. 2-(2,5-Dimethoxyphenoxy)isoindoline-1,3-dione 3 was obtained with a yield of 71% after column chromatography. The structure of compound 3 was characterized by ¹H and ¹³C NMR spectroscopy, high-resolution mass spectrometry, FT-IR spectroscopy (Figures S1-S4, Supplementary Materials), and elemental analysis.

3. Materials and Methods

3.1. General

All commercially available reagents and solvents were used without further purification. ¹H and ¹³C NMR spectra were taken with a Bruker AM-300 machine (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300 and 75 MHz) in CDCl₃. using the residual solvent peak as a reference. J values are given in Hz. The high-resolution mass spectrum was measured on a Bruker microTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray ionization (ESI). FT-IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer. The TLC analysis was carried out on silica gel chromatography plates Macherey-Nagel Alugram UV254; sorbent: Silica 60, specific surface (BET)~500 m²/g, mean pore size 60 Å, specific pore volume 0.75 mL/g, particle size 5–17 µm; binder: highly polymeric product, which is stable in almost all organic solvents and is resistant toward aggressive visualization reagents. The melting points were determined on a Kofler hot-stage apparatus. Chromatography of the final product was performed on silica gel (0.060–0.200 mm, 60 Å, CAS 7631-86-9).

3.2. 2-(2,5-Dimethoxyphenoxy)isoindoline-1,3-dione (3)

Mn(OAc)₃·2H₂O (536 mg, 2.0 mmol) was added in small portions to a solution of 1,4-dimethoxybenzene (1) (69 mg, 0.5 mmol) and N-hydroxyphthalimide (2) (163 mg, 1.0 mmol) in HFIP (5 mL). The mixture was stirred at 20–25 °C for 1 h and diluted with EtOAc (20 mL). Resulting precipitate was filtered through celite plug, and filtrate was washed with water (20 mL); then, water phase was extracted with EtOAc (2 × 25 mL). Combined organic phases were dried over anhydrous Na₂SO₄ and rotary evaporated. The crude product was purified by column chromatography (EtOAc/hexane, 1:1, v/v) to afford 107 mg (71%) of target compound 3 as a yellow solid, R_f 0.43 (EtOAc/hexane, 1:1, v/v). Recrystallization from hexane/chloroform (1:1, v/v) mixture gave yellow needles. m.p. = 107–109 °C (hexane/chloroform 1:1 v/v). ¹H NMR (ppm): δ 7.85–7.69 (m, 4H), 6.59 (d, J = 10.1, 1H), 6.24 (dd, J = 10.1, 2.4, 1H), 5.61 (d, J = 2.4, 1H), 3.81 (s, 3H), 3.45 (s, 3H). ¹³C NMR (ppm): δ 190.6, 168.8, 167.3, 136.0, 134.4, 132.0, 125.7, 123.5, 99.6, 82.8, 55.9, 53.0. IR spectrum, ν, cm⁻¹: 1776, 1726, 1666, 1584, 1466, 1406, 1370, 1319, 1251, 1207, 1107, 868, 818, 715. HRMS (ESI-TOF), m/z: calcd for C₁₆H₁₃NO₅ [M+K]⁺, 338.0425, found, 338.0428. Anal. Calcd for C₁₆H₁₃NO₅: C, 64.21; H, 4.38; N, 4.68. Found: C, 64.05; H, 4.34; N, 4.57.

4. Conclusions

A novel 2-(2,5-dimethoxyphenoxy)isoindoline-1,3-dione (3) was produced with 71% yield in the reaction between 1,4-dimethoxybenzene and N-hydroxyphthalimide under the action of manganese triacetate as the oxidant. The structure of the compound was confirmed by NMR spectroscopy, mass spectrometry, elemental analysis, and IR analysis.