Dearomatisation approaches to spirocyclic dienones via the electrophilic activation of alkynes

Abstract

Two complementary dearomatising spirocyclisation protocols to generate spirocyclic dienones from anisole and phenol-tethered ynones are described, each proceeding via electrophilic alkyne activation. The first approach focuses on the spirocyclisation of para-substituted anisoles using either SnCl₂·2H₂O or Cu(OTf)₂. The second approach, which enables the spirocyclisation of both ortho- and para-substituted phenols, uses silica-supported AgNO₃ to generate similar scaffolds with much greater efficiency. Initial asymmetric studies are also outlined.

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Introduction

Spirocyclic dienones are key structural features in numerous bioactive natural products isolated from a variety of trees, plants and bacteria, with representative examples 1–6 shown in Fig. 1.^1a–e

Fig. 1 Natural products containing spirocyclic dienone motifs.

A popular approach to synthesise spirocyclic dienones is via the dearomatisation and ipso-cyclisation of a phenol or anisole derivative, with this typically achieved using one of two methods (Scheme 1). The most common method is based on the oxidation of a substituted phenol (Scheme 1a); following oxidation of the phenol, an intramolecular nucleophilic ipso-cyclisation reaction can take place with a range of C-nucleophiles including alkenes/alkynes,^2a enamides,^2b allyl silanes,^2c,d enols/enolates,^2e aromatics,^2f nitro compounds^2g and diazo compounds.^2h,i Alternatively, the flow of electron density can be reversed and a substituted phenol/anisole can react directly with a tethered electrophilic species (Scheme 1b); examples of electrophilic ipso-cyclisation with sulfonates,^3a–c nitriles,^3d epoxides,^3e activated allenes,^3f activated aryl halides,^3g propargyl bromides/carbonates,^3h activated alkynes/alkenes^3i–k and allylic carbonates^3l,m have all been reported.

Scheme 1 General methods for spirocyclic dienone synthesis.

In this manuscript, two complementary protocols which generate spirocyclic dienones are outlined (Scheme 1c), with both methods promoted by the activation of a tethered alkyne moiety.⁴ The first approach focuses on the spirocyclisation of para-substituted anisoles using either SnCl₂·2H₂O or Cu(OTf)₂ to activate the alkyne towards nucleophilic attack, while the second uses silica-supported AgNO₃ to generate similar scaffolds from analogous phenol precursors with greater efficiency and scope. Substrate scoping studies are described for each reaction series, while comparisons between the two reaction types, synthetic extensions and preliminary asymmetric results are also outlined.

Results and discussion

This research program began during a project to synthesise the spirocyclic natural product spirobacillene A (6, Fig. 1).^5,6 In this published work, it was found that treating anisole-tethered ynone 7 with five equivalents of SnCl₂·2H₂O ⁷ at RT in CH₂Cl₂ resulted in its efficient conversion into spirocyclic dienone 8, which was isolated in 89% yield (Scheme 2). The ease and scalability of this key step was instrumental in allowing us to complete the synthesis of spirobacillene A 6, which was published in 2013.^5,8

Scheme 2 Sn(II)-mediated synthesis of spirobacillene A.

This initial discovery inspired the development of a number of other classes of dearomatising spirocyclisation reactions⁹ in our group in the following years.^10,11 However, prior to this publication, the conversion of ynone 7 into spirocycle 8 remained the only reported reaction of its type in the literature,¹² hence it was decided to further optimise this process and to evaluate its scope.

Initial results were disappointing, with unsubstituted and alkyl substituted ynones 9a and 9b both failing to react with SnCl₂·2H₂O under the conditions used during the total synthesis of spirobacillene A (Table 1, entries 1 and 2). Phenyl substituted ynone 9c also failed to react at room temperature (entry 3), although a small amount of cyclisation was observed upon heating at reflux (entry 4). A plausible explanation for this poor reactivity is that the more electron-rich the alkyne, the more readily it can interact with acidic additives, promoting spirocyclisation. Support for this theory was found when examining the cyclisation of anisole-substituted ynone 9d; under the standard SnCl₂·2H₂O mediated conditions, a more respectable 75% conversion into spirocyclic dienone 10d was observed (entry 5, 57% isolated yield). Pleasingly, the spirocyclisation was improved significantly by changing the catalyst; full details of reaction optimisation are included in the ESI,† with the highlight being the discovery that Cu(OTf)₂ promoted the complete cyclisation of ynone 9d within 1 h, with spirocycle 10d isolated in 80% isolated yield (entry 6). However, Cu(OTf)₂ did not lead to any improvement in the reactivity of substrates 9a–9c, forcing us to concede that an electron donating group on the alkyne terminus is a requirement for this transformation.

Table 1 Optimisation of the spirocyclisation of anisole-tethered ynones

Entry	Ynone	Reagent	Equiv./time [h]/temp. [°C]	Conversion^a^,^b (isolated yield in brackets)
a All reactions were performed using 0.09–0.20 mmol of the ynone 9a–d in CH2Cl2 (0.1 M). b Conversion measured by analysis of the ^1H NMR spectra of the unpurified reaction mixture.
1	9a	SnCl2·2H2O	5/20/RT or 45	No reaction
2	9b	SnCl2·2H2O	5/20/RT or 45	No reaction
3	9c	SnCl2·2H2O	5/20/RT	No reaction
4	9c	SnCl2·2H2O	5/20/45	10%
5	9d	SnCl2·2H2O	5/20/RT	75% (57%)
6	9d	Cu(OTf)2	1/1/RT	>95% (80%)

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With this in mind, a series of anisoles tethered to electron-rich ynones (9d–l) were made and tested using both SnCl₂·2H₂O and Cu(OTf)₂ to activate the alkyne (Table 2). Spirocycle 10e was formed in just 1 h from aniline-substituted ynone 9e using one equivalent of SnCl₂·2H₂O. Alternatively, the same product could be made using catalytic Cu(OTf)₂ (0.1 equivalents), albeit with a longer reaction time. Thiophene-substituted ynone 9f reacted more slowly; the cyclisation was incomplete following treatment with SnCl₂·2H₂O at room temperature for 3 days, but proceeded more efficiently with Cu(OTf)₂ to afford 10f in a 73% yield. Substitution around either ring system is well tolerated, evidenced by the efficient syntheses of compounds 10g–i. Vinyl sulfide product 10j could also be isolated in a reasonable yield using Cu(OTf)₂, demonstrating compatibility with non-aromatic-tethered ynones. Additionally, the reaction is not limited to the synthesis of spirocyclic cyclopentenones; spirocyclic cyclohexenones 10k and 10l were both formed in good yields, although the reactions were slower and thus required additional heating or a longer reaction time.

Table 2 Substrate scope of spirocyclisation of anisole-tethered ynones using SnCl₂·2H₂O (A) and Cu(OTf)₂ (B)

a All reactions were performed in CH₂Cl₂ (0.1 M) at RT with 1 equiv. of reagent unless specified. Where stated, reaction conversions were measured by analysis of the ¹H NMR spectra of the unpurified reaction mixture. b 5 equiv. of SnCl₂·2H₂O used. c 0.1 equiv. of Cu(OTf)₂ used. d Reaction performed at 50 °C.

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To summarise this reaction series, para-substituted anisoles tethered to electron-rich ynones can be converted into spirocyclic dienones in high yield using either a Sn(II) or Cu(II) reagent. The simplicity of the synthetic procedure and mild reaction conditions are the most pleasing aspects of this method, although the use of relatively large quantities of Sn(II) and Cu(II) reagents and the requirement to use electron-rich ynones were both identified as areas with potential for improvement.

It was reasoned that both of the above limitations might be addressed by using a more active catalyst. Silver(I) catalysts were identified as particularly promising candidates, given that they have generally been found to be the best catalyst class in related alkyne activation processes,¹⁰ but disappointingly, the Ag(I) catalysts tested were ineffective for the spirocyclisation of anisole system 9d. However, by switching the nucleophilic component in the starting material from an anisole to the analogous phenol, the desired spirocyclic product 10d could indeed be formed, and with Ag(I) catalysts now viable for this transformation, significant improvements in the scope and efficiency soon emerged. The use of silica-supported AgNO₃ (10 mol%) in CH₂Cl₂ at RT was found to be a particularly active and convenient catalyst system and was chosen for the substrate scoping studies, which were performed on ynone tethered phenols (11c,d,m–v). For clarity, five of these examples (denoted in the table with a *) were included in an earlier publication,^10c while the other seven substrates are novel examples (Table 3). It should also be noted that AgNO₃·SiO₂ is a much more reactive catalyst than unsupported AgNO₃; ynones 11c,d,m,o,q–v did not react in the presence of unsupported AgNO₃ and only a 7% conversion to spirocyclic dienone 10n was observed for ynone 11n when using unsupported AgNO₃.¹³

Table 3 Substrate scope of AgNO₃·SiO₂-catalysed dearomatisation/spirocyclisations

a All reactions were performed using 1 wt% AgNO₃·SiO₂ in CH₂Cl₂ (0.1 M) at RT unless specified otherwise. b Reaction performed at 40 °C. Compounds highlighted with a * were featured in our earlier publication (see ref. 10c); all other examples are novel.

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It quickly became apparent that by changing the catalyst and starting material, the requirement for an electron-donating substituent on the ynone had been removed; simple alkyl chains and aromatic substituents in the R¹ position were all well tolerated, generating spirocyclic dienone products 10c, 10d, 10n in high yields. Alkyl substituted ynones bearing protected amine and alcohol groups (11o and 11p) also reacted smoothly to furnish their corresponding spirocyclic dienones (10o and 10p). The incorporation of terminal cyclopropane and cyclopentane rings appeared to increase the reactivity of the ynone; dienones 10q and 10r were produced in near-quantitative yields in 2–6 h which is notably faster than most of the other reactions explored in this study. Pleasingly, we were also able to perform the spirocyclisation on ortho-substituted phenols 11s–v; there are relatively few literature examples of dearomatisation and ipso-cyclisation reactions of ortho-substituted phenols, and so the efficient syntheses of chiral spirocyclic products 12s–v in 90–99% yields are especially pleasing.^2d,14

The superior reactivity of the Ag(I) mediated reaction system compared to the earlier Sn(II)/Cu(II) reactions is best demonstrated by a direct comparison. Thus, our published synthesis of spirocyclic dienone 8, which is a key intermediate en route to spirobacillene A, required five equivalents of SnCl₂·2H₂O and 18 h to generate the product in 89% yield.⁵ In contrast, the same product was generated from phenol 13 in near-quantitative yield in just 7 h using 10 mol% AgNO₃·SiO₂ (Scheme 3).

Scheme 3 Previous and improved routes to spirobacillene A precursor 8.

The potential of the spirocyclic dienone products to undergo additional complexity generating reactions has also been briefly demostrated; spirocyclic products 10o and 10p were each found to undergo protecting group cleavage and cyclisation in one-pot to furnish novel tricyclic products 14 and 15 as single diastereomers and in reasonable, unoptimised yields (Scheme 4).

Scheme 4 One-pot deprotection and cyclisation of spirocyclic dienones 10o and 10p.

Finally, having shown that ortho-substituted phenols can be converted into chiral spirocyclic dienones, the possibility of performing this reaction asymmetrically has also been briefly examined. Preliminary studies show that spirocyclisation can be achieved with a modest amount of asymmetric induction (23% ee) using the BINOL-based chiral phosphoric acid silver(I) salt 16 (Scheme 5). It is envisaged that optimisation of the reaction conditions and the nature of the silver(I) catalyst¹⁵ should lead to improve enatioselectivity in this process.

Scheme 5 Asymmetric spirocyclisation reaction using silver salt of CPA 16.

Conclusions

In summary, two mild and efficient methods for the synthesis of spirocyclic dienones are described. Both were briefly introduced by our group in previous publications, but the significantly expanded substrate scoping studies outlined in this manuscript mean that each can now be considered as general and versatile synthetic approach to this important compound class. Both methods work well on a variety of easy-to-synthesise ynone precursors. The use of catalytic AgNO₃·SiO₂ to promote the spirocyclisation of ynone tethered phenols is likely to be of particular interest, in view of the excellent isolated yields in this series, the simple product purification and the capacity to recover the active catalyst by filtration.

Experimental

Except where stated, all reagents were purchased from commercial sources and used without further purification. ¹H NMR and ¹³C NMR spectra were recorded on a JEOL ECX400 or JEOL ECS400 spectrometer, operating at 400 MHz and 100 MHz respectively. All spectral data were acquired at 295 K. Chemical shifts (δ) are quoted in parts per million (ppm). The residual solvent peak, δ_H 7.26 and δ_C 77.0 for CDCl₃ and δ_H 2.50 and δ_C 39.5 for DMSO-d₆. Coupling constants (J) are reported in Hertz (Hz) to the nearest 0.5 Hz. The multiplicity abbreviations used are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Signal assignment was achieved by analysis of DEPT, COSY, NOESY, HMBC and HSQC experiments where required. Infrared (IR) spectra were recorded on a PerkinElmer UATR 2 Spectrometer as a thin film dispersed from either CH₂Cl₂ or CDCl₃ and are reported in wavenumbers (cm⁻¹). Mass-spectra were obtained by the University of York Mass Spectrometry Service, using electrospray ionisation (ESI) on a Bruker Daltonics, Micro-tof spectrometer. Melting points were determined using Gallenkamp apparatus and are uncorrected. Reactions were monitored using thin layer chromatography (TLC), which was carried out on Merck silica gel 60F₂₅₄ pre-coated aluminium foil sheets and were visualised using UV light (254 nm) and stained with basic aqueous potassium permanganate. Flash column chromatography was carried out using slurry packed Fluka silica gel (SiO₂), 35–70 μm, 60 Å, under a light positive pressure, eluting with the specified solvent system. Compounds 9d¹⁶ and 9e^10a were prepared according to literature procedures.

General experimental

General procedure A: Weinreb amide synthesis I

To a suspension of acid (1.00 mmol) in DCM (2 mL) at RT was added CDI (220 mg, 1.20 mmol). A homogeneous solution quickly formed, and was stirred at RT for 1 h, after which time MeNH(OMe)·HCl (107 mg, 1.10 mmol) and stirring continued for a further 2 h. The crude reaction mixture was then poured into water (10 mL) and basified to ca. pH 10 with 2 M aq. NaOH extracted with EtOAc (3 × 30 mL) and washed with 10% aq. HCl (15 mL). The organic extracts were dried over MgSO₄ and concentrated in vacuo, affording the Weinreb amide product which was used without further purification.

General procdure A2: Weinreb amide synthesis II

To a stirred solution of acid (1.00 mmol), MeNH(OMe)·HCl (107 mg, 1.10 mmol) and DIPEA (0.52 mL, 3.00 mmol) in CH₂Cl₂ (2.5 mL) was added T3P 50% in EtOAc (955 mg, 1.50 mmol). The solution was stirred at RT until completion was observed by TLC. The reaction mixture was poured into water (10 mL) and acidified using 10% aq. HCl (5 mL). The organics were collected and the aqueous extracted with EtOAc (3 × 30 mL). The organics were combined, washed with aq. 2 M NaOH (10 mL), brine (10 mL), dried over MgSO₄ and concentrated in vacuo to afford the Weinreb amide product which was used without further purification.

General procedure B: ynone formation I

To a solution of terminal alkyne (1.50 mmol) in THF (10 mL) at −78 °C was added n-BuLi (0.875 mL, 1.4 mmol, 1.6 M in hexanes). The resulting yellow solution was stirred at −78 °C for 30 min, then transferred via cannula to a cooled (−78 °C) solution of Weinreb amide (1.00 mmol) in THF (5 mL). The mixture was stirred at −78 °C for 5 min then warmed to −10 °C and stirred for a further 1 h. The reaction was then re-cooled to −78 °C and quenched with sat. aq. NH₄Cl (30 mL), allowed to warm to RT, diluted with water (70 mL), extracted with EtOAc (3 × 100 mL), dried over MgSO₄ and concentrated in vacuo. Purification by flash column chromatography (10 : 1 petrol : EtOAc to elute the excess alkyne, then 5 : 1 petrol : EtOAc to elute the product) afforded the ynone product.

General procedure B2: ynone formation II

To a stirred solution of alkyne (3.00 mmol) in THF (3 mL) at −78 °C under argon was added n-BuLi (1.00 mL, 2.5 mmol, 2.5 M in hexanes) dropwise. The mixture was stirred for 30 min at −78 °C and then transferred via cannula to a −78 °C solution of Weinreb amide (1.00 mmol) in THF (5 mL). Upon complete transfer the mixture was warmed to RT and stirred for the specified amount of time. The reaction was quenched with sat. aq. NH₄Cl (30 mL), diluted with water (70 mL) and extracted with EtOAc (3 × 100 mL). The organics were combined, washed with brine (100 mL), dried over MgSO₄, concentrated in vacuo and purified by flash column chromatography to afford the ynone product.

General procedure C: spirocyclisation using Sn(II)/Cu(II)

To a solution of ynone (1.00 mmol) in CH₂Cl₂ (10 mL) was added an acid catalyst (0.1–5.0 equiv.). The resulting suspension was stirred at the specified temperature until completion was observed by TLC, before adding an excess of solid K₂CO₃ and stirring for an additional 10 min. The mixture was then filtered, rinsed with CH₂Cl₂ and concentrated in vacuo. Purification by flash column chromatography afforded the spirocyclic product.

General procedure C2: spirocyclisation using AgNO₃·SiO₂

To a solution of ynone (1 mmol) in CH₂Cl₂ (10 mL) was added AgNO₃·SiO₂ (0.01–0.1 equiv., 1 wt% AgNO₃ on SiO₂). The mixture was stirred at the specified temperature until completion was observed by TLC. The reaction mixture was filtered, washing the catalyst with EtOAc (10 mL), then concentrated in vacuo to afford the spirocyclic product.

Compound synthesis

4-(4-Methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10d). Synthesised using general procedure C from ynone 9d (25.0 mg, 0.0892 mmol) and copper(II) triflate (32.3 mg, 0.0892 mmol) for 1 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc) afforded the title compound10d as a brown solid (19 mg, 80%); mp. 135–137 °C; R_f 0.20 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1669, 1639, 1579, 1541, 1488, 1234, 1163, 1013, 848, 822; δ_H (400 MHz, CDCl₃) 2.75 (2 H, s), 3.81 (3 H, s), 6.46 (2 H, d, J = 10.0), 6.62 (1 H, s), 6.85 (2 H, d, J = 9.0), 6.95 (2 H, d, J = 10.0), 7.48 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 46.8, 51.0, 55.4, 114.3, 125.3, 127.5, 129.4, 130.0, 152.0, 162.3, 173.1, 184.7, 203.0; HRMS (ESI⁺): Found: 289.0825; C₁₇H₁₄NaO₃ (MH⁺) Requires 289.0835 (3.5 ppm error). Spectroscopic data matched those previously reported in the literature.¹⁶

4-(4-(Dimethylamino)phenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10e). Synthesised using general procedure C from ynone 9e (32 mg, 0.109 mmol) and SnCl₂·2H₂O (2.5 mg, 0.0109 mmol) for 20 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc) afforded the title compound10e as a yellow solid (29 mg, 95%); mp. 199–201 °C; R_f 0.20 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1656, 1636, 1581, 1548, 1500, 1353, 1182, 1156, 719; δ_H (400 MHz, CDCl₃) 2.72 (2 H, s), 3.02 (6 H, s), 6.46 (2 H, d, J = 10.0), 6.55 (1 H, s), 6.58 (2 H, d, J = 9.0), 6.98 (2 H, d, J = 10.0), 7.43 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 39.9, 46.7, 50.9, 111.3, 119.9, 124.0, 129.2, 129.5, 152.3, 152.9, 173.3, 185.0, 203.0; HRMS (ESI⁺): Found: 280.1334; C₁₈H₁₈NO₂ (MH⁺) Requires 280.1332 (0.8 ppm error). Spectroscopic data matched those previously reported in the literature.^10a

1-(4-Methoxyphenyl)-4-(thiophen-2-yl)but-3-yn-2-one (9f). Synthesised using general procedure B from 2-ethynylthiophene¹⁷ (303 mg, 2.80 mmol) and N-methoxy-2-(4-methoxyphenyl)-N-methylacetamide¹⁸ (391 mg, 1.87 mmol). Purification by flash column chromatography afforded the title compound9f as a pale yellow oil (310 mg, 65%); R_f 0.73 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2148, 1636, 1586, 1489, 1230, 1019, 704; δ_H (400 MHz, CDCl₃) 3.80 (3 H, s), 3.85 (2 H, s), 6.90 (2 H, d, J = 8.5), 7.03 (1 H, dd, J = 5.0, 3.5) 7.22 (2 H, d, J = 8.5), 7.40 (1 H, d, J = 3.5), 7.47 (1 H, d, J = 5.0); δ_C (100 MHz, CDCl₃) 50.9, 55.2, 86.7, 92.4, 114.1, 119.6, 125.1, 127.6, 130.8, 131.8, 136.7, 158.9, 189.1; HRMS (ESI⁺): Found: 257.0625; C₁₅H₁₃O₂S (MH⁺) Requires 257.0631 (1.7 ppm error).

4-(Thiophen-2-yl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10f). Synthesised using general procedure C from ynone 9f (40 mg, 0.156 mmol) and copper(II) triflate (56.4 mg, 0.156 mmol) for 20 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc) afforded the title compound10f as a pale yellow oil (28 mg, 73%); R_f 0.50 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1691, 1661, 1576, 1246, 1027, 907, 859, 724; δ_H (400 MHz, CDCl₃) 2.77 (2 H, s), 6.49 (2 H, d, J = 10.0), 6.58 (1 H, s), 6.92 (2 H, d, J = 10.0), 7.03 (1 H, dd, J = 4.5, 3.5) 7.32 (1 H, d, J = 3.5), 7.52 (1 H, d, J = 4.5); δ_C (100 MHz, CDCl₃) 46.3, 50.9, 127.3, 128.7, 130.2, 130.5, 131.4, 135.8, 150.9, 166.3, 184.7, 202.6; HRMS (ESI⁺): Found: 243.0480; C₁₄H₁₁O₂S (MH⁺) Requires 243.0474 (−2.3 ppm error).

N-Methoxy-2-(4-methoxyphenyl)-N-methylbutanamide (S1). Synthesised using general procedure A from 2-(4-methoxyphenyl)butanoic acid¹⁹ (1.07 g, 5.51 mmol) affording the title compoundS1 as a colourless oil (1.31 g, 100%); ν_max (thin film)/cm⁻¹ 1656, 1510, 1461, 1380, 1247, 1178, 997, 822; δ_H (400 MHz, CDCl₃) 0.85 (3 H, t, J = 7.5), 1.64–1.75 (1 H, m), 1.98–2.10 (1 H, m), 3.14 (3 H, s), 3.49 (3 H, s), 3.76 (3 H, s), 3.78–3.86 (1 H, m), 6.82 (2 H, d, J = 8.5), 7.23 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 12.2, 27.2, 32.1, 48.3, 55.1, 61.2, 113.8, 129.1, 132.2, 158.4, 175.0; HRMS (ESI⁺): Found: 238.1438; C₁₃H₂₀NO₃ (MH⁺) Requires 238.1438 (0 ppm error).

1,4-Bis(4-methoxyphenyl)hex-1-yn-3-one (9g). Synthesised using general procedure B from 4-ethynyl-anisole (0.41 mL, 3.17 mmol) and Weinreb amide S1 (500 mg, 2.11 mmol). Purification by flash column chromatography afforded the title compound9g as a yellow oil (482 mg, 74%); R_f 0.71 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2188, 1658, 1601, 1508, 1248, 1058, 1027, 831, 540; δ_H (400 MHz, CDCl₃) 0.91 (3 H, t, J = 7.5), 1.77–1.89 (1 H, m), 2.16–2.27 (1 H, m), 3.63–3.67 (1 H, m), 3.79 (3 H, s), 3.82 (3 H, s), 6.85 (2 H, d, J = 9.0), 6.89 (2 H, d, J = 9.0), 7.24 (2 H, d, J = 9.0), 7.41 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 12.0, 24.8, 55.2, 55.4, 61.7, 87.5, 93.5, 111.9, 114.1, 114.2, 129.7, 130.0, 135.0, 158.9, 161.5, 188.4; HRMS (ESI⁺): Found: 309.1490; C₂₀H₂₁O₃ (MH⁺) Requires 309.1485 (−1.6 ppm error).

1-Ethyl-4-(4-methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10g). Synthesised using general procedure C from ynone 9g (60.0 mg, 0.195 mmol) and copper(II) triflate (70.5 mg, 0.195 mmol) for 20 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc) afforded the title compound10g as a pale brown oil (43 mg, 75%); R_f 0.50 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1696, 1661, 1590, 1509, 1257, 1177, 1030, 908, 832, 725; δ_H (400 MHz, CDCl₃) 0.97 (3 H, t, J = 7.5), 1.25–1.35 (1 H, m), 1.75–1.84 (1 H, m), 2.66 (1 H, t, J = 7.0), 3.81 (3 H, s), 6.47 (1 H, dd, J = 10.0, 1.5), 6.56 (1 H, s), 6.56 (1 H, dd, J = 10.0, 1.5), 6.80 (1 H, dd, J = 10.0, 3.0), 6.84 (2 H, d, J = 9.0), 6.96 (1 H, dd, J = 10.0, 3.0), 7.44 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 12.6, 20.0, 55.4, 55.8, 58.9, 114.3, 125.6, 126.9, 129.3, 130.0, 131.6, 151.0, 152.2, 162.1, 171.5, 185.3, 205.1; HRMS (ESI⁺): Found: 295.1324; C₁₉H₁₉O₃ (MH⁺) Requires 295.1329 (1.6 ppm error).

2-(2,4-Dimethoxyphenyl)-N-methoxy-N-methylacetamide (S2). Synthesised using general procedure A from 2-(2,4-dimethoxyphenyl)acetic acid (981 mg, 5.00 mmol) affording the title compoundS2 as a pale yellow oil (1.13 g, 91%); ν_max (thin film)/cm⁻¹ 1641, 1590, 1486, 1442, 1273, 1191, 1139, 1021; δ_H (400 MHz, CDCl₃) 3.19 (3 H, s), 3.67 (3 H, s), 3.69 (2 H, s), 3.78 (6 H, s), 6.42–6.47 (2 H, m), 7.07–7.11 (1 H, m); δ_C (100 MHz, CDCl₃) 32.4, 32.7, 55.3, 55.4, 61.1, 98.5, 104.1, 116.1, 131.1, 158.2, 159.8, 173.0; HRMS (ESI⁺): Found: 240.1232; C₁₂H₁₈NO₄ (MH⁺) Requires 240.1230 (1.0 ppm error).

1-(2,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-one (9h). Synthesised using general procedure B from 4-ethynyl-anisole (741 mg, 5.61 mmol) and Weinreb amide S2 (894 mg, 3.74 mmol). Purification by trituration with ether afforded the title compound9h as a pale yellow crystalline solid (789 mg, 68%); mp. 102–104 °C; R_f 0.68 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2184, 1664, 1601, 1589, 1508, 1256, 1211, 1124, 1071, 1027, 835, 786, 575; δ_H (400 MHz, CDCl₃) 3.77–3.84 (11 H, m), 6.46–6.50 (2 H, m), 6.84 (2 H, d, J = 8.5), 7.11 (1 H, d, J = 8.5), 7.37 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 46.0, 55.3, 55.3, 55.4, 87.7, 92.7, 98.5, 104.2, 111.9, 114.2, 115.1, 131.7, 135.1, 158.7, 160.4, 161.5, 186.2; HRMS (ESI⁺): Found: 311.1284; C₁₉H₁₉O₄ (MH⁺) Requires 311.1278 (2.1 ppm error).

6-Methoxy-4-(4-methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10h). Synthesised using general procedure C from ynone 9h (60.3 mg, 0.200 mmol) and SnCl₂·2H₂O (78 mg, 0.200 mmol) for 20 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc, then 1 : 1 petrol : EtOAc) afforded the title compound10h as a white solid (51 mg, 89%); mp. 169–171 °C; R_f 0.19 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1689, 1652, 1588, 1360, 1244, 1177, 1027, 989, 858, 840; δ_H (400 MHz, CDCl₃) 2.61 (1 H, d, J = 18.0), 2.86 (1 H, d, J = 18.0), 3.65 (3 H, s), 3.79 (3 H, s), 5.76 (1 H, d, J = 1.5), 6.34 (1 H, dd, J = 10.0, 1.5), 6.61 (1 H, s), 6.64 (1 H, d, J = 10.0), 6.83 (2 H, d, J = 9.0), 7.43 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 47.7, 52.5, 55.4, 56.2, 103.4, 114.3, 125.1, 128.3, 128.4, 128.9, 147.4, 162.1, 171.6, 175.5, 187.2, 203.6; HRMS (ESI⁺): Found: 297.1112; C₁₈H₁₇O₄ (MH⁺) Requires 297.1121 (1.9 ppm error).

4-(2,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)but-3-yn-2-one (9i). Synthesised using general procedure B from 1-ethynyl-2,4-dimethoxybenzene²⁰ (420 mg, 2.59 mmol) and N-methoxy-2-(4-methoxyphenyl)-N-methylacetamide²¹ (361 mg, 1.73 mmol). Purification by flash column chromatography afforded the title compound9i as a pale yellow oil (340 mg, 63%); R_f 0.60 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2185, 1652, 1600, 1505, 1296, 1244, 1210, 1026, 819; δ_H (400 MHz, CDCl₃) 3.79 (3 H, s), 3.82 (3 H, s), 3.84–3.87 (5 H, m), 6.39 (1 H, d, J = 2.0), 6.45 (1 H, dd, J = 8.5, 2.0), 6.86 (2 H, d, J = 8.5), 7.25 (2 H, d, J = 8.5), 7.34 (1 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 51.3, 55.2, 55.5, 55.7, 91.3, 91.9, 98.2, 101.5, 105.4, 114.0, 125.6, 130.9, 136.5, 158.7, 163.2, 163.6, 185.5; HRMS (ESI⁺): Found: 311.1272; C₁₉H₁₉O₄ (MH⁺) Requires 311.1278 (1.9 ppm error).

4-(2,4-Dimethoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10i). Synthesised using general procedure C from ynone 9i (55.0 mg, 0.177 mmol) and SnCl₂·2H₂O (40.0 mg, 0.177 mmol) for 20 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc, then 1 : 1 petrol : EtOAc) afforded the title compound10i as a pale brown solid (48 mg, 91%); mp. 172–174 °C; R_f 0.19 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1688, 1660, 1605, 1551, 1233, 1213, 1026, 859; δ_H (400 MHz, CDCl₃) 2.67 (2 H, s), 3.80 (3 H, s), 3.84 (3 H, s), 6.37 (1 H, dd, J = 8.5, 2.5), 6.40 (2 H, d, J = 10.0), 6.46 (1 H, d, J = 2.5), 6.95 (2 H, d, J = 10.0), 6.97 (1 H, s), 7.26 (1 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 46.1, 52.4, 55.4, 55.5, 98.9, 104.4, 115.0, 129.2, 130.2, 131.6, 152.9, 160.1, 163.2, 168.8, 184.9, 204.7; HRMS (ESI⁺): Found: 297.1113; C₁₈H₁₇O₄ (MH⁺) Requires 297.1121 (2.6 ppm error).

1-(4-Methoxyphenyl)-4-(phenylthio)but-3-yn-2-one (9j). Synthesised using general procedure B from ethynyl(phenyl)sulfane²² (671 mg, 5.00 mmol) and N-methoxy-2-(4-methoxyphenyl)-N-methylacetamide²¹ (697 mg, 3.33 mmol). Purification by flash column chromatography afforded the title compound9j as a yellow oil (313 mg, 33%); R_f 0.81 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2115, 1651, 1510, 1246, 1176, 1120, 738, 686; δ_H (400 MHz, CDCl₃) 3.79 (2 H, s), 3.80 (3 H, s), 6.89 (2 H, d, J = 8.5), 7.17–7.35 (7 H, m); δ_C (100 MHz, CDCl₃) 50.2, 55.2, 87.6, 100.7, 114.2, 125.0, 127.0, 127.8, 129.5, 129.6, 130.9, 158.9, 183.3; HRMS (ESI⁺): Found: 283.0786; C₁₇H₁₅O₂S (MH⁺) Requires 283.0787 (0.1 ppm error).

4-(Phenylthio)spiro[4.5]deca-3,6,9-triene-2,8-dione (10j). Synthesised using general procedure C from ynone 9j (70.6 mg, 0.250 mmol) and copper(II) triflate (90.4 mg, 0.250 mmol) for 2 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc, then 1 : 1 petrol : EtOAc) afforded the title compound10j as a pale orange solid (43 mg, 64%); mp. 113–115 °C; R_f 0.25 (1 : 1 petrol : ethyl acetate); ν_max (thin film)/cm⁻¹ 1687, 1665, 1548, 860, 752; δ_H (400 MHz, CDCl₃) 2.74 (2 H, s), 5.63 (1 H, s), 6.47 (2 H, d, J = 10.0), 6.79 (2 H, d, J = 10.0), 7.42–7.49 (5 H, m); δ_C (100 MHz, CDCl₃) 46.2, 51.3, 125.8, 128.4, 130.2, 130.4, 130.6, 134.5, 149.2, 182.5, 184.5, 199.8; HRMS (ESI⁺): Found: 269.0621; C₁₆H₁₃O₂S (MH⁺) Requires 269.0631 (3.0 ppm error).

1,5-Bis(4-methoxyphenyl)pent-1-yn-3-one (9k). Synthesised using general procedure B from 4-ethynylanisole (488 mg, 3.70 mmol) and N-methoxy-3-(4-methoxyphenyl)-N-methylpropanamide²³ (550 mg, 2.46 mmol). Purification by flash column chromatography afforded the title compound9k as a yellow solid (500 mg, 69%); mp. 58–60 °C; R_f 0.80 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2185, 1659, 1601, 1508, 1293, 1245, 117, 1084, 1026, 830; δ_H (400 MHz, CDCl₃) 2.92–3.02 (4 H, m), 3.78 (3 H, s), 3.83 (3 H, s), 6.83 (2 H, d, J = 8.5), 6.89 (2 H, d, J = 8.5), 7.14 (2 H, d, J = 8.5), 7.51 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 29.2, 47.1, 55.2, 55.4, 87.7, 92.3, 111.6, 113.9, 114.3, 129.3, 132.4, 135.1, 158.0, 161.6, 187.1; HRMS (ESI⁺): Found: 295.1317; C₁₉H₁₉O₃ (MH⁺) Requires 295.1329 (3.7 ppm error).

7-(4-Methoxyphenyl)spiro[5.5]undeca-1,4,7-triene-3,9-dione (10k). Synthesised using general procedure C from ynone 9k (62.0 mg, 0.204 mmol) and copper(II) triflate (73.7 mg, 0.204 mmol) for 20 h at 50 °C. Purification by flash column chromatography (1 : 1 petrol : EtOAc) afforded the title compound10k as a pale yellow solid (46 mg, 78%); mp. 165–167 °C; R_f 0.25 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1657, 1623, 1603, 1510, 1243, 1178, 1030, 859, 731; δ_H (400 MHz, CDCl₃) 2.25 (2 H, t, J = 6.5), 2.68 (2 H, t, J = 6.5), 3.78 (3 H, s), 6.30 (1 H, s), 6.42 (2 H, d, J = 10.0), 6.79 (2 H, d, J = 9.0), 7.06 (2 H, d, J = 10.0), 7.19 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 34.0, 37.7, 45.5, 55.3, 114.0, 127.7, 128.1, 130.1, 130.4, 152.6, 159.2, 161.0, 184.7, 196.9; HRMS (ESI⁺): Found: 281.1179; C₁₈H₁₇O₃ (MH⁺) Requires 281.1172 (2.5 ppm error).

1-(4′-Methoxybiphenyl-2-yl)-3-(4-methoxyphenyl)prop-2-yn-1-one (9l). Synthesised using general procedure B from 4-ethynylanisole (190 mg, 1.44 mmol) and N,4′-dimethoxy-N-methyl-[1,1′-biphenyl]-2-carboxamide²⁴ (260 mg, 0.958). Purification by flash column chromatography (10 : 1 petrol : EtOAc, then 5 : 1 petrol : EtOAc) afforded the title compound9l as a pale yellow oil (141 mg, 43%); R_f 0.70 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 2184, 1620, 1599, 1508, 1289, 1248, 1027, 999, 830, 760; δ_H (400 MHz, CDCl₃) 3.77 (3 H, s), 3.80 (3 H, s), 6.79 (2 H, d, J = 9.0), 6.94 (2 H, d, J = 8.5), 7.22 (2 H, d, J = 9.0), 7.35 (2 H, d, J = 8.5), 7.40–7.45 (2 H, m), 7.53–7.58 (1 H, m), 7.92 (1 H, d, J = 7.5); δ_C (100 MHz, CDCl₃) 55.3, 55.4, 88.9, 94.9, 112.0, 113.8, 114.0, 127.0, 129.9, 130.7, 130.9, 131.9, 132.9, 135.0, 138.1, 142.3, 159.4, 161.4, 180.8; HRMS (ESI⁺): Found: 343.1324; C₂₃H₁₉O₃ (MH⁺) Requires 343.1329 (1.0 ppm error).

2′-(4-Methoxyphenyl)-4′H-spiro[cyclohexa[2,5]diene-1,1′-naphthalene]-4,4′-dione (10l). Synthesised using general procedure C from ynone 9l (66.0 mg, 0.193 mmol) and copper(II) triflate (69.6 mg, 0.193 mmol) for 48 h at RT. Purification by flash column chromatography (2 : 1 petrol : EtOAc) afforded the title compound10l as a pale yellow oil (47 mg, 74%); R_f 0.25 (1 : 1 petrol : EtOAc); ν_max (thin film)/cm⁻¹ 1655, 1602, 1510, 1331, 1251, 1031, 836; δ_H (400 MHz, CDCl₃) 3.797 (3 H, s), 6.44 (2 H, d, J = 9.5), 6.72 (1 H, s), 6.74 (2 H, d, J = 9.5), 6.82 (2 H, d, J = 9.0), 7.25–7.29 (3 H, m), 7.48–7.57 (2 H, m), 8.25 (1 H, d, J = 7.0); δ_C (100 MHz, CDCl₃) 50.7, 55.3, 113.7, 127.3, 128.2, 128.7, 128.9, 129.6, 130.0, 130.0, 130.2, 133.2, 138.3, 150.0, 156.0, 160.6, 183.6, 185.2; HRMS (ESI⁺): Found: 329.1170; C₂₂H₁₇O₃ (MH⁺) Requires 329.1172 (0.8 ppm error).

2-(4-)-N-Methoxy-N-methylacetamide (S3). Synthesised using general procedure A2 from 2-(4-hydroxyphenyl)acetic acid (2.40 g, 15.8 mmol) stirring at RT for 1 h. Afforded the title compoundS3 as a white solid (3.00 g, 100%); mp 110–112 °C; R_f 0.58 (9 : 1 EtOAc : hexane); ν_max (thin film)/cm⁻¹ 3264, 1631, 1614, 1594, 1515, 1446, 1233, 1172, 1002, 798; δ_H (400 MHz, CDCl₃) 3.22 (3 H, s), 3.65 (3 H, s), 3.70 (2 H, s), 6.68 (2 H, d, J = 8.5), 7.07 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 32.3, 38.2, 61.3, 115.6, 125.9, 130.4, 155.2, 173.3; HRMS (ESI⁺): Found: 218.0788; C₁₀H₁₃NNaO₃ (MNa⁺) Requires 218.0788 (−0.3 ppm error), Found: 196.0975; C₁₀H₁₄NO₃ (MH⁺) Requires 196.0968 (−3.2 ppm error).

1-(4-Hydroxyphenyl)-4-phenylbut-3-yn-2-one (11c). Synthesised using general procedure B2 from phenylacetylene (0.34 mL, 3.07 mmol) and Weinreb amide S3 (200 mg, 1.02 mmol) stirring at RT for 30 min. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 1 : 1 hexane : EtOAc) afforded the title compound11c as a pale yellow solid (135 mg, 56%); mp 96–98 °C; R_f 0.51 (6 : 4 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3368, 2202, 1655, 1514, 1224, 1079, 758, 688; δ_H (400 MHz, CDCl₃) 3.87 (2 H, s), 5.42 (1 H, br s), 6.83–6.88 (2 H, m), 7.16–7.21 (2 H, m), 7.33–7.39 (2 H, m), 7.42–7.50 (3 H, m); δ_C (100 MHz, CDCl₃) 51.3, 87.7, 93.3, 115.7, 119.7, 125.1, 128.6, 130.9, 131.1, 133.1, 155.1, 186.1; HRMS (ESI⁺): Found: 259.0731; C₁₆H₁₂NaO₂ (MNa⁺) Requires 259.0730 (−0.6 ppm error), Found: 237.0919; C₁₆H₁₃O₂ (MH⁺) Requires 237.0910 (−3.8 ppm error).

4-Phenylspiro[4.5]deca-3,6,9-triene-2,8-dione (10c). Synthesised using general procedure C2 from ynone 11c (100 mg, 0.423 mmol) and AgNO₃·SiO₂ (719 mg, 0.0423 mmol) for 24 h at 40 °C. Afforded the title compound10c without further purification as a pale brown solid (94.0 mg, 94%); mp 124–126 °C; R_f 0.31 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3068, 1693, 1658, 1592, 1251, 859, 764; δ_H (400 MHz, CDCl₃) 2.80 (2 H, s), 6.49 (2 H, d, J = 10.0), 6.71 (1 H, s), 6.96 (2 H, d, J = 10.0), 7.34–7.40 (2 H, m), 7.42–7.48 (1 H, m), 7.49–7.54 (2 H, m); δ_C (100 MHz, CDCl₃) 46.9, 51.2, 127.4, 129.0, 129.9, 130.0, 131.6, 132.9, 151.4, 173.9, 184.7, 203.3; HRMS (ESI⁺): Found: 259.0732; C₁₆H₁₂NaO₂ (MNa⁺) Requires 259.0730 (−0.9 ppm error). Spectroscopic data matched those previously reported in the literature.²⁵

1-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-one (11d). Synthesised using general procedure B from 1-ethynyl-4-methoxybenzene (983 mg, 7.44 mmol) and Weinreb amide S3 (484 mg, 2.48 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11d as a yellow solid (502 mg, 76%); mp 86–88 °C; R_f 0.62 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3353, 2195, 1651, 1600, 1510, 1254, 1170, 1076, 834; δ_H (400 MHz, CDCl₃) 3.83 (3 H, s), 3.85 (2 H, s), 5.52 (1 H, br s), 6.86 (4 H, m), 7.17 (2 H, d, J = 8.0), 7.41 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 51.1, 55.4, 87.8, 94.7, 111.5, 114.3, 115.6, 125.4, 131.1, 135.2, 155.1, 161.7, 186.3; HRMS (ESI⁺): Found: 289.0839; C₁₇H₁₄NaO₃ (MNa⁺) Requires 289.0835 (−1.4 ppm error).

4-(4-Methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10d). Synthesised using general procedure C2 from ynone 11d (100 mg, 0.376 mmol) and AgNO₃·SiO₂ (638 mg, 0.0376 mmol) for 3 h at 40 °C. Afforded the title compound10d without further purification as a brown solid (100 mg, 100%). Data for this compound is reported above.

2-(4-Hydroxy-3-methoxyphenyl)-N-methoxy-N-methylacetamide (S4). Synthesised using general procedure A2 from 2-(4-hydroxy-3-methoxyphenyl)acetic acid (1.15 g, 6.34 mmol) stirring at RT for 1 h. Afforded the title compoundS4 as a clear and colourless oil (810 mg, 48%); R_f 0.21 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3316, 2939, 1639, 1514, 1432, 1271, 1200, 1151, 1033; δ_H (400 MHz, CDCl₃) 3.19 (3 H, s), 3.62 (3 H, s), 3.70 (2 H, s), 3.87 (3 H, s), 5.35 (1 H, br s), 6.75 (1 H, d, J = 8.0), 6.82–6.86 (2 H, m); δ_C (100 MHz, CDCl₃) 32.2, 38.8, 55.8, 61.3, 111.7, 114.2, 122.1, 126.5, 144.5, 146.5, 172.7; HRMS (ESI⁺): Found: 248.0884; C₁₁H₁₅NNaO₄ (MNa⁺) Requires 248.0893 (3.7 ppm error), Found: 226.1070; C₁₁H₁₆NO₄ (MH⁺) Requires 226.1074 (1.6 ppm error).

1-(4-Hydroxy-3-methoxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-one (11m). Synthesised using general procedure B2 from 1-ethynyl-4-methoxybenzene (880 mg, 6.66 mmol) and Weinreb amide S4 (500 mg, 2.22 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11m as a yellow solid (443 mg, 58%); mp 61–63 °C; R_f 0.20 (7 : 3 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3437, 2195, 1655, 1601, 1509, 1254, 1237, 1170; δ_H (400 MHz, CDCl₃) 3.84 (5 H, s), 3.89 (3 H, s), 5.63 (1 H, br s), 6.78–6.95 (5 H, m), 7.43 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 51.7, 55.4, 55.9, 87.7, 94.1, 111.6, 112.0, 114.3, 114.5, 122.8, 125.2, 135.1, 144.9, 146.6, 161.7, 185.7; HRMS (ESI⁺): Found: 319.0939; C₁₈H₁₆NaO₄ (MNa⁺) Requires 319.0941 (0.7 ppm error).

7-Methoxy-4-(4-methoxyphenyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10m). Synthesised using general procedure C2 from ynone 11m (59.0 mg, 0.199 mmol) and AgNO₃·SiO₂ (338 mg, 0.0199 mmol) for 24 h at 40 °C. Purification by flash column chromatography (8 : 2 hexane : EtOAc) afforded the title compound10m an off-white oil (50.9 mg, 86%); R_f 0.14 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1691, 1664, 1636, 1603, 1587, 1509, 1258, 1208, 1177, 831; δ_H (400 MHz, CDCl₃) 2.78 (1 H, d, J = 18.5), 2.86 (1 H, d, J = 18.5), 3.66 (3 H, s), 3.83 (3 H, s), 5.86 (1 H, d, J = 2.5), 6.50 (1 H, d, J = 9.5), 6.61 (1 H, s), 6.85 (2 H, d, J = 8.5), 6.97 (1 H, dd, J = 9.5, 2.5), 7.48 (2 H, d, J = 8.5); δ_C (100 MHz, CDCl₃) 48.0, 51.6, 55.2, 55.4, 114.3, 119.4, 125.3, 127.1, 129.0, 129.4, 151.7, 152.4, 162.2, 173.7, 180.1, 203.4; HRMS (ESI⁺): Found: 319.0947; C₁₈H₁₆NaO₄ (MNa⁺) Requires 319.0941 (−2.0 ppm error).

1-(4-Hydroxyphenyl)oct-3-yn-2-one(11n). Synthesised using general procedure B2 from hex-1-yne (0.35 mL, 3.07 mmol) and Weinreb amide S3 (200 mg, 1.02 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11n as a yellow oil (181 mg, 82%); R_f 0.76 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3373, 2959, 2933, 2209, 1652, 1514, 1224, 796; δ_H (400 MHz, CDCl₃) 0.89 (3 H, t, J = 7.5), 1.35 (2 H, qt, J = 7.5, 7.5), 1.48 (2 H, tt, J = 7.5, 7.0), 2.32 (2 H, t, J = 7.0), 3.74 (2 H, s), 5.93 (1 H, br s), 6.80 (2 H, d, J = 8.0), 7.09 (2 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) 13.4, 18.6, 21.8, 29.5, 51.3, 80.7, 97.3, 115.6, 124.9, 130.9, 155.1, 186.7; HRMS (ESI⁺): Found: 239.1050; C₁₄H₁₆NaO₂ (MNa⁺) Requires 239.1043 (−3.2 ppm error).

4-Butylspiro[4.5]deca-3,6,9-triene-2,8-dione(10n). Synthesised using general procedure C2 from ynone 11n (85.4 mg, 0.395 mmol) and AgNO₃·SiO₂ (671 mg, 0.0395 mmol) for 24 h at RT. Afforded the title compound10n without further purification as a pale yellow solid (80.3 mg, 94%); mp 100–102 °C; R_f 0.35 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 2959, 2929, 2875, 2857, 1720, 1696, 1657, 1614, 1599, 1255, 1232, 862; δ_H (400 MHz, CDCl₃) 0.90 (3 H, t, J = 7.5), 1.33 (2 H, qt, J = 7.5, 7.5), 1.52 (2 H, tt, J = 7.5, 7.5), 2.10 (2 H, t, J = 7.5), 2.65 (2 H, s), 6.22 (1 H, s), 6.45 (2 H, d, J = 9.0), 6.66 (2 H, d, J = 9.0); δ_C (100 MHz, CDCl₃) 13.7, 22.2, 28.8, 29.5, 45.0, 52.6, 130.58, 130.61, 150.0, 181.6, 184.9, 204.6; HRMS (ESI⁺): Found: 239.1043; C₁₄H₁₆NaO₂ (MNa⁺) Requires 239.1043 (−0.3 ppm error), Found: 217.1219; C₁₄H₁₇O₂ (MH⁺) Requires 217.1223 (2.0 ppm error). Spectroscopic data matched those previously reported in the literature.²⁶

tert-Butyl (6-(4-hydroxyphenyl)-5-oxohex-3-yn-1-yl)(methyl)carbamate (11o). Synthesised using general procedure B2 from tert-butyl but-3-yn-1-yl(methyl)carbamate^10d (568 mg, 3.10 mmol) and Weinreb amide S3 (202 mg, 1.03 mmol) stirring at RT for 2.5 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 1 : 1 hexane : EtOAc) afforded the title compound11o as a yellow oil (241 mg, 74%); R_f 0.62 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3331, 2977, 2212, 1663, 1515, 1395, 1366, 1225, 1145, 730; δ_H (400 MHz, CDCl₃) 1.47 (9 H, s), 2.54 (2 H, t, J = 7.0), 2.86 (3 H, s), 3.36 (2 H, t, J = 7.0), 3.71 (2 H, s), 6.07 (1 H, br s), 6.81 (2 H, d, J = 8.0), 7.08 (2 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) 18.6, 28.4, 35.0, 47.2, 51.2, 80.3, 81.7, 92.9, 115.8, 124.8, 130.9, 155.6, 155.6, 185.4; HRMS (ESI⁺): Found: 340.1522; C₁₈H₂₃NNaO₄ (MNa⁺) Requires 340.1519 (−0.9 ppm error). Note: majority of peaks broadened in ¹H NMR spectrum due to presence of rotamers.

tert-Butyl (2-(3,8-dioxospiro[4.5]deca-1,6,9-trien-1-yl)ethyl)(methyl)carbamate (10o). Synthesised using general procedure C2 from ynone 11o (73.5 mg, 0.232 mmol) and AgNO₃·SiO₂ (394 mg, 0.0232 mmol) for 10 h at RT. Afforded the title compound10o without further purification as a pale yellow oil (68.5 mg, 93%); R_f 0.22 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 2975, 1720, 1688, 1662, 1624, 1615, 1392, 1365, 1165, 1144, 860; δ_H (400 MHz, CDCl₃) 1.43 (9 H, s), 2.31 (2 H, t, J = 7.0), 2.62 (2 H, s), 2.81 (3 H, s), 3.39 (2 H, t, J = 7.0), 6.20 (1 H, s), 6.43 (2 H, d, J = 9.5), 6.65–6.73 (2 H, br m); δ_C (100 MHz, CDCl₃) 27.2, 28.4, 34.2, 45.1, 47.1, 52.8, 80.0, 130.9, 132.0, 149.4, 155.5, 176.9, 184.5, 203.8; HRMS (ESI⁺): Found: 340.1522; C₁₈H₂₃NNaO₄ (MNa⁺) Requires 340.1519 (−0.8 ppm error). Note: majority of peaks broadened in ¹H NMR spectrum due to presence of rotamers.

6-((tert-Butyldimethylsilyl)oxy)-1-(4-hydroxyphenyl)hex-3-yn-2-one (11p). To an oven-dried 100 mL round-bottom flask containing (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane²⁷ (753 mg, 4.09 mmol) and freshly distilled THF (15 mL) at −78 °C under argon was added n-BuLi (1.3 mL, 4.3 mmol, 2.5 M in hexanes) drop-wise over 10 min. After stirring at −78 °C for 60 min, the alkyne solution was transferred via cannula into an oven-dried round-bottom flask containing Weinreb amide S3 (266 mg, 1.36 mmol) in THF (15 mL) and stirred at −78 °C for 10 min. The resulting suspension was warmed to RT, quenched with saturated aqueous NH₄Cl (20 mL), extracted successively with EtOAc (3 × 15 mL), and the combined organics washed with brine (20 mL), dried (MgSO₄), and concentrated under vacuum to yield a crude product. The crude product was purified by flash column chromatography (9 : 1 hexane : EtOAc, then 6 : 4 hexane : EtOAc) to afford the title compound11p as a yellow oil (367 mg, 84%); R_f 0.56 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3379, 2953, 2929, 2857, 2213, 1670, 1514, 1253, 1106, 836, 795, 778; δ_H (400 MHz, CDCl₃) 0.06 (6 H, s), 0.88 (9 H, s), 2.53 (2 H, t, J = 7.0), 3.71 (2 H, t, J = 7.0), 3.73 (2 H, s), 6.77 (2 H, app. d, J = 8.5), 7.06 (2 H, app. d, J = 8.5); δ_C (100 MHz, CDCl₃) −5.2, 18.4, 23.5, 25.9, 51.3, 60.8, 81.5, 93.7, 115.7, 124.8, 131.0, 155.2, 186.3; HRMS (ESI⁺): Found: 341.1536; C₁₈H₂₆NaO₃Si (MNa⁺) Requires 341.1543 (2.3 ppm error).

4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)spiro[4.5]deca-3,6,9-triene-2,8-dione (10p). Synthesised using general procedure C2 from ynone 11p (55.0 mg, 0.170 mmol) and AgNO₃·SiO₂ (293 mg, 0.0170 mmol) 16 h at RT. Purification by flash column chromatography (8 : 2 hexane : EtOAc, then 1 : 1 hexane : EtOAc) afforded the title compound10p as an orange solid (49.0 mg, 89%); R_f 0.42 (1 : 1 hexane : EtOAc); mp 76–80 °C; ν_max (thin film)/cm⁻¹ 2928, 2857, 1721, 1698, 1657, 1621, 1254, 1102, 864, 834, 775; δ_H (400 MHz, CDCl₃) 0.01 (6 H, s), 0.85 (9 H, s), 2.28 (2 H, dt, J = 6.0, 1.5), 2.26 (2 H, s), 3.75 (2 H, t, J = 6.0), 6.31 (1 H, t, J = 1.5), 6.42 (2 H, app. d, J = 10.0), 6.64 (2 H, app. d, J = 10.0); δ_C (100 MHz, CDCl₃) −5.35, 18.3, 25.9, 32.3, 44.9, 52.7, 60.6, 130.8, 132.0, 149.8, 178.0, 184.9, 204.8; HRMS (ESI⁺): Found: 341.1541; C₁₈H₂₆NaO₃Si (MNa⁺) Requires 341.1543 (0.7 ppm error).

4-Cyclopropyl-1-(4-hydroxyphenyl)but-3-yn-2-one (11q). Synthesised using general procedure B2 from ethynylcyclopropane (0.40 mL, 4.61 mmol) and Weinreb amide S3 (300 mg, 1.54 mmol) stirring at RT for 1 h. Purification by flash column chromatography (1 : 1 hexane : EtOAc) afforded the title compound11q as a white solid (276 mg, 90%); mp 81–83 °C; R_f 0.59 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3367, 2201, 1647, 1514, 1222; δ_H (400 MHz, CDCl₃) 0.80–0.85 (2 H, m), 0.92–0.98 (2 H, m), 1.31–1.39 (1 H, m), 3.71 (2 H), 5.30 (1 H, br s), 6.80 (2 H, d, J = 8.0), 7.09 (2 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) −0.3, 9.9, 51.1, 76.5, 101.6, 115.5, 125.3, 130.9, 154.9, 186.0; HRMS (ESI⁺): Found: 223.0734; C₁₃H₁₂NaO₂ (MNa⁺) Requires 223.0730 (−2.1 ppm error), Found: 201.0906; C₁₃H₁₃O₂ (MH⁺) Requires 201.0910 (1.9 ppm error).

4-Cyclopropylspiro[4.5]deca-3,6,9-triene-2,8-dione (10q). Synthesised using general procedure C2 from ynone 11q (101 mg, 0.504 mmol) and AgNO₃·SiO₂ (857 mg, 0.0504 mmol) for 2 h at RT. Afforded the title compound10q without further purification as a white solid (100 mg, 99%); mp 109–111 °C; R_f 0.45 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1689, 1666, 1624, 1605, 1401, 1252, 860; δ_H (400 MHz, CDCl₃) 0.77–0.82 (2 H, m), 1.11–1.17 (2 H, m), 1.18–1.24 (1 H, m), 2.64 (2 H, s), 5.75 (1 H, s), 6.45 (2 H, d, J = 10.0), 6.72 (2 H, d, J = 10.0); δ_C (100 MHz, CDCl₃) 11.0, 13.8, 45.0, 52.8, 123.5, 130.6, 150.0, 184.9, 185.6, 204.2; HRMS (ESI⁺): Found: 223.0733; C₁₃H₁₂NaO₂ (MNa⁺) Requires 223.0730 (−1.7 ppm error), Found: 201.0906; C₁₃H₁₃O₂ (MH⁺) Requires 201.0910 (2.2 ppm error).

4-Cyclopentyl-1-(4-hydroxyphenyl)but-3-yn-2-one (11r). Synthesised using general procedure B2 from ethynylcyclopentane (0.36 mL, 3.07 mmol) and Weinreb amide S3 (200 mg, 1.02 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11r as a pale yellow oil (207 mg, 89%); R_f 0.74 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3376, 2961, 2871, 2205, 1650, 1514, 1224, 1172; δ_H (400 MHz, CDCl₃) 1.50–1.76 (6 H, m), 1.83–1.97 (2 H, m), 2.73 (1 H, tt, J = 7.5, 7.5), 3.74 (2 H, s), 5.49 (1 H, br s), 6.80 (2 H, d, J = 8.0), 7.10 (2 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) 25.1, 30.0, 33.0, 51.3, 80.2, 101.3, 115.5, 125.2, 130.9, 154.9, 186.6; HRMS (ESI⁺): Found: 251.1041; C₁₅H₁₆NaO₂ (MNa⁺) Requires 251.1043 (0.7 ppm error).

4-Cyclopentylspiro[4.5]deca-3,6,9-triene-2,8-dione (10r). Synthesised using general procedure C2 from ynone 11r (60.2 mg, 0.264 mmol) and AgNO₃·SiO₂ (448 mg, 0.0264 mmol) for 6 h at RT. Afforded the title compound10r without further purification as a white solid (60.0 mg, 100%); mp 129–131 °C; R_f 0.43 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 2958, 1697, 1657, 1621, 1609, 1403, 1249, 864; δ_H (400 MHz, CDCl₃) 1.37–1.50 (2 H, m), 1.52–1.67 (2 H, m), 1.68–1.82 (2 H, m), 1.83–1.95 (2 H, m), 2.30 (1 H, tt, J = 8.0, 8.0), 2.64 (2 H, s), 6.22 (1 H, s), 6.44 (2 H, d, J = 10.0), 6.69 (2 H, d, J = 10.0); δ_C (100 MHz, CDCl₃) 25.5, 34.8, 40.2, 45.0, 53.0, 129.0, 130.5, 150.0, 185.0, 186.8, 204.7; HRMS (ESI⁺): Found: 251.1033; C₁₅H₁₆NaO₂ (MNa⁺) Requires 251.1043 (3.9 ppm error), Found: 229.1215; C₁₅H₁₇O₂ (MH⁺) Requires 229.1223 (3.7 ppm error).

2-(2-Hydroxyphenyl)-N-methoxy-N-methylacetamide (S5). Synthesised using general procedure A2 from 2-(2-hydroxyphenyl)acetic acid (2.00 g, 13.1 mmol) stirring at RT for 1.5 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 1 : 1 hexane : EtOAc) afforded the title compoundS5 as a white solid (788 mg, 31%); mp 63–65 °C; R_f 0.39 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3260, 1628, 1596, 1456, 1246, 1000, 753; δ_H (400 MHz, CDCl₃) 3.24 (3 H, s), 3.80 (3 H, s), 3.87 (2 H, s), 6.85 (1 H, dd, J = 8.0, 7.5), 6.99 (1 H, d, J = 8.0), 7.09 (1 H, d, J = 7.5), 7.19 (1 H, dd, J = 8.0, 8.0), 9.50 (1 H, s); δ_C (100 MHz, CDCl₃) 32.0, 35.1, 62.0, 118.2, 120.2, 120.9, 129.1, 130.9, 156.8, 173.5; HRMS (ESI⁺): Found: 218.0794; C₁₀H₁₃NNaO₃ (MNa⁺) Requires 218.0788 (−3.0 ppm error), Found: 196.0967; C₁₀H₁₄NO₃ (MH⁺) Requires 196.0968 (−0.8 ppm error).

4-Cyclopropyl-1-(2-hydroxyphenyl)but-3-yn-2-one (11s). Synthesised using general procedure B2 from ethynylcyclopropane (0.65 mL, 7.68 mmol) and Weinreb amide S5 (500 mg, 2.56 mmol) stirring at RT for 45 min. Purification by flash column chromatography (1 : 1 hexane : EtOAc) afforded the title compound11s as an off-white solid (452 mg, 88%); mp 98–100 °C; R_f 0.78 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3369, 2202, 1649, 1458, 1269, 755; δ_H (400 MHz, CDCl₃) 0.87–0.92 (2 H, m), 0.97–1.04 (2 H, m), 1.37–1.45 (1 H, m), 3.85 (2 H, s), 6.70 (1 H, br s), 6.88–6.93 (2 H, m), 7.11 (1 H, app. d, J = 7.5), 7.19 (1 H, app. dd, J = 8.0, 8.0); δ_C (100 MHz, CDCl₃) −0.1, 10.2, 47.5, 76.8, 103.2, 117.1, 120.6, 120.9, 129.2, 131.3, 154.9, 187.2; HRMS (ESI⁺): Found: 223.0738; C₁₃H₁₂NaO₂ (MNa⁺) Requires 223.0730 (−3.6 ppm error), Found: 201.0918; C₁₃H₁₃O₂ (MH⁺) Requires 201.0910 (−3.8 ppm error).

4-Cyclopropylspiro[4.5]deca-3,7,9-triene-2,6-dione (12s). Synthesised using general procedure C2 from ynone 11s (108 mg, 0.538 mmol) and AgNO₃·SiO₂ (915 mg, 0.0538 mmol) for 2 h at RT. Afforded the title compound12s without further purification as a yellow oil (104 mg, 96%); R_f 0.34 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1694, 1660, 1632, 1607, 1557, 1200, 862; δ_H (400 MHz, CDCl₃) 0.68–0.79 (2 H, m), 0.97–1.09 (2 H, m), 1.20–1.28 (1 H, m), 2.39 (1 H, d, J = 18.0), 2.77 (1 H, d, J = 18.0), 5.72 (1 H, s), 6.23 (1 H, d, J = 9.5), 6.28 (1 H, d, J = 9.0), 6.47 (1 H, dd, J = 9.0, 5.5), 7.19 (1 H, ddd, J = 9.5, 5.5, 1.5); δ_C (100 MHz, CDCl₃) 11.0, 11.9, 13.2, 46.8, 62.7, 122.8, 123.9, 126.7, 142.5, 142.8, 184.5, 200.3, 206.2; HRMS (ESI⁺): Found: 223.0732; C₁₃H₁₂NaO₂ (MNa⁺) Requires 223.0730 (−1.3 ppm error), Found: 201.0907; C₁₃H₁₃O₂ (MH⁺) Requires 201.0910 (1.3 ppm error).

1-(2-Hydroxyphenyl)-4-phenylbut-3-yn-2-one (11t). Synthesised using general procedure B2 from phenylacetylene (2.0 mL, 18.1 mmol) and Weinreb amide S5 (1.18 g, 6.04 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11t as a yellow solid (1.33 g, 93%); mp 106–108 °C; R_f 0.67 (6 : 4 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3333, 2982, 2202, 1661, 1489, 1458, 1156, 753; δ_H (400 MHz, CDCl₃) 4.01 (2 H, s), 6.27 (1 H, br s), 6.94–6.98 (2 H, m), 7.19–7.26 (2 H, m), 7.39 (2 H, m), 7.45–7.50 (1 H, m), 7.51–7.55 (2 H, m); δ_C (100 MHz, CDCl₃) 47.5, 87.8, 94.0, 116.8, 119.6, 120.4, 121.0, 128.6, 129.3, 131.1, 131.5, 133.3, 154.8, 187.0; HRMS (ESI⁺): Found: 259.0722; C₁₆H₁₂NaO₂ (MNa⁺) Requires 259.0730 (3.1 ppm error), Found: 237.0914; C₁₆H₁₃O₂ (MH⁺) Requires 237.0910 (−1.5 ppm error).

4-Phenylspiro[4.5]deca-3,7,9-triene-2,6-dione (12t). Synthesised using general procedure C2 from ynone 11t (115 mg, 0.487 mmol) and AgNO₃·SiO₂ (826 mg, 0.0487 mmol) for 24 h at RT. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 1 : 1 hexane : EtOAc) afforded the title compound12t a pale yellow oil (103 mg, 90%); R_f 0.22 (7 : 3 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1694, 1659, 1595, 1195, 760; δ_H (400 MHz, CDCl₃) 2.54 (1 H, d, J = 18.0), 2.78 (1 H, d, J = 18.0), 6.34 (1 H, d, J = 10.0), 6.44–6.49 (2 H, m), 6.77 (1 H, s), 7.24–7.30 (1 H, m), 7.30–7.38 (4 H, m), 7.38–7.44 (1 H, m); δ_C (100 MHz, CDCl₃) 48.3, 60.5, 121.8, 126.5, 127.3, 129.0, 129.5, 131.5, 132.3, 142.3, 144.6, 173.7, 200.2, 204.6; HRMS (ESI⁺): Found: 259.0723; C₁₆H₁₂NaO₂ (MNa⁺) Requires 259.0730 (2.5 ppm error), Found: 237.0906; C₁₆H₁₃O₂ (MH⁺) Requires 237.0910 (1.9 ppm error).

The title compound was also prepared in an enantioenriched form using CPA 16¹⁵ (56% conv., 23% ee, see Scheme 4); [α]²¹_D = +5.6 (c = 0.2, CHCl₃).

1-(2-Hydroxyphenyl)-4-(4-methoxyphenyl)but-3-yn-2-one (11u). Synthesised using general procedure B2 from 1-ethynyl-4-methoxybenzene (1.01 g, 7.68 mmol) and Weinreb amide S5 (500 mg, 2.56 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11u as a yellow solid (478 mg, 70%); mp 108–110 °C; R_f 0.29 (7 : 3 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3364, 2193, 1645, 1599, 1508, 1254, 1080, 834; δ_H (400 MHz, CDCl₃) 3.85 (3 H, s), 3.99 (2 H, s), 6.64 (1 H, s), 6.87–6.96 (4 H, m), 7.17–7.24 (2 H, m), 7.49 (2 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) 47.6, 55.4, 87.0, 95.8, 111.2, 114.4, 117.1, 120.7, 121., 129.2, 131.5, 135.5, 154.9, 162.0, 187.2; HRMS (ESI⁺): Found: 289.0833; C₁₇H₁₄NaO₃ (MNa⁺) Requires 289.0835 (0.6 ppm error).

4-(4-Methoxyphenyl)spiro[4.5]deca-3,7,9-triene-2,6-dione (12u). Synthesised using general procedure C2 from ynone 11u (50 mg, 0.188 mmol) and AgNO₃·SiO₂ (319 mg, 0.0188 mmol) for 24 h at RT. Afforded the title compound12u without further purification as a yellow oil (49.5 mg, 99%); R_f 0.25 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1689, 1659, 1602, 1587, 1510, 1262, 1179, 1026, 833, 731; δ_H (400 MHz, CDCl₃) 2.51 (1 H, d, J = 18.0), 2.75 (1 H, d, J = 18.0), 3.81 (3 H, s), 6.34 (1 H, d, J = 9.5), 6.45–6.47 (2 H, m), 6.68 (1 H, s), 6.85 (2 H, d, J = 8.5), 7.25–7.31 (3 H, m); δ_C (100 MHz, CDCl₃) 48.3, 55.4, 60.4, 114.4, 121.5, 124.8, 126.5, 127.2, 129.2, 142.3, 145.0, 162.2, 173.4, 200.5, 204.5; HRMS (ESI⁺): Found: 289.0834; C₁₇H₁₄NaO₃ (MNa⁺) Requires 289.0835 (0.4 ppm error), Found: 267.1004; C₁₇H₁₅O₃ (MH⁺) Requires 267.1016 (4.2 ppm error).

4-(4-Fluorophenyl)-1-(2-hydroxyphenyl)but-3-yn-2-one (11v). Synthesised using general procedure B2 from 1-ethynyl-4-fluorobenzene (923 mg, 7.68 mmol) and Weinreb amide S5 (500 mg, 2.56 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 7 : 3 hexane : EtOAc) afforded the title compound11v as a yellow solid (430 mg, 66%); mp 115–117 °C; R_f 0.46 (7 : 3 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3357, 2203, 1651, 1598, 1505, 1458, 1234, 1082, 838, 754; δ_H (400 MHz, CDCl₃) 3.99 (2 H, s), 6.25 (1 H, s), 6.89–6.97 (2 H, m), 7.08 (2 H, dd, ³J_HH = 8.5, ³J_HF 8.5), 7.18–7.25 (2 H, m), 7.51 (2 H, dd, ³J_HH = 8.5, ⁴J_HF = 5.5); δ_C (100 MHz, CDCl₃) 47.4, 87.7, 92.8, 115.7 (d, ⁴J_CF = 4.0), 116.2 (d, ²J_CF = 22.0), 116.8, 120.4, 121.1, 129.3, 131.5, 135.6 (d, ³J_CF = 8.5), 154.7, 164.1 (d, ¹J_CF = 255), 186.8; HRMS (ESI⁺): Found: 277.0628; C₁₆H₁₁FNaO₂ (MNa⁺) Requires 277.0635 (2.5 ppm error).

4-(4-Fluorophenyl)spiro[4.5]deca-3,7,9-triene-2,6-dione (12v). Synthesised using general procedure C2 from ynone 11v (98.8 mg, 0.389 mmol) and AgNO₃·SiO₂ (661 mg, 0.0389 mmol) for 48 h at RT. Purification by flash column chromatography (8 : 2 EtOAc : hexane) afforded the title compound12v a yellow oil (88.7 mg, 90%); R_f 0.36 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1694, 1659, 1601, 1582, 1508, 1238, 1193, 1163, 836; δ_H (400 MHz, CDCl₃) 2.53 (1 H, d, J = 18.0), 2.76 (1 H, d, J = 18.0), 6.33 (1 H, d, J = 9.5), 6.42–6.50 (2 H, m), 6.70 (1 H, s), 7.03 (2 H, dd, ³J_HH = 8.5, ³J_HF 8.5), 7.25–7.29 (1 H, m), 7.29–7.34 (2 H, m); δ_C (100 MHz, CDCl₃) 48.4, 60.5, 116.2 (d, ²J_CF = 22.0), 121.9, 126.5, 128.6 (d, ⁴J_CF = 3.0), 129.2, 129.5 (d, ³J_CF = 8.5), 142.4, 144.3, 164.3 (d, ¹J_CF = 254), 172.3, 200.1, 204.3; HRMS (ESI⁺): Found: 277.0642; C₁₆H₁₁FNaO₂ (MNa⁺) Requires 277.0635 (−2.4 ppm error), Found: 255.0818; C₁₆H₁₂FO₂ (MH⁺) Requires 255.0816 (−0.7 ppm error).

tert-Butyl 3-(4-(4-hydroxyphenyl)-3-oxobut-1-yn-1-yl)-1H-indole-1-carboxylate (13). Synthesised using general procedure B2 from tert-butyl 3-ethynyl-1H-indole-1-carboxylate⁵ (738 mg, 3.06 mmol) and Weinreb amide S3 (199 mg, 1.02 mmol) stirring at RT for 1 h. Purification by flash column chromatography (9 : 1 hexane : EtOAc, then 8 : 2 hexane : EtOAc) afforded the title compound13 as a yellow oil (306 mg, 80%); R_f 0.37 (7 : 3 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 3374, 2980, 2188, 1743, 1369, 1232, 1150, 1072; δ_H (400 MHz, CDCl₃) 1.70 (9 H, s), 3.89 (2 H, s), 4.98 (1 H, br s), 6.87 (2 H, d, J = 8.0), 7.23 (2 H, d, J = 8.0), 7.32 (1 H, dd, J = 8.0, 7.5), 7.38 (1 H, dd, J = 8.0, 7.5), 7.51 (1 H, d, J = 8.0), 7.91 (1 H, s), 8.14 (1 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) 28.2, 51.2, 85.3, 86.8, 92.4, 100.5, 115.5, 115.8, 120.1, 123.8, 125.7, 125.8, 129.9, 131.2, 133.1, 134.8, 148.6, 155.2, 185.3; HRMS (ESI⁺): Found: 398.1357; C₂₃H₂₁NNaO₄ (MNa⁺) Requires 398.1363 (1.5 ppm error). Note: some peaks broadened in ¹³C NMR spectrum due to presence of rotamers.

tert-Butyl 3-(3-oxo-5-(4-oxocyclohexa-2,5-dien-1-yl)cyclopent-1-en-1-yl)-1H-indole-1-carboxylate (8). Synthesised using general procedure C2 from ynone 13 (68.4 mg, 0.182 mmol) and AgNO₃·SiO₂ (310 mg, 0.0182 mmol) for 7 h at RT. Afforded the title compound8 without further purification as a pale brown solid (67.9 mg, 99%); mp 190–192 °C; R_f 0.46 (1 : 1 hexane : EtOAc); ν_max (thin film)/cm⁻¹ 1742, 1694, 1662, 1595, 1370, 1351, 1228, 1148, 1109, 861, 732; δ_H (400 MHz, CDCl₃) 1.63 (9 H, s), 2.76 (2 H, s), 6.50 (2 H, d, J = 9.5), 6.91 (1 H, s), 6.97 (2 H, d, J = 9.5), 7.34–7.45 (2 H, m), 7.78 (1 H, d, J = 8.0), 7.93 (1 H, s), 8.25 (1 H, d, J = 8.0); δ_C (100 MHz, CDCl₃) 28.0, 45.6, 51.9, 85.4, 114., 115.7, 120.3, 124.2, 125.7, 127.8, 128.2, 128.4, 129.7, 135.8, 148.4, 151.9, 165.9, 184.3, 203.4. Note: some peaks broadened in ¹³C NMR spectrum due to presence of rotamers. Spectroscopic data matched those previously reported in the literature.⁵

5-Methyl-4a,5,6,7-tetrahydrocyclopenta[d]quinoline-3,9(4H,10H)-dione(14). To a stirred solution of tert-butyl (2-(3,8-dioxospiro[4.5]deca-1,6,9-trien-1-yl)ethyl)(methyl)carbamate 10o (64.2 mg, 0.202 mmol) in CH₂Cl₂ (2 mL) at 0 °C was added TFA (0.2 mL) dropwise. The mixture was warmed to RT and stirred for 2 h. The reaction was quenched by the addition of sat. aq. NaHCO₃ (5 mL). The organic layer was separated and the aqueous layer extracted with CH₂Cl₂ (2 × 5 mL). The organics were combined, washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude material was purified by flash column chromatography (9 : 1 EtOAc : MeOH) to afford the title compound14 as a colourless oil (29.2 mg, 66%); R_f 0.47 (9 : 1 EtOAc : MeOH); ν_max (thin film)/cm⁻¹ 2790, 1709, 1684, 1632, 1209; δ_H (400 MHz, CDCl₃) 2.23–2.32 (4 H, m), 2.45–2.54 (2 H, m), 2.58–2.75 (4 H, m), 2.87 (1 H, dd, J = 16.0, 2.5), 3.10 (1 H, ddd, J = 11.0, 5.5, 2.5), 6.00 (1 H, s), 6.09 (1 H, d, J = 10.0), 6.41 (1 H, dd, J = 10.0, 2.5); δ_C (100 MHz, CDCl₃) 29.7, 40.0, 42.1, 45.9, 49.4, 56.7, 70.2, 127.7, 129.2, 149.8, 181.3, 196.1, 204.9; HRMS (ESI⁺): Found: 218.1170; C₁₃H₁₆NO₂ (MH⁺) Requires 218.1176 (2.5 ppm error).

4,4a,6,7-Tetrahydro-3H-cyclopenta[d]chromene-3,9(10H)-dione (15). To a 10 mL reaction vial containing 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)spiro[4.5]deca-3,6,9-triene-2,8-dione 10p (31.0 mg, 0.097 mmol) in THF (3 mL) was added 10% aqueous HCl (0.1 mL) and the reaction stirred under argon at RT. After 1.5 h, the reaction was quenched with saturated aqueous NaHCO₃ (10 mL), extracted successively with EtOAc (3 × 10 mL), the combined organics washed with brine (10 mL), dried over Na₂SO₄ and concentrated to yield a crude product. The product was purified by flash column chromatography (8 : 2 hexane : EtOAc, then 8 : 2 EtOAc : hexane) to afford the title compound15 as an off-white solid (15.0 mg, 75%); R_f 0.47 (EtOAc); mp 115–120 °C; ν_max (thin film)/cm⁻¹ 3564, 2961, 2925, 2856, 1706, 1682, 1629, 1404, 1234, 1204, 1060, 1009, 781, 701; δ_H (400 MHz, CDCl₃) 2.40 (1 H, d, J = 18.5), 2.55 (1 H, d, J = 18.5), 2.60–2.75 (4 H, m), 3.50 (1 H, dt, J = 11.5, 3.0), 3.81–3.83 (1 H, m), 4.22 (1 H, ddd, J = 11.5, 5.5, 2.5), 6.08 (1 H, d, J = 1.5), 6.13 (1 H, d, J = 10.0), 6.42 (1 H, dd, J = 10.0, 3.0); δ_C (100 MHz, CDCl₃) 30.1, 41.5, 44.3, 48.9, 68.1, 81.5, 128.8, 129.7, 148.2, 179.5, 195.1, 204.3; HRMS (ESI⁺): Found: 227.0680; C₁₂H₁₂NaO₃ (MNa⁺) Requires 227.0679 (−0.6 ppm error).

Acknowledgements

The authors would like to thank the University of York (A. K. C., J. D. C., W. P. U.), the EPSRC (J. T. R. L. EP/M018601/01) and the Leverhulme Trust (for an Early Career Fellowship, ECF-2015-013, W. P. U.) for financial support. We would also like to thank Jack Partington, Harry Kirby, Jamie Rose and Richard Bickford-Smith (University of York undergraduate students) for assistance during preliminary studies.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Optimisation table and NMR spectra. See DOI: 10.1039/c6ob02426b

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