A radical addition/cyclization of diverse ethers to 2-isocyanobiaryls under mildly basic aqueous conditions

Abstract

Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogenative addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution (BHAS).

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Introduction

Phenanthridine is the scaffold of many naturally occurring products¹ that exhibit a wide range of bioactivities, such as antitumor,² antituberculosis,³ antimicrobial,⁴ antiviral,⁵ acaricidal,⁶ and fungicidal activities.⁷ Some phenanthridine derivatives have also found application in biological chemistry as dyes for cytofluorometric assays⁸ or even in materials science due to their optoelectronic properties.⁹ Recently, the assembly of the phenanthridine framework has been elegantly achieved with a cascade that involves the addition of radicals to somophilic 2-isocyanobiphenyls, followed by intramolecular homolytic aromatic substitution.^10,11 In this context, and given the progress made in the C_α–H oxidation of ethers with peroxides to form radicals,¹² the oxidative addition of ethers to 2-isocyanobiphenyls has been successfully achieved using different conditions.¹³ This transformation requires a dual selective C–H bond functionalization, and constitutes a powerful tool to increase molecular complexity with high atom-economy, where only hydrogen is lost (Scheme 1). Moreover, ethers are very important raw materials and they are also common substructures of natural and synthetic bioactive products.¹⁴ Consequently, the development of methods that make use of relatively unreactive ethers to build complex molecules, is highly demanded by organic and medicinal chemists.

Scheme 1 Oxidative addition of 1,4-dioxane to 2-isocyanobiphenyls: a radical cascade.

It is worth noting that 1,4-dioxane is the model substrate for C–H bond functionalization of ethers in most of the reported studies.¹³ This symmetric ether presents all eight C–H bonds adjacent to an oxygen atom, which stabilizes the radical by hyperconjugation with the non-bonding electrons. Moreover, theoretical studies suggest that the release of ring strain upon radical formation is greater in 1,4-dioxane than in other cyclic ethers such as tetrahydrofuran.¹⁵ As a matter of fact, when TBPB was used as the oxidant in the insertion of 2-isocyanobiaryls with ethers, only 1,4-dioxane was successful and THF failed.^13a Notably, when benzoyl peroxide was used in the same transformation, another three ethers could be inserted with moderate results (40–45%).^13b To the best of our knowledge, the greatest number of ethers tolerated in this reaction (seven examples) has been possible with the use of DTBP as the oxidant, FeCl₃ as the catalyst and DBU as the cocatalyst.^13c With these precedents we decided to develop a new protocol for this reaction aimed at accommodating a range of ethers, free of transition-metal catalysts and using economical and environmentally friendly conditions (Scheme 2).

Scheme 2 Previous results and our reaction conditions for THF.

Results and discussion

To explore new reaction conditions we selected 2-isocyanobiphenyl (1a) and THF (2a) as model substrates. In a control experiment we performed the reaction using BPO as the oxidant at 100 °C and we obtained 35% yield of the desired product 3aa, a similar result to the one obtained by the Cheng group,^13b together with byproduct 4a (Table 1, entry 1). Surprisingly, the addition of K₂CO₃ and H₂O completely inhibited the formation of 3aa (entry 2). Prompted by the excellent results in oxidative transformations achieved with Bu₄NI as the catalyst and TBHP,¹⁶ we tried this combination, but 3aa was obtained in low yield (entry 3). The use of DTBP or (NH₄)₂S₂O₈ in combination with Bu₄NI was also unsuccessful in this transformation (entries 4–6). It is reported that TBPB fails to afford product 3aa in this reaction and that only compound 4a is obtained.^13a To our surprise, the inclusion of H₂O in this reaction mixture afforded product 3aa, although in low yield (entry 7). We were pleased to find that the same oxidant, but in the presence of K₂CO₃ and H₂O, allowed full conversion of 1a to obtain compound 3aa in good yield (entry 10). While the addition of Bu₄NI had no important impact on the reaction, the amount of base and the control of the reaction temperature were crucial to obtain good and reliable results (entries 8–11). Similar results were obtained with Na₂HPO₄, and lower yields were obtained for the desired product when non-nucleophilic organic bases were used in substoichiometric amounts (entries 12–14).

Table 1 Screening of reaction conditions

Entry	Oxidant (mol%)/additive (mol%)	Base (mol%)	Conv.^a (%)	(3aa : 4a)^b
a By GC of the crude reaction mixture. b Yield calculated by ^1H-NMR of the crude reaction mixture using durene as the internal standard. c Formation of other products is observed by GC. d The conversion was 90% at 80 °C and 0% at 60 °C. BPO = benzoyl peroxide. DTBP = di-tert-butylperoxide. TBPB = tert-butylperoxybenzoate. DABCO = 1,4-diazabicyclo[2.2.2]octane. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
1^c	BPO (120)	None	100	35 : 22
2	BPO (120)	K2CO3 (150)	37	—
3	TBHP (300)/Bu4NI (20)	K2CO3 (150)	45	20 : 5
4	DTBP (300)/Bu4NI (20)	None	0	—
5	DTBP (300)/Bu4NI (20)	K2CO3 (150)	0	—
6	(NH4)2S2O8 (220)	K2CO3 (150)	0	—
7	TBPB (220)	None	100	12 : 4^c
8	TBPB (120)/Bu4NI (20)	K2CO3 (150)	55	—
9	TBPB (220)	K2CO3 (100)	70	—
10	TBPB (220)	K 2 CO 3 (150)	100	77 : 23
11	TBPB (220)/Bu4NI (50)	K2CO3 (150)	100	75 : 25
12	TBPB (220)	Na2HPO4 (150)	90	75 : 25
13^c	TBPB (220)	DABCO (50)	100	18 : 0
14^c	TBPB (220)	DBU (50)	100	40 : 0

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Having found very simple optimized conditions for the model reaction, we evaluated its scope using different 2-isocyanobiaryls and THF (Scheme 3). We first examined substrates with substituents on the upper aromatic ring. Methyl-substituted products 3ba and 3ca were obtained in good to moderate yields, without observing any benzylic oxidation. During the formation of 3ca, some compound 3aa was also observed (GC-MS), likely by ipso-homolytic aromatic substitution, and its isolated yield was affected due to difficulties in the chromatographic purification. A more electron-donating group such as methoxy was compatible with this protocol, affording compound 3da in reasonably good yield, as well as the corresponding byproduct 4d (detected by GC-MS and ¹H-NMR). When 2-(2-isocyanophenyl)-naphthalene was used, compound 3ea was the only regioisomer isolated in moderate yield, despite the steric hindrance between the ether moiety and the extra aromatic ring.¹⁷ Electron-withdrawing groups, such as acetyl, trifluoromethyl, chloro and fluoro, were suitable substituents in the upper aromatic ring, furnishing products (3fa, 3ga, 3ha and 3ia) in good isolated yields. Interestingly, when meta-substituted substrates 1j and 1k were used, both possible regioisomers were isolated after column chromatography. While the ratio of 3ja/3′ja was 1 : 1, for 1k the major product was the most crowded regioisomer (3ka).¹⁸ We also examined isocyanobiaryls substituted in the lower aromatic ring by electron-donating and electron-withdrawing groups, obtaining uniformly moderate yields in all cases (3la–3oa).

Scheme 3 Scope of 2-isocyanobiaryls with THF. ^a Measured temperature of the sand bath. ^b Yields after purification of isolated products and in parentheses are yields of 6-H phenanthridines 4 estimated by GC-MS of crude reaction mixtures. ^c Product 3aa was also formed and purification of 3ca was more difficult. *The other regioisomer isolated (3′).

We further explore the performance of different ethers using the optimized procedure (Scheme 4). 1,4-Dioxane (2b) and THP (2c) were also suitable for this protocol, obtaining products 3ab and 3ac in moderate yields after purification, as well as compound 4a as the byproduct. With THP, minor amounts of regioisomers were formed (see the ESI† for GC-MS of isomers), complicating the isolation of 3ac in a pure form. Acyclic ethers such as i-Pr₂O (2d), n-Bu₂O (2e) and t-BuOMe (2g) afforded the corresponding products in good to excellent yields, with linear n-Bu₂O providing the best yield. 2-MeTHF (2f) was also examined, affording the more substituted compound 3af as the major product and regioisomer 3′af as an inseparable trans/cis mixture. Surprisingly, when Bn₂O (2h) was examined, the expected product (3ah) was obtained in only 17% yield and the addition of a benzyl radical took place preferentially (3′ah). It seems reasonable that after H-abstraction from Bn₂O, a β-fragmentation gives rise to the benzyl radical, which is finally added to 1a. The addition of phthalan (2i) was also possible, but compound 3ai was obtained in lower yield. Importantly, acetals 2j and 2k led, respectively, to products 3aj and 3ak in synthetically useful yields. These compounds could be easily hydrolyzed to obtain the corresponding 6-formylphenanthridine and the acetal moiety has the potential to be transformed into other functionalities.¹⁹

Scheme 4 Scope of ethers. ^a Measured temperature of the sand bath. ^b Yields after purification of isolated products and in parentheses are yields of 4a.

Investigation of the reaction mechanism

To gain insight into the reaction mechanism we performed some experiments. As shown in Scheme 5a, the use of TEMPO as a radical scavenger in our model reaction, under standard conditions, completely inhibited the formation of 3aa and the coupling product 5 was detected by MS. Since compounds 4 are consistent byproducts of the radical cyclization studied here, we were intrigued about their formation and we have not found any experimental evidence of this in the literature.²⁰

Scheme 5 Mechanistic investigations.

When the reaction was conducted using D₂O and D₈-THF (Scheme 5b), the expected product D₇-3aa was obtained, accompanied by phenanthridine 4a. Importantly, the byproduct of this reaction is not deuterated, indicating that neither THF nor H₂O is the source of hydrogen for the formation of this phenanthridine. We also studied the intermolecular kinetic isotopic effect (KIE) by competition experiments of equimolar amounts of THF and D₈-THF with 1a at the initial stage of the reaction (Scheme 5c). The large KIE obtained (k_H/k_D = 3.16) suggests that the cleavage of the C(sp³)–H bond is involved in the rate determining step of this reaction. In addition, we also performed competition experiments at the initial state of the reaction, using equimolar quantities of 1a and 2-isocyanobiphenyls substituted in position 4′ by methyl or fluoro groups. The results shown in Scheme 4d suggested that electron-withdrawing substituents in the upper aromatic ring accelerate the reaction. Since this class of group stabilizes the LUMO of the upper aromatic ring, this result is also consistent with a radical cyclization pathway.²¹

An important feature of this protocol is the crucial role of K₂CO₃ and H₂O in a successful transformation (Table 1, entries 6 and 9). Since the seminal contribution of Studer and Curran,²² several known reactions have been recognized as “base promoted homolytic substitutions” (BHAS) and many new transformations have been developed with this concept.¹¹ Based on literature precedents and our own results, we believe that this reaction is an example of BHAS. A possible reaction mechanism is depicted in Scheme 6. Firstly, homolysis of TBPB takes place upon heating. From the two generated radicals, it is reported that t-BuO˙ abstracts a hydrogen atom from THF faster than Bz˙·to generate the α-furanyl radical.²³ Addition of this intermediate to isonitrile 1a, followed by intramolecular addition to the upper aromatic ring, is well documented in a number of examples.¹¹ DFT studies performed by the Studer group indicate that cyclohexadienyl radicals, such as I, are extremely strong acids (pK_a ∼ −15 in H₂O).²⁴ Therefore, this radical intermediate can be deprotonated under mild basic aqueous conditions (e.g. K₂CO₃ in H₂O) to generate a radical anion II. This species is a potent reductant that can easily transfer an electron to radical Bz˙ or to oxidant TBPB, while generating product 3aa. In addition, intermediate I can transfer a hydrogen atom to 1a, which after a similar BHAS process leads to the formation of byproduct 4a. This explanation is consistent with our observation that neither THF nor H₂O was the hydrogen source of 4a.²⁵

Scheme 6 Plausible mechanism.

Conclusions

In conclusion, we have demonstrated that TBPB can be used under mildly basic aqueous conditions to promote the radical addition of a range of ethers to 2-isocyanobiaryls followed by cyclization. Mechanistic investigations suggest that this transformation is an example of BHAS and a plausible explanation is provided for the formation of byproduct 4. Some salient features of the developed methodology are: (a) neither transition metals nor any expensive additives are needed; (b) the wastes generated are harmless inorganic salts and can be easily removed by aqueous workup; (c) the reaction medium is constituted by the reactant ethers and water.

Experimental section

General remarks

All starting isonitriles were prepared according to a reported method.^10b TLC was performed on silica gel 60 F₂₅₄, using aluminium plates and visualized by exposure to ultraviolet light. Flash chromatography was carried out on hand-packed columns of silica gel 60 (230–400 mesh). Infrared (IR) spectra were recorded with a spectrophotometer equipped with an ATR component; wavenumbers are given in cm⁻¹. LRMS were obtained using a mass spectrometer coupled with a gas chromatographer (GC); the mobile phase was helium (2 mL min⁻¹); HP-1 column of 12 m was used; temperature program starts at 80 °C for 3 min, then up to 270 °C at a rate of 20 °C min⁻¹, and 17.5 min at 270 °C. HRMS analyses were carried out using Electron Impact (EI) mode at 70 eV by Q-TOF. ¹H NMR spectra were recorded at 300 or 400 MHz for ¹H-NMR and 75 or 100 MHz for ¹³C-NMR, using CDCl₃ as the solvent and TMS as an internal standard (0.00 ppm). The data are being reported as (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br s = broad signal, coupling constant(s) in Hz, integration). ¹³C-NMR spectra were recorded with ¹H-decoupling at 100 MHz and referenced to CDCl₃ at 77.16 ppm. DEPT-135 experiments were performed to assign CH, CH₂ and CH₃.

General procedure for the synthesis of compounds 3

Into a pressure tube were added K₂CO₃ (103 mg, 0.75 mmol) and H₂O (0.82 mL). Then, to it were added sequentially the 2-isocyanobiaryl derivative 1 (0.50 mmol), ether 2 (2.5 mL) and tert-butyl peroxibenzoate (TBPB) (213 μL, 1.10 mmol). The reaction mixture was stirred under an Ar atmosphere for 12–14 h at 110 °C (sand bath temperature). Upon full conversion of the isonitrile (TLC or GC), a saturated solution of NaHCO₃ (5 mL) and EtOAc (10 mL) was added to the reaction mixture. After phase separation, the aqueous phase was extracted with EtOAc (3 × 15 mL) and the combined organic layers were washed with brine (5 mL), dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the desired product.

6-(Tetrahydrofuran-2-yl)phenanthridine (3aa)^13c. Following the general procedure, compound 3aa was obtained after column chromatography (hexane/EtOAc 9 : 1) as a yellow pale solid (91 mg, 0.36 mmol, 73%): R_f 0.23 (95 : 5 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.63 (dd, J = 8.2, 1.3 Hz, 1H), 8.55 (dd, J = 8.0, 1.5 Hz, 1H), 8.45 (dd, J = 8.7, 1.0 Hz, 1H), 8.19 (dd, J = 7.9, 1.6 Hz, 1H), 7.83 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.75–7.61 (m, 3H), 5.78 (t, J = 6.9 Hz, 1H), 4.26–4.15 (m, 1H), 4.13–4.01 (m, 1H), 2.82–2.65 (m, 1H), 2.50–2.35 (m, 1H), 2.30–2.03 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.4 (C), 143.4 (C), 133.4 (C), 130.6 (CH), 130.4 (CH), 128.6 (CH), 127.3 (CH), 127.0 (CH), 126.6 (CH), 124.9 (C), 124.2 (C), 122.5 (CH), 122.0 (CH), 79.7 (CH), 69.1 (CH₂), 30.1 (CH₂), 26.1 (CH₂) ppm; IR ν 3073, 2981, 2881, 1583, 1444, 1300, 1057, 727 cm⁻¹; LRMS (EI) m/z (%) = 249 (M⁺, 5), 220 (15), 206 (100), 193 (48), 178 (15).

8-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine (3ba). Following the general procedure, compound 3ba was obtained after column chromatography (hexane/EtOAc 93 : 7) as a yellow pale solid (80 mg, 0.31 mmol, 61%): R_f 0.20 (93 : 7 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.54–8.48 (m, 2H), 8.20 (br s, 1H), 8.16 (dd, J = 8.1, 1.1 Hz, 1H), 7.71–7.59 (m, 3H), 5.79–5.74 (m, 1H), 4.23–4.15 (m, 1H), 4.10–4.03 (m, 1H), 2.83–2.72 (m, 1H), 2.60 (s, 3H), 2.46–2.35 (m, 1H), 2.27–2.17 (m, 1H), 2.17–2.06 (m, 1H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.0 (C), 143.1 (C), 137.2 (C), 132.1 (CH), 131.2 (C), 130.5 (CH), 128.1 (CH), 126.9 (CH), 126.0 (CH), 125.1 (C), 124.3 (C), 122.3 (CH), 121.8 (CH), 79.5 (CH), 69.1 (CH₂), 30.0 (CH₂), 26.1 (CH₂), 22.1 (CH₃) ppm; IR ν 2955, 2867, 1577, 1460, 1052, 760 cm⁻¹; LRMS (EI) m/z (%) = 263 (M⁺, 6), 234 (10), 220 (100), 207 (57); HRMS (EI) m/z calcd for C₁₈H₁₇NO 263.1310, found 263.1307.

10-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine (3ca). Following the general procedure, compound 3ca was obtained after column chromatography (hexane/EtOAc 95 : 5–9 : 1) as a yellow pale solid (54 mg, 0.20 mmol, 41%): R_f 0.20 (95 : 5 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.77 (br d, J = 8.2 Hz, 1H), 8.35 (dd, J = 8.1, 1.6 Hz, 1H), 8.23 (dd, J = 8.1, 1.5 Hz, 1H), 7.70 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.67–7.55 (m, 3H), 5.81–5.75 (t, J = 6.8 Hz, 1H), 4.25–4.15 (m, 1H), 4.10–4.01 (m, 1H), 3.11 (s, 3H), 2.84–2.67 (m, 1H), 2.48–2.32 (m, 1H), 2.27–2.00 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.6 (C), 144.5 (C), 135.6 (C), 134.6 (CH), 132.9 (C), 130.9 (CH), 127.8 (CH), 126.7 (CH), 126.5 (CH), 126.4 (C), 126.1 (CH), 125.6 (C), 124.9 (CH), 79.7 (CH), 69.1 (CH₂), 30.1 (CH₂), 27.1 (CH₂), 26.1 (CH₃) ppm; IR ν 3069, 2968, 2871, 1587, 1437, 1054, 760 cm⁻¹; LRMS (EI) m/z (%) = 263 (M⁺, 8), 234 (18), 220 (100), 207 (59), 204 (21), 165 (18); HRMS (EI) m/z calcd for C₁₈H₁₇NO 263.1310, found 263.1306.

8-Methoxy-6-(tetrahydrofuran-2-yl)phenanthridine (3da). Following the general procedure, compound 3da was obtained after column chromatography (hexane/EtOAc 95 : 5–75 : 25) as a white solid (78 mg, 0.28 mmol, 55%): R_f 0.20 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 9.1 Hz, 1H), 8.47–8.41 (m, 1H), 8.17–8.12 (m, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.68–7.56 (m, 2H), 7.44 (dd, J = 9.1, 2.6 Hz, 1H), 5.69 (t, J = 6.9 Hz, 1H), 4.24–4.12 (m, 1H), 4.12–4.01 (m, 1H), 3.98 (s, 3H), 2.87–2.71 (m, 1H), 2.47–2.32 (m, 1H), 2.28–2.05 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 158.6 (C), 158.4 (C), 142.5 (C), 130.5 (CH), 127.8 (C), 127.6 (CH), 127.0 (CH), 126.3 (C), 124.3 (C), 124.1(CH), 121.5 (CH), 120.8 (CH), 107.1 (CH), 80.1 (CH), 69.1 (CH₂), 55.6 (CH₃), 29.8 (CH₂), 26.2 (CH₂) ppm; IR ν 3000, 2964, 2858, 1571, 1059, 754 cm⁻¹; LRMS (EI) m/z (%) = 279 (M⁺, 12), 250 (8), 236 (100), 223 (44), 207 (35); HRMS (EI) m/z calcd for C₁₈H₁₇NO₂ 279.1259, found 279.1261.

5-(Tetrahydrofuran-2-yl)benzo[i]phenanthridine (3ea). Following the general procedure, compound 3ea was obtained after column chromatography (hexane/EtOAc 98 : 2–95 : 5) as a white solid (57 mg, 0.19 mmol, 38%): R_f 0.35 (96 : 4 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 9.19 (H-1, d, J = 8.5 Hz, 1H), 8.57 (H-12 + H-4, dd, J = 8.7, 5.2 Hz, 2H), 8.23 (H-7, dd, J = 8.2, 1.1 Hz, 1H), 8.10 (H-11, d, J = 8.9 Hz, 1H), 7.98 (H-10, d, J = 7.9 Hz, 1H), 7.78–7.71 (H-2 + H-8, m, 2H), 7.68–7.63 (H-3 + H-9, m, 2H), 5.91 (H-2′, t, J = 6.4 Hz, 1H), 4.47–4.38 (H-5′, m, 1H), 4.20–4.13 (H-5′, m, 1H), 2.99–2.86 (H-3′, m, 1H), 2.59–2.37 (H-4′, m, 1H), 2.27–2.07 (H-3′ + H-4′, m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 157.7 (C), 144.0 (C), 133.8 (C), 133.2 (C), 131.9(C), 130.1 (CH), 129.9 (C), 128.8 (CH), 128.7 (CH), 128.4 (CH), 127.2 (CH), 126.9 (CH), 126.7 (CH), 123.7(C), 123.0 (C), 122.5 (CH), 120.2 (CH), 80.5 (CH), 69.4 (CH₂), 31.3 (CH₂), 26.8 (CH₂) ppm; IR ν 3019, 2961, 2937, 1561, 1465, 1350, 1051, 750 cm⁻¹; LRMS (EI) m/z (%) = 299 (M⁺, 14), 256 (100), 242 (28), 227 (19); HRMS (EI) m/z calcd for C₂₁H₁₇NO 299.1310, found 299.1304.

1-(6-(Tetrahydrofuran-2-yl)phenanthridin-8-yl)ethan-1-one (3fa). Following the general procedure, compound 3fa was obtained after column chromatography (hexane/EtOAc 8 : 2) as a yellow pale solid (77 mg, 0.27 mmol, 53%): R_f 0.20 (8 : 2 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 9.10 (br s, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.35 (dd, 2H), 8.19 (dd, J = 8.1, 1.2 Hz, 1H), 7.77 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.67 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 5.77 (t, J = 7.0 Hz, 1H), 4.22–4.13 (m, 1H), 4.13–4.04 (m, 1H), 2.88–2.79 (m, 1H), 2.77 (s, 3H), 2.52–2.37 (m, 1H), 2.31–2.10 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 197.5 (C), 159.8 (C), 144.2 (C), 136.5 (C), 135.3 (C), 130.7 (C), 129.8 (CH), 128.8 (CH), 128.2 (CH), 127.4 (CH), 124.5 (C), 123.5 (C), 122.9 (CH), 122.6 (CH), 79.9 (CH), 69.2 (CH₂), 29.9 (CH₂), 26.9 (CH₂), 26.2 (CH₃) ppm; IR ν 2977, 2921, 2856, 1683, 1615, 1251, 1052, 760 cm⁻¹; LRMS (EI) m/z (%) = 291 (M⁺, 5), 263 (20), 248 (100), 235 (65), 207 (17); HRMS (EI) m/z calcd for C₁₉H₁₇NO₂ 291.1259, found 291.1265.

6-(Tetrahydrofuran-2-yl)-8-(trifluoromethyl)phenanthridine (3ga). Following the general procedure, compound 3ga was obtained after column chromatography (hexane/EtOAc 95 : 5–9 : 1) as a yellow pale solid (111 mg, 0.35 mmol, 70%): R_f 0.25 (95 : 5 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.81 (s, 1H), 8.72 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 5.72 (t, J = 6.9 Hz, 1H), 4.19–4.12 (m, 1H), 4.12–4.03 (m, 1H), 2.88–2.75 (m, 1H), 2.48–2.35 (m, 1H), 2.30–2.08 (m, 2H); ¹³C-NMR (101 MHz, CDCl₃) δ 159.2 (C), 144.0 (C), 135.6 (C), 130.7 (CH), 129.8 (CH), 129.1(CH), 129.0 (C-8, d, ²J_C–F = 32.4 Hz), 127.6 (CH), 126.3 (CH, q, ³J_C–F = 3.3 Hz), 124.5 (CH, q, ³J_C–F = 4.3 Hz), 124.4 (CH), 124.25 (d, ¹J_C–F = 272.2 Hz), 123.5 (CH), 123.3 (C), 122.4 (CH), 80.0 (CH), 69.2 (CH₂), 29.8 (CH₂), 26.2 (CH₂) ppm; IR ν 2966, 2874, 1722, 1625, 1173, 1122, 763 cm⁻¹; LRMS (EI) m/z (%) = 317 (M⁺, 4), 288 (8), 274 (100), 261 (73), 247 ([(M + 1)⁺ − THF], 14), 226 (12); HRMS (EI) m/z calcd for C₁₄H₈F₃N, 247.0609, found 247.0612.

8-Chloro-6-(tetrahydrofuran-2-yl)phenanthridine (3ha). Following the general procedure, compound 3ha was obtained after column chromatography (hexane/EtOAc 95 : 5) as an orange pale solid (92 mg, 0.32 mmol, 65%): R_f 0.25 (95 : 5 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 8.9 Hz, 1H), 8.46 (dd, J = 7.5, 1.8 Hz, 2H), 8.16 (dd, J = 8.1, 1.1 Hz, 1H), 7.78–7.68 (m, 2H), 7.64 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 5.65 (t, J = 6.9 Hz, 1H), 4.20–4.11 (m, 1H), 4.11–4.01 (m, 1H), 2.87–2.71 (m, 1H), 2.47–2.30 (m, 1H), 2.29–2.00 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 158.3 (C), 143.3 (C), 133.3 (C), 131.8 (C), 130.9 (CH), 130.7 (CH), 128.9 (CH), 127.4 (CH), 126.2 (CH), 126.0 (C), 124.2 (CH), 123.6 (C), 121.9 (CH), 79.8 (CH), 69.1 (CH₂), 29.7 (CH₂), 26.1 (CH₂) ppm; IR ν 3063, 2939, 2839, 1617, 1460, 1220, 1038, 759 cm⁻¹; LRMS (EI) m/z (%) = 283 (M⁺, 8), 254 (15), 240 ([M⁺ − C₂H₃O], 100), 217 (12), 207 (65), 177 (39); HRMS (EI) m/z calcd for C₁₅H₁₁ClN 240.0580, found 240.0586.

8-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine (3ia). Following the general procedure, compound 3ia was obtained after column chromatography (hexane/EtOAc 95 : 5–8 : 2) as a yellow pale solid (80 mg, 0.30 mmol, 60%): R_f 0.21 (95 : 5 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.60 (H-10, dd, J_H–F = 9.1, 5.4 Hz, 1H), 8.46 (dd, J = 8.1, 1.1 Hz, 1H), 8.17 (dd, J = 8.1, 1.2 Hz, 1H), 8.12 (H-7, dd, J_H–F = 10.2, 2.6 Hz, 1H), 7.70 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H), 7.64 (ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 7.56 (H-9, ddd, J_H–F = 9.1, 8.0, 2.7 Hz, 1H), 5.63 (H-2′, t, J = 6.9 Hz, 1H), 4.20–4.13 (H-5′, m, 1H), 4.09–4.02 (H-5′, m, 1H), 2.84–2.71 (m, 1H), 2.44–2.34 (m, 1H), 2.27–2.06 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 161.33 (C-8, d, ¹J_C–F = 248.0 Hz), 158.53 (C, d, ⁴J_C–F = 4.3 Hz), 142.94 (C), 130.62 (CH), 130.11 (C), 128.51 (CH), 127.43 (CH), 126.24 (C-6a, d, ³J_C–F = 7.8 Hz), 124.93 (C-10, d, ³J_C–F = 8.5 Hz), 123.82 (C), 121.76 (CH), 119.64 (CH, d, ²J_C–F = 23.9 Hz), 111.59 (CH, d, ²J_C–F = 21.8 Hz), 80.08 (CH), 69.14 (CH₂), 29.79 (CH₂), 26.08 (CH₂); IR ν 2958, 2873, 1773, 1697, 1480, 1196, 1054,759 cm⁻¹; LRMS (EI) m/z (%) = 267.1 (M⁺, 5), 238 (12), 224 (100), 211 (59), 197 (19), 169 (11); HRMS (EI) m/z calcd for C₁₇H₁₄FNO 267.1059, found 267.1042.

7-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine (3ja). Following the general procedure, compound 3ja was obtained after column chromatography (hexane/EtOAc 98 : 2–95 : 5) as a yellow pale solid (38 mg, 0.14 mmol, 28%): R_f 0.16 (98 : 2 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.53 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.12 (dd, J = 8.1, 1.4 Hz, 1H), 7.71–7.57 (m, 3H), 7.49 (d, J = 7.2 Hz, 1H), 5.97 (dd, J = 6.9, 5.2 Hz, 1H), 4.20–4.12 (m, 1H), 4.04–3.95 (m, 1H), 3.09 (s, 3H), 2.89–2.80 (m, 1H), 2.32–2.12 (m, 2H), 2.11–1.96 (m, 1H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.4 (C), 142.5 (C), 136.5 (C), 134.9 (C), 132.0 (CH), 130.2 (CH), 129.6 (CH), 128.4 (CH), 126.9 (CH), 125.4 (C), 124.4 (C), 122.2 (CH), 120.9 (CH), 80.3 (CH), 68.9(CH₂), 30.3 (CH₂), 25.8 (CH₂), 25.2 (CH₃) ppm; IR ν 2959, 2874, 1573, 1449, 1286, 1048, 749 cm⁻¹; LRMS (EI) m/z (%) = 263 (M⁺, 8), 248 (6), 234 (13), 220 (100), 207 (13), 193 (19); HRMS (EI) m/z calcd for C₁₈H₁₇NO 263.1310, found 263.1312.

9-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine (3′ja). From the same reaction where compound 3ja was obtained, and after column chromatography (hexane/EtOAc 95 : 5–100% EtOH), isomer 3′ja was isolated as a yellow pale solid (37 mg, 0.14 mmol, 28%): R_f 0.19 (95 : 5 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.52 (dd, J = 8.1, 1.5 Hz, 1H), 8.40 (H-10, s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 8.1, 1.0 Hz, 1H), 7.68 (ddd, J = 8.2, 7.1, 1.4 Hz, 1H), 7.60 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.50 (dd, J = 8.4, 1.4 Hz, 1H), 5.73 (t, J = 6.9 Hz, 1H), 4.23–4.16 (m, 1H), 4.11–4.00 (m, 1H), 2.76–2.65 (m, 1H), 2.62 (s, 3H), 2.46–2.32 (m, 1H), 2.27–2.04 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.3 (C), 143.6 (C), 140.7 (C), 133.5 (C), 130.5 (CH), 129.0 (CH), 128.4 (CH), 126.7 (CH), 126.4 (CH), 124.1 (C), 123.0 (C), 122.1 (CH), 121.9 (CH), 79.8 (CH), 69.1 (CH₂), 30.2 (CH₂), 26.1 (CH₂), 22.3 (CH₃) ppm; IR ν 2875, 2868, 1618, 1460, 1053, 760; LRMS (EI) m/z (%) = 263 (M⁺, 5), 234 (13), 220 (100), 207 (51), 192 (23); HRMS (EI) m/z calcd for C₁₈H₁₇NO 263.1310, found 263.1312.

7-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine (3ka). Following the general procedure, compound 3ka was obtained after column chromatography (hexane/EtOAc 93 : 7) as a white solid (51 mg, 0.19 mmol, 38%): R_f 0.19 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.22 (dd, J = 8.2, 1.2 Hz, 1H), 7.82–7.70 (m, 2H), 7.64 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.36 (ddd, J = 12.5, 7.9, 1.0 Hz, 1H), 6.02 (dt, J = 8.2, 4.3 Hz, 1H), 4.43–4.32 (m, 1H), 4.17–4.05 (m, 1H), 2.60–2.45 (m, 1H), 2.40–2.23 (m, 1H), 2.13–1.96 (m, 1H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 160.2 (C-7, d, ¹J_C–F = 255.2 Hz), 158.8 (C, d, ³J_C–F = 7.9 Hz), 143.3 (CH), 136.0 (C, d, ⁴J_C–F = 4.4 Hz), 131.0 (C-9, d, ³J_C–F = 9.8 Hz), 130.8 (CH), 129.3 (CH), 127.3 (CH), 122.7 (C, d, ⁵J_C–F = 2.7 Hz), 122.3 (CH), 118.7 (C-10, d, ⁴J_C–F = 4.0 Hz), 114.2 (CH), 114.1 (CH), 114.0 (C-6a, d, ²J_C–F = 24.6 Hz), 81.9 (C-2′, d, ⁴J_C–F = 14 Hz), 69.3 (CH₂), 31.7 (CH₂), 25.1 (CH₂) ppm; IR ν 2970, 2870, 1581, 1451, 1240, 757 cm⁻¹; LRMS (EI) m/z (%) = 267 (M⁺, 2), 224 (100), 211 (64), 197 (19), 169 (9); HRMS (EI) m/z calcd for C₁₇H₁₄FNO 267.1059, found 267.1050.

9-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine (3′ka). From the same reaction where compound 3ka was obtained, and after column chromatography (hexane/EtOAc 95 : 5), isomer 3′ka was isolated as a white solid (24 mg, 0.09 mmol, 18%): R_f 0.27 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.52 (H-7, dd, J = 9.1, 5.8 Hz, 1H), 8.41 (H-1, dd, J = 8.2, 1.1 Hz, 1H), 8.22 (H-10, dd, J = 10.5, 2.6 Hz, 1H), 8.17 (H-4, dd, J = 8.3, 1.2 Hz, 1H), 7.74 (ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 7.64 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.42 (H-8, ddd, J = 9.1, 8.2, 2.6 Hz, 1H), 5.70 (H-2′, t, J = 6.9 Hz, 1H), 4.21–4.11 (H-5′, m, 1H), 4.10–4.01 (H-5′, m, 1H), 2.88–2.71 (m, 1H), 2.47–2.31 (m, 1H), 2.29–2.05 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 163.70 (C-9, d, ¹J_C–F = 251.5 Hz); 158.7 (C), 143.6 (C), 135.9 (C-10a, d, ³J_C–F = 9.4 Hz), 130.6 (CH), 129.8 (C-7, d, ³J_C–F = 9.3 Hz), 129.3 (CH), 127.1 (CH), 123.8 (C-6a, d, ⁴J_C–F = 4.1 Hz), 122.2 (CH), 122.0 (C-6, d, ⁵J_C–F = 2 Hz), 116.3 (C-10/C-8, d, ²J_C–F = 23.7 Hz), 107.5 (C-8/C-10, d, ²J_C–F = 22.1 Hz), 80.0 (CH), 69.1 (CH₂), 29.8 (CH₂), 26.1 (CH₂) ppm; IR ν 2962, 2877, 1619, 1496, 1195, 1052, 760 cm⁻¹; LRMS (EI) m/z (%) = 267 (M⁺, 3), 238 (13), 224 (100), 211 (55), 197 (17), 169 (9); HRMS (EI) m/z calcd for C₁₇H₁₄FNO 267.1059, found 267.1054.

2-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine (3la). Following the general procedure, but from 0.30 mmol of 1l, compound 3la was obtained after column chromatography (hexane/EtOAc 94 : 6–93 : 7) as a yellow pale solid (43 mg, 0.16 mmol, 55%): R_f 0.17 (93 : 7 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.61 (d, J = 8.3 Hz, 1H), 8.42 (dd, J = 8.3, 0.7 Hz, 1H), 8.31 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.79 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.66 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.53 (dd, J = 8.3, 1.6 Hz, 1H), 5.74 (t, J = 6.9 Hz, 1H), 4.25–4.14 (m, 1H), 4.11–4.00 (m, 1H), 2.83–2.66 (m, 1H), 2.61 (s, 3H), 2.48–2.33 (m, 1H), 2.28–2.02 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 158.3 (C), 141.7 (C), 136.8 (C), 133.1 (C), 130.3 (CH), 130.3 (CH), 130.1(CH), 127.1 (CH), 126.5 (CH), 125.0 (C), 124.0 (C), 122.4 (CH), 121.6 (CH), 79.8 (CH), 69.1 (CH₂), 30.1 (CH₂), 26.1 (CH₂), 22.1 (CH₃) ppm; IR ν 2971, 2923, 2867, 1582, 1496, 1295, 1051, 822, 729 cm⁻¹; LRMS (EI) m/z (%) = 263 (M⁺, 6), 234 (12), 220 (100), 207 (47), 192 (15), 165 (12); HRMS (EI) m/z calcd for C₁₈H₁₇NO 263.1310, found 263.1312.

6-(Tetrahydrofuran-2-yl)-2-(trifluoromethoxy)phenanthridine (3ma). Following the general procedure, but from 0.45 mmol of 1m, compound 3ma was obtained after column chromatography (hexane/EtOAc 94 : 6) as a red solid (84 mg, 0.25 mmol, 55%): R_f 0.20 (93 : 7 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.55 (d, J = 8.3 Hz, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.87 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.75 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.57 (ddd, J = 8.9, 2.6, 1.1 Hz, 1H), 5.77 (t, J = 6.9 Hz, 1H), 4.23–4.15 (m, 1H), 4.12–4.04 (m, 1H), 2.81–2.65 (m, 1H), 2.50–2.35 (m, 1H), 2.31–2.06 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 160.1 (C), 147.7 (C), 141.7 (C), 132.8 (C), 132.5 (CH), 130.7 (CH), 128.2 (CH), 126.8 (CH), 125.1 (C-2, d, ³J_C–F = 10.5 Hz), 122.6 (CH), 121.9 (CH), 120.8 (q, ¹J_C–F = 257.5 Hz), 113.7 (CH), 79.6 (CH), 69.2 (CH₂), 30.1 (CH₂), 26.1 (CH₂) ppm; IR ν 2964, 2860, 1619, 1587, 1492, 1254, 1214 cm⁻¹; LRMS (EI) m/z (%) = 333 (M⁺, 5), 304 (24), 290 (100), 277 (51), 263 (8); HRMS (EI) m/z calcd for C₁₈H₁₄F₃NO₂ 333.0977, found 333.0950.

2-Chloro-6-(tetrahydrofuran-2-yl)phenanthridine (3na). Following the general procedure, but from 0.30 mmol of 1n, compound 3na was obtained after column chromatography (hexane/EtOAc 94 : 6–93 : 7) as a white solid (42 mg, 0.15 mmol, 50%): R_f 0.20 (93 : 7 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.87–7.79 (m, 1H), 7.71 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 5.74 (t, J = 6.9 Hz, 1H), 4.24–4.14 (m, 1H), 4.11–4.01 (m, 1H), 2.79–2.65 (m, 1H), 2.49–2.34 (m, 1H), 2.28–2.03 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.7 (C), 141.8 (C), 132.9 (C), 132.4 (C), 132.0 (CH), 130.7 (CH), 129.1 (CH), 128.0 (CH), 126.7 (CH), 125.3 (C), 125.1 (C), 122.5 (CH), 121.7 (CH), 79.6 (CH), 69.2 (CH₂), 30.0 (CH₂), 26.1(CH₂) ppm; IR ν 2967, 2869, 1584, 1495, 1255, 1054, 822, 767 cm⁻¹; LRMS (EI) m/z (%) = 283 (M⁺, 4), 254 (16), 240 ([M⁺ − C₂H₃O], 100), 227 (51), 213 (13) 177 (29); HRMS (EI) m/z calcd for C₁₅H₁₁ClN 240.0580, found 240.0576.

3-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine (3oa). Following the general procedure, but from 0.30 mmol of 1o, compound 3oa was obtained after column chromatography (hexane/EtOAc 96 : 4) as a brown oil (36 mg, 0.13 mmol, 45%): R_f 0.20 (93 : 7 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.54 (d, J = 8.3 Hz, 1H), 8.49 (H-1, dd, J = 9.1, 5.9 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 7.87–7.78 (m, 2H), 7.67 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.38 (H-2, ddd, J = 8.9, 8.1, 2.7 Hz, 1H), 5.76 (t, J = 6.9 Hz, 1H), 4.24–4.14 (m, 1H), 4.11–4.01 (m, 1H), 2.78–2.64 (m, 1H), 2.48–2.34 (m, 1H), 2.29–2.03 (m, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 162.7 (C-3, d, ¹J_C–F = 247.6 Hz), 160.9 (C), 144.7 (C-4a, d, ³J_C–F = 11.9 Hz), 133.2 (C), 130.8 (CH), 127.2 (CH), 126.7 (CH), 124.5 (C, d, ⁴J_C–F = 1.0 Hz), 123.9 (C-1, d, ³J_C–F = 9.5 Hz), 122.3 (CH), 120.9 (d, J_C–F = 2.1 Hz), 116.0 (CH, d, ²J_C–F = 23.7 Hz), 115.0 (CH, d, ²J_C–F = 20.5 Hz), 79.5 (CH), 69.2 (CH₂), 30.1 (CH₂), 26.1(CH₂) ppm; IR ν 2972, 2871, 1618, 1580, 1484, 1459, 1053, 764 cm⁻¹; LRMS (EI) m/z (%) = 267 (M⁺, 5), 238 (15), 224 (100), 211 (55), 196 (17); HRMS (EI) m/z calcd for C₁₇H₁₄FNO 267.1059, found 267.1048.

6-(1,4-Dioxan-2-yl)phenanthridine (3ab)^13a. Following the general procedure, compound 3ab was obtained after column chromatography (hexane/EtOAc 85 : 15–75 : 25) as a white solid (69 mg, 0.26 mmol, 52%): R_f 0.25 (8 : 2 hexane/EtOAc). ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (d, J = 8.3 Hz, 1H), 8.60–8.52 (m, 1H), 8.48–8.39 (m, 1H), 8.26–8.15 (m, 1H), 7.90–7.80 (m, 1H), 7.78–7.63 (m, 3H), 5.49 (p, J = 6.3 Hz, 1H), 4.34–4.29 (m, 2H), 4.21–4.06 (m, 2H), 3.99–3.88 (m, 2H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 156.2 (C), 143.3 (C), 133.3 (C), 130.6 (CH), 130.6 (CH), 128.7 (CH), 127.5 (CH), 127.4 (CH), 126.2 (CH), 124.6 (C), 124.1 (C), 122.6 (CH), 122.0 (CH), 76.3 (CH), 70.2 (CH₂), 67.9 (CH₂), 66.7 (CH₂) ppm; IR ν 2965, 2856, 1114, 10 856, 912, 759 cm⁻¹; LRMS (EI) m/z (%) = 265 (M⁺, 4), 206 (100), 179 (24), 151 (12), 102 (5).

6-(Tetrahydro-2H-pyran-2-yl)phenanthridine (3ac)^13c. Following the general procedure, compound 3ac was obtained after column chromatography (hexane/EtOAc 98 : 2–9 : 1) as a white solid (57 mg, 0.22 mmol, 43%): R_f 0.20 (95 : 5 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.62 (ddd, J = 8.2, 1.3, 0.6 Hz, 1H), 8.56–8.50 (m, 2H), 8.25–8.19 (m, 1H), 7.80 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.74–7.66 (m, 2H), 7.65–7.57 (m, 1H), 5.20 (dd, J = 11.1, 2.2 Hz, 1H), 4.34–4.24 (m, 1H), 3.81 (td, J = 11.6, 2.4 Hz, 1H), 2.37–2.19 (m, 1H), 2.15–2.00 (m, 2H), 1.96–1.77 (m, 2H), 1.74–1.63 (m, 1H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 159.6 (C), 143.4 (C), 133.5 (C), 130.5 (CH), 130.3 (CH), 128.6 (CH), 127.1 (CH), 127.0 (CH), 126.8 (CH), 124.5 (C), 124.1 (C), 122.4 (CH), 121.9 (CH), 80.7 (CH), 69.6 (CH₂), 30.6 (CH₂), 26.1 (CH₂), 24.0 (CH₂) ppm; IR ν 3075, 2930, 2839, 1083, 1039, 754, 723 cm⁻¹; LRMS (EI) m/z (%) = 262 (M⁺ − 1, 1), 235 (20), 206 (100), 193 (12).

6-(2-Isopropoxypropan-2-yl)phenanthridine (3ad)^13c. Following the general procedure, compound 3ad was obtained after column chromatography (100% hexane to hexane/EtOAc 98 : 2) as a brown pale oil (79 mg, 0.28 mmol, 57%): R_f 0.29 (100% hexane); ¹H-NMR (300 MHz, CDCl₃) δ 9.25 (ddd, J = 8.5, 1.4, 0.6 Hz, 1H), 8.70–8.64 (m, 1H), 8.57 (dd, J = 8.0, 1.6 Hz, 1H), 8.17–8.12 (m, 1H), 7.81 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.77–7.61 (m, 3H), 3.75 (p, J = 6.1 Hz, 1H), 1.92 (s, 6H), 1.02 (d, J = 6.1 Hz, 6H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 163.7 (C), 142.9 (C), 133.9 (C), 130.6 (CH), 130.3 (CH), 129.9 (CH), 128.5 (CH), 127.0 (CH), 126.1 (CH), 124.5 (C), 124.1 (C), 122.3 (CH), 121.9 (CH), 81.8 (C), 67.0 (CH), 29.1 (CH₃), 24.8 (CH₃); IR ν 2983, 2933, 1578, 1379, 1162, 1110, 996, 760, 730 cm⁻¹; LRMS (EI) m/z (%) = 264 (M⁺, 0.2), 236 (18), 221 ([M⁺ − C₅H₇O], 100), 204 (34), 179 (54), 150 (18); HRMS (EI) m/z calcd for C₁₆H₁₄N 220.1126, found 220.1128.

6-(1-Butoxybutyl)phenanthridine (3ae)^13b. Following the general procedure, compound 3ae was obtained after column chromatography (hexane/EtOAc 99 : 1–98 : 2) as a yellow oil (123 mg, 0.40 mmol, 80%): R_f 0.65 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.94–8.89 (m, 1H), 8.69–8.64 (m, 1H), 8.57 (dd, J = 8.0, 1.6 Hz, 1H), 8.20–8.15 (m, 1H), 7.84 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.77–7.62 (m, 3H), 4.98 (dd, J = 8.8, 5.4 Hz, 1H), 3.52–3.33 (m, 2H), 2.28–2.13 (m, 1H), 2.01–1.87 (m, 1H), 1.76–1.46 (m, 4H), 1.40–1.23 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 161.9 (C), 143.4 (C), 133.5 (C), 130.5 (CH), 130.2 (CH), 128.7 (CH), 127.0 (CH), 124.5 (C), 124.1 (C), 122.4 (CH), 122.0 (CH), 86.5 (CH), 69.5 (CH₂), 38.3 (CH₂), 32.2 (CH₂), 20.0 (CH₂), 19.5 (CH₂), 14.1 (CH₃), 14.0 (CH₃) ppm; IR ν 2957, 2932, 2870, 1759, 1459, 1092, 727 cm⁻¹; LRMS (EI) m/z (%) = 265 (M⁺ − C₃H₆, 12), 250 (9), 235 (37), 206 (100), 151 (9).

6-(2-Methyltetrahydrofuran-2-yl)phenanthridine (3af). Following the general procedure, compound 3af was obtained after column chromatography (hexane/EtOAc 99 : 1–9 : 1) as a colorless oil (43 mg, 0.16 mmol, 33%): R_f 0.75 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 9.14 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.53 (dd, J = 8.1, 1.5 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.78 (ddd, J = 8.1, 6.6, 1.2 Hz, 1H), 7.72–7.58 (m, 3H), 4.14–4.03 (m, 1H), 3.80–3.69 (m, 1H), 3.66–3.56 (m, 1H), 2.10–1.88 (m, 3H), 1.83 (s, 3H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 163.1, 142.9, 134.0, 130.4, 130.0, 129.3, 128.4, 126.9, 126.6, 124.4, 124.1, 122.4, 121.9, 88.7, 68.1, 37.4, 28.2, 25.2 ppm; IR ν 3065, 2970, 2930, 2872, 1570, 1097, 758 cm⁻¹; LRMS (EI) m/z (%) = 263 (M⁺, 18), 235 (48), 207 (86), 179 (55), 85 (100); HRMS (EI) calcd for C₁₈H₁₇NO 263.1310, found 263.1308.

6-(5-Methyltetrahydrofuran-2-yl)phenanthridine (3′af). From the same reaction where compound 3af was obtained, and after column chromatography (hexane/EtOAc 99 : 1–9 : 1), isomer 3′af was isolated as a white solid (26 mg, 0.10 mmol, 21%) [trans/cis mixture in a 58 : 42 ratio (¹H-NMR)]): R_f 0.75 (9 : 1 hexane/EtOAc); ¹H-NMR (400 MHz, CDCl₃) δ 8.62 (d, J = 8.3 Hz, 1.10H), 8.53 (d, J = 8.2 Hz, 1.51H), 8.46 (d, J = 7.9 Hz, 0.6H), 8.21–8.15 (m, 1H), 7.81 (ddt, J = 8.3, 7.0, 1.3 Hz, 1.09H), 7.75–7.59 (m, 3.58H), 5.91 (t, J = 6.9 Hz, 0.58H), 5.69 (t, J = 7.1 Hz, 0.42H), 4.53–4.43 (m, 0.64H), 4.37–4.27 (m, 0.47H), 2.91–2.73 (m, 1.06H), 2.52–2.42 (m, 0.62H), 2.42–2.27 (m, 1.02H), 2.27–2.14 (m, 0.44H), 1.87–1.67 (m, 1.5H), 1.39 (dd, J = 6.1, 3.3 Hz, 3H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 159.9 (C), 159.2 (C), 143.34 (C), 143.28 (C), 133.43 (C), 133.42 (C), 130.5 (CH), 130.4 (CH), 128.6 (CH), 128.6 (CH), 127.3 (CH), 127.3 (CH), 127.0 (CH), 126.9 (CH), 126.7 (CH), 125.1 (C), 124.9 (C), 124.3 (C), 124.2 (C), 122.5 (CH), 122.4 (CH), 122.0 (CH), 80.6 (CH), 79.2 (CH), 76.1 (CH₂), 33.9 (CH₂), 33.2 (CH₂), 30.6 (CH₂), 30.0 (CH₂), 21.6 (CH₃), 21.4 (CH₃) ppm; IR ν 3074, 2971, 2929, 2877, 2861, 1583, 1444, 1073, 725 cm⁻¹; LRMS (EI) m/z (%) = 263 (M⁺, 11), 220 (72), 208 (100), 179 (58); HRMS (EI): calcd for C₁₈H₁₇NO 263.1310, found 263.1301.

6-(tert-Butoxymethyl)phenanthridine (3ag)^13c. Following the general procedure, compound 3ag was obtained after column chromatography (hexane/EtOAc 95 : 5–93 : 2) as a yellow solid (53 mg, 0.20 mmol, 40%): R_f 0.24 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.61 (d, J = 8.3 Hz, 1H), 8.53 (td, J = 8.1, 1.3 Hz, 2H), 8.17 (dd, J = 7.8, 1.4 Hz, 1H), 7.87–7.79 (m, 1H), 7.75–7.61 (m, 3H), 5.09 (s, 2H), 1.40 (s, 9H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 158.7 (C), 143.6 (C), 133.4 (C), 130.6 (CH), 130.2 (CH), 128.6 (CH), 127.6 (CH), 127.3 (CH), 127.1 (CH), 125.7 (C), 124.5 (C), 122.2 (CH), 122.0, 74.7 (CH), 66.9 (CH₂), 27.9 (3CH₃) ppm; IR ν 2974, 2932, 1719, 1364, 1145, 760 cm⁻¹; LRMS (EI) m/z (%) = 265 ([(M + 1)⁺ − CH₃], 1), 235 (37), 208 (100), 192 (48), 180 (51), 165 (25).

6-((Benzyloxy)(phenyl)methyl)phenanthridine (3ah). Following the general procedure, compound 3ah was obtained after column chromatography (hexane/EtOAc 99 : 1–98 : 2) as a yellow solid (32 mg, 0.08 mmol, 17%): R_f 0.5 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.65–8.55 (m, 3H), 8.30–8.25 (m, 1H), 7.81–7.66 (m, 3H), 7.57–7.43 (m, 3H), 7.39–7.25 (m, 7H), 7.24–7.19 (m, 1H), 6.27 (s, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 159.9 (C), 143.4 (C), 140.8 (C), 138.3 (C), 133.9 (C), 130.5 (CH), 130.5 (CH), 128.8 (CH), 128.4 (CH), 128.3 (CH), 128.0 (CH), 127.7 (CH), 127.4 (CH), 127.1 (CH), 126.3 (CH), 124.5 (C), 124.3 (C), 122.3 (CH), 122.1 (CH), 86.5 (CH), 71.7 (CH₂) ppm; IR ν 3060, 3029, 2915, 2850, 1572, 1449, 1067, 722 cm⁻¹. LRMS (EI-DIP) m/z (%) = 284 (M⁺ − C₇H₇, 52), 269 (100), 268 (52), 178 (16), 91 (32); HRMS (EI) calcd for C₂₇H₂₁NO 375.1623, found 375.1605.

6-Benzylphenanthridine (3′ah)²⁶. From the same reaction where compound 3ah was obtained, and after column chromatography (hexane/EtOAc 99 : 1–98 : 2), compound 3′ah was isolated as a yellow solid (62 mg, 0.23 mmol, 46%): R_f 0.5 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 8.56 (br d, J = 8.3 Hz, 1H), 8.51 (dd, J = 8.2, 1.4 Hz, 1H), 8.18 (ddd, J = 9.7, 8.1, 1.3 Hz, 2H), 7.72 (ddd, J = 8.2, 7.0, 1.4 Hz, 2H), 7.61 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.53 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.33–7.28 (m, 2H), 7.26–7.10 (m, 4H), 4.74 (s, 2H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 160.2 (C), 143.8 (C), 139.2 (C), 133.3 (C), 130.4 (CH), 129.9 (CH), 128.7 (CH), 128.6 (2CH), 127.4 (CH), 127.1 (CH), 126.7 (CH), 126.4 (CH), 125.4 (C), 124.0 (C), 122.5 (CH), 122.0 (CH), 43.2 (CH₂) ppm; IR ν 3062, 3025, 1684, 1581, 1362, 723 cm⁻¹. LRMS (EI-DIP) m/z (%) = 269 (M⁺, 41), 268 (M⁺ − 1, 100), 254(6), 134 (11), 57 (6).

6-(1,3-Dihydroisobenzofuran-1-yl)phenanthridine (3ai). Following the general procedure, compound 3ai was obtained after column chromatography (hexane/EtOAc 99 : 1–98: 2) as a yellow crystalline solid (52 mg, 0.17 mmol, 35%): R_f 0.4 (9 : 1 hexane/EtOAc); mp 120–121 °C (3 : 1 EtOAc/MeOH); ¹H-NMR (400 MHz, CDCl₃) δ 8.65 (br d, J = 8.3 Hz, 1H), 8.56 (dd, J = 8.1, 1.4 Hz, 1H), 8.25 (br d, J = 8.3 Hz, 1H), 8.17 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (s, 1H), 7.72 (ddd, J = 8.2, 7.0, 1.6 Hz, 1H), 7.66 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.59 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.41–7.37 (m, 1H), 7.35–7.30 (m, 1H), 7.23–7.13 (m, 2H), 6.97 (t, J = 2.5 Hz, 1H), 5.59 (dd, J = 12.3, 2.7 Hz, 1H), 5.42 (dd, J = 12.3, 2.0 Hz, 1H) ppm; ¹³C-NMR (101 MHz, CDCl₃) δ 158.8 (C), 143.4 (C), 140.9 (C), 139.2 (C), 133.9 (C), 130.7 (CH), 130.4 (CH), 128.7 (CH), 128.0 (CH), 127.5 (CH), 127.3 (CH), 127.3 (CH), 126.6 (CH), 124.6 (C), 124.4 (C), 122.8 (CH), 122.6 (CH), 122.0 (CH), 121.3(CH), 87.8 (CH), 73.8 (CH₂) ppm; IR ν 3074, 2851, 1572, 1027, 720 cm⁻¹. LRMS (EI) m/z (%) = 297 (M⁺, 2), 268 (100), 251 (3), 119 (12); HRMS (EI) calcd for C₂₁H₁₅NO 297.1154, found 297.1141.

6-(1,3,5-Trioxan-2-yl)phenanthridine (3aj). Following the general procedure, compound 3aj was obtained after column chromatography (100% hexane to hexane/EtOAc 8 : 2) as a white solid (96 mg, 0.26 mmol, 52%): R_f 0.2 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 9.10–9.04 (m, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.60–8.55 (m, 1H), 8.23–8.18 (m, 1H), 7.90–7.83 (m, 1H), 7.79–7.67 (m, 1H), 6.48 (s, 1H), 5.50 (q, J = 6.5 Hz, 4H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 153.6 (C), 142.8 (C), 134.0 (C), 131.0 (CH), 130.6 (CH), 128.9 (CH), 128.3 (CH), 128.1 (CH), 127.4 (CH), 125.0 (C), 123.7 (C), 122.2 (₂CH), 106.1(CH), 94.2 (2CH₂) ppm; IR ν 3037, 2884, 1418, 1199, 1100, 1047, 944, 750, 723 cm⁻¹; LRMS (EI) m/z (%) = 267 (M⁺, 1), 208 (67), 179 (100), 151 (31); HRMS (EI) calcd for C₁₆H₁₃NO₃ 267.0895, found 267.0879.

6-(Benzo[d][1,3]dioxol-2-yl)phenanthridine (3ak). Following the general procedure, compound 3ak was obtained after column chromatography (hexane/EtOAc 99 : 1–98 : 2) as a white crystalline solid (90 mg, 0.3 mmol, 60%): R_f 0.49 (9 : 1 hexane/EtOAc); mp 105–107 °C (MeOH); ¹H-NMR (300 MHz, CDCl₃) δ 8.64 (br d, J = 8.3 Hz, 1H), 8.56 (dd, J = 8.0, 1.4 Hz, 1H), 8.30–8.21 (m, 2H), 7.82 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.79–7.66 (m, 2H), 7.60 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.43 (s, 1H), 7.04–6.91 (m, 4H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 152.5 (C), 147.5 (2C), 142.9 (C), 133.9 (C), 130.9 (2CH), 129.0 (CH), 128.4 (CH), 127.7 (CH), 125.9 (CH), 125.0 (C), 123.8 (C), 122.6 (CH), 122.3 (2CH), 122.1 (CH), 112.2 (CH), 109.4 (2CH) ppm; IR ν 3078, 2909, 1479, 1338, 1229, 724 cm⁻¹; LRMS (EI) m/z (%) = 299 (M⁺, 2), 270 (100), 241 (9), 178 (7); HRMS (EI) calcd for C₂₀H₁₃NO₂ 299.0946, found 299.0949.

Phenanthridine (4a)^13a. This compound was obtained as the by-product of 3aa and of all compounds represented in Scheme 3. After purification by column chromatography (hexane/EtOAc 9 : 1), it was isolated as a white solid. R_f 0.25 (9 : 1 hexane/EtOAc); ¹H-NMR (300 MHz, CDCl₃) δ 9.28 (s, 1H), 8.63–8.54 (m, 1H), 8.20 (dd, J = 8.1, 1.3 Hz, 1H), 8.03 (br d, J = 7.9 Hz, 1H), 7.84 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.78–7.63 (m, 2H) ppm; ¹³C-NMR (75 MHz, CDCl₃) δ 153.7 (CH), 144.6 (C), 132.7 (C), 131.1 (CH), 130.3 (CH), 128.9 (CH), 128.8 (CH), 127.6 (CH), 127.2 (CH), 126.5 (C), 124.2 (C), 122.3 (CH), 122.0 (CH) ppm; IR ν 2924, 2851, 1457, 1245, 890, 745 cm⁻¹; LRMS (EI) m/z (%) = 179 (M⁺, 100), 151 (13), 76(100), 179 (8).

Acknowledgements

We thank the Ministerio de Economia y Competitividad (CTQ2015-66624-P) and the University of Alicante (VIGROB-173) for financial support. C. A.-T. thanks the ISO for a grant.

Notes and references

1. Examples can be found in: O. B. Abdel-Halim, T. Morikawa, S. Ando, H. Matsuda and M. Yoshikawa, J. Nat. Prod., 2004, 67, 1119.
2. (a) Y. L. Janin, A. Croisy, J.-F. Riou and E. Bisagni, J. Med. Chem., 1993, 36, 3686; (b) S. D. Fang, L. K. Wang and S. M. Hecht, J. Org. Chem., 1993, 58, 5025; (c) T. Nakanishi, M. Suzuki, A. Saimoto and T. Kabasawa, J. Nat. Prod., 1999, 62, 864; (d) I. Slaninova, K. Pencikova, J. Urbanova, J. Slanina and E. Taborska, Phytochem. Rev., 2014, 13, 51.
3. T. Ishikawa, Med. Res. Rev., 2001, 21, 61.
4. (a) X. Yang, Y. Yao, Y. Qin, Z. Hou, R. Yang, F. Miao and L. Zhou, Chem. Pharm. Bull., 2013, 61, 731; (b) J. Hu, X. Shi, J. Chen, X. Mao, L. Zhu, L. Yu and J. Shi, Food Chem., 2014, 148, 437.
5. E. Vanquelef, M. Amoros, J. Boustie, M. A. Lynch, R. D. Waigh and O. Duval, J. Enzyme Inhib. Med. Chem., 2004, 19, 481.
6. F. Miao, X.-J. Yang, Y.-N. Ma, F. Zheng, X.-P. Song and L. Zhou, Chem. Pharm. Bull., 2012, 60, 1508.
7. M. Zhang, L. Liu, H. Xiao, T. Zhao, L. Yang and X. Xu, J. Heterocycl. Chem., 2016, 53, 234.
8. H. Lecoeur, Exp. Cell Res., 2002, 277, 1.
9. (a) N. Stevens, N. O'Connor, H. Vishwasrao, D. Samaroo, E. Kandel, D. L. Akins, C. M. Drain and N. J. Turro, J. Am. Chem. Soc., 2008, 130, 7182; (b) Y. Chen, W. Huang, C. Li and Z. Bo, Macromolecules, 2010, 43, 10216.
10. For pioneer studies, see: (a) D. Nanni, P. Pareschi, C. Rizzoli, P. Sagarabotto and A. Tundo, Tetrahedron, 2010, 51, 9045; (b) M. Tobisu, K. Koh, T. Furukawa and N. Chatani, Angew. Chem., Int. Ed., 2012, 51, 11363.
11. For a recent comprehensive review, see: B. Zhang and A. Studer, Chem. Soc. Rev., 2015, 44, 3505.
12. For some selected examples, see: (a) T. Yoshimitsu, Y. Arano and H. Nagaoka, J. Org. Chem., 2005, 70, 2342; (b) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X. Wan, Chem. – Eur. J., 2011, 17, 4085; (c) G. S. Kumar, B. Pieber, K. R. Reddy and C. O. Kappe, Chem. – Eur. J., 2012, 18, 6124; (d) Z.-Q. Liu, L. Zhao, X. Shang and Z. Cui, Org. Lett., 2012, 14, 3218; (e) S.-R. Guo, Y.-Q. Yuan and J.-N. Xiang, Org. Lett., 2013, 15, 4654; (f) D. Liu, C. Liu, H. Li and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 4453.
13. (a) J.-J. Cao, T.-H. Zhu, S.-Y. Wang, Z.-Y. Gu, X. Wang and S.-J. Ji, Chem. Commun., 2014, 50, 6439; (b) L. Wang, W. Sha, Q. Dai, X. Feng, W. Wu, H. Peng, B. Chen and J. Cheng, Org. Lett., 2014, 16, 2088; (c) C. Pan, J. Han and Z. ChengJian, Sci. China: Chem., 2014, 57, 1172; (d) During the preparation of the manuscript, the following paper was published: Y. Xu, Y. Chen, W. Li, Q. Xie and L. Shao, J. Org. Chem., 2016, 81, 8426.
14. For reviews on the synthesis of oxacyclic natural products, see: (a) E. Kang and E. Lee, Chem. Rev., 2005, 105, 4348; (b) T. Nakata, Chem. Rev., 2005, 105, 4314.
15. F. Agapito, B. J. Costa Cabral and J. A. Martinho Simoes, J. Mol. Struct.: THEOCHEM, 2005, 719, 109.
16. For a recent review, see: X.-F. Wu, J.-L. Gong and X. Qi, Org. Biomol. Chem., 2014, 12, 5807.
17. A similar result was observed by the group of Ji (ref. 13a) with 1,4-dioxane and TBPB as the oxidant.
18. This regiochemistry was observed by the group of Chen, using 1,4-dioxane and BPO as the oxidant. A plausible explanation is given in ref. 13b.
19. For selected examples, see: (a) T. Akindele, Y. Yamamoto, M. Maekawa, H. Umeki, K.-I. Yamada and K. Tomioka, Org. Lett., 2006, 8, 5729; (b) I. Hayakawa, H. Watanabe and H. Kigoshi, Tetrahedron, 2008, 64, 5873.
20. It is worth noting that compound 4a is significantly formed with TBPB in the absence of base (ref. 13a and checked by us in Table 1, entry 7); or with BPO in neutral media (ref. 13b and checked by us in Table 1, entry 1).
21. S. Z. Zard, Radical Reactions in Organic Synthesis, Oxford University Press, 2003, pp. 26–30.
22. (a) A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2011, 50, 5018; (b) For a recent excellent review, see: A. Studer and D. P. Curran, Nat. Chem., 2014, 6, 765.
23. The following rate constants are reported for α-hydrogen abstraction of THF: k (t-BuO˙) ∼ 8.3 × 10⁶vs. k (PhCOO˙) ∼ 2.5 × 10³ M⁻¹ s⁻¹. See: J. Fossy, D. Lefort and J. Sorba, Free Radicals in Organic Chemistry, John Wiley & Sons, 1995, p. 290.
24. B. Zhang, C. Mück-Lichtenfeld, C. D. Daniliue and A. Studer, Angew. Chem., Int. Ed., 2013, 52, 10792.
25. An intramolecular electrophilic aromatic substitution might also be considered as a plausible pathway for the formation of byproduct 4a. Due to the extremely high acidity of cyclohexadienyl radical I, a proton transfer to the isonitrile moiety of 1a would form a cationic intermediate that could undergo Friedel–Crafts-type cyclization to give 4a.
26. Z. Liang, L. Ju, Y. Xie, L. Huang and Y. Zhang, Chem. – Eur. J., 2012, 18, 15816.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details for mechanistic studies and copies of NMR spectra. See DOI: 10.1039/c6ob02103d

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