Direct metal-free synthesis of diarylamines from 2-nitropropane via the twofold C–H functionalization of arenes

Abstract

Synthesis of symmetric diarylamines via a twofold intermolecular electrophilic C–H functionalization of electron-rich arenes by umpolung-activated nitroalkane in polyphosphoric acid is demonstrated.

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Introduction

Diarylamines have been the spotlight of many recent SAR studies as versatile pharmacophores and as convenient, easily tunable platforms for the development of new drug candidates.¹ Nearly all currently used approaches to diarylamines employ anilines as starting materials (Scheme 1). By far the most powerful and abundantly used methodology is the transition metal-catalyzed C–N cross-coupling reaction between aniline derivatives and aryl halides developed by Buchwald and Hartwig (Scheme 1, path A).² The reaction of anilines³ or aniline surrogates, such as nitrosoarenes,⁴ nitroarenes,⁵ or arylazides,⁶ with stoichiometric arylmetal species have also been demonstrated (path B). A single example of catalytic arylation of anilines with arenes, involving activation of one aromatic C–H bond has recently been reported by Chang (path C).⁷ At the same time, synthesis of diarylamines with one-pot installation of both C–N bonds via functionalization of two C–H bonds are extremely rare and are limited to nucleophilic amination of electron-poor arenes⁸ and oxidative radical C–H aromatic amination.⁹ Herein we wish to report a direct metal-free, synthesis of symmetric diarylamines 2 from 2-nitropropane and electron-rich arenes 1 proceeding via successive electrophilic activation of two aromatic C–H bonds (Scheme 1).

Scheme 1

Results and discussion

We have been employing polyphosphoric acid (PPA) activated nitroalkenes and nitroalkanes in C–H functionalization reactions for synthesis of medicinally relevant heterocyclic compounds.¹⁰ All of these transformations take advantage of a stable Lewis acid–Lewis base complex produced between the nitro group and PPA that allows for accumulation of the strongly electrophilic aci-species 5 in the reaction medium. It was originally used in the Nef reaction,¹¹ where strongly acidic aqueous conditions resulted in rapid hydrolysis of 5 producing an aldehyde (Scheme 2, route a). In moisture-free and mildly acidic PPA, nucleophilic additions involving other species can be realized, as we have demonstrated in several C–C and C–N bond forming transformations. Thus, the reaction of anilines (N-nucleophiles) with 5 allowed for efficient preparation of imidamides 6 and their subsequent cyclization into benzimidazoles 7 or benzoxazoles 8 (route b).¹² The nucleophilic attack by electron-rich arenes on 5 derived from primary nitroalkanes affords phosphorylated N-hydroxyhydroxylamine species 9, possessing a hydrogen atom at α-position, which undergoes facile elimination of H₃PO₄ to furnish phosphorylated oxime 10. The reactivity of the latter is strongly dependent on the nature of substituent R¹. Thus, aldoximes (R¹ = H) undergo elimination of the second molecule of H₃PO₄ to afford nitriles, which upon acid-mediated hydrolysis provide primary amines 11 or parent carboxylic acids (Scheme 2, route c).¹³ Ketoximes 10 (R¹ = Alk) on the other hand underwent Beckman rearrangement with migration of the aryl group providing the corresponding anilides 12 (Scheme 2, route d).¹⁴

Scheme 2

We rationalized that alternative reaction pathways involving C–N migrations can be opened by blocking the possibilities for elimination of H₃PO₄. To this end, we tested a reaction of anisole (1a) with 2-nitropropane that was expected to produce aci-species 13 (Scheme 4) possessing no alpha-hydrogens. Heating the mixture at 100 °C in 86% PPA for 5 h resulted in the formation of bis(4-methoxyphenyl)amine (2a) along with small amounts of p-methoxyaniline (3a) (Table 1). Remarkably, the nitroalkane in this case served both as an internal oxidant for the electrophilic para-selective two-fold C–H functionalization of the arene and as a donor of nitrogen atom for the amine moiety. Optimization of the reaction conditions showed that formation of side product 3a could be substantially suppressed by lowering the temperature to 90 °C. Decreasing the concentration of PPA by using a mixture of diphosphoric acid (H₄P₂O₇) and ortho-phosphoric acid (commercial 85% H₃PO₄), corresponding to 75% of P₂O₅ content, allowed for significant improvement of the yield (Table 1, entry 6). Furthermore, it was found that efficient extraction of less basic 2a can be achieved at lower pH, with more basic aniline 3a remaining in the aqueous solution, which can subsequently be recovered upon neutralization of the aqueous phase with ammonia.

Table 1 Optimization of the PPA-mediated amination of arenes with 2-nitropropane

	Content of P2O5 in PPA, %	Me2CHNO2 : 1a ratio^a	2a yield^a, %	3a yield^a, %
a Determined by ^1H NMR of crude reaction mixtures.b A total of 5 equiv. of 2-nitropropane was used in three portions added every two hours.c Additional 0.5 equiv. of 2-nitropropane was added 4 h after the reaction has started.
1	86	0.5	12	8
2	86	1	18	11
3	86	3 × 1.67^b	33	24
4	80	3 × 1.67^b	64	18
5	78	1 + 0.5^c	74	8
6	75	1 + 0.5^c	77	7

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Using this protocol, the analytically pure diarylamine 2a was isolated in good yield without chromatographic purification (Fig. 1). Structure of 2a was unambiguously confirmed by X-ray crystallography (CCDC 1417939†) (Fig. 2).

Fig. 1 Diarylamines obtained in PPA-mediated amination of arenes with 2-nitropropane. Isolated yields are shown.

Fig. 2 ORTEP drawing of bis(4-methoxyphenyl)amine (2a) (CCDC 1417939†) showing 50% probability amplitude displacement ellipsoids.

With optimized conditions in hand, we probed the reactivity of other electron-rich aromatic substrates. 1,2-Dimethoxybenzene (1c) provided somewhat better yield as compared to 1,4-(1d) and 1,3-isomers (1b), presumably due to increased steric demands in the latter (Fig. 1). Under similar conditions benzo-1,4-dioxane (1e) afforded diarylamine 2e in good yield. Resorcinol and hydroquinone derivatives (1b, d) possessing large substituent next to their reactive sites provided less sound results. The same trend was observed in the reactions of alkylated anisoles (1f–h): the highest yield in this series was obtained for the least hindered product 2h (Fig. 1). Expectedly, less electron-rich substrates gave no reaction or poor conversion. Thus, reactions of benzene (at 80 °C) and toluene did not take place, while o-xylene (1i) afforded the corresponding product 2i in marginal yield. These results confirm that strongly electron-donating substituents are crucial for the successful amination. p-Cumenol (1j) was tested to evaluate reaction compatibility with a non-protected phenol function. Although two-fold ortho-amination of 1j proceeded readily, isolation of product 2j was complicated by its rapid aerobic oxidation under the reaction conditions.

We also envisioned this method as a potentially useful tool for linking together advanced aromatic synthons or two large aromatic units, such as benzo-crown ethers. Compounds possessing two benzo-crown ethers connected by a short tether have found application as ion-selective sensors¹⁵ or ion-guided self-assembling building blocks;¹⁶ however, their synthesis is typically lengthy and challenging. We therefore tested our method for a short-cut assembly of nitrogen-linked bis-crown ethers using commercially available benzo-crowns. To this end, we treated 15-crown-5 1k with 2-nitropropane in 75% PPA under our typical reaction conditions, which resulted in desired diarylamine 2k obtained as a minor product in a mixture with the corresponding aniline 3k (Scheme 3). Despite poor chemoselectivity and low preparative yield, the demonstrated single step reaction is still the most efficient of the known approaches to binuclear crown ethers.

Scheme 3 Synthesis of bis(benzo-15-crown-5)amine: isolated yields are provided, NMR yields are shown in parentheses.

Schemes 4 and 5 summarize our current mechanistic hypothesis for the discovered transformation. Initially, treatment of 2-nitropropane with PPA provides a stabilized aci-species 13 (Scheme 4). Subsequent nucleophilic attack of 13 by electron-rich arene 1 (first C–H functionalization) would lead to the formation of diphosphorylated form of N-hydroxyhydroxylamine 14, which possesses a quaternary α-carbon, and therefore cannot undergo elimination of H₃PO₄ to form the C=N bond of oxime as described in Scheme 2. Instead, the partially hydrolyzed form 15 undergoes elimination of H₃PO₄ to furnish nitroso-alkane 16.

Scheme 4

Scheme 5

Formation of an intermediate possessing a nitroso function is also supported by observation of a deep spruce-green coloration of the mixture at the initial stages of the reaction. The second C–H functionalization represents a direct acid-mediated aminoxylation of arene 1 to give hydroxylamine 17. This step can also be viewed as an aza-analog of Friedel–Crafts acylation of arenes with a carbonyl compound. Although intermolecular metal-free electrophilic reactions of this type are unknown, a related intramolecular¹⁷ process as well as the Rh-catalyzed equivalent¹⁸ have been reported. Next, acid-assisted loss of water to give nitrenium ion 19 followed by 1,2-aryl shift, affords hemi-aminal 20, that could be detected by HRMS analysis of the crude reaction mixtures. This step can also be viewed as aza-analog of Wagner–Meerwein rearrangement.

A closely related rearrangement of N-chloride derivatives involving a 1,2-alkyl shift was previously reported in literature.¹⁹ In the final step hemi-aminal 20 undergoes acid-mediated cleavage with extrusion of acetone to form diarylamine 2. Formation of acetone by-product was confirmed by GC-analysis of vapor phase over the mixture during the post-reaction work-up.

Formation of the aniline side product could be rationalized as follows. Instead of undergoing the aminoxylation step (16 → 17, Scheme 4), 2-aryl-2-nitrosopropane 16 can experience a 1,2-aryl shift, followed by rapid proton transfer, to afford tautomeric N-vinylhydroxylamine 22, which in concentrated PPA exists in a form of phosphate 23 (Scheme 5). This step is in agreement with the known rearrangement of tertiary nitrosocompounds into vinylhydroxylamines proceeding via a 1,2-alkyl shift.²⁰ Intermediate 23 once formed undergoes a [3,3]-sigmatropic phosphate migration to produce imine 24. Aqueous work up at the end converts imine 24 into aniline 3 and hydroxyacetone 25, which rapidly polymerizes under the reaction conditions (Scheme 5). The six-electron pericyclic rearrangement 23 → 24 represents an auto-redox reaction, that provides the requisite reduction of hydroxylamine with simultaneous oxidation of the adjacent methylene into a hydroxymethyl group (Scheme 5). The presence of phosphorylated species 23 is also supported by the fact that formation of side product 3 proceeds easier in PPA with higher P₂O₅ content and is suppressed in more diluted medium.

Conclusions

By shutting down alternate reaction pathways through rational substrate design, we have discovered a novel cascade transformation that provides convenient access to symmetrical diarylamines possessing electron-rich substituents from easily available precursors. The reaction commences with the PPA-induced umpolung of nitroalkanes and electrophilic C–H functionalization of the first arene molecule. The subsequent steps involve formation of a nitroso intermediate and a direct acid-mediated aminoxylation of the second molecule of arene to provide hydroxylamine, which further undergoes 1,2-aryl shift affording diarylamines.

Experimental part

¹H and ¹³C NMR spectra were recorded on a Bruker Avance-III spectrometer (400 or 100 MHz, respectively) equipped with BBO probe in CDCl₃ or DMSO-d₆, using TMS as internal standard. High-resolution mass spectra were registered with a Bruker Maxis spectrometer (electrospray ionization, in MeCN solution, using HCO₂Na–HCO₂H for calibration). All reactions were performed in oven-dried 5 mL Erlenmeyer flasks open to the atmosphere, employing overhead stirring. Reaction progress and purity of isolated compounds were controlled by TLC eluting with EtOAc. All reagents and solvents were purchased from commercial vendors and used as received.

Bis(4-methoxyphenyl)amine (2a)²¹ (typical procedure)

5 mL Erlenmeyer flask was charged with anisole (217 μL, 216 mg, 2.00 mmol), 2-nitropropane (182 μL, 180 mg, 2.02 mmol) 85% phosphoric acid (0.7 g), and 80% polyphosphoric acid (1.9 g), and the mixture was stirred at 110 °C for 4 h. Then the mixture was poured into cold water (50 mL), extracted with ethyl acetate (4 × 50 mL), and the organic phase was concentrated in vacuum. Crude product was purified by re-crystallization from petroleum ether to afford the titled compound as colorless flakes, mp 101–103 °C (petroleum ether), R_f 0.70 (hexane/EtOAc 3 : 1). Yield 179 mg (0.78 mmol, 78%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (br. s, 1H), 6.91 (d, J = 8.9 Hz, 4H), 6.81 (d, J = 8.9 Hz, 4H), 3.68 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆) δ 152.9 (2C), 138.0 (2C), 118.1 (4C), 114.6 (4C), 55.2 (2C); IR (NaCl, film, cm⁻¹): 3424, 2958, 1512, 1243, 1030, 833, 761; EA: calcd for C₁₄H₁₅NO₂ C 73.34, H 6.59, N 6.11; found C 73.46, H 6.51, N 6.14; HRMS (ESI TOF) calcd for C₁₄H₁₆NO₂ (M + H) 230.1176, found 230.1181 (2.1 ppm).

4-Methoxyaniline (3a)

Aqueous phase after extraction of diarylamine 2a was neutralized with aqueous ammonia and extracted with ethyl acetate (3 × 50 mL). The extract was concentrated and the residue was purified by column chromatography on silica gel eluting with mixture of ethyl acetate and hexane (1 : 3) applying gradient to reach proportion of 1 : 1 to obtain aniline 3a as yellowish oil, R_f 0.48 (hexane/EtOAc 3 : 1). Yield 10 mg (0.08 mmol, 4%). This material was identical to commercially available authentic sample.

Bis(2,4-dimethoxyphenyl)amine (2b)

Colorless crystals, mp 96–97 °C (EtOH), R_f 0.29 (hexane/EtOAc 3 : 1). Yield 150 mg (0.52 mmol, 52%). ¹H NMR (400 MHz, CDCl₃) δ 7.05 (d, J = 8.3 Hz, 2H), 6.47 (s, 2H), 6.45 (dd, J = 8.3, 2.3 Hz, 2H), 5.33 (br. s, 1H), 3.80 (s, 6H), 3.72 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 152.2 (2C), 149.2 (2C), 132.2 (2C), 127.5 (2C), 104.1 (2C), 102.1 (2C), 55.9 (2C), 55.4 (2C); IR (NaCl, film, cm⁻¹): 3455, 2945, 1502, 1263, 1034, 833, 787; HRMS (ESI TOF) calcd for C₁₆H₂₀NO₄ (M + H)⁺ 290.1387, found 290.1391 (1.4 ppm).

Bis(3,4-dimethoxyphenyl)amine (2c)²²

Yellowish oil, R_f 0.31 (hexane/EtOAc 3 : 1). Yield 176 mg (0.61 mmol, 61%). ¹H NMR (400 MHz, CDCl₃) δ 6.79 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 2.5 Hz, 2H), 6.54 (dd, J = 8.5, 2.5 Hz, 2H), 5.34 (br. s, 1H), 3.85 (s, 6H), 3.82 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 149.9 (2C), 144.0 (2C), 138.3 (2C), 112.6 (2C), 110.0 (2C), 103.6 (2C), 56.5 (2C), 56.0 (2C); IR (NaCl, film, cm⁻¹) 3379, 3010, 2939, 2835, 1605, 1502, 1463, 1130, 1027, 749; EA: calcd for C₁₆H₁₉NO₄ C 66.42, H 6.62, N 4.84; found C 66.59, H 6.57, N 4.78; HRMS (ESI TOF) calcd for C₁₆H₂₀NO₄ (M + H)⁺ 290.1387, found 290.1389 (0.7 ppm).

3,4-Dimethoxyaniline (3c)

Yellowish oil, R_f 0.21 (hexane/EtOAc 3 : 1). Yield 21 mg (0.14 mmol, 7%). ¹H NMR (400 MHz, CDCl₃) δ 6.69 (d, J = 8.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 6.22 (d, J = 8.5, 2.5 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.47 (br. s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 149.9, 142.2, 140.6, 113.1, 106.4, 100.8, 56.6, 55.7; HRMS (ESI TOF) calcd for C₈H₁₂NO₂ (M + H)⁺ 154.0863, found 154.0859 (2.6 ppm).

Bis(2,5-dimethoxyphenyl)amine (2d)

Colorless crystals, mp 87–89 °C (EtOH), R_f 0.27 (hexane/EtOAc 3 : 1). Yield 136 mg (0.47 mmol, 47%). ¹H NMR (400 MHz, CDCl₃) δ 6.68 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 2.9 Hz, 2H), 6.23 (dd, J = 8.7, 2.9 Hz, 2H), 5.36 (br. s, 1H), 3.78 (s, 6H), 3.71 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 154.5 (2C), 142.0 (2C), 137.3 (2C), 111.4 (2C), 102.2 (2C), 102.0 (2C), 56.2 (2C), 55.6 (2C); IR (NaCl, film, cm⁻¹) 3411, 2952, 2336, 1664, 1599, 1512, 1460, 1198, 991, 865; HRMS (ESI TOF) calcd for C₁₆H₂₀NO₄ (M + H)⁺ 290.1387, found 290.1392 (1.7 ppm).

Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amine (2e)

Yield 208 mg (0.73 mmol, 73%); colorless crystals, mp 103–105 °C (EtOH); R_f 0.28 (hexane/EtOAc 3 : 1); ¹H NMR (400 MHz, CDCl₃) δ 6.75 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 2.6 Hz, 2H), 6.49 (dd, J = 8.6, 2.6 Hz, 2H), 5.26 (br. s, 1H), 4.25–4.19 (m, 8H); ¹³C NMR (101 MHz, CDCl₃) δ 144.0 (2C), 138.4 (2C), 138.2 (2C), 117.7 (2C), 111.9 (2C), 107.3 (2C), 64.7 (2C), 64.4 (2C); IR (NaCl, film, cm⁻¹): 3393, 2931, 1620, 1587, 1495, 1307, 1280, 1241, 1211, 1063, 888, 815, 792; EA: calcd for C₁₆H₁₅NO₄ C 67.36, H 5.30, N 4.91; found C 67.47, H 5.26, N 4.87; HRMS (ESI TOF) calcd for C₁₆H₁₆NO₄ (M + H)⁺ 286.1074, found 286.1084 (3.5 ppm).

2,3-Dihydrobenzo[b][1,4]dioxin-6-amine (3e)

Yellowish oil, R_f 0.21 (hexane/EtOAc 3 : 1). Yield 30 mg (0.20 mmol, 10%). ¹H NMR (400 MHz, CDCl₃) δ 6.67 (d, J = 8.5 Hz, 1H), 6.24 (d, J = 2.6 Hz, 1H), 6.20 (dd, J = 8.5, 2.6 Hz, 1H), 4.24–4.16 (m, 4H); ¹³C NMR (101 MHz, CDCl₃) δ 144.1, 140.9, 136.6, 117.8, 108.9, 104.3, 64.9, 64.3; IR (NaCl, film, cm⁻¹): 3367, 2931, 1634, 1587, 1502, 1310, 1280, 1247, 1214, 1168, 1063, 924, 891; HRMS calcd for C₈H₁₀NO₂ (M + H)⁺: 152.0706, found 152.0709 (2.0 ppm).

Bis(2,4-dimethoxy-3-methylphenyl)amine (2f)

Yellowish oil, R_f 0.33 (hexane/EtOAc 3 : 1). Yield 187 mg (0.59 mmol, 59%). ¹H NMR (400 MHz, CDCl₃) δ 6.90 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 8.8 Hz, 2H), 5.85 (br. s, 1H), 3.67 (s, 6H), 3.61 (s, 6H), 2.08 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 152.4 (2C), 149.1 (2C), 130.9 (2C), 120.5 (2C), 114.2 (2C), 106.2 (2C), 60.0 (2C), 55.9 (2C), 30.9 (2C); IR (NaCl, film, cm⁻¹) 3409, 3010, 2939, 2831, 1607, 1502, 1468, 1130, 1037, 746; HRMS (ESI TOF) calcd for C₁₈H₂₄NO₄ (M + H)⁺ 318.1700, found 318.1703 (0.9 ppm).

Bis(4-methoxy-2-methylphenyl)amine (2g)²³

Yellowish oil, R_f 0.46 (hexane/EtOAc 3 : 1). Yield 108 mg (0.42 mmol, 42%). ¹H NMR (400 MHz, CDCl₃) δ 6.78 (d, J = 2.8 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 6.66 (dd, J = 8.6, 2.8 Hz, 2H), 3.77 (s, 6H), 2.23 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 154.4 (2C), 136.6 (2C), 129.6 (2C), 120.0 (2C), 116.5 (2C), 111.7 (2C), 55.5 (2C), 18.0 (2C); IR (NaCl, film, cm⁻¹): 3362, 2933, 2338, 1652, 1506, 1379, 1248, 1101, 979; HRMS (ESI TOF) calcd for C₁₆H₂₀NO₂ (M + H)⁺ 258.1489, found 258.1483 (2.3 ppm).

Bis(4-methoxy-3-methylphenyl)amine (2h)

Yellowish oil, R_f 0.51 (hexane/EtOAc 3 : 1). Yield 178 mg (0.69 mmol, 69%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.34 (br. s, 1H), 6.77 (m, 6H), 3.71 (s, 6H), 2.09 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆) δ 151.3 (2C), 138.1 (2C), 126.5 (2C), 120.3 (2C), 115.3 (2C), 111.6 (2C), 55.8 (2C), 16.5 (2C); IR (NaCl, film, cm⁻¹) 3366, 2945, 2337, 1654, 1505, 1379, 1247, 1101, 988; HRMS (ESI TOF) calcd for C₁₆H₂₀NO₂ (M + H)⁺ 258.1489, found 258.1489 (0.0 ppm).

4-Methoxy-3-methylaniline (3h)

Yellowish oil, R_f 0.42 (hexane/EtOAc 3 : 1). Yield 21 mg (0.15 mmol, 8%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.67 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 6.41 (d, J = 8.4, 2.1 Hz, 1H), 4.57 (br. s, 2H), 3.69 (s, 3H), 2.08 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 149.1, 142.2, 126.1, 117.3, 112.1, 111.9, 55.9, 16.3; HRMS (ESI TOF) calcd for C₈H₁₂NO (M + H)⁺ 138.0913, found 138.0913 (0.0 ppm).

Bis(3,4-dimethylphenyl)amine (2i)²⁴

Colorless crystals, mp 108–110 °C (EtOH), R_f 0.54 (hexane/EtOAc 3 : 1). Yield 54 mg (0.24 mmol, 24%). ¹H NMR (400 MHz, CDCl₃) δ 7.01 (d, J = 1.5 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 6.79 (dd, J = 8.2, 1.5 Hz, 2H), 5.27 (br. s, 1H), 2.22 (s, 6H), 2.17 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 141.8 (2C), 137.3 (2C), 130.6 (2C), 129.1 (2C), 119.7 (2C), 115.5 (2C), 20.2 (2C), 19.2 (2C); HRMS (ESI TOF) calcd for C₁₆H₂₀N (M + H)⁺ 226.1590, found 226.1594 (1.6 ppm).

2,2′-Azanediylbis(4-isopropylphenol) (2j)

Reaction was carried out at 90 °C. Yellowish oil, R_f = 0.42 (hexane/EtOAc 1 : 1). Yield 77 mg (0.27 mmol, 27%). ¹H NMR (400 MHz, CDCl₃) δ 6.59 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 2.0 Hz, 2H), 6.47 (dd, J = 8.0, 2.0 Hz, 2H), 5.26 (br. s, 1H), 4.25 (br. s, 2H), 2.77 (septet, J = 6.9 Hz, 2H), 1.12 (d, J = 6.9 Hz, 12H); ¹³C NMR (101 MHz, CDCl₃) δ 142.5 (2C), 142.2 (2C), 134.3 (2C), 117.4 (2C), 115.5 (2C), 115.3 (2C), 33.6 (2C), 24.4 (4C); IR (NaCl, film, cm¹): 3385, 3295, 2971, 2926, 2861, 1602, 1615, 1463, 1289, 1204, 810; HRMS (ESI TOF) calcd for C₁₈H₂₄NO₂ (M + H)⁺ 286.1802, found: 286.1799 (0.7 ppm).

Bis(2,3,5,6,8,9,11,12-octahydrobenzo[b][1,4,7,10,13]pentaoxacyclopentadecin-15-yl)amine (2k)

Reaction was carried out according to the typical procedure employing commercial benzo-15-crown-5 (268 mg, 1.00 mmol) and 2-nitropropane (182 μL, 180 mg, 2.02 mmol). Upon completion the reaction mixture was poured into cold water (50 mL), neutralized with aqueous ammonia and extracted with anisole (4 × 30 mL). Combined organic phases were concentrated in vacuum and residual brown amorphous solid was purified by preparative column chromatography on silica gel, eluting with mixture EtOAc/EtOH 1 : 1. The titled compound was isolated as colorless amorphous solid, mp 281–283 °C; R_f 0.26 (EtOH). Yield 44 mg (0.08 mmol, 16%). ¹H NMR (400 MHz, CDCl₃) δ 6.78 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 2.4 Hz, 2H), 6.50 (dd, J = 8.4, 2.4 Hz, 2H), 4.11–4.04 (m, 8H), 3.92–3.88 (m, 8H), 3.75 (br. s, 16H); ¹³C NMR (101 MHz, CDCl₃) δ 150.2 (2C), 143.7 (2C), 138.9 (2C), 116.3 (2C), 110.8 (2C), 105.4 (2C), 71.04 (2C), 70.98 (2C), 70.8 (2C), 70.5 (2C), 70.2 (2C), 69.9 (2C), 69.6 (2C), 68.8 (2C); IR (NaCl, film, cm⁻¹) 3392, 2926, 2867, 1602, 1505, 1450, 1360, 1227, 1133, 1062, 936; HRMS (ESI TOF) calcd for C₂₈H₃₉NNaO₁₀⁺ (M + Na) 572.2466, found: 572.2480 (2.4 ppm); calcd for C₂₈H₃₉NNa₂O₁₀²⁺ (M + 2Na) 595.2358, m/z = 297.6179, found: 297.6190 (3.7 ppm).

2,3,5,6,8,9,11,12-Octahydrobenzo[b][1,4,7,10,13]pentaoxacyclopentadecin-15-amine (3k)²⁵

Isolated by preparative column chromatography as colorless crystalline side product, mp 72–74 °C (n-BuOH); R_f 0.54 (EtOH). Yield 68 mg (0.24 mmol, 24%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.64 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 6.05 (dd, J = 8.4, 2.4 Hz, 1H), 4.68 (br. s, 2H), 3.94 (m, 2H), 3.89 (m, 2H), 3.76–3.70 (m, 4H), 3.60 (br. s, 8H); ¹³C NMR (101 MHz, DMSO-d₆) δ 150.0, 144.0, 139.4, 117.5, 105.6, 101.0, 70.3, 70.18, 70.17, 70.1, 69.7, 69.3, 68.9, 67.8; HRMS (ESI TOF) calcd for C₁₄H₂₁NNaO₅⁺ (M + Na) 306.1312, found: 306.1319 (2.2 ppm).

Acknowledgements

This work was executed in a frame of the State Assignment to Higher Education Institutions by Russian Ministry of Education and Science (projects #547 and #1361). We are grateful for financial support by Russian Foundation for Basic Research (grant #13-03-00304a), and President Grant for Government Support of Young Russian Scientists (grant MΚ-5733.2015.3).

Notes and references

1. For recent examples, see: (a) K. Ohta, Y. Chiba, T. Ogawa and Y. Endo, Bioorg. Med. Chem. Lett., 2008, 18, 5050; (b) X.-F. Wang, X.-T. Tian, E. Ohkoshi, B. Qin, Y.-N. Liu, P.-C. Wu, M.-J. Hour, H.-Y. Hung, K. Qian, R. Huang, K. F. Bastow, W. P. Janzen, J. Jin, S. L. Morris-Natschke, K.-H. Lee and L. Xie, Bioorg. Med. Chem. Lett., 2012, 22, 6224; (c) K. Ohta, Y. Chiba, A. Kaise and Y. Endo, Bioorg. Med. Chem., 2015, 23, 861; (d) M. A. Soussi, O. Provot, G. Bernadat, J. Bignon, J. Wdzieczak-Bakala, D. Desravines, J. Dubois, J.-D. Brion, S. Messaoudia and M. Alami, Eur. J. Med. Chem., 2014, 78, 178.
2. See, for example: (a) D. Tsvelikhovsky and S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 14048; (b) T. Noel, J. R. Naber, R. L. Hartman, J. P. McMullen, K. F. Jensen and S. L. Buchwald, Chem. Sci., 2011, 2, 287; (c) N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott and S. P. Nolan, J. Am. Chem. Soc., 2006, 128, 4101; (d) R. A. Green and J. F. Hartwig, Org. Lett., 2014, 16, 4388; (e) N. H. Park, G. Teverovskiy and S. L. Buchwald, Org. Lett., 2014, 16, 220.
3. (a) J.-P. Cloutier, B. Vabre, B. Moungang-Soume and D. Zargarian, Organometallics, 2015, 34, 133; (b) N. Iranpoor, H. Firouzabadi, E. Etemadi Davan, A. Rostami and A. Nematollahi, J. Organomet. Chem., 2013, 740, 123; (c) L. Ilies, T. Matsubara and E. Nakamura, Org. Lett., 2012, 14, 5570; (d) Y. Nakamura, L. Ilies and E. Nakamura, Org. Lett., 2011, 13, 5998; (e) S. Lavy, J. J. Miller, M. Pazicky, A.-S. Rodrigues, F. Rominger, C. Jaekel, D. Serra, N. Vinokurov and M. Limbach, Adv. Synth. Catal., 2010, 352, 2993.
4. V. Dhayalan, C. Saemann and P. Knochel, Chem. Commun., 2015, 51, 3239.
5. (a) J. D. Sanchez, R. Egris, S. Perumal, M. Villacampa and J. C. Menendez, Eur. J. Org. Chem., 2012, 2375; (b) J. D. Sanchez, C. Avendano and J. C. Menendez, Synlett, 2008, 1371.
6. H. J. Kim, M. J. Ajitha, Y. Lee, J. Ryu, J. Kim, Y. Lee, Y. Jung and S. Chang, J. Am. Chem. Soc., 2014, 136, 1132.
7. (a) H. Kim, K. Shin and S. Chang, J. Am. Chem. Soc., 2014, 136, 5904 . For intramolecular versions, see; (b) J. Yuan, C. Liu and A. Lei, Chem. Commun., 2015, 51, 1394.
8. (a) O. V. Krylova, V. N. Elokhina, A. S. Nakhmanovich, L. I. Larina and V. A. Lopyrev, Russ. J. Org. Chem., 2001, 37, 887; (b) I. A. Titova, T. I. Vakul'skaya, L. I. Larina, M. I. Mizandrontsev, V. A. Volkov, G. V. Dolgushin and V. A. Lopyrev, Russ. J. Org. Chem., 2005, 41, 1306.
9. (a) C. Balboni, L. Benati, P. C. Montevecchi and P. Spagnolo, J. Chem. Soc., Perkin Trans. 1, 1983, 2111; (b) B. Ivanova and M. Spiteller, Catal. Sci. Technol., 2013, 3, 1129.
10. (a) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, L. V. Frolova, A. Kornienko, I. V. Magedov and M. Rubin, Chem. Commun., 2013, 49, 9305; (b) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, A. S. Bijieva and M. Rubin, Org. Biomol. Chem., 2014, 12, 9786; (c) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, J. P. Matheny and M. Rubin, RSC Adv., 2015, 5, 8647; (d) A. V. Aksenov, A. N. Smirnov, I. V. Magedov, M. R. Reisenauer, N. A. Aksenov, I. V. Aksenova, A. L. Pendleton, G. Nguyen, R. K. Johnston, M. Rubin, A. de Carvalho, R. Kiss, V. Mathieu, F. Lefranc, J. Correa, D. A. Cavazos, A. J. Brenner, B. A. Bryan, S. Rogelj, A. Kornienko and L. Frolova, J. Med. Chem., 2015, 58, 2206.
11. See, for recent review: R. Ballini and M. Petrini, Adv. Synth. Catal., 2015, 357, 2371.
12. A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, A. S. Bijieva, I. V. Aksenova and M. Rubin, Org. Biomol. Chem., 2015, 13, 4289.
13. A. V. Aksenov, N. A. Aksenov, O. N. Nadein and I. V. Aksenova, Synth. Commun., 2012, 42, 541.
14. (a) A. V. Aksenov, N. A. Aksenov, O. N. Nadein and I. V. Aksenova, Chem. Heterocycl. Compd., 2011, 46, 1405; (b) A. V. Aksenov, N. A. Aksenov, O. N. Nadein and A. E. Tsys, Chem. Heterocycl. Compd., 2010, 46, 1405; (c) A. V. Aksenov, N. A. Aksenov, O. N. Nadein and I. V. Aksenova, Synlett, 2010, 2628.
15. See, for example: (a) L. Kikot, A. Lyapunov, T. Bogaschenko, S. Smola, C. Kulygina and T. Kirichenko, Synth. Commun., 2015, 45, 488; (b) H. R. Kricheldorf, N. Lomadze and G. Schwarz, Macromolecules, 2007, 40, 4818; (c) Y. Liu, H.-Y. Zhang, L.-X. Chen, X.-W. He, T. Wada and Y. Inoue, J. Org. Chem., 2000, 65, 2870.
16. See, for example: (a) S. P. Gromov, A. I. Vedernikov, N. A. Lobova, L. G. Kuzmina, S. S. Basok, Y. A. Strelenko, M. V. Alfimov and J. A. K. Howard, New J. Chem., 2011, 35, 724; (b) S. Inokuma, T. Funaki, S. Kondo and J. Nishimura, Tetrahedron, 2004, 60, 2043.
17. T. L. Gilchrist, P. F. Gordon and C. W. Rees, J. Chem. Res., Synop., 1988, 148.
18. B. Zhou, J. Du, Y. Yang, H. Feng and Y. Li, Org. Lett., 2013, 15, 6302.
19. J. W. Davies, J. R. Malpass and M. P. Walker, J. Chem. Soc., Chem. Commun., 1985, 21, 686.
20. Y. L. Chow and S. K. Pillay, Heterocycles, 1976, 5, 171.
21. J. McNulty, S. Cheekoori, T. P. Bender and J. A. Coggan, Eur. J. Org. Chem., 2007, 1423.
22. K. Hori and M. Mori, J. Am. Chem. Soc., 1998, 120, 7651.
23. R. Kuwano, Y. Matsumoto, T. Shige, T. Tanaka, S. Soga and Y. Hanasaki, Synlett, 2010, 1819.
24. B. A. Kamino, J. Castrucci and T. P. Bender, Silicon, 2011, 3, 125.
25. N. Launay, A.-M. Caminade and J.-P. Majoral, J. Am. Chem. Soc., 1995, 117, 3282.

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Footnote

† Electronic supplementary information (ESI) available: Spectral data. CCDC 1417939. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra17668a

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