Multi-bond forming and iodo-selective base-promoted homolytic aromatic substitution

Abstract

Base-promoted homolytic aromatic substitution (BHAS) has been applied as a means to effect multi-bond forming reactions. Using the dioxepine framework to illustrate the concept, BHAS was used to rapidly access regio-defined polycycles in merely 2 or 3 steps from iodophenol. Both liquid and solid arenes of an electronically-diverse nature were used as the coupling partner/solvent. DMSO additive was found to promote this multi-BHAS reaction. A pathway consistent with these observations is suggested, this hypothesis was exploited to further develop an iodo-selective BHAS reaction.

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Introduction

Since Ullmann's copper-mediated synthesis of the biaryl bond, this most crucial¹ of carbon–carbon connections has been the subject of extensive synthetic advances. As a result, most methods which have been developed for the construction of multiple biaryl bonds in a single operation have hitherto relied on transition metal-catalysis. Arguably the most promising metal-free alternative² to established transition metal-mediated methods of cross-catalysis³ and C–H functionalization⁴ is the recently-discovered Base-promoted Homolytic Aromatic Substitution (BHAS). BHAS features the use of a tert-butoxide base⁵ alongside a sub-stoichiometric amount of diamine (or other) initiator to generate aryl radical species^6a and is a hot topic in the contemporary iteration of a ‘radical renaissance’.^6b

Multi-bond forming reactions⁷ provide expedient, selective and often high-yielding access to desirable targets and synthetic intermediates with minimal expenditure of chemical resources. Early BHAS work has demonstrated its potential to generate multiple C–C bond formations via twofold substitutions^5b,c,8,9 and showcased interesting cyclizations.¹⁰ Initial multi-BHAS examples have been restricted to substitution of two halide functional handles upon a single arene core with benzene as coupling partner (Scheme 1); further advances appear not to have been made on this aspect of BHAS methodology to date. In this work, a multi-bond forming methodology has been developed to effect both an intramolecular BHAS to a tethered arene and an intermolecular BHAS with the arene solvent/reactant. Uniquely for multi-bond forming BHAS reactions: (i) the two reactive halo-functionalities of the multi-bond forming reaction are located on separate arenes; (ii) the H-arene is not limited to benzene; and (iii) conditions have been found for effective control of iodo- (over bromo-) arene selectivity. Mechanistic reasoning suggests that this reaction may comprise elements of each ‘domino’ and ‘multi-bond forming transformation of independent’ reactions.^7d

Scheme 1 Existing and new classes of BHAS transformation.

Break-through publications on transition metal-free, alkali-metal tert-butoxide-promoted C–H substitutions have been contributed by Itami and co-workers^5a and the groups of Hayashi and Shirakawa,^5b Lei and Kwong,^5c and Shi.^5d The literature has since seen a rapidly-increasing interest in BHAS, which has demonstrated that it may be promoted photolytically⁹ or with a variety of additives¹¹ to effect cyclization,¹⁰ arene–arene coupling,¹² and Heck-like substitution.¹³ Studer and Curran described^6a the mechanism of this homolytic aromatic substitution as a radical chain-reaction, where the electron is passed from reactant to reactant¹⁴ – i.e. the ‘electron is a catalyst’.^6c The source of the initial electron (the initiation step) in this reaction is the subject of some debate – several suggestions have been made.¹⁵

Inspired by both the ‘lactone method’¹⁶ and the innovative early BHAS cyclization work of Charette and co-workers,^10a the ‘acetal method’ is a strategy for the synthesis of 2,2′(ortho,ortho-)biphenols via dibenzo[1,3]dioxepines utilizing BHAS for the key ring-closing reaction.¹⁷ Expanding on this initial work, non-symmetrical aryl-substituted dibenzo[1,3]dioxepines were chosen as targets to explore BHAS in the context of multi-bond forming reactions.

Results

Synthesis of non-symmetrical and symmetrical di(haloaryloxy)methylene ethers by the previously-reported method^17b saw conversion of 4-iodophenol to the mixed O,S-methylene diether, 2 (Scheme 2), which was substituted in a two-stage one-pot reaction with sulfuryl chloride and then 2-bromophenol, delivering bromoaryl-iodoarene 4 in 84% yield (over 2 steps). This sequence with 2-iodophenol led to 2,4′-diiodoaryloxy ether 6 (79% over 2 steps). 2-Iodophenol was also converted to 2,3′-diiodoaryloxy methane 10 (by way of 8, 87%, two steps) and to bis-(2-iodoaryloxy)methane 7 (93%, one step).

Scheme 2 Dihaloarene substrates for multi-bond forming BHAS. Conditions: (a) NaH, then ClCH₂SCH₃, DMF, r.t.; (b/i) SO₂Cl₂, CH₂Cl₂, r.t., (ii) halophenol, NaH, DMF, r.t., then mixture from (b/i) in DMF; (c) NaH, CH₂I₂, DMF, r.t.

The cascade reaction was explored utilizing 2-bromophenoxy-4′-iodophenoxymethane, 4, with the conditions optimised by Charette¹⁸ and previously successful for the simple cyclization to dioxepines: potassium tert-butoxide (6.0 equiv., i.e. 3.0 equivalents per halogen moiety), 1,10-phenanthroline (80%) at 140 °C with benzene and pyridine as substrate and solvent, respectively (ratio = 1 : 7, entry 1, Table 1). These initial conditions proved to be unsatisfactory, as only traces of desired product 11 were observed. Using benzene as both solvent/reactant delivered the multi-BHAS compound in 23% yield, albeit as part of a complex mixture of at least four identifiable products (11–14). These (by)products result from coupling and 7-ortho-cyclization (11),^17b and de-halogenation (12),¹⁹ then 6-ipso-cyclization^10a then C → O transposition²⁰ and elimination of formaldehyde (to 13),^17b and aryl alkoxylation by nucleophilic or radical aromatic substitution (14).¹⁹ Change of the substrate to diiodide 6 gave an improved ratio between the products (entry 3), but the yield of 11 remained low (21%).

Table 1 Optimization of the multi-bond forming BHAS^a

Entry, substrate	Solvent	Conc. (M)	DMSO (equiv.)	Time (h)	11 (%)	12 (%)	13 (%)	14 (%)
a Conditions: 1,10-phen. (80 mol%), KOtBu (6.0 equiv.), Ar–H (20–40 equiv.), DMSO (5.0 equiv.), microwave irradiation (MWI), 140 °C. All yields are isolated. *1,10-Phenanthroline was excluded. ND = none detected.
1, 4	Pyr./PhH (7 : 1)	0.25	—	120	ND	24	ND	ND
2, 4	C6H6	0.25	—	240	23	5	12	50
3, 6	C6H6	0.125	—	120	21	12	11	30
4, 6	C6H6	0.125	5.0	240	59	19	14	ND
5, 6*	C6H6	0.125	5.0	240	ND	ND	ND	ND

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Rossi and co-workers have discovered that DMSO improves BHAS yields under photoactivation at room temperature.⁹ Happily, when a small amount of DMSO was included as an additive with the conditions above (5.0 equiv., entry 4), the outcome of this thermally-promoted reaction was also greatly improved in terms of yield and selectivity. DMSO additive increased the isolated yield of cascade product 11 from 59%, and prevented generation of alkoxy-substituted byproduct 14. A control experiment with DMSO in the absence of 1,10-phenanthroline showed that DMSO alone is not capable of promoting the reaction (entry 5).

With satisfactory conditions determined, the cascade BHAS was then applied to cyclization/coupling with several electronically-diverse arene partners. Complementing the usual use of liquid arenes (benzene and 1,4-difluorobenzene) some of these were solids at room temperature (1,4-dimethoxybenzene, pyrazine, naphthalene, Scheme 3). Physical separation of the base and initiator in distinct layers of the reaction vessel prior to heating ensured that the reaction did not commence until the arene was liquefied (see Fig. 1, ESI†). Diiodides 6 and 7 produced 2- and 4-aryl-substituted dioxepines 15–18 and 19–24a/b in moderate to good yields (50–71%, Scheme 3), and meta-iodo substrate 10 gave a mixture of each of the two possible products (24a/b). Coupling of symmetrical diiodide 7 with benzene to afford 20 was notably poor in yield (38%-unsubstituted dioxepine was consistently isolated in 12–14% yield). These yields are satisfactory when considered in light of the two discrete C–C bond forming events that must take place. All 4 possible Ph-substituted isomers (11, 20, 24a and 24b) were isolated and characterized.

Scheme 3 Multi-bond forming to aryl-substituted dibenzo[1,3]dioxepines. Conditions: 1,10-phen. (80 mol%), KOtBu (6.0 equiv.), Ar–H (10–30 equiv.), DMSO (5.0 equiv.), MWI, 140 °C, 4 h.

Although multiple equivalents of arene are used in this method, the low cost of these coupling partners makes their use nonetheless advantageous. In contrast with typical cross-coupling substrates to form biaryls (aryl-zincs, -boronic acids, etc.), standard H-arenes not requiring preactivation or in situ preparation, are cheap,²¹ non-toxic, do not require careful preparation, and are readily to hand in most chemistry laboratories.

Discussion

A reaction pathway accounting for observations and isolated byproducts is proposed (Scheme 4). EPR studies have demonstrated the generation of radicals in BHAS reactions,^22a,b and a recent report by Jutand and Lei has investigated the reaction with cyclic voltametry.^22c Single-electron-transfer (SET) is thought to initially result in a radical anion located upon the haloarene – the observed non-reactivity of substrate 6 in the presence of 1,4-dinitrobenzene an established radical anion scavenger,²³ further supports the role of a radical anion (see Scheme 3).

Scheme 4 Proposed mechanism for the multi-BHAS to form 11–14.

The multi-BHAS from diiodoaryl 6 exhibits a uniform arene-coupling outcome at the (formerly iodo-bearing) C-(para) position, whereas there are at least four modes of reaction for the C-(ortho) position, as evidenced by the products isolated (their distribution varies with reaction conditions, see Table 1). These results suggest that in addition to the most straightforward ortho-σ-radical pathway to 11 via initially-cyclised 26,²⁴ there is some degree of independently-operating pathway where initial substitution is at the apparently more reactive para-iodo-substituted position of 6 to form radical intermediate 25 then 28. This cyclohexadienyl radical undergoes rapid transfer of its (extremely acidic) proton^25,22a then either intramolecular ET (to 29 then 11) or intermolecular ET to another iodoarenyl moiety on a different molecule (6 or 30), and continuation of the chain process. Intermediate ortho-σ-type radical 29 can apparently follow one of four divergent pathways: pathway 1 involves 7-ortho cyclization to also result in 11, pathway 2 sees 6-ipso cyclization, then C → O transposition and loss of ‘CH₂O’ to (relatively) stable phenoxyl radical then phenol 13, in pathway 3 the ortho-σ-radical abstracts hydrogen or is quenched to anion with another free electron in situ then protonated, giving 12. Lastly, butoxyl substituted 14 may be generated by either a radical^19a or nucleophilic aromatic substitution^11m,19b pathway, from 29 or 30, respectively (or perhaps both).^19c Having previously established that 2-bromo substrate 4 gave more of t-butyl ether 14 than 2-iodo 6 (see Table 1), the latter pathway is suggested. It is likely that the pathways from substrates 7 and 10 are similarly complex.

The role of DMSO co-solvent in promoting formation of 11 and suppressing the side-reactions to, e.g. tert-butoxyl substituted arene 14, is not yet clear, but may be to enhance the domino pathway over the ‘multiple independent reaction’ pathway. Visually, these reactions exhibited a more rapid formation of the dark coloration linked to initiation, and enhanced radical-initiation is a strong possibility.

The addition of KOt-Bu to DMSO rapidly forms an equilibrium mixture with t-BuOH/dimsyl potassium superbase (KCH₂SOCH₃, 34, Scheme 5).²⁶ In the presence of 1,10-phenanthroline, the potassium dimsyl salt may be chelating to form a potassium amide superbase 38 analogous to 1,3-diaminopropane which makes KAPA (potassium 3-aminopropy-1-amide, 36)^27a still more basic than potassium dimsyl by a factor of 10⁵ to 10⁶.^27b Such a species may undergo an inner-sphere electron-transfer to form phen˙⁻ and tBuO˙ as suggested by Lei and Jutand,^22c or perhaps promote the formation of the attractive super electron donor 39, proposed by Tuttle and Murphy, which requires deprotonations of 1,10-phenanthroline, 37.^15a To present a further possibility, Wilden and co-workers have recently described a dynamic equilibrium between ‘nearly-covalent’ KOt-Bu (29), its charge-separated form (39a), and a charge separated form with a loosely-bound electron (40a), which alone can provide for the initial SET to the haloarene at elevated temperatures (160 °C).²⁸ It may be the case that a shifting in the equilibrium position to favor the latter of these species (39 and 40) is enhanced in the presence of cation-stabilising DMSO. An alternative is that the dimsyl potassium superbase, which is a strong electrolyte itself,²⁹ also has a loosely-bound electron form which can be donated. Regardless, the effect of DMSO addition is enhancement of the pathway to 11, outcompeting that to 14.

Scheme 5 Possible roles of DMSO in promoting the BHAS initiation.

Given the postulated mechanism above, it was hoped that the reaction conditions could be tuned so as to block reactivity of the 2-halo position upon the initially-used bromoaryl species 4. Selectivity for the p-iodo functionality BHAS was convincingly obtained by excluding the DMSO additive, decreasing the reaction temperature to 100 °C, and shortening the duration of the reaction to 60 minutes, conditions which maintained the 2′-bromoaryl functionality intact (43–46, 50–86% yield). Chemo-/regio-selective control is so far poorly controllable in the BHAS reaction, but could allow for sequential BHAS/BHAS and BHAS/TM-catalysis coupling sequences, e.g. in divergent synthesis. The scope of para-iodo-selective coupling partners matched that of the multi-BHAS (Scheme 6).

Scheme 6 Iodoarene-selective BHAS in the presence of a bromoarene moiety. Conditions: 1,10-phen. (40 mol%), KOtBu (3.0 equiv.), Ar–H (20–40 equiv.), MWI, 100 °C, 1 h.

Conclusion

The BHAS reaction should be considered a synthetic option when multi-bond forming reactions are desired for rapid, modular generation of polycycles or other compounds with multiple biaryl connections. A multi-BHAS approach can work well, eschewing the use of transition-metals. Iodo-selective conditions were also established to allow attachment of only one arene to the scaffold, leaving the bromoarene intact for a host of potential subsequent reaction methods. The multi-bond and stepwise BHAS methods make use of relatively cheap and environmentally benign substrates/reagents, and thus holds promise for efficient transformations in chemical Industry, decreasing costs ‘on scale’ and precluding trace amounts of toxic transition metals. Continuation of studies focusing on the further scope of the multi-bond forming BHAS and role of DMSO is currently underway in the laboratory.

Experimental section

General experimental

Chemicals and solvents were used as commercially supplied without further purification, unless otherwise noted. Potassium tert-butoxide (95%), 1,10-phenanthroline (99%), sodium hydride (60% dispersion in mineral oil), dimethyl sulfoxide (Reagentplus ≥99.5% purity), chloromethyl methylsulfide (95%), 1,4-dimethoxybenzene (99%), pyrazine (≥99%), naphthalene (99+%), sulfuryl chloride (97%) and dimethylformamide (99.5%, anhydrous) were supplied by Aldrich. Benzene (analytical reagent grade, obtained from Chemsupply Australia) was dried over anhydrous molecular sieves prior to use. Optimal results for this methodology required the storage of potassium tert-butoxide in a desiccator, and commercially-available 1,10-phenanthroline was dried of water prior to use by addition of dry toluene azeotroping out on the rotavap (repeat ×2). Microwave reactions were performed in a Biotage Initiator⁺ with a maximum power of 400 W, reactions were in new vials with securely-sealed (crimped) microwave tubes. Column chromatography was performed on Davisil (LC60A, 40–63 μm Grace). Preparative HPLC was performed on an Agilent HPLC with a C₁₈ column (25 × 200 mm) using tetrahydrofuran and water (both HPLC grade, Merck). NMR data were recorded on a Varian Infinity-Plus 400 spectrometer (¹H at 400 MHz; ¹³C at 100 MHz), and resonances are reported in terms of chemical shift (δ) in parts per million (ppm) referenced to the solvent peak; coupling constants (J) are given in Hertz (Hz) and the number of protons per signal as nH. Splitting is reported as br. = broad, s = singlet, d = doublet and m = multiplet.

General procedures (1–4)

Multi-bond BHAS reactions with arenes (solids at room temperature). To a 2–5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially 1,10-phenanthroline (72 mg, 0.40 mmol), half the solid arene (10–20 mmol), the halo-substituted substrate (0.50 mmol), DMSO (195 mg, 2.5 mmol), the second half of the arene substrate (10–20 mmol) and lastly potassium tert-butoxide (336 mg, 3.0 mmol) under a shower of argon. The reagents were layered with portions of arene separating them, such that the phenanthroline and potassium tert-butoxide did not come into contact until such time as the arene has melted (see Fig. 1 in the ESI†). The vial was capped and the atmosphere cautiously removed by vacuum through an inserted needle with stirring, then replaced with argon (repeat three times). The reaction mixture was then heated to 140 °C via microwave irradiation for 240 minutes (reactions involving pyrazine were brought to this temperature with 10 minutes ramp time to ensure that exotherms did not occur). After this time, the blackish-coloured reaction mixture was allowed to cool to room temperature, then layered onto a plug of silica gel, which was then flushed with ethyl acetate (150 mL). The volatiles were removed by rotary evaporation under diaphragm pump vacuum (to 30 Mbar), then the crude was purified by column chromatography on silica gel with mixtures of hexane and co-eluent (see specific compounds for details).

Multi-bond BHAS reactions with arenes (liquids at room temperature). To a 2–5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially the 1,10-phenanthroline (72 mg, 0.40 mmol) the dihalo-substituted substrate (0.50 mmol) and potassium tert-butoxide (336 mg, 3.00 mmol) and anhydrous benzene (40 mmol) or 1,4-difluorobenzene (2.5 g, 22 mmol) added, followed by DMSO (195 mg, 2.50 mmol). The vial was capped and cooled 0 °C and the atmosphere cautiously removed by vacuum through an inserted needle with stirring, then replaced with argon (repeat three times). The reaction mixture was then heated to 140 °C via microwave irradiation for 240 minutes (reactions involving pyrazine were brought to this temperature with 10 minutes ramp time to ensure that exotherms did not occur). After this time, the blackish-coloured reaction mixture was allowed to cool to room temperature, then layered onto a plug of silica gel, which was then flushed with ethyl acetate (150 mL). The volatiles were removed by rotary evaporation under diaphragm pump vacuum (to 30 Mbar), then the crude was purified by column chromatography on silica gel with mixtures of hexane and co-eluent (see specific compounds for details).

Iodo-selective BHAS reactions with arenes (solids at room temperature). To a 2–5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially 1,10-phenanthroline (36 mg, 0.20 mmol), half the solid arene (10–20 mmol), the halo-substituted substrate (0.50 mmol), the second half of the arene substrate (10–20 mmol) and lastly potassium tert-butoxide (168 mg, 1.5 mmol) under a shower of argon. The reagents were layered with portions of arene separating them, such that the phenanthroline and potassium tert-butoxide did not come into contact until such time as the arene has melted (see labelled photograph). The vial was capped and the remainder of the procedure carried out as in general procedure 1, except that the reaction mixture was only heated to 100 °C for 60 minutes.

Iodo-selective BHAS reactions with arenes (liquids at room temperature). To a 2–5 mL microwave vial (Biotage) fitted with a stirring bar were added sequentially the 1,10-phenanthroline (36 mg, 0.20 mmol) the dihalo-substituted substrate (0.50 mmol) and potassium tert-butoxide (168 mg, 2.00 mmol) and anhydrous benzene (30 mmol) or 1,4-difluorobenzene (2.5 g, 22 mmol) added, followed by DMSO (195 mg, 2.50 mmol). The vial was capped and cooled 0 °C and the atmosphere cautiously removed by vacuum through an inserted needle with stirring, then replaced with argon (repeat three times). The remainder of the procedure carried out as in general procedure 2, except that the reaction mixture was only heated to 100 °C for 60 minutes.

Preparation of specific compounds

Compound 2/((4-iodophenoxy)methyl) (methyl)sulfane. To a dried 250 mL round-bottomed flask fitted with a stirring bar and maintained under a positive pressure of argon were added 4-iodophenol (11.0 g, 50.0 mmol), DMF (50 mL) and the two stirred to −5 °C in a salt/ice bath. Sodium hydride (2.40 g, 60.0 mmol, 1.2 equiv., 60% dispersion in mineral oil) was added under argon and the reaction mixture stirred until gas evolution had ceased (∼10 minutes) and then allowed to warm up to room temperature (∼20 minutes), before recooling. To the opaque reaction mixture was added dropwise chloromethyl methyl sulfide (5.0 mL, 60.0 mmol, 1.2 equiv.) and the reaction mixture stirred at room temperature for 12–14 hours. After this time, the mixture was poured into H₂O (300 mL) and extracted with CH₂Cl₂/hexanes (1 : 1, 150 mL, ×2). The organics were washed with H₂O (200 mL × 2), brine (50 mL) and dried over sodium sulfate. Filtration and removal of the volatiles by rotary evaporation under diaphragm pump vacuum (to 30 Mbar) followed, then the crude was purified by column chromatography on silica gel with hexane/CH₂Cl₂ (9 : 1). Isolated as a colourless semi-solid, 13.14 g, 46.9 mmol, 94% yield. MP: ca. room temperature; ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (dt, J = 9.0, 2.0 Hz, 2H), 6.73 (dd, J = 9.0, 2.3 Hz, 2H), 5.11 (s, 2H), 2.23 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.8, 138.3, 118.3, 84.2, 72.4, 14.6; LRMS (+EI, GCMS): found 280.0; HRMS (+EI): calculated [C₈H₉IOS]˙⁺: 279.9419; found:279.9419.

Compound 4/1-bromo-2-((4-iodophenoxy)methoxy)benzene..
Stage 1. Prepared in a 2-stage pseudo-1-pot reaction from compound 2 and 2-bromophenol by a modification of the method of Masters and Bräse (two stages, 89%).¹⁷ To a stirred solution of [(4-iodophenoxy)methyl] (methyl)sulfane 2 (1.40 g, 5.00 mmol) in dry CH₂Cl₂ (25 mL) under argon in a 100 mL round-bottomed flask held at −5 °C in a salt/ice bath was added dropwise sulfuryl chloride (410 mL, 5.125 mmol, 1.025 equiv.). The ice bath was removed and the reaction mixture was stirred up to room temperature over 60 minutes, becoming pale-yellow. After this time the volatiles were removed by rotary evaporation under diaphragm pump vacuum (to 30 Mbar; this should be done with a rotary evaporator in a fume-cupboard). The crude product is invariably obtained with complete conversion and in quantitative yield, and can be checked if desired (¹H-NMR, CDCl₃). This crude material was taken up in dry, non-hydrolyzed or amine-free DMF and added directly to the deprotonated phenols in stage 2.
Stage 2. To a stirred solution of 2-bromophenol (951 mg, 5.5 mmol, 1.1 equiv.) in dry, non-hydrolyzed or amine-free DMF (27.5 mL) under argon and at 0 °C was added sodium hydride (240 mg, 6.0 mmol, 1.2 equiv., 60% dispersion in mineral oil) and the mixture stirred for 30 minutes with warming to room temperature. After re-cooling to 0 °C, the aryloxymethylenechloride from stage 1 was added dropwise as a solution in DMF (5.0 mL, 2 mL washings). After stirring overnight, the reaction mixture was heated at 50 °C for 4 hours, then poured into H₂O (70 mL) and extracted with CH₂Cl₂/hexanes (1 : 1, 50 mL, ×2). The combined organics were washed with H₂O (50 mL × 2), then brine (20 mL) and dried over sodium sulfate. Filtration and removal of the volatiles by rotary evaporation under diaphragm pump vacuum (to 30 Mbar) followed, then the crude was purified by column chromatography on silica gel with hexane/CH₂Cl₂ (9 : 1). Isolated as a colourless oil which solidified overnight, recrystallization from MeOH/CH₂Cl₂ yielded the compound as colourless needles, 1.80 g, 4.45 mmol, 89% yield. MP: 40–42 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.57 (m, 2H), 7.54 (dd, J = 1.6, 7.8 Hz, 1H), 7.30–7.26 (m, 1H), 7.23–7.16 (m, 1H), 6.98–6.85 (m, 3H), 5.74 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.8, 153.2, 138.4, 133.6, 128.5, 124.0, 118.8, 116.7, 113.1, 91.4, 85.3; LRMS (+EI, GCMS): found 403.9; HRMS (+EI): calculated [C₁₃H₁₀BrIO₂]˙⁺: 403.8903; found: 403.8909.

Compound 6/1-iodo-2-((4-iodophenoxy)methoxy)benzene. Prepared in a 2-stage pseudo-1-pot reaction from compound 2 and 2-iodophenol (two steps, 84%) by a close modification of the procedure to prepare compound 4. Starting from ((4-iodophenoxy)methyl)(methyl)sulfane 2 (2.45 g, 8.75 mmol), compound 6 was delivered as colourless needles, 3.98 g, 7.35 mmol, 84% yield. MP: 85–86 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.76 (dd, J = 1.6, 7.8 Hz, 1H), 7.66–7.53 (m, 2H), 7.29 (ddd, J = 1.6, 7.2, 8.4 Hz, 1H), 7.13 (dd, J = 1.2, 8.2 Hz, 1H), 6.96–6.88 (m, 2H), 6.78 (dt, J = 1.4, 7.5 Hz, 1H), 5.72 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.7, 155.5, 139.6, 138.4, 129.5, 124.4, 118.8, 115.2, 91.2, 87.2, 85.3; LRMS (+EI, GCMS): found 451.9; HRMS (+EI): calculated [C₁₃H₁₀I₂O₂]˙⁺: 451.8765; found: 451.8770.

Compound 7/bis(2-iodophenoxy)methane. To a stirred solution of 2-iodophenol (2.50 g, 12.3 mmol) in dimethylformamide under argon was added potassium carbonate (4.23 g, 30.6 mmol, 2.50 equiv.) then methyl iodide (0.77 mL, 1.75 g, 12.3 mmol. 2.0 eq.), and the resulting reaction mixture heated to 40 °C with stirring for 12 h. After this time, the reaction mixture was partitioned between H₂O and diethyl ether (each 30 mL) and the aqueous phase extracted with diethyl ether twice more. The combined organics were washed with H₂O (30 mL) once more, then with brine (5 mL) and dried over sodium sulphate. The volatiles were removed by rotary evaporation under diaphragm pump vacuum (to 30 Mbar), then the crude was purified by column chromatography on silica gel with hexane and CH₂Cl₂ (8 : 1). Isolated as a colourless solid, recrystallization from MeOH/CH₂Cl₂ yielded the compound as colourless needles, 5.18 g, 93% yield. MP: 94–95 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.79 (d, J = 7.8 Hz, 2H), 7.39–7.32 (m, 2H), 7.28 (s, 2H), 6.81 (t, J = 7.6 Hz, 2H), 5.82 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 155.7, 139.6, 129.7, 124.4, 115.5, 91.7, 87.1; LRMS (+EI, GCMS): found 451.9; HRMS (+EI): calculated [C₁₃H₁₀I₂O₂]˙⁺: 451.8765; found: 451.8768.

Compound 8/((2-iodophenoxy)methyl) (methyl)sulfane. Prepared by modification of the procedure to prepare compound 2. 2-Iodophenol (5.50 g, 25.0 mmol.) was converted to compound 9, isolated as a colourless liquid, 6.52 g, 23.3 mmol, 93% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (dd, J = 7.8, 2.0 Hz, 1H), 7.26–7.34 (m, 1H), 6.88 (dd, J = 8.4, 1.4 Hz, 1H), 6.75 (td, J = 7.5, 1.4 Hz, 1H), 5.20 (s, 2H), 2.28 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ = 155.5, 139.7, 129.2, 123.6, 114.3, 87.8, 73.3, 14.; LRMS (+EI, GCMS): found 280.1; HRMS (+EI): calculated [C₈H₉IOS]˙⁺: 279.94188; found: 279.9422.

Compound 10/1-iodo-2-((3-iodophenoxy)methoxy)benzene. Prepared in a 2-stage pseudo 1-pot reaction from compound 8 and 3-iodophenol (two steps, 84%) by a close modification of the procedure to prepare compound 4. Starting from ((4-iodophenoxy)methyl)(methyl)sulfane 9 (2.67 g, 9.5 mmol), compound 10 was delivered as colourless needles, 4.27 g, 8.93 mmol, 94% yield. MP: 40 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.31 (td, J = 8.6, 2.0 Hz, 1H), 7.10–7.17 (m, 2H), 7.03 (dd, J = 8.6, 7.4 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 5.74 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.3, 155.4, 139.7, 131.8, 130.9, 129.5, 125.8, 124.4, 115.8, 115.2, 94.2, 91.1, 87.2; LRMS (+EI, GCMS): found 451.9; HRMS (+EI): calculated [C₁₃H₁₀I₂O₂]˙⁺: 451.8765; found: 451.8770.

Compound 11/2-phenyldibenzo[d,f][1,3]dioxepine. Chromatography was performed with CH₂Cl₂ in hexane fraction as eluent (gradient, 0% to 10%). Isolated as a colourless oil, 81.0 mg, 0.295 mmol, 59% yield. ¹H NMR (400 MHz, CDCl₃) δ = 7.85 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 1.4, 7.6 Hz, 1H), 7.63–7.57 (m, 2H), 7.51 (dd, J = 2.3, 8.2 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.38–7.29 (m, 2H), 7.27–7.19 (m, 2H), 7.17 (dd, J = 1.2, 8.2 Hz, 1H), 5.64 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 155.5, 154.6, 140.7, 137.7, 129.6, 129.2, 129.1, 128.9, 128.8, 127.7, 127.6, 127.3, 127.1, 124.7, 121.3, 121.0, 99.3; LRMS (+EI, GCMS): found 274.1; HRMS (+EI): calculated [C₁₉H₁₄O₂]˙⁺: 274.0988; found: 274.0988.

Compound 12/4-(phenoxymethoxy)-1,1′-biphenyl. Isolated from the test reaction to produce 2-phenyldibenzo[d,f][1,3]dioxepine (compound 11) after continuation of the column with CH₂Cl₂ in hexane fraction as eluent (gradient, 0% to 10%, eluted just prior to the dioxepine). Isolated as a colourless oil, 16.7 mg, 0.060 mmol, 12% yield. ¹H NMR (400 MHz, CDCl₃) δ = 7.55–7.50 (m, 4H), 7.43–7.38 (m, 2H), 7.33–7.28 (m, 3H), 7.19–7.15 (m, 2H), 7.12 (dd, J = 1.0, 8.8 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 5.76 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.9, 156.4, 140.6, 135.5, 129.6, 128.7, 128.2, 126.9, 126.8, 122.5, 116.7, 116.4, 91.1; LRMS (+EI, GCMS): found 276.1; HRMS (+EI): calculated [C₁₉H₁₆O₂]˙⁺: 276.1150; found: 276.1150.

Compound 13/[1,1′:3′,1′′-terphenyl]-4′-ol. Isolated from the test reaction to produce 2-phenyldibenzo[d,f][1,3]dioxepine (compound 11) after continuation of the column with Et₂O in hexane fraction as eluent (10%). Isolated as a colourless solid, 13.0 mg, 0.054 mmol, 11% yield. ¹H NMR (400 MHz, CDCl₃) δ = 7.72 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.41–7.35 (m, 1H), 7.32–7.22 (m, 2H), 7.05–6.97 (m, 2H), 5.25 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ = 152.5, 140.7, 140.5, 136.0, 130.2, 129.5, 129.2, 128.9, 127.9, 127.7, 127.5, 127.1, 120.9, 115.9; LRMS (+EI, GCMS): found 246.1; HRMS (+EI): calculated [C₁₈H₁₄O]˙⁺: 246.1039; found: 246.1045.

Compound 14/4-((2-(tert-butoxy)phenoxy)methoxy)-1,1′-biphenyl. Isolated from the test reaction to produce 2-phenyldibenzo[d,f][1,3]dioxepine (compound 11) after continuation of the column with Et₂O in hexane fraction as eluent (gradient, 3% to 10%). Isolated as a milky gum, 51.8 mg, 0.149 mmol, 30% yield. ¹H NMR (400 MHz, CDCl₃) δ = 7.49–7.65 (m, 4H), 7.37–7.46 (m, 2H), 7.27–7.36 (m, 1H), 7.03–7.24 (m, 3H), 6.87 (dq, J = 8.2, 1.0 Hz, 1H), 6.80 (t, J = 2.2 Hz, 1H), 6.70 (dq, J = 8.1, 0.9 Hz, 1H), 5.74 (m, 2H), 1.36 ppm (m, 9H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.4, 156.6, 156.4, 140.7, 135.5, 129.5, 129.2, 128.7, 128.2, 126.9, 126.8, 118.1, 116.7, 112.5, 111.3, 91.1, 78.7, 28.8; HRMS (+EI, GCMS): found 348.2 (11%), 333 (8%), 292.1 (100%), 183.1 (85%); HRMS (+EI): calculated [C₂₃H₂₄O₃]˙⁺: 348.1720; found: 348.1727.

Compound 15/2-(dibenzo[d,f][1,3]dioxepin-2-yl)pyrazine. Prepared by general procedure 1. Chromatography was performed with (CH₃)₂CO in hexane fraction (12.5%) as eluent. Isolated as a colourless waxy solid, 93.4 mg, 0.338 mmol, 68% yield. ¹H NMR (400 MHz, CDCl₃) δ = 9.06 (br. s, 1H), 8.63 (br. s, 1H), 8.51 (br. s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 2.2, 8.4 Hz, 1H), 7.82 (dd, J = 1.2, 7.8 Hz, 1H), 7.37–7.29 (m, 1H), 7.29–7.23 (m, 2H), 7.16 (dd, J = 1.4, 8.0 Hz, 1H), 5.64 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.7, 156.0, 144.1, 142.7, 141.8, 132.3, 129.2, 128.8, 128.8, 128.2, 127.9, 127.2, 124.7, 121.6, 120.9, 98.6; LRMS (+EI, GCMS): found 276.1; HRMS (+EI): calculated [C₁₇H₁₂N₂O₂]˙⁺: 276.0893; found: 276.0899.

Compound 16/2-(2,5-dimethoxyphenyl)dibenzo[d,f][1,3]dioxepine. Prepared by general procedure 1. Chromatography was performed with (CH₃)₂CO in hexane fraction (12.5%) as eluent. Isolated as a pale brown gum, 84.0 mg, 0.252 mmol, 50% yield. ¹H NMR (400 MHz, CDCl₃) δ = 7.81 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 7.8, 1.2 Hz, 1H), 7.46 (dd, J = 8.2, 2.3 Hz, 1H), 7.27–7.32 (m, 1H), 7.11–7.23 (m, 3H), 6.90–6.95 (m, 2H), 6.83–6.87 (m, 1H), 5.63 (s, 2H), 3.80 (s, 3H), 3.76 ppm (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 155.5, 154.3, 153.7, 150.7, 134.5, 130.9, 130.6, 130.6, 130.0, 129.9, 128.8, 128.8, 128.3, 124.4, 120.8, 120.4, 116.6, 113.0, 112.6, 99.0, 56.3, 55.8; LRMS (+EI, GCMS): found 334.2; HRMS (+EI): calculated [C₂₁H₁₈O₄]˙⁺; 334.1205; found: 334.1206.

Compound 17a and compound 17b. Prepared by general procedure 1. Chromatography was performed with CH₂Cl₂ in hexane fraction as eluent (gradient, 5% to 20%). The 1-napthyl regioisomer (17a) was isolated as a colourless gum, 54.0 mg, 0.15 mmol, 33% yield. Later fractions were combined and subjected to chromatography with toluene in hexane fraction (gradient, 15–30%) to deliver the 2-naphthyl isomer 17b, which was not able to be completely separated from a coupled but not cyclized compound with a mass of 326.1 (as determined by GCMS). Isolated as a colourless gum, 44.8 mg, 0.14 mmol, 28% yield.

Compound 17a/2-(naphthalen-1-yl)dibenzo[d,f][1,3]dioxepine. ¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 6.7 Hz, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.49–7.52 (m, 2H), 7.46–7.48 (m, 3H), 7.42–7.45 (m, 2H), 7.38 (d, J = 1.6 Hz, 1H), 7.31–7.34 (m, 1H), 7.22–7.25 (m, 2H), 6.90 (d, J = 7.4 Hz, 2H), 5.56–5.63 ppm (m, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.2, 154.5, 134.5, 133.8, 133.4, 132.1, 130.9, 129.1, 128.3, 128.0, 127.7, 127.4, 126.8, 126.6, 126.0, 125.8, 125.6, 125.4, 125.2, 122.6, 116.0, 115.5, 91.2 ppm; LRMS (+EI, GCMS): found 324.1; HRMS (+EI): calculated [C₂₃H₁₆O₂]˙⁺: 324.1145; found: 324.1152.

Compound 17b/2-(naphthalen-2-yl)dibenzo[d,f][1,3]dioxepine. ¹H NMR (400 MHz, CDCl₃): δ = 7.91–7.98 (m, 2H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.67–7.70 (m, 1H), 7.49–7.58 (m, 2H), 7.48 (s, 1H), 7.42–7.47 (m, 2H), 7.30–7.34 (m, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.17–7.22 (m, 2H), 5.71 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 155.6, 154.5, 139.5, 136.9, 133.8, 131.7, 130.5, 130.4, 129.0, 128.9, 128.7, 128.6, 128.3, 127.7, 127.0, 126.2, 125.9, 125.8, 125.4, 124.5, 121.0, 120.8, 99.1; LRMS (+EI, GCMS): found: 324.1; HRMS (+EI): calculated [C₂₃H₁₆O₂]˙⁺: 324.1145; found: 324.1152.

Compound 18/2-(2,5-difluorophenyl)dibenzo[d,f][1,3]dioxepine. Prepared by general procedure 2. Chromatography was performed with (CH₃)₂CO in hexane fraction (12.5%) as eluent. Isolated as a colourless oil, 83.4 mg, 0.27 mmol, 54% yield. Caution: Product somewhat volatile from toluene. ¹H NMR (400 MHz, CDCl₃) δ = 7.83 (s, 1H), 7.71 (dd, J = 7.8, 1.6 Hz, 1H), 7.47 (dt, J = 8.5, 1.8 Hz, 1H), 7.30–7.36 (m, 1H), 7.20–7.26 (m, 2H), 7.15–7.20 (m, 2H), 7.12 (dd, J = 9.4, 4.7 Hz, 1H), 6.97–7.05 (m, 1H), 5.65 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 155.7, 155.1, 130.9, 129.5, 129.3, 129.1, 128.7, 128.7, 124.7, 121.2, 120.9, 117.3, 117.1, 116.9, 116.6, 116.4, 115.3, 115.1, 99.0; LRMS (+EI, GCMS): found 310.1; HRMS (+EI): calculated [C₁₉H₁₂F₂O₂]˙⁺: 310.0800: found: 310.0809.

Compound 20/4-phenyldibenzo[d,f][1,3]dioxepine. Prepared by general procedure 2. Chromatography was performed with CH₂Cl₂ in hexane fraction as eluent (gradient, 0% to 10%). Isolated as a colourless waxy solid, 52.6 mg, 0.192 mmol, 38% yield. MP: ¹H NMR (400 MHz, CDCl₃) δ = 7.64 (dd, J = 1.8, 7.6 Hz, 1H), 7.62–7.58 (m, 1H), 7.58–7.53 (m, 2H), 7.48–7.42 (m, 2H), 7.42–7.38 (m, 2H), 7.32 (s, 2H), 7.31–7.26 (m, 1H), 7.20 (dd, J = 1.2, 7.8 Hz, 1H), 5.52 (s, 2H); ¹³C NMR (101 MHz, CDCl₃) δ = 153.8, 151.5, 137.9, 134.7, 132.2, 130.9, 130.3, 129.5, 129.2, 129.1, 128.1, 128.0, 127.3, 125.0, 124.8, 121.0, 101.0; HRMS (+EI, GCMS): found 274.1; HRMS (+EI): calculated (C₁₉H₁₄O₂⁺): 274.0988; found: 274.0998.

Compound 21/2-(dibenzo[d,f][1,3]dioxepin-4-yl)pyrazine. Prepared by general procedure 1. Chromatography was performed with MeOH in CH₂Cl₂ as eluent (gradient, 0.5% to 1.0%). Isolated as a pale-beige gum, 98 mg, 0.356 mmol, 71% yield. ¹H NMR (400 MHz, CDCl₃): δ = 9.06 (s, 1H), 8.69 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 7.80–7.75 (m, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.44–7.34 (m, 3H), 7.29 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 5.64 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 154.0, 152.3, 151.7, 145.9, 144.2, 142.7, 132.2, 130.3, 130.3, 130.1, 129.4, 129.1, 125.3, 124.9, 121.0, 116.2, 100.9; LRMS (+EI, GCMS): found 276.0; HRMS (+EI): calculated [C₁₇H₁₂N₂O₂]˙⁺: 276.0893; found: 276.0900.

Compound 22/4-(2,5-dimethoxyphenyl)dibenzo[d,f][1,3]dioxepine. Prepared by general procedure 1. Chromatography was performed with EtOAc in hexane fraction as eluent (gradient, 2% to 5%). A second column was required for complete isolation; CH₂Cl₂ in hexane fraction (gradient, 40% to 50%). Isolated as a colourless waxy solid, 96.2 mg, 0.288 mmol, 57% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (dd, J = 1.8, 7.6 Hz, 2H), 7.34–7.25 (m, 2H), 7.25–7.20 (m, 2H), 7.13 (dd, J = 7.8, 1.2 Hz, 1H), 6.92–6.85 (m, 2H), 6.82 (d, J = 2.0 Hz, 1H), 5.52 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ = 154.0, 153.3, 152.7, 151.2, 131.5, 131.2, 130.6, 129.9, 129.2, 129.0, 128.2, 128.1, 124.5, 124.3, 120.9, 117.0, 113.5, 111.9, 100.2, 56.2, 55.7; LRMS (+EI, GCMS): found 334.2; HRMS (+EI): calculated [C₂₁H₁₈O₄]˙⁺; 334.1205; found: 334.1205.

Compounds 23a and 23b. Prepared by general procedure 1. After initial separation of two main components containing 23a and 23b, (initial yield: 112 mg, 70% yield, ratio of 1-naphthyl to 2-naphthyl = 7 : 3, respectively). Further separated with CH₂Cl₂ in hexane (gradient, 12–20%) to deliver 23a. The earlier-eluting fraction was subjected to chromatography with toluene in hexane fraction (gradient, 15–30%) to deliver the 2-naphthyl isomer 23b, which was not able to be completely separated from a coupled but not cyclized compound with a mass of 326 (as determined by GCMS).

Compound 23a/4-(naphthalen-1-yl)dibenzo[d,f][1,3]dioxepine. MP: 143–145 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (dd, J = 3.9, 8.2 Hz, 2H), 7.69 (ddd, J = 1.8, 3.7, 7.4 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.57–7.52 (m, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.46–7.41 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.37–7.27 (m, 4H), 7.14 (dd, J = 1.4, 7.6 Hz, 1H), 5.32 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ 154.0, 152.2, 136.1, 133.5, 133.4, 132.4, 131.8, 131.3, 130.9, 129.1, 129.0, 128.3, 128.1, 127.9, 127.1, 126.2, 126.0, 125.8, 125.2, 124.8, 124.7, 121.0, 101.0. LRMS (+EI, GCMS): found 324.2; HRMS (+EI): calculated [C₂₃H₁₆O₂]˙⁺: 324.1145; found: 324.1149.

Compound 23b 4-(naphthalen-2-yl)dibenzo[d,f][1,3]dioxepine. ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (s, 1H), 7.86–7.92 (m, 3H), 7.60–7.71 (m, 3H), 7.47–7.54 (m, 3H), 7.34–7.40 (m, 2H), 7.30 (d, J = 7.83 Hz, 1H), 7.18 (d, J = 7.83 Hz, 1H), 5.48–5.52 (m, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 153.8, 151.6, 135.4, 134.6, 133.3, 132.5, 132.3, 130.5, 129.2, 129.0, 128.4, 128.1, 128.1, 127.9, 127.6, 127.4, 127.1, 126.1, 126.0, 125.1, 124.8, 121.0, 100.9; LRMS (+EI, GCMS): found 324.2; HRMS (+EI): calculated [C₂₃H₁₆O₂]˙⁺: 324.1145; found: 324.1149.

Compounds 24a and 24b. Prepared by general procedure 1. Chromatography was performed on silica gel with toluene in hexane fraction as eluent (gradient, 20% to 30%) delivered first 44a then 44b, as well as some of the 4-phenyl coupled but not cyclised side product (15%). Caution: Products somewhat volatile from toluene.

Compound 24a/1-phenyldibenzo[d,f][1,3]dioxepine. Isolated as a colourless oil, 47 mg, 0.172 mmol, 34% yield. ¹H NMR: δ = 7.77 (dd, J = 9.8, 8.6 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.48 (dd, J = 7.8, 5.1 Hz, 3H), 7.40–7.42 (m, 1H), 7.35 (td, J = 5.1, 1.6 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.66 (d, J = 0.8 Hz, 2H); ¹³C NMR (chloroform-d, 101 MHz): δ = 155.8, 155.7, 141.8, 139.7, 139.7, 129.6, 129.1, 128.9, 128.8, 128.6, 127.7, 124.4, 122.9, 122.9, 120.9, 119.2, 98.4; HRMS (+EI): calculated [C₁₉H₁₄O₂]˙⁺: 274.0988; found: 274.0992.

Compound 24b/3-phenyldibenzo[d,f][1,3]dioxepine. Isolated as a colourless solid, 24.5 mg, 0.091 mmol, 18% yield. ¹H NMR: δ = 7.41 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.4, 1.2 Hz, 1H), 7.24–7.28 (m, 4H), 7.22–7.23 (m, 1H), 7.18–7.21 (m, 3H), 6.86 (ddd, J = 7.8, 6.3, 2.0 Hz, 1H), 6.66–6.69 (m, 1H), 5.64–5.66 (m, 2H); ¹³C NMR: δ = 153.3, 141.9, 140.6, 131.9, 131.8, 131.0, 129.9, 128.8, 128.6, 128.2, 128.1, 127.9, 126.9, 124.2, 121.0, 120.2, 102.7; HRMS (+EI): calculated [C₁₉H₁₄O₂]˙⁺: 274.0988; found: 274.0997.

Compound 43/4-((2-bromophenoxy)methoxy)-1,1′-biphenyl. Prepared by general procedure 4. Chromatography was performed with CH₂Cl₂ in hexane fraction as eluent (gradient, 8% to 20%). Isolated as a colourless oil, 108 mg, 0.304 mmol, 61% yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.54 (d, J = 9.0 Hz, 5H), 7.39–7.44 (m, 2H), 7.29–7.34 (m, 1H), 7.26–7.28 (m, 2H), 7.20–7.24 (m, 2H), 6.90–6.95 (m, 1H), 5.81 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.3, 153.4, 140.5, 135.6, 133.5, 128.7, 128.5, 128.2, 126.9, 126.8, 123.7, 116.7, 116.6, 113.0, 91.5; HRMS (+EI): calculated [C₁₉H₁₅BrO₂]˙⁺: 354.0250; found: 354.0253.

Compound 44/2-(4-((2-bromophenoxy)methoxy)phenyl)pyrazine. Prepared by general procedure 3. Chromatography was performed with acetone in hexane fraction as eluent (gradient, 12.5% to 17.5%). Isolated as an off-white amorphous solid, 124 mg, 0.347 mmol, 69% yield. ¹H NMR (400 MHz, CDCl₃): δ = 8.98 (d, J = 0.8 Hz, 1H), 8.59 (dd, J = 2.3, 1.6 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.98–8.03 (m, 2H), 7.55 (dd, J = 7.8, 1.2 Hz, 1H), 7.25–7.32 (m, 4H), 6.90–6.97 (m, 1H), 5.84 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 158.4, 153.3, 152.3, 144.1, 142.4, 141.8, 133.6, 130.7, 128.5, 128.4, 124.0, 116.9, 116.8, 113.2, 91.2; HRMS (+EI): calculated [C₁₇H₁₃BrN₂O₂]˙⁺: 356.0155; found: 356.0162.

Compound 45/4′-((2-bromophenoxy)methoxy)-2,5-dimethoxy-1,1′-biphenyl. Prepared by general procedure 3. Chromatography was performed with EtOAc in hexane fraction as eluent (gradient, 2% to 5%). A second column was required for complete isolation; CH₂Cl₂ in hexane fraction (gradient, 25% to 50%). Isolated as a colourless solid, 105 mg, 0.253 mmol, 50% yield. MP: 62–64 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.56 (dd, J = 8.0, 0.9 Hz, 1H), 7.50–7.53 (m, 2H), 7.25–7.31 (m, 2H), 7.22 (d, J = 8.5 Hz, 2H), 6.88–6.96 (m, 3H), 6.84 (dd, J = 8.6, 3.4 Hz, 1H), 5.79–5.84 (m, 2H), 5.81 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.1, 153.7, 153.5, 150.7, 133.5, 132.7, 131.0, 130.7, 128.5, 123.7, 116.7, 116.6, 116.0, 113.0, 112.8, 112.5, 91.5, 56.3, 55.8; HRMS (+EI): calculated [C₂₁H₁₉BrO₄]˙⁺; 414.0461; found: 414.0469.

Compounds 46a and 46b. Prepared by general procedure 3. Chromatography was performed on silica gel with CH₂Cl₂ in hexane fraction as eluent (gradient, 5% to 10%), by which the 1-naphthyl and 2-naphthyl isomers were separable save a small mixed fraction between the two. The second compound was further cleaned by running on silica gel with toluene in hexane (gradient, 10% to 25%). Isolated as colourless solids, 176 mg, 0.43 mmol, 87% yield; 1-Np to 2-Np ratio = 6 : 4.

Compound 46a/1-(4-((2-bromophenoxy)methoxy)phenyl)naphthalene. Isolated as a colourless solid, 85 mg, 0.21 mmol, 42% yield. MP: 80–82 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.47–7.54 (m, 2H), 7.39–7.47 (m, 4H), 7.30–7.36 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 5.87 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.3, 153.5, 139.6, 135.1, 133.8, 133.6, 131.7, 131.3, 128.6, 128.3, 127.5, 127.0, 126.0, 126.0, 125.8, 125.4, 123.8, 116.7, 116.3, 116.3, 113.1, 91.6; HRMS (+EI): calculated [C₂₃H₁₇BrO₂]˙⁺: 404.0406; found: 404.0410.

Compound 46b/2-(4-((2-bromophenoxy)methoxy)phenyl)naphthalene. Isolated as a colourless solid, 69 mg, 0.172 mmol, 34% yield. MP: 73–75 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (s, 1H), 7.88 (q, J = 8.2 Hz, 3H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 7.66–7.70 (m, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.44–7.52 (m, 2H), 7.26–7.31 (m, 4H), 6.91–6.97 (m, 1H), 5.84 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ = 156.5, 137.9, 135.6, 135.6, 133.7, 133.5, 132.4, 128.6, 128.5, 128.4, 128.1, 127.6, 126.3, 125.8, 125.4, 125.3, 123.8, 116.8, 116.8, 113.1, 91.6; HRMS (+EI): calculated [C₂₃H₁₇BrO₂]˙⁺: 404.0406; found: 404.0408.

Acknowledgements

This work was supported by a Vice-Chancellor's Research Fellowship from the Queensland University of Technology. Mass spectra were acquired by Ms Anithahini (Anitha) Jeyasingham with support from Prof. Stephen Blanksby and QUT's Central Analytical Facility (CARF). K.-S. M. acknowledges valuable mentoring from Prof. Steven Bottle and Prof. Stefan Bräse.

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Footnote

† Electronic supplementary information (ESI) available: Full ¹H and ¹³C NMR spectra for 26 new compounds and a representation showing the set-up for coupling of solid at room-temperature arenes (Fig. S1) is compiled in a word document. See DOI: 10.1039/c5ra03460d

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