Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone

Abstract

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

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Introduction

Alicyclic ring-fused benzimidazolequinones are potent anti-tumour agents (Scheme 1a), studied as synthetic alternatives to mitomycin C.^1–4 Cerium(IV) ammonium nitrate oxidizes p-dimethoxybenzenes to p-benzoquinones,⁵ and to dimeric adducts.⁶ Bis-chloromethylbenzimidazolequinone 1 was reported in 38% yield (Scheme 1b) from the oxidation of 2-(chloromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole using CAN (2.9 equiv.).⁷ Bis-p-quinone 1 exhibited greater cytotoxicity against solid tumour cell lines than monomeric benzimidazolequinones. Recently, the CAN oxidation of 4,7-dimethoxybenzimidazole alkoxyamine 2 was used to give the bis-benzimidazolequinone 3 (Scheme 1c).⁸ Dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) 4a was obtained in high yield (86%) when using less CAN, and in contrast to bis-p-quinone 3, DMBBQ 4a was insensitive to light. Radical trifluoromethylation of 4a using Langlois’ reagent (NaSO₂CF₃) occurred at the quinone to give 4b in 54% yield.⁸

Scheme 1 Development of DMBBQs as precursors to difunctionalized bis-benzimidazolequinones.

Elemental chlorine and bromine are corrosive, toxic, and ordinarily inconvenient for synthesis. The useful halogen is however generated in situ from the oxidation of a benign and inexpensive alkali metal halide.⁹ Oxone (2KHSO₅·KHSO₄·K₂SO₄) is a stable, safe and cheap external oxidant.¹⁰ The active ingredient of Oxone is potassium peroxymonosulfate (KHSO₅) and when accompanied by stoichiometric equivalents of halide (NaX) can generate molecular halogen (X₂) for electrophilic chlorination and bromination (Scheme 1d). The halide with Oxone gives oxidative transformations with an accompanying halogenation of naphthols and phenols,¹¹ and with and without halogenation for indoles.^12,13 Other metal-free oxidations, such as N-bromosuccinimde (NBS) with a small amount of H₂SO₄,^14,15 and PhI(OCOCF₃)₂ (PIFA),^8,16,17 are reported to induce conversion of p-dimethoxybenzenes to p-quinones without halogenation. The disadvantage of using NBS and PIFA is the generation of organic waste products. Moreover, the combination of H₂O₂ with HX gives chlorinated and brominated alicyclic [1,2-a] ring-fused benzimidazolequinones from p-dimethoxybenzene precursors.¹⁸ The accompanying aromatic halogenation is considered advantageous, since it offers further functionalization opportunities. However, unlike monomeric benzimidazoles, milder room-temperature conditions are required for Cl₂ and Br₂ generation when using DMBBQs as the substrates (see below), which led us to use NaX/Oxone. The use of Oxone is unprecedented in oxidative demethylations to give p-quinones. Herein, we disclose selective chlorination and bromination of novel CAN-derived alicyclic ring-fused DMBBQs at the aromatic site, despite possible activation at the quinone (Scheme 1e). Electrophilic aromatic halogenation of DMBBQs 5a–5d (Scheme 1f) is accompanied by one-pot quinone formation.

Results and discussion

Five to seven-membered alicyclic ring-fused dimethoxybenzimidazoles 6a–6c are readily available,¹⁷ and used to prepare new DMBBQs 5a–5c. DMBBQ 5b was prepared in 73% yield by optimizing the conditions for CAN-oxidation of 6b in MeCN/H₂O (Scheme 2).^5–8 The latter solvent system also gave pyrido[1,2-a]benzimidazolequinone 7 in 15% yield. Replacing the MeCN with hexafluoroisopropanol (HFIP) improved the yield of the required DMBBQ 5b to 87% with no monomeric benzimidazolequinone 7 detected. Similar high yields (88 and 84%) using HFIP/H₂O were obtained for the formation of pyrrolo- and azepino ring-fused DMBBQs 5a and 5c from 6a and 6c, respectively. The formation of 7 requires the intervention of a water molecule at the CAN generated radical cation to prevent dimerization.^6,18 The persistence of radical cation intermediates in HFIP,¹⁹ and their shielding from water due to the formation of heterogeneous environments,²⁰ may account for the exclusive CAN-mediated dimerization.

Scheme 2 Synthesis of alicyclic ring-fused DMBBQs.

DMBBQs 5a–5c were insufficiently crystalline for X-ray crystallography. However, the premise for the regioselective halogenation was supported by the preparation of bis(chloromethyl)-substituted DMBBQ 8 (76% yield), in an analogous fashion to 1 (see above),^7,8 but using less CAN (2.0 equiv.). The crystal structure of dimethylchloride 8 showed that the aromatic and quinone rings adopt an out-of-plane conformation with respect to each other (Scheme 3 and Fig. S1†). The torsion angle (θ) of 67.6° describes the angle between the planes of the benzimidazole and benzimidazolequinone, which prevents effective orbital overlap over both rings, ruling out resonance activation of the 6-quinone position. Cyclic voltammetry and TD-DFT on DMBBQ 4a, provides further support for the site-selectivity for the electrophilic substitution with localized HOMO and LUMO at the respective dimethoxybenzimidazole and benzimidazolequinone motifs.⁸

Scheme 3 Evidence for MeO-activation at only the aromatic-CH.

Chlorination of pyrrolo-fused dimer 5a was initially attempted using H₂O₂ with HCl under conditions which mediated the regioselective chlorination of anilines (Table 1).¹⁷ Reaction monitoring by TLC indicated the complete consumption of 5a after 1 h of reflux, but a low yield of 7′-chloride 9a (21%) was attributed to the formation of intractable baseline decomposition products. The requirement for milder conditions, led us to investigate the room temperature Oxone/NaCl reaction.

Table 1 Optimization^a

Entry	NaCl (mmol)	KHSO5 ^b (mmol)	Solvent	Yield^c (%) of 9a	Yield^c (%) of 10a
a Conditions: DMBBQ 5a (0.20 mmol), MeCN or HFIP (2 mL), H2O (0.1 mL). b Used as Oxone. c Isolated yields. Values in parentheses recovered 5a. d H2O2 (4 mmol), HCl (0.20 mmol), MeCN (2 mL), reflux, 1 h. e Intractable mixture. f 16 h. g HFIP (2 mL), H2O (0.2 mL), 9 h.
1^d	—	—	MeCN	21	0^e
2	0.20	0.24	MeCN/H2O	39 (52)	0
3	0.20	0.24	HFIP/H2O	51 (43)	0
4	0.40	0.24	HFIP/H2O	79	12
5^f	0.80	0.80	HFIP/H2O	15	71
6^g	0.80	0.80	HFIP/H2O	0	89

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Addition of an aqueous solution of NaCl (1 equiv.) and Oxone (KHSO₅, 1.2 equiv.) to 5a in MeCN gave chloride 9a in 39% yield, with column chromatography providing 52% recovery of 5a (Table 1). Polyfluorinated alcohols improve yields for NaCl/Oxone-mediated aliphatic and aromatic chlorinations,²¹ and are known to accelerate aromatic chlorination in systems that generate in situ Cl₂.²² The reaction solvent was thus changed from MeCN to HFIP, with a greater consumption of substrate 5a observed, and 9a isolated in an improved yield of 51%. The highest yield of 9a (79%) after 5 h was obtained using a greater amount of NaCl (2 equiv.) with chlorination also accompanied by oxidation to give the bis-p-quinone 10a in 12% yield. Cl₂ and water are responsible for conversion of the p-dimethoxybenzimidazole to benzimidazolequinone.¹⁸ Thus, optimized conditions for one-pot chlorination and quinone formation were achieved by increasing the amount of KHSO₅ (4 equiv.) and NaCl (4 equiv.), so increasing the likelihood of NaCl reaction with HOCl, over HOCl reaction with the substrate 5a (Scheme 1d). These conditions favoured Cl₂ formation and gave bis-benzimidazolequinone 10a in 71% yield, with an increase in water from 5 to 10% relative to HFIP giving exclusively 10a in 89% yield after 9 h.

The conditions which favored selective chlorination over quinone formation (entry 4, Table 1) were applied to pyrido and azepino-ring fused DMBBQs 5b and 5c to respectively give 9b (75%) and 9c (72%) (Method A, Scheme 4). In these cases, column chromatography removed co-eluting mixtures of substrates 5b and 5c with respective bis-p-quinones 10b and 10c. The optimized conditions for quinone formation (entry 6, Table 1) were applied to 5b and 5c to respectively give 10b and 10c in isolated yields of 88 and 74%, with only the latter giving some dimethoxybenzene intermediate, 9c in 12% yield (Method B, Scheme 4).

Scheme 4 Halogenation and quinone formation. Conditions: Method A is the same as Table 1, entry 4. Method B is the same as Table 1, entry 6. Isolated yields. ^a X-ray crystal structure (Fig. S2†) with thermal ellipsoids set at 50% probability, except for the hydrogen atoms at a fixed radius of 0.2 Å. The torsional angle highlighted is 79.2°. ^b Inseparable with 5b or 5c.

NaBr replaced NaCl to facilitate regioselective bromination of 5a–5c (using entry 4, Table 1 conditions). There was a marginal decrease in the tendency for bromination compared to chlorination. Complete consumption of 5a occurred with the difference in R_f values allowing separation of 7′-bromo-DMBBQ 11a from bis-p-quinone 12a by column chromatography in respective yields of 76% and 10% (Method A, Scheme 4). X-ray crystallographic structure determination for 11a supported the site for bromination (Scheme 4 and Fig. S2†).

Under the same conditions, the pyrido- and azepino[1,2-a]-fused dimers 5b and 5c gave selectively brominated DMBBQs 11b and 11c in respective yields of 68% and 71%. In a similar manner to the chlorinations, ring-expanded DMBBQs 5b and 5c were less reactive towards bromination than the pyrrolo-fused DMBBQ 5a with unreacted material separated by column chromatography as inseparable mixtures with respective bis-p-quinones 12b and 12c. One-pot bromination and quinone formation (entry 6, Table 1 conditions) gave mostly the brominated dimeric quinones 12a–12c (69–75% yield), however column chromatography separated some dimethoxybenzimidazole intermediates 11a–11c (13–22% yield). The lower yields (with Method B) of brominated quinones 12a–12c are presumably due to the inferior oxidizing ability of Br₂ relative to Cl₂.²³ The presence of a red-brown vapour in the NaBr/Oxone-mediated oxidative brominations is evidence for the in situ formation of Br₂ (Fig. S3†).

Functionalization at both available alicyclic ring-fused DMBBQ CH-positions was established. Trifluoromethylation at the quinone of 5b gave substrate 5d in a similar moderate yield (51%, Scheme 5) to that reported for DMBBQ 4b.⁸ Using the Langlois’ reagent, intractable baseline products were observed and Baran et al. have attributed peroxide reaction with sulfinate as a significant wastage reaction.²⁴ The ˙CF₃ radical is considered weakly nucleophilic,²⁵ and reported CH-alkylations occur at the ‘electron-poor’ quinone.^26,27 Chlorination with quinone formation to give the fully functionalized bis-p-quinone 14 can be carried out in one or two steps with 5d depending on the desire to isolate more of the intermediate chloride 13. Using the optimized conditions for chlorination only (Table 1, entry 4 conditions) gave 13 in 73% yield, with the regioselectivity confirmed by the X-ray crystal structure (Scheme 5 and Fig. S4†). The torsional angle is almost identical to that of 8, indicating the substituents of 13 have no influence on the adopted solid-state geometry. Oxidation of isolated DMBBQ 13 using NaCl and Oxone gave bis-p-quinone 14 in 85% yield. Increasing the amount of NaCl and Oxone to favour one pot oxidative chlorination (Table 1, entry 6 conditions), gave bis-p-quinone 14 from 5d in 68% yield, with some intermediate DMBBQ 13 (19%) separated by column chromatography. The smaller yields for chlorides 13 and 14 reflect the deactivation of the trifluoromethylated DMBBQs 5d and 13 towards the electrophilic oxidizing mixture.

Scheme 5 Radical and electrophilic functionalization.

NaX/Oxone system is clearly an efficient system for ring-fused DMBBQs, allowing one-pot halogenation and quinone formation. The reality is transformations developed for our specific heterocyclic system (ring-fused DMBBQs) are not readily transferable to other similar systems. According to the literature,²⁸ halogenation using NaX/Oxone would not be site-selective where there are other available heterocyclic CH-positions, e.g. the non-functionalised imidazole-2-position. Nevertheless, future work will aim to take advantage of the difference in reactivity between the two DMBBQ-CHs to increase scope to other site-selective functionalizations.

Conclusions

New alicyclic [1,2-a] ring-fused DMBBQs undergo one-pot electrophilic aromatic substitution and oxidative demethylation to give halogenated bis-p-quinones using the harmless and inexpensive NaX/Oxone system. The tuneable system gives mainly the site-selective chlorination and bromination intermediate at lower halogen concentrations. The torsion angle in DMBBQs supports the chemoselectivity by lack of MeO-activation at the quinone-CH. HFIP enhances the oxidative aromatic halogenation and for the first time is used in CAN-mediated oxidative aromatic couplings, which formed DMBBQs. Overall, this article details the synthesis in good to excellent yields of new ring-fused bis-benzimidazolequinone heterocyclic systems, and provides reliable late-stage methods for incorporating two different substituents into bis-p-quinones.

Experimental

Materials

All chemicals obtained from commercial sources used as received. 5,8-Dimethoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (6a), 6,9-dimethoxy-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole (6b), and 1,4-dimethoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole (6c) were prepared in 89%, 72% and 91% yield respectively, according to our reported oxidative ring-closure of the appropriate 3,6-dimethoxy-2-(cycloamino)aniline.¹⁷ 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole-6,9-dione (7) has melting point, chromatographic and spectroscopic data consistent with that previously reported.²⁹ 2-(Chloromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole was prepared in 85% yield by N-methylation and chlorination of (4,7-dimethoxy-1H-benzimidazol-2-yl)methanol.⁸ Thin layer chromatography (TLC) was performed on TLC silica gel 60 F₂₅₄ plates. Flash column chromatography was carried out on silica gel (Apollo Scientific 60/40–63 μm) and dry column vacuum chromatography used Apollo Scientific silica gel (ZEOprep 60 and 15–35 µm particle size).³⁰

Measurements

All melting points were measured on a Stuart Scientific melting point apparatus SMP1. IR spectra were recorded using a PerkinElmer Spec 1 with ATR attached.

All NMR spectra were recorded using a Bruker Avance III 400 MHz spectrometer equipped with a 5 mm BBFO+, broadband autotune probe and controlled with TopSpin 3.5.7 acquisition software and IconNMR 5.0.7 automation software Copyright © 2017 Bruker BioSpin GmbH. The exception was 2,2′-bis(chloromethyl)-4′,7′-dimethoxy-1,1′-dimethyl-1H,1′H-[5,5′-bibenzimidazole]-4,7-dione (8) recorded on a JEOL ECX 400 MHz NMR spectrometer equipped with a DEC AXP 300 computer workstation. The chemical shifts are in ppm relative to TMS. ¹³C NMR spectra at 100 MHz are with complete proton decoupling. NMR assignments are supported by DEPT-135. ¹⁹F NMR spectra were obtained at 376 MHz using automatic digital lock correction in the absence of an internal standard.

HRMS spectra were obtained at the National Mass Spectrometry Facility at Swansea University using a Waters Xevo G2-S or Thermo Scientific LTQ Orbitrap XL 1 mass spectrometer with an Atmospheric Solids Analysis Probe (ASAP), except for DMBBQ 8 obtained at NUI Galway using ESI time-of-flight mass spectrometer (TOFMS) in positive mode using a Waters LCT Mass Spectrometer. The precision of all accurate mass measurements was better than 5 ppm.

A single crystal of 8 was grown by slow evaporation from 10% MeOH/CH₂Cl₂ at room temperature (Fig. S1†). Single crystal data for 8 was collected at 299 K using an Oxford Diffraction Xcalibur (equipped with a Mo Kα X-ray source and a Sapphire detector) using the CrysAlis^Pro software at NUI Galway.

Single crystals of 7′-bromo-5′,8′-dimethoxy-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,8-dione (11a) and 8′-chloro-6′,9′-dimethoxy-8-(trifluoromethyl)-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,9-dione (13) were grown at room temperature by slow evaporation from 1,2-dichloroethane and vapour diffusion of hexane into 1,2-dichloroethane, respectively (Fig. S2 and S4†). X-ray diffraction data on single crystals of compounds 11a and 13 were collected using an Agilent Oxford Diffraction SuperNova (equipped with a microfocus Cu Kα X-ray source, a Cryojet5®, and an Atlas CCD detector) using the CrysAlis^Pro software at University College London.

The crystal structures of 8, 11a, and 13 were solved using SHELXT³¹ and refined using SHELXL,³² both of which were operated from within either the Oscail³³ or the OLEX2³⁴ software packages. For compound 11a, a split atom model for the disorder of the methoxy group containing atom O(3) was used to model the disorder, which refined to 72.5% for the methyl group of C(13A) compared to 27.5% for the methyl group of C(13B).

Crystallographic data for compounds 8, 11a and 13 were deposited with the Cambridge Data Centre with deposition numbers CCDC 1948449, 2022191, and 2022190,† respectively.

Synthesis of alicyclic ring-fused DMBBQs (5a–5c)

CAN (8.793 g, 16.04 mmol) in H₂O (80 mL) was added over 30 min to ring-fused benzimidazoles 6a–6c (8.00 mmol) in HFIP (20 mL) at 0 °C. The solution was stirred for 30 min and evaporated to dryness. H₂O (200 mL) was added, and the mixture extracted with CH₂Cl₂ (4 × 150 mL). The organic extracts were dried (MgSO₄), evaporated, and purified by flash column chromatography using gradient elution of CH₂Cl₂/MeOH.

5′,8′-Dimethoxy-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,8-dione (5a). (1.423 g, 88%); red solid; R_f 0.33 (19 : 1 CH₂Cl₂/MeOH); mp 189–191 °C; ν_max (neat, cm⁻¹) 1674 (C=O), 1650 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.64 (s, 1H, 7-H), 6.42 (s, 1H, 7′-H), 4.33–4.25 (m, 4H), 4.16 (s, 3H, Me), 3.88 (s, 3H, Me), 3.07–2.97 (m, 4H), 2.80–2.65 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 180.0, 177.9 (both C=O), 160.7, 160.3, 147.6, 146.4, 143.5, 141.7, 141.6 (all C), 133.0 (7-CH), 129.5, 125.7, 117.2 (all C), 104.3 (7′-CH), 61.2, 55.9 (both Me), 45.1, 45.0, 26.54, 26.51, 23.4, 22.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₂H₂₁N₄O₄ 405.1563; found 405.1557; m/z 407 (4%), 406 (27), 405 (C₂₂H₂₁N₄O₄, 100).

6′,9′-Dimethoxy-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,9-dione (5b). (1.502 g, 87%); red solid; R_f 0.34 (19 : 1 CH₂Cl₂/MeOH); mp 176–177 °C; ν_max (neat, cm⁻¹) 1675 (C=O), 1645 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.64 (s, 1H, 8-H), 6.41 (s, 1H, 8′-H), 4.44 (t, J = 5.3 Hz, 2H), 4.39–4.32 (m, 2H), 4.13 (s, 3H, Me), 3.86 (s, 3H, Me), 3.10–2.99 (m, 4H), 2.11–1.92 (m, 8H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 180.3, 178.4 (both C=O), 151.7, 150.9, 146.7, 143.3, 142.7, 141.7, 136.5 (all C), 133.9 (8-CH), 130.0, 127.3, 117.3 (all C), 104.5 (8′-CH), 61.3, 55.9 (both Me), 45.6, 45.4, 25.7, 24.9, 23.1, 22.3, 20.5, 19.8 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₄H₂₅N₄O₄ 433.1876; found 433.1871; m/z 435 (5%), 434 (27), 433 (C₂₄H₂₅N₄O₄, 100).

1′,4′-Dimethoxy-7,7′,8,8′,9,9′,10,10′-octahydro-6H,6′H-[3,3′-biazepino[1,2-a]benzimidazole]-1,4-dione (5c). (1.545 g, 84%); red solid; R_f 0.40 (19 : 1 CH₂Cl₂/MeOH); mp 169–171 °C; ν_max (neat, cm⁻¹) 1674 (C=O), 1650 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.63 (s, 1H, 2-H), 6.45 (s, 1H, 2′-H), 4.70–4.55 (m, 4H), 4.16 (s, 3H, Me), 3.88 (s, 3H, Me), 3.12–3.01 (m, 4H), 1.98–1.72 (m, 12H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 180.4, 179.0 (both C=O), 158.1, 157.4, 146.3, 143.7, 142.0, 141.1, 136.2 (all C), 134.2 (2-CH), 130.4, 127.8, 116.6 (all C), 105.1 (2′-CH), 61.4, 55.9 (both Me), 46.1, 45.8, 30.9, 30.8, 29.8, 29.3, 28.9, 28.3, 25.6, 25.0 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₆H₂₉N₄O₄ 461.2189; found 461.2187; m/z 463 (5%), 462 (29), 461 (C₂₆H₂₉N₄O₄), 431 (5).

Synthesis of 2,2′-bis(chloromethyl)-4′,7′-dimethoxy-1,1′-dimethyl-1H,1′H-[5,5′-bibenzimidazole]-4,7-dione (8). CAN (0.438 g, 0.80 mmol) in H₂O (5 mL) was added dropwise to 2-(chloromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole (96 mg, 0.40 mmol) in MeCN (5 mL) at 0 °C. The solution was stirred for 20 min and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were dried (MgSO₄), evaporated, and the residue purified by dry column vacuum chromatography with EtOAc and hexanes as eluent to give the title compound8 (68 mg, 76%); red crystals; mp >350 °C; R_f 0.35 (4 : 1 EtOAc : hexanes); ν_max (neat, cm⁻¹) 1655 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.70 (s, 1H), 6.47 (s, 1H), 4.79 (s, 2H), 4.76 (s, 2H), 4.15 (s, 3H, OMe), 4.09 (s, 3H, NMe), 4.07 (s, 3H, NMe), 3.89 (s, 3H, OMe); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.7, 178.7 (both C=O), 149.6, 148.7, 147.0, 144.2, 142.7, 141.1, 136.1 (all C), 134.5 (CH), 131.8, 128.8, 117.1 (all C), 105.9 (CH), 61.6, 56.1 (both OMe), 36.8, 35.6 (both CH₂), 33.0, 32.6 (both NMe); HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₀H₁₉N₄O₄³⁵Cl₂ 449.0783; found 449.0778.

H₂O₂/HCl-mediated chlorination

H₂O₂ (50% w/v in water, 0.227 mL, 4.0 mmol) and HCl (37% w/v in water, 17 μL, 0.20 mmol) were sequentially added dropwise to a stirred solution of DMBBQ 5a (81 mg, 0.20 mmol) in MeCN (2 mL), and heated at reflux for 1 h. The solution was cooled and EtOAc (2 mL) added, and washed with Na₂CO₃ (satd., 2 mL). The organic extract was dried (MgSO₄), evaporated, and the residue purified by flash column chromatography using gradient elution of CH₂Cl₂/MeOH to give 7′-chloro-5′,8′-dimethoxy-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,8-dione (9a) (18 mg, 21%); orange crystals; R_f 0.41 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >206 °C); ν_max (neat, cm⁻¹) 1674 (C=O), 1653 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.58 (s, 1H, 7-H), 4.30 (t, J = 7.2 Hz, 4H), 4.17 (s, 3H, Me), 3.94 (s, 3H, Me), 3.09–2.97 (m, 4H), 2.80–2.70 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.4, 177.7 (both C=O), 160.9, 160.8, 146.3, 145.7, 144.5, 140.1, 137.2 (all C), 135.5 (7-CH), 129.7, 128.8, 119.2, 117.3 (all C), 62.6, 61.3 (both Me), 45.1, 44.5, 26.6, 26.5, 23.3, 22.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₂H₂₀N₄O₄³⁵Cl 439.1173; found 439.1171; m/z 442 (9%), 441 (C₂₂H₂₀N₄O₄³⁷Cl, 36), 440 (25), 439 (C₂₂H₂₀N₄O₄³⁵Cl, 100).

NaX/Oxone-mediated halogenation (method A)

Oxone (74 mg, 0.12 mmol, containing KHSO₅, 0.24 mmol) and NaCl (23 mg, 0.40 mmol) or NaBr (41 mg, 0.40 mmol) in H₂O (0.1 mL) were added over the course of 5 min to a stirred solution of DMBBQ 5a–5d (0.20 mmol) in HFIP (2 mL) at room temperature, and stirred for 5 h.

NaX/Oxone-mediated halogenation and quinone formation (method B)

Oxone (0.246 g, 0.40 mmol, containing KHSO₅, 0.80 mmol) and NaCl (47 mg, 0.80 mmol) or NaBr (82 mg, 0.80 mmol) in H₂O (0.2 mL) were added over the course of 5 min to a stirred solution of DMBBQ 5a–5d (0.20 mmol) in HFIP (2 mL) at room temperature, and stirred for 9 h.

Reaction work-up for methods A and B

H₂O (5 mL) was added, and the mixture extracted with CH₂Cl₂ (3 × 5 mL). The organic extracts were dried (MgSO₄), evaporated to dryness, and purified by flash column chromatography using gradient elution of CH₂Cl₂/MeOH.

7′-Chloro-5′,8′-dimethoxy-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,8-dione (9a). (Method A: 69 mg, 79%); (Method B: 0%); orange crystals; spectroscopic data and melting point were consistent with the above.

7-Chloro-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,5′,8,8′-tetrone (10a). (Method A: 10 mg, 12%); (Method B: 73 mg, 89%); yellow crystals; R_f 0.35 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >207 °C); ν_max (neat, cm⁻¹) 1659 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.55 (s, 1H, 7′-H), 4.31 (q, J = 7.6 Hz, 4H), 3.06–2.98 (m, 4H), 2.83–2.73 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.2, 176.3, 176.2, 168.9 (all C=O), 162.2, 161.3, 146.4, 145.8, 141.6, 140.6, 138.1 (all C), 135.3 (7′-CH), 129.6, 128.7 (both C), 45.5, 45.2, 26.5, 26.4, 23.1, 22.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₀H₁₄N₄O₄³⁵Cl 409.0703; found 409.0703; m/z 412 (8%), 411 (C₂₀H₁₄N₄O₄³⁷Cl, 35), 410 (23), 409 (C₂₀H₁₄N₄O₄³⁵Cl, 100).

8′-Chloro-6′,9′-dimethoxy-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,9-dione (9b). (Method A: 70 mg, 75%); (Method B: 0%); orange crystals; R_f 0.39 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >197 °C); ν_max (neat, cm⁻¹) 1676 (C=O), 1653 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.56 (s, 1H, 8-H), 4.46–4.32 (m, 4H), 4.13 (s, 3H, Me), 3.94 (s, 3H, Me), 3.11–3.01 (m, 4H), 2.16–1.95 (m, 8H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.6, 178.2 (both C=O), 151.7, 151.5, 145.5, 143.8, 141.6, 138.1 (all C), 136.3 (8-CH), 135.1, 130.24, 130.19, 119.6, 117.7 (all C), 62.5, 61.4 (both Me), 45.4, 44.8, 25.7, 25.0, 23.0, 22.3, 20.4, 19.8 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₄H₂₄N₄O₄³⁵Cl 467.1486; found 467.1482; m/z 471 (2%), 470 (9), 469 (C₂₄H₂₄N₄O₄³⁷Cl, 35), 468 (27), 467 (C₂₄H₂₄N₄O₄³⁵Cl, 100).

8-Chloro-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,6′,9,9′-tetrone (10b). (Method A: inseparable with 5b, 0%); (Method B: 77 mg, 88%); yellow crystals; R_f 0.34 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >212 °C); ν_max (neat, cm⁻¹) 1655 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.54 (s, 1H, 8′-H), 4.37 (q, J = 5.9 Hz, 4H), 3.04 (t, J = 6.3 Hz, 4H), 2.13–1.96 (m, 8H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.4, 176.8, 176.4, 169.1 (all C=O), 153.3, 152.3, 142.4, 141.7, 141.2, 139.9, 137.4 (all C), 136.2 (8′-CH), 130.2, 129.3 (both C), 45.8, 45.5, 25.0, 24.9, 22.2, 22.1, 19.7, 19.5 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₂H₁₈N₄O₄³⁵Cl 437.1017; found 437.1016; m/z 440 (8%), 439 (C₂₂H₁₈N₄O₄³⁷Cl, 35), 438 (25), 437 (C₂₂H₁₈N₄O₄³⁵Cl, 100).

2′-Chloro-1′,4′-dimethoxy-7,7′,8,8′,9,9′,10,10′-octahydro-6H,6′H-[3,3′-biazepino[1,2-a]benzimidazole]-1,4-dione (9c). (Method A: 71 mg, 72%); (Method B: 12 mg, 12%); orange crystals; R_f 0.43 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >234 °C); ν_max (neat, cm⁻¹) 1675 (C=O), 1651 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.56 (s, 1H, 2-H), 4.73–4.46 (m, 4H), 4.15 (s, 3H, Me), 3.90 (s, 3H, Me), 3.15–3.01 (m, 4H), 1.99–1.74 (m, 12H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.7, 178.7 (both C=O), 158.2, 157.9, 145.7, 143.4, 140.9, 137.5 (all C), 136.7 (2-CH), 134.7, 130.5, 130.3, 120.1, 117.1 (all C), 61.59, 61.56 (both Me), 45.9, 45.3, 30.9, 30.8, 29.7, 29.3, 28.9, 28.1, 25.5, 24.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₆H₂₈N₄O₄³⁵Cl 495.1799; found 495.1801; m/z 499 (2%), 498 (10), 497 (C₂₆H₂₈N₄O₄³⁷Cl, 36), 496 (29), 495 (C₂₆H₂₈N₄O₄³⁵Cl, 100).

2-Chloro-7,7′,8,8′,9,9′,10,10′-octahydro-6H,6′H-[3,3′-biazepino[1,2-a]benzimidazole]-1,1′,4,4′-tetrone (10c). (Method A: inseparable with 5c, 0%); (Method B: 69 mg, 74%); yellow crystals; R_f 0.40 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >237 °C); ν_max (neat, cm⁻¹) 1659 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.50 (s, 1H, 2′-H), 4.75–4.61 (m, 2H), 4.61–4.51 (m, 2H), 3.16–2.99 (m, 4H), 2.03–1.69 (m, 12H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.4, 177.3, 176.3, 169.7 (all C=O), 159.7, 158.8, 142.6, 141.1, 140.5, 139.5, 137.0 (all C), 136.5 (2′-CH), 130.5, 129.7 (both C), 46.3, 46.0, 30.73, 30.65 (all CH₂), 29.3 (2 × CH₂), 28.1, 28.0, 24.8, 24.7 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₄H₂₂N₄O₄³⁵Cl 465.1330; found 465.1326; m/z 468 (9%), 467 (C₂₄H₂₂N₄O₄³⁷Cl, 36), 466 (27), 465 (C₂₄H₂₂N₄O₄³⁵Cl, 100).

7′-Bromo-5′,8′-dimethoxy-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,8-dione (11a). (Method A: 73 mg, 76%); (Method B: 12 mg, 13%); orange crystals; R_f 0.38 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >209 °C); ν_max (neat, cm⁻¹) 1674 (C=O), 1652 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.55 (s, 1H, 7-H), 4.31 (t, J = 7.2 Hz, 4H), 4.16 (s, 3H, Me), 3.93 (s, 3H, Me), 3.09–2.99 (m, 4H), 2.81–2.71 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.3, 177.8 (both C=O), 160.81, 160.79, 146.3, 146.1, 145.9, 140.8, 138.2 (all C), 135.4 (7-CH), 129.7, 128.9, 118.9, 109.6 (all C), 62.8, 61.4 (both Me), 45.1, 44.5, 26.6, 26.5, 23.3, 22.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₂H₂₀N₄O₄⁷⁹Br 483.0668; found 483.0670; m/z 487 (5%), 486 (24), 485 (C₂₂H₂₀N₄O₄⁸¹Br, 100), 484 (24), 483 (C₂₂H₂₀N₄O₄⁷⁹Br, 97).

7-Bromo-2,2′,3,3′-tetrahydro-1H,1′H-[6,6′-bipyrrolo[1,2-a]benzimidazole]-5,5′,8,8′-tetrone (12a). (Method A: 12 mg, 13%); (Method B: 68 mg, 75%); yellow crystals; R_f 0.33 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >209 °C); ν_max (neat, cm⁻¹) 1662 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.53 (s, 1H, 7′-H), 4.31 (q, J = 6.6 Hz, 4H), 3.07–2.97 (m, 4H), 2.83–2.71 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.1, 176.4, 175.7, 169.0 (all C=O), 162.0, 161.3, 146.2, 145.8, 142.5, 141.9, 136.8 (all C), 134.8 (7′-CH), 129.7, 128.4 (both C), 45.4, 45.2, 26.5, 26.4, 23.1, 22.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₀H₁₄O₄N₄⁷⁹Br 453.0193; found 453.0180; m/z 456 (22%), 455 (C₂₀H₁₄O₄N₄⁸¹Br, 97), 454 (22), 453 (C₂₀H₁₄O₄N₄⁷⁹Br, 100).

8′-Bromo-6′,9′-dimethoxy-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,9-dione (11b). (Method A: 69 mg, 68%); (Method B: 18 mg, 18%); orange crystals; R_f 0.37 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >186 °C); ν_max (neat, cm⁻¹) 1675 (C=O), 1652 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.54 (s, 1H, 8-H), 4.47–4.34 (m, 4H), 4.11 (s, 3H, Me), 3.93 (s, 3H, Me), 3.11–3.02 (m, 4H), 2.16–1.96 (m, 8H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.6, 178.2 (both C=O), 151.8, 151.5, 145.6, 145.4, 141.6, 139.1 (all C), 136.2 (8-CH), 135.8, 130.4, 130.2, 119.4, 110.1 (all C), 62.7, 61.5 (both Me), 45.4, 44.8, 25.7, 25.0, 23.1, 22.3, 20.4, 19.8 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₄H₂₄N₄O₄⁷⁹Br 511.0981; found 511.0984; m/z 515 (6%), 514 (26), 513 (C₂₄H₂₄N₄O₄⁸¹Br, 100), 512 (26), 511 (C₂₄H₂₄N₄O₄⁷⁹Br, 97).

8-Bromo-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,6′,9,9′-tetrone (12b). (Method A: inseparable with 5b, 0%); (Method B: 69 mg, 72%); yellow crystals; R_f 0.34 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >220 °C); ν_max (neat, cm⁻¹) 1655 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.51 (s, 1H, 8′-H), 4.37 (t, J = 5.6 Hz, 4H), 3.05 (t, J = 6.3 Hz, 4H), 2.14–1.96 (m, 8H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.3, 176.9, 175.9, 169.3 (all C=O), 153.2, 152.3, 141.7, 141.6, 141.19, 141.17, 137.9 (all C), 135.6 (8′-CH), 130.2, 129.0 (both C), 45.7, 45.5, 25.0, 24.9, 22.2, 22.1, 19.7, 19.5 (all CH₂); HRMS (ASAP) m/z: calcd for [M + H]⁺ C₂₂H₁₈N₄O₄⁷⁹Br 481.0511; found 481.0512; m/z 485 (3%), 484 (24), 483 (C₂₂H₁₈N₄O₄⁸¹Br, 97), 482 (26), 481 (C₂₂H₁₈N₄O₄⁷⁹Br, 100).

2′-Bromo-1′,4′-dimethoxy-7,7′,8,8′,9,9′,10,10′-octahydro-6H,6′H-[3,3′-biazepino[1,2-a]benzimidazole]-1,4-dione (11c). (Method A: 76 mg, 71%); (Method B: 24 mg, 22%); orange crystals; R_f 0.42 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >243 °C); ν_max (neat, cm⁻¹) 1675 (C=O), 1651 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.53 (s, 1H, 2-H), 4.73–4.45 (m, 4H), 4.14 (s, 3H, Me), 3.89 (s, 3H, Me), 3.15–3.00 (m, 4H), 1.99–1.69 (m, 12H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 179.7, 178.8 (both C=O), 158.3, 157.9, 145.9, 145.0, 140.9, 138.4 (all C), 136.6 (2-CH), 135.5, 130.5, 130.4, 118.8, 110.8 (all C), 61.7, 61.6 (both Me), 45.9, 45.3, 30.89, 30.85, 29.7, 29.4, 28.9, 28.2, 25.5, 24.9 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₆H₂₈N₄O₄⁷⁹Br 539.1294; found 539.1297; m/z 543 (5%), 542 (27), 541 (C₂₆H₂₈N₄O₄⁸¹Br, 100), 540 (28), 539 (C₂₆H₂₈N₄O₄⁷⁹Br, 97).

2-Bromo-7,7′,8,8′,9,9′,10,10′-octahydro-6H,6′H-[3,3′-biazepino[1,2-a]benzimidazole]-1,1′,4,4′-tetrone (12c). (Method A: inseparable with 5c, 0%); (Method B: 70 mg, 69%); yellow crystals; R_f 0.40 (19 : 1 CH₂Cl₂/MeOH); mp (decomp >232 °C); ν_max (neat, cm⁻¹) 1659 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.49 (s, 1H, 2′-H), 4.78–4.64 (m, 2H), 4.62–4.48 (m, 2H), 3.16–2.99 (m, 4H), 2.05–1.68 (m, 12H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.4, 177.3, 175.9, 169.8 (all C=O), 159.6, 158.7, 141.3, 141.0, 140.8, 140.5, 138.2 (all C), 135.9 (2′-CH), 130.5, 129.3 (both C), 46.2, 46.0, 30.74, 30.66 (all CH₂), 29.3 (2 × CH₂), 28.1, 28.0, 24.8, 24.7 (all CH₂); HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₄H₂₂N₄O₄⁷⁹Br 509.0824; found 509.0826; m/z 513 (4%), 512 (26), 511 (C₂₄H₂₂N₄O₄⁸¹Br, 100), 510 (26), 509 (C₂₄H₂₂N₄O₄⁷⁹Br, 97).

Synthesis of 6′,9′-dimethoxy-8-(trifluoromethyl)-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,9-dione (5d). t-BuOOH (0.864 mL, 9.09 mmol) was added over the course of 10 min to a stirred solution of DMBBQ 5b (0.543 g, 1.26 mmol), NaSO₂CF₃ (0.591 g, 3.78 mmol) and Cu(OTf)₂ (45 mg, 0.12 mmol) in MeCN (15 mL) at room temperature, and the mixture stirred for 2 h. H₂O (60 mL) was added, and the mixture extracted with CH₂Cl₂ (3 × 45 mL). The combined organic extracts were dried (MgSO₄), evaporated to dryness and purified by flash column chromatography using gradient elution of CH₂Cl₂/MeOH to give the title compound5d (0.321 g, 51%); amorphous red solid; R_f 0.39 (19 : 1 CH₂Cl₂/MeOH); mp 177–179 °C; ν_max (neat, cm⁻¹) 1682 (C=O), 1663 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 6.24 (s, 1H, 8′-H), 4.52–4.32 (m, 4H), 4.12 (s, 3H, Me), 3.84 (s, 3H, Me), 3.06 (q, J = 6.5 Hz, 4H), 2.13–1.92 (m, 8H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 178.5, 174.1 (both C=O), 153.1, 150.8, 147.73, 147.70, 142.3, 141.0, 135.6 (all C), 130.2 (q, ²J_C–F = 27.2 Hz, 8-C), 129.9, 127.4 (C), 121.8 (q, ¹J_C–F = 276.6 Hz, CF₃), 114.4 (C), 103.6 (d, J = 2.1 Hz, 8′-CH), 61.0, 55.9 (both Me), 45.7, 45.6, 25.7, 25.0, 23.1, 22.2, 20.5, 19.6 (all CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ: −56.48; HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₅H₂₄N₄O₄F₃ 501.1750; found 501.1752; m/z 503 (5%), 502 (28), 501 (C₂₅H₂₄N₄O₄F₃, 100).

8′-Chloro-6′,9′-dimethoxy-8-(trifluoromethyl)-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,9-dione (13). (Method A: 78 mg, 73%); (Method B: 11 mg, 19%); brown crystals; R_f 0.44 (19 : 1 CH₂Cl₂/MeOH); mp 163–166 °C; ν_max (neat, cm⁻¹) 1683 (C=O), 1668 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 4.48–4.36 (m, 4H), 4.15 (s, 3H, Me), 3.93 (s, 3H, Me), 3.07 (q, J = 6.6 Hz, 4H), 2.15–2.06 (m, 4H), 2.06–1.96 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 177.7, 173.7 (both C=O), 153.1, 151.4 (both C), 144.29–144.17 (m, C), 144.1, 141.0, 137.7, 134.3 (all C), 131.7 (q, ²J_C–F = 27.5 Hz, 8-C), 130.4, 130.1 (both C), 121.5 (q, ¹J_C–F = 276.4 Hz, CF₃), 118.5, 115.2 (both C), 62.6, 61.1 (both Me), 45.7, 44.8, 25.7, 25.0, 23.0, 22.2, 20.4, 19.6 (all CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ: −58.95; HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₅H₂₃N₄O₄F₃³⁵Cl 535.1360; found 535.1357; m/z 539 (2%), 538 (9), 537 (C₂₅H₂₃N₄O₄F₃³⁷Cl, 35), 536 (27), 535 (C₂₅H₂₃N₄O₄F₃³⁵Cl, 100).

8-Chloro-8′-(trifluoromethyl)-1,1′,2,2′,3,3′,4,4′-octahydro[7,7′-bipyrido[1,2-a]benzimidazole]-6,6′,9,9′-tetrone (14). (Method A: trace); (Method B: 69 mg, 68%); orange crystals; R_f 0.49 (19 : 1 CH₂Cl₂/MeOH); mp (decomp. >239 °C); ν_max (neat, cm⁻¹) 1669 (C=O); ¹H NMR (400 MHz, CDCl₃) δ: 4.39 (t, J = 5.9 Hz, 4H), 3.05 (t, J = 6.2 Hz, 4H), 2.15–2.06 (m, 4H), 2.06–1.96 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ: 175.7, 175.5, 172.1, 168.6 (all C=O), 153.7, 153.4, 141.6, 140.7, 140.5, 139.8, 137.1 (all C), 132.0 (q, ²J_C–F = 28.3 Hz, 8′-C), 130.2, 129.5 (both C), 121.0 (q, ¹J_C–F = 277.0 Hz, CF₃), 45.9, 45.8, 25.00, 24.99 (all CH₂), 22.1 (2 × CH₂), 19.51, 19.48 (both CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ: −59.03; HRMS (ASAP) m/z: [M + H]⁺ calcd for C₂₃H₁₇N₄O₄F₃³⁵Cl 505.0891; found 505.0889; m/z 508 (12%), 507 (C₂₃H₁₇N₄O₄F₃³⁷Cl, 34), 506 (25), 505 (C₂₃H₁₇N₄O₄F₃³⁵Cl, 100).

Oxidation of DMBBQ 13

Oxone (74 mg, 0.12 mmol, containing KHSO₅, 0.24 mmol) and NaCl (14 mg, 0.24 mmol) in H₂O (0.12 mL) were added over the course of 5 min to a stirred solution of DMBBQ 13 (64 mg, 0.12 mmol) in HFIP (1.2 mL) at room temperature, and stirred for 4 h. H₂O (3 mL) was added, and the mixture extracted with CH₂Cl₂ (3 × 3 mL). The organic extracts were dried (MgSO₄), evaporated to dryness, and purified by flash column chromatography using gradient elution of CH₂Cl₂/MeOH to give bis-p-quinone 14 (51 mg, 85%); orange crystals; spectral data and melting point were consistent with the above.

Author contributions

D. Conboy – investigation, methodology and writing; P. Kielty – investigation and visualization; J. C. Bear – investigation (X-ray); J. K. Cockcroft – investigation (X-ray); P. Farràs – supervision; P. McArdle – investigation (X-ray); R. J. Singer – resources; D. A. Smith – supervision; F. Aldabbagh – conceptualization, funding acquisition, main supervision and writing.

Conflicts of interest

There are no conflicts to declare.

Note after first publication

This article replaces the version published on 05 March 2021, in which part of Scheme 1 was missing.

Acknowledgements

We thank Kingston University for a PhD Scholarship for Darren Conboy and the Irish Research Council for an Enterprise Partnership Postgraduate Scholarship for Patrick Kielty.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Fig. S1–S4 and X-ray crystallography Tables S1–S3 and ¹H, ¹³C and ¹⁹F NMR spectra (PDF). CIF files available for compounds 8, 11a and 13. CCDC 1948449 2022191 2022190. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ob00032b

‡ Present address: Kingston University.

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