Palladium-catalyzed dearomative 1,4-hydroamination

Abstract

A dearomative 1,4-hydroamination of nonactivated arenes has been developed, using a key arene–arenophile photocycloaddition strategy to disrupt aromaticity. Palladium catalysis with K-Selectride^® as a hydride source uniquely enables selective reactivity and provides access to a range of substituted 1,4-cyclohexadienes from aromatic starting materials. We demonstrate a few synthetic applications of this scalable procedure by preparing highly-functionalized small molecules in three to four steps from naphthalene.

1. Introduction

Dearomative functionalization as a synthetic tool enables the rapid elaboration of abundant aromatic feedstocks to diverse chemical building blocks [1]. By increasing the saturation of molecules, greater structural and stereochemical diversity is accessible. A greater fraction of sp³-hybridized carbons has also been correlated to an improved likelihood of success in drug candidates [2]. Novel methods of dearomative functionalization can create facile access to underexplored chemical space, expanding the landscape of drug discovery [3,4].

Towards this end, our group has dedicated extensive study over the last decade to the development of dearomative functionalization using the arenophile N-methyl-1,2,4-triazoline-3,5-dione (MTAD, 1) [5]. Under visible light irradiation, MTAD undergoes a photochemical para-cycloaddition with nonactivated arenes (2) to provide cycloadducts (I) that can be further elaborated through allylic substitution (Fig. 1a) [6–12]. Using this strategy, carbon [6–8] nitrogen [9,10], oxygen [11], and hydrogen [12] nucleophiles can be added to construct a variety of aminofunctionalized cyclohexadienes. The substitution patterns of the resultant dienes have been highly metal-specific, with Pd-catalysis providing exclusively syn-1,4-functionalized products (3), and Ni- and Cu-catalysis providing trans-1,2-functionalized products (4). Recently, we employed a Cu-catalyzed dearomative 1,2-hydroamination of benzene in the total synthesis of an aminoglycoside antibiotic [12]. Motivated by this powerful transformation, we wondered if we could extend the Pd-catalyzed 1,4-selective paradigm to enable a dearomative 1, 4-hydroamination of nonactivated arenes.

Fig. 1.

(a) Previous work in arenophile-mediated dearomative aminofunctionalization. (b) Precedented examples of dearomative 1,4-hydroamination. (c) Biologically active natural products that could be accessed via a dearomative 1,4-hydroamination. (d) This work.

Precedent for a dearomative 1,4-hydroamination in the literature is rare, with one example requiring harsh UV photoexcitation of benzene in the presence of solvent quantities of an amine, providing a mixture of 1,2- and 1,4-hydroamination products with no selectivity and in low yield (Fig. 1b) [13]. Another instance involves the photooxidation of 2-alkoxynaphthalenes using 1,3-dicyanobenzene (m-DCB) as a photocatalyst, but this reactivity is limited in arene scope [14]. Moreover, the products of a dearomative 1,4-hydroamination could be leveraged to gain rapid synthetic access to biologically active natural products, such as huperzine A (5) [15] or nangustine (6) (Fig. 1c) [16]. With a lack of efficient and general dearomative 1,4-hydroamination reactions known, we sought to address this unmet need. Herein, we report these efforts, including the discovery and optimization of such a transformation, the exploration of arene scope, and synthetic applications of the reaction (Fig. 1d).

2. Results and discussion

We began our studies by testing various hydride sources precedented for the Pd-catalyzed hydrogenolysis of allylic electrophiles (Table 1) [17]. The widely used combination of formic acid and triethylamine failed to produce the desired 1,4-cyclohexadiene 7a (entry 1). Surprisingly, the use of Bu₃SnH as a transmetallation reagent provided the target compound 7a in low yield as a mixture with the 1,3-cyclohexadiene 8a (entry 2). This competitive 1,2-hydroamination product [12] was unexpected, because during our previous studies of arenophile-mediated dearomative functionalization we have never observed a deviation from syn-1,4-selectivity using Pd catalysis. Diisobutylaluminum hydride (DIBAL) and lithium triethylborohydride (Super-Hydride^®) only provided diene 8a (entries 3–4), but the bulky and electron-rich lithium tri-sec-butylborohydride (L-Selectride^®) was uniquely effective in providing 7a as the major product, with 43 % overall yield (entry 5). We found that quenching the reaction with citric acid, rather than HCl, increased the combined yield to 66 % (entry 6), which shifted our focus to investigating different Pd catalysts for improved selectivity. Employing Pd(dba)₂ as a precatalyst, we screened a series of phosphine ligands (entries 7–10) and found 1,1′-bis(diphenylphosphino)ferrocene (dppf) to be optimal, providing 7a in 68 % yield with only trace amounts of 8a (entry 10). Finally, using potassium tri-sec-butylborohydride (K-Selectride^®) proved more effective, increasing the yield to 73 % (entry 11). The 1,4-cyclohexadiene 7a was unstable to column chromatography but could be obtained in 65 % isolated yield and high purity following trituration in diethyl ether and filtration. Treating a solution of the isolated 7a dissolved in THF with 1 M aqueous HCl caused partial rearomatization but notably 8a was not observed by NMR analysis, supporting our hypothesis that the product distribution is determined primarily by the ligand, rather than the quench.

Table 1.

Optimization of reaction conditions^a.

entry	[Pd] (5 mol%)	ligand (10 mol%)	hydride (2.0 equiv.)	acid quench	yieldb 7a (%)	yieldb 8a (%)
1	Pd (PPh3)4	none	Et3N/HCO2H	HCl	<5	<5
2	Pd (PPh3)4	none	Bu3SnH	HCl	7	12
3	Pd (PPh3)4	none	DIBAL	HCl	<5	6
4	Pd (PPh3)4	none	Super-Hydride®	HCl	<5	15
5	Pd (PPh3)4	none	L-Selectride®	HCl	37	6
6	Pd (PPh3)4	none	L-Selectride®	citric	44	22
7	Pd (dba)2	Xantphos	L-Selectride®	citric	42	18
8	Pd (dba)2	dppb	L-Selectride®	citric	48	12
9	Pd (dba)2	SPhos	L-Selectride®	citric	59	<5
10	Pd (dba)2	dppf	L-Selectride®	citric	68	<5
11	Pd (dba) 2	dppf	K-Selectride®	citric	73 (65) c	< 5

^aStandard reaction conditions: MTAD (1, 0.5 mmol, 1.0 equiv.), benzene (2a, 5.0 mmol, 10 equiv.), CH₂Cl₂ (0.1 M), visible light, −78 °C, 12 h; then solution of catalyst [Pd (0.025 mmol, 5 mol%), ligand (0.050 mmol, 10 mol%), tetrahydrofuran (THF, 0.25 M)]; then hydride [1.0 mmol, 2.0 equiv], either added neat or as a commercially available solution. See experimental section for more details.

^bReported yields were determined by ¹H NMR of reaction mixtures after workup using nitromethane as internal standard.

^cIsolated yield in parentheses.

With optimized conditions in hand, we explored the scope of arenes that were amenable to dearomative 1,4-hydroamination (Table 2). Alkyl substituted arenes 2b and 2c provided products 7b and 7c in moderate yields with exclusive 1,4-selectivity and as single constitutional isomers. Notably, the methyl ester present in 7c was tolerated under these reductive conditions, as no evidence of ester reduction was observed in recovered 2c or the reaction mixture. This chemoselectivity is likely a result of both the cyrogenic reaction conditions and the steric hindrance of the ester. Arenes bearing halide substituents provided 7d and 7e, which were formed in lower yield. Despite the possible intermediacy of a Pd–H species during this reaction, these potentially labile aryl halides were compatible with the present dearomative functionalization. Again, we saw no evidence of the competitive hydrodehalogenation process in either the recovered starting materials or the crude reaction mixtures.

Table 2.

Arene scope of dearomative 1,4-hydroamination^a.

^aStandard reaction condition: MTAD (1, 0.5 mmol, 1.0 equiv.), arene [5.0 mmol (10 equiv.) for 7a−7h or 1.0 mmol (2.0 equiv.) for 7i−7m], CH₂CI₂ (0.1 M), visible light, −78 °C, 12 h; then solution of catalyst [Pd(dba)₂ (14.4 mg, 0.025 mmol, 5 mol%), ligand (0.050 mmol, 10 mol%), tetrahydrofuran (THF, 0.25 M)]; then K-Selectride^® (1.0 M solution in THF, 1.0 mL, 1.0 mmol, 2.0 equiv.). See experimental section for more details. Unless otherwise noted, reported yields are of isolated products, with ratio of constitutional isomers (in parentheses) determined by ¹H NMR of the crude reaction mixtures.

^bFor gram-scale reactions, L-Selectride^® (1.0 M solution in THF, 1.0 mL, 1.0 mmol, 2.0 equiv.) was used instead.

^cDue to product instability, reported yields were determined by ¹H NMR of reaction mixtures after workup using nitromethane as internal standard.

^dSPhos (20.5 mg, 0.050 mmol, 10 mol%) was used as ligand.

^eDavePhos (19.7 mg, 0.050 mmol, 10 mol%) was used as ligand.

Next, we employed acetal- and orthoester-protected arenes 2f, 2g, and 2h in the 1,4-hydroamination. While we had evidence that esters could be tolerated under these conditions, the unprotected aldehyde and ketone were predicted to react competitively. Furthermore, the initial photochemical arene–arenophile cycloaddition fails when carbonyl functional groups are conjugated with the arene π-system [18]. After dearomative 1,4-hydroamination and acetal deprotection with citric acid, products 7f, 7g, and 7h were obtained in low to moderate yields, with the same exclusive 1,4-selectivity and the same regioselectivity as previous arenes.

We turned our attention to polynuclear arene substrates, beginning with naphthalene 2i. While the optimal ligand for mononuclear arenes, dppf, worked well to provide the desired alkene 7i, other substrates failed to react in productive yields. This finding prompted us to reexamine other ligands for Pd, and we identified Buchwald-type 2-(dicyclohexylphosphino)biphenyl ligands as the most suitable (see Supporting Information for more details) [19]. The electron-rich, bulky RuPhos (2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) typically outperformed other ligands, providing 7i in 65 % yield. Using the related ligand SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), product 7j was derived from phenanthrene 2j in moderate yield as a mixture of separable constitutional isomers (major isomer shown). Interestingly, 2-phenylnaphthalene 2k displayed an unexpected degree of regioselectivity under these conditions, with 7k formed in lower yield but as the exclusive constitutional isomer. Heterocyclic arenes were also suitable substrates for this reaction, with 7l and 7m formed in acceptable to good yields. Other polynuclear arenes with bromide and pivalate ester substituents failed to react productively (see Supporting Information for additional unreactive substrates).

Furthermore, we demonstrated this transformation on gram scale to both showcase the practicality of the reaction and enable exploration of downstream functionalization of the products. Due to the higher commercial price of K-Selectride^® solution as compared to L-Selectride^®, we opted to use the cheaper hydride source for these large-scale experiments. However, it should be noted that control experiments revealed a significant relationship between the yield and the cation of the hydride source, specifically when considering substituted arenes. For most substrates, reactivity plummeted when L-Selectride^® was used. With the unencumbered benzene 2a and naphthalene 2i, however, these larger-scale experiments proceeded smoothly, with 7a obtained in 63 % isolated yield and 7i in a slightly diminished 48 % yield.

Having prepared ample quantities of 7i, we began to study downstream synthetic applications of the products (Fig. 2). Dihydroxylation of the olefin provided diol 9, which could be oxidized to the ketone 10 using household bleach [6,7,20]. This oxidation proceeded in poor yield, likely due to the facile rearomatization of reaction intermediates, since a mixture of unidentified aromatic compounds composed the remainder of the mass balance. The acetonide-protected diol 11 was found to decompose under basic conditions, unfortunately preventing access to the corresponding primary amine. Oxidation of this substrate proceeded with unexpected acetonide deprotection to provide ketone 10 in a similarly low yield. Despite the low yield of these oxidations, the overall 3-step sequence provides rapid access to underexplored chemical space from abundant starting materials. Next, employing Denmark’s modified Simmons-Smith cyclopropanation conditions [21] furnished cyclopropane 12 in moderate yield due to competitive rearomatization of the substrate. Following alkylation and urazole hydrolysis, urea 14 was produced in moderate yield. NOESY correlations confirm a relative syn-stereochemistry between the urazole and cyclopropane, suggesting that the cyclopropanation is directed [22].

Fig. 2.

Derivatization of naphthalene-derived product 7i. Reagents and conditions: (a) OsO₄ (cat.), NMO, citric acid, 48 %, >20:1 dr. (b) NaOCl, 22 %. (c) 2,2-DMP, TsOH, 83 %. (d) ^tBuOCl, AcOH, 18 %. (e) Et₂Zn, ICH₂Cl, 36 %, >20:1 dr. (f) α-bromoacetophenone, K₂CO₃, 76 %. (g) KOH, 41 %.

3. Conclusion

Overall, this dearomative 1,4-hydroamination of nonactivated arenes provides access to a complementary structural motif relative to our previous arenophile-based dearomatization chemistry. With this work, we can perform Pd-catalyzed 1,4-aminofunctionalization of aromatic π-systems to construct C–C, C–N, C–O, and C–H bonds. We have demonstrated reactivity with a range of diverse arene substrates and have prepared multiple grams of the dearomatized products. Last, we produced a pair of functionalized small molecules with excellent stereocontrol that would be difficult to synthesize using other means. We hope that this transformation will find applications in medicinal chemistry and provide access to underexplored chemical space.

4. Experimental

4.1. General experimental

Unless otherwise noted, all reactions were carried out under an inert atmosphere. All chemicals were purchased from commercial suppliers and used as received. N-methyl-1,2,4-triazoline-3,5-dione (MTAD, 1) was prepared based on the literature procedure [23] and resublimed before use. Bis(dibenzylideneacetone)palladium(0) [Pd(dba)₂], 1,1′-bis (diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2′, 6′-diisopropoxybiphenyl (RuPhos), 2-dicyclohexylphosphino-2′, 6′-dimethoxybiphenyl (SPhos), and 2-dicyclohexylphosphino-2’-(N, N-dimethylamino)biphenyl (DavePhos) were purchased from Ambeed. Diisobutylaluminum hydride (DIBAL, 1.0 M solution in CH₂Cl₂), Super-Hydride^® (1.0 M solution in THF), L-Selectride^® (1.0 M solution in THF), and K-Selectride^® (1.0 M solution in THF) were purchased from MilliporeSigma. Dry dichloromethane (CH₂Cl₂) and tetrahydrofuran (THF) were obtained by passing commercially available anhydrous, oxygen-free HPLC-grade solvents through activated alumina columns. Analytical thin-layer chromatography was performed on Merck silica gel 60 F 254 glass plates. Visualization was accomplished with UV light and potassium permanganate (KMnO₄) stain. Retention factor (R_f) values reported were measured using a 5 × 3 cm TLC plate in a developing chamber containing the solvent system described. Flash column chromatography was performed using Silicycle SiliaFlash^® P60 (SiO₂, 40–63 μm particle size, 230–400 mesh). ¹H and ¹³C spectra were recorded on a Bruker 500 spectrometer (500 MHz, ¹H; 126 MHz, ¹³C) or a Bruker 600 spectrometer (600 MHz, ¹H; 151 MHz, ¹³C). Spectra are referenced to residual chloroform (δ = 7.26 ppm, ¹H; 77.16 ppm, ¹³C) or residual methanol (δ = 3.31 ppm, ¹H; 49.0 ppm, ¹³C). Chemical shifts are reported in parts per million (ppm). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Coupling constants J are reported in Hertz (Hz). Mass spectrometry (MS) was performed by the University of Illinois Mass Spectrometry Laboratory. Electron Impact (EI⁺) spectra were performed at 70 eV using methane as the carrier gas, with time-of-flight (TOF) mass analyzer. Electrospray ionization (ESI⁺) spectra were performed using a time-of-flight (TOF) mass analyzer. Data are reported in the form of m/z (intensity relative to the base peak = 100). For several compounds, Waters Q-TOF Ultima ESI and Agilent 6230 ESI TOF LC/MS spectrometers were used to obtain the high-resolution mass spectra. Infrared spectra were measured neat on a Perkin–Elmer spectrum BX FT-IR spectrometer. The visible–light spectrum of the LED was recorded using an Avantes Sensline Avaspec-ULS TEC Spectrometer. Generic cool white light LED corn bulbs were used for the photochemical experiments. These can be obtained from several manufacturers over amazon.com and proved to give consistent results as well as identical visible spectra.

4.2. General procedures

4.2.1. General procedure A

N-methyl-1,2,4-triazoline-3,5-dione (1, MTAD, 56.7 mg, 0.5 mmol, 1.0 equiv.) was placed in a test tube under nitrogen atmosphere, dissolved in CH₂Cl₂ (5.0 mL, 0.1 M), and cooled to −78 °C. Arene (5.0 mmol, 10 equiv.) was added dropwise, and the resulting pink solution was stirred under irradiation with LED lights at −78 °C until the solution became colorless (approximately 12 h). Upon decolorization, the LED lights were turned off and a solution of Pd(dba)₂ (14.4 mg, 0.025 mmol, 5 mol%) and dppf (27.7 mg, 0.050 mmol, 10 mol%) in THF (2.0 mL, pre-stirred at room temperature for 30 min) was added, followed by dropwise addition of K-Selectride^® (1.0 M solution in THF, 1.0 mL, 1.0 mmol, 2.0 equiv.). The resulting solution was allowed to warm to −20 °C over 6 h, then was stirred at this temperature for an additional 10 h. Upon completion, the reaction was quenched by the addition of water (2.5 mL) at −20 °C, and the resulting mixture was stirred vigorously for 15 min at room temperature. The crude mixture was transferred to a separatory funnel, and the organic phase was drained and discarded. The aqueous phase (pH ~ 9) was acidified using aq. citric acid (2 mL, 1.0 M) to pH ~ 4, followed by extraction with CH₂Cl₂ (5 × 5 mL). The organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The products were either purified by trituration in diethyl ether and filtration, or by flash chromatography. The ratio of constitutional isomers was determined by ¹H NMR prior to chromatography.

4.2.2. General procedure B

N-methyl-1,2,4-triazoline-3,5-dione (1, MTAD, 56.7 mg, 0.5 mmol, 1.0 equiv.) was placed in a test tube under nitrogen atmosphere, dissolved in CH₂Cl₂ (5.0 mL, 0.1 M), and cooled to −78 °C. Arene (1.0 mmol, 2 equiv.) was added dropwise, and the resulting pink solution was stirred under irradiation with LED lights at −78 °C until the solution became colorless (approximately 12 h). Upon decolorization, the LED lights were turned off and a solution of Pd(dba)₂ (14.4 mg, 0.025 mmol, 5 mol%) and RuPhos (23.3 mg, 0.050 mmol, 10 mol%) in THF (2.0 mL, pre-stirred at room temperature for 30 min) was added, followed by dropwise addition of K-Selectride^® (1.0 M solution in THF, 1.0 mL, 1.0 mmol, 2.0 equiv.). The resulting solution was transferred to a −20 °C bath and stirred at this temperature for 4 h. Upon completion, the reaction was quenched by the addition of water (2.5 mL) at −20 °C, and the resulting mixture was stirred vigorously for 15 min at room temperature. The crude mixture was transferred to a separatory funnel, and the organic phase was drained and discarded. The aqueous phase (pH ~ 9) was acidified using aq. citric acid (2 mL, 1.0 M) to pH ~ 4, followed by extraction with CH₂Cl₂ (5 × 5 mL). The organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The products were either purified by trituration in diethyl ether and filtration, or by flash chromatography. The ratio of constitutional isomers was determined by ¹H NMR prior to chromatography.

4.2.3. 1-(cyclohexa-2,5-dien-1-yl)-4-methyl-1,2,4-triazoline-3,5-dione (7a)

Following General Procedure A, the crude residue was triturated in diethyl ether and the resulting suspension was filtered to provide 7a as an off-white solid (63 mg, 0.33 mmol, 65 %). ¹H NMR (500 MHz, CDCl₃): δ 6.68 (br, 1H), 6.14 (dtt, J = 10.5, 3.7, 1.7 Hz, 2H), 5.67 (ddt, J = 10.5, 4.0, 2.0 Hz, 2H), 5.23 (ddtd, J = 8.7, 6.9, 3.4, 1.7 Hz, 1H), 3.09 (s, 3H), 2.82–2.64 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 155.0, 154.7, 131.5, 121.9, 50.7, 26.4, 25.4. IR (ATR, neat, cm⁻¹): 3070 (w), 1771 (m), 1684 (s), 1485 (m), 1229 (w), 1033 (w), 769 (m). HRMS (ESI-TOF, m/z): calcd. for C₉H₁₀N₃O₂ [M−2H + H]⁺ calc.: 192.0773; found: 192.0777.

Gram-scale: N-methyl-1,2,4-triazoline-3,5-dione (1, MTAD, 1.00 g, 8.84 mmol, 1.0 equiv.) was placed in a 500 mL media bottle under nitrogen atmosphere, dissolved in CH₂Cl₂ (44 mL, 0.2 M), and cooled to −78 °C. Benzene (7.9 mL, 88 mmol, 10 equiv.) was added in a single portion, and the resulting pink solution was stirred under irradiation with LED lights at −78 °C until the solution became colorless (approximately 24 h). Upon decolorization, the LED lights were turned off and a solution of Pd(dba)₂ (254 mg, 0.442 mmol, 5 mol%) and dppf (490 mg, 0.884 mmol, 10 mol%) in THF (35 mL, pre-stirred at room temperature for 30 min) was cooled to −78 °C and cannulated into the reaction vessel. L-Selectride^® (1.0 M solution in THF, 17.7 mL, 17.7 mmol, 2.0 equiv.) was cooled to −78 °C and cannulated into the reaction vessel. The resulting solution was allowed to warm to −20 °C over 6 h, then was stirred at this temperature for an additional 10 h. Upon completion, the reaction was quenched by the addition of water (50 mL) at −20 °C, and the resulting mixture was stirred vigorously for 15 min at room temperature. The crude mixture was transferred to a separatory funnel, and the organic phase was drained and discarded. The aqueous phase (pH ~ 9) was acidified using aq. citric acid (10 mL, 1.0 M) to pH ~ 4, followed by extraction with CH₂Cl₂ (5 × 40 mL). The organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was triturated in diethyl ether and the resulting suspension was filtered to provide 7a as an off-white solid (1.07 g, 5.54 mmol, 62 %).

4.2.4. 1-(2-(tert-butyl)cyclohexa-2,5-dien-1-yl)-4-methyl-1,2,4-triazoline-3,5-dione (7b)

Following General Procedure A, 7b was obtained as an off-white solid after extraction. The yield was determined by ¹H NMR with 0.167 mmol of nitromethane as internal standard, due to instability during column chromatography (0.19 mmol, 38 %, r.r. > 20:1). An analytically pure sample was obtained by trituration in diethyl ether, albeit with low mass recovery. ¹H NMR (500 MHz, CDCl₃): δ 6.35 (br, 1H), 6.18–6.10 (m, 2H), 5.70 (dd, J = 9.4, 4.7 Hz, 1H), 5.42 (q, J = 4.7 Hz, 1H), 3.08 (s, 3H), 2.85–2.66 (m, 2H), 1.15 (s, 9H). ¹³C NMR (126 MHz, CDCl₃): δ 153.7, 139.9, 131.6, 126.3, 121.9, 50.3, 35.6, 30.1, 27.8, 25.3. IR (ATR, neat, cm⁻¹): 2959 (w), 1684 (s), 1478 (m), 767 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₃H₁₈N₃O₂ [M−2H + H]⁺ calc.: 248.1399; found: 248.1391.

4.2.5. Methyl 2-methyl-2-(6-(4-methyl-3,5-dioxo-1,2,4-triazolidin-1-yl) cyclohexa-1,4-dien-1-yl)propanoate (7c)

Following General Procedure A, the crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 99:1) to provide 7c as an off-white solid (55 mg, 0.19 mmol, 38 %, r.r. > 20:1). Rf = 0.40 (CH₂Cl₂: MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 6.82 (br, 1H), 6.17 (t, J = 4.0 Hz, 1H), 6.12–6.05 (m, 1H), 5.55 (dq, J = 9.8, 2.4 Hz, 1H), 5.35 (q, J = 5.9 Hz, 1H), 3.59 (d, J = 0.8 Hz, 3H), 3.05 (s, 3H), 2.90 (ddq, J = 23.3, 5.9, 2.8 Hz, 1H), 2.81–2.69 (m, 1H), 1.44 (s, 3H), 1.43 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 178.4, 155.7, 155.5, 133.9, 130.2, 128.7, 121.7, 52.7, 51.5, 45.9, 27.5, 26.6, 25.4, 23.2. IR (ATR, neat, cm⁻¹): 3234 (br), 2950 (w), 1764 (w), 1727 (m), 1692 (s), 1477 (m), 1257 (w), 1149 (m), 763 (w). HRMS (ESI-TOF, m/z): calcd. for C₁₄H₁₉N₃O₄Na [M+Na]⁺ calc.: 316.1273; found: 316.1276.

4.2.6. 1-(2-chlorocyclohexa-2,5-dien-1-yl)-4-methyl-1,2,4-triazoline-3,5-dione (7d)

Following General Procedure A, the crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 97:3) to provide 7d as an off-white solid (27 mg, 0.12 mmol, 24 %, r.r. > 20:1). Rf = 0.35 (CH₂Cl₂: MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.17 (br, 1H), 6.26–6.21 (m, 1H), 6.15–6.09 (m, 1H), 5.68 (ddt, J = 9.9, 3.7, 2.1 Hz, 1H), 5.32 (tdd, J = 7.3, 3.7, 1.7 Hz, 1H), 3.10 (s, 3H), 3.00–2.78 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 155.3, 155.0, 130.1, 128.9, 127.2, 122.1, 55.3, 28.5, 25.53. IR (ATR, neat, cm⁻¹): 3157 (w), 1770 (m), 1690 (s), 1477 (m), 764 (m). HRMS (ESI-TOF, m/z): calcd. for C₉H₉N₃O₂Cl [M−2H + H]⁺ calc.: 226.0383; found: 226.0375.

4.2.7. 1-(2-bromocyclohexa-2,5-dien-1-yl)-4-methyl-1,2,4-triazoline-3,5-dione (7e)

Following General Procedure A, the crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 97:3) to provide 7e as an off-white solid (35 mg, 0.13 mmol, 26 %, r.r. > 20:1). Rf = 0.35 (CH₂Cl₂: MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.19 (br, 1H), 6.49 (td, J = 3.7, 1.9 Hz, 1H), 6.15 (ddt, J = 11.6, 3.5, 1.5 Hz, 1H), 5.66 (ddt, J = 9.9, 3.7, 1.9 Hz, 1H), 5.35 (tdt, J = 6.7, 2.9, 1.5 Hz, 1H), 3.11 (s, 3H), 2.84 (ttd, J = 7.3, 3.5, 1.9 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 155.3, 154.7, 133.5, 129.9, 122.1, 117.5, 56.3, 29.4, 25.5. IR (ATR, neat, cm⁻¹): 3156 (w), 3092 (w), 1766 (w), 1694 (s), 1479 (m), 764 (w). HRMS (ESI-TOF, m/z): calcd. for C₉H₉N₃O₂Br [M−2H + H]⁺ calc.: 269.9878; found: 269.9886.

4.2.8. 6-(4-methyl-3,5-dioxo-1,2,4-triazolidin-1-yl)cyclohexa-1,4-diene-1-carbaldehyde (7f)

Following General Procedure A, the aqueous phase (pH ~ 9) was acidified using aq. citric acid (10 mL, 1.0 M), then the aqueous phase was stirred for 30 min at room temperature. The aqueous phase was extracted with CH₂Cl₂ (5 × 5 mL), then the organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. 7f was obtained as an off-white solid after extraction. The yield was determined by ¹H NMR with 0.167 mmol of nitromethane as internal standard, due to instability during column chromatography (0.19 mmol, 37 %, r.r. > 20:1). An analytically pure sample was obtained by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 99:1), albeit with low mass recovery. Rf = 0.40 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 9.48 (s, 1H), 7.68 (br, 1H), 7.18 (tt, J = 3.1, 1.2 Hz, 1H), 6.13 (dtd, J = 10.1, 3.4, 1.7 Hz, 1H), 5.80 (ddd, J = 10.1, 4.0, 2.1 Hz, 1H), 5.50 (q, J = 5.7 Hz, 1H), 3.18 (ddq, J = 25.2, 5.7, 2.9 Hz, 1H), 3.06 (m, 4H). ¹³C NMR (126 MHz, CDCl₃): δ 192.1, 155.5, 154.3, 152.1, 135.5, 128.6, 123.1, 48.1, 27.9, 25.4. IR (ATR, neat, cm⁻¹): 3099 (br), 1764 (w), 1690 (s), 1481 (m), 761 (w). HRMS (ESI-TOF, m/z): calcd. for C₁₀H₁₁N₃O₃Na [M+Na]⁺ calc.: 244.0698; found: 244.0700.

4.2.9. 1-(2-acetylcyclohexa-2,5-dien-1-yl)-4-methyl-1,2,4-triazoline-3,5-dione (7g)

Following General Procedure A, the aqueous phase (pH ~ 9) was acidified using aq. citric acid (10 mL, 1.0 M), then the aqueous phase was stirred for 30 min at room temperature. The aqueous phase was extracted with CH₂Cl₂ (5 × 5 mL), then the organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂: MeOH = 97:3) to provide 7g as an off-white solid (30 mg, 0.13 mmol, 26 %, r.r. > 20:1). Rf = 0.30 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.24–7.13 (m, 2H), 6.10 (dd, J = 9.2, 4.3 Hz, 1H), 5.80 (dp, J = 9.9, 2.0 Hz, 1H), 5.47 (q, J = 5.9 Hz, 1H), 3.16–3.06 (m, 1H), 3.05 (s, 3H), 3.02–2.90 (m, 1H), 2.35 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 197.7, 155.5, 153.9, 143.0, 134.3, 128.4, 122.9, 49.3, 27.8, 25.6, 25.3. IR (ATR, neat, cm⁻¹): 3084 (br), 1763 (w), 1693 (s), 1481 (m), 1396 (w), 1252 (w), 765 (w). HRMS (ESI-TOF, m/z): calcd. for C₁₁H₁₃N₃O₃Na [M+Na]⁺ calc.: 258.0855; found: 258.0854.

4.2.10. Methyl 6-(4-methyl-3,5-dioxo-1,2,4-triazolidin-1-yl)cyclohexa-1,4-diene-1-carboxylate (7h)

Following General Procedure A, the aqueous phase (pH ~ 9) was acidified using aq. citric acid (10 mL, 1.0 M), then the aqueous phase was stirred for 30 min at room temperature. The aqueous phase was extracted with CH₂Cl₂ (5 × 5 mL), then the organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂: MeOH = 97:3) to provide 7h as an off-white solid (50 mg, 0.20 mmol, 40 %, r.r. > 20:1). Rf = 0.35 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.36 (q, J = 3.0 Hz, 1H), 7.03 (br, 1H), 6.14–6.07 (m, 1H), 5.80–5.73 (m, 1H), 5.55 (q, J = 6.2 Hz, 1H), 3.75 (s, 3H), 3.07 (m, 4H), 2.96–2.83 (m, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 165.8, 155.4, 154.3, 143.1, 128.9, 125.6, 122.8, 52.2, 49.9, 27.5, 25.4. IR (ATR, neat, cm⁻¹): 3153 (w), 1764 (w), 1694 (s), 1480 (m), 1263 (m), 765 (w). HRMS (ESI-TOF, m/z): calcd. for C₁₁H₁₃N₃O₄Na [M+Na]⁺ calc.: 274.0804; found: 274.0798.

4.2.11. 1-(1,4-dihydronaphthalen-1-yl)-4-methyl-1,2,4-triazolidine-3,5-dione (7i)

Following General Procedure B, the crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 97:3) to provide 7i as an off-white solid (78 mg, 0.33 mmol, 65 %). Rf = 0.40 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.38 (dd, J = 7.5, 1.7 Hz, 1H), 7.30–7.27 (m, 1H), 7.26–7.22 (m, 1H), 7.19 (dd, J = 7.5, 1.4 Hz, 1H), 6.68 (br, 1H), 6.38–6.30 (m, 1H), 5.92–5.82 (m, 2H), 3.55–3.46 (m, 1H), 3.45–3.34 (m, 1H), 3.07 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 155.0, 154.8, 135.8, 132.0, 130.8, 128.8, 128.4 (2C overlap by HSQC), 127.3, 122.1, 53.4, 29.6, 25.4. IR (ATR, neat, cm⁻¹): 3151 (w), 3035 (w), 1762 (w), 1688 (s), 1478 (m), 753 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₃H₁₂N₃O₂ [M−2H + H]⁺ calc.: 242.0930; found: 242.0925.

Gram-scale: N-methyl-1,2,4-triazoline-3,5-dione (1, MTAD, 1.00 g, 8.84 mmol, 1.0 equiv.) was placed in a 500 mL media bottle under nitrogen atmosphere, dissolved in CH₂Cl₂ (44 mL, 0.2 M), and cooled to −78 °C. Naphthalene (2.27 g, 17.7 mmol, 2 equiv.) was added in a single portion, and the resulting pink solution was stirred under irradiation with LED lights at −78 °C until the solution became colorless (approximately 24 h). Upon decolorization, the LED lights were turned off and a solution of Pd(dba)₂ (254 mg, 0.442 mmol, 5 mol%) and RuPhos (412 mg, 0.884 mmol, 10 mol%) in THF (35 mL, pre-stirred at room temperature for 30 min) was cooled to −78 °C and cannulated into the reaction vessel. L-Selectride^® (1.0 M solution in THF, 17.7 mL, 17.7 mmol, 2.0 equiv.) was cooled to −78 °C and cannulated into the reaction vessel. The resulting solution was allowed to warm to −20 °C over 6 h, then was stirred at this temperature for an additional 10 h. Upon completion, the reaction was quenched by the addition of water (50 mL) at −20 °C, and the resulting mixture was stirred vigorously for 15 min at room temperature. The crude mixture was transferred to a separatory funnel, and the organic phase was drained and discarded. The aqueous phase (pH ~ 9) was acidified using aq. citric acid (10 mL, 1.0 M) to pH ~ 4, followed by extraction with CH₂Cl₂ (5 × 40 mL). The organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂: MeOH = 97:3) to provide 7i as an off-white solid (1.03 g, 4.24 mmol, 48 %).

4.2.12. 1-(1,4-dihydrophenanthren-1-yl)-4-methyl-1,2,4-triazolidine-3,5-dione (7j)

Following General Procedure B and using SPhos (20.5 mg, 0.050 mmol, 10 mol%) as ligand, the crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 99:1) to provide 7j as an off-white solid and as a mixture of two constitutional isomers (56 mg, 0.19 mmol, 38 %, r.r. = 2.6:1). Upon further purification by flash chromatography, the major constitutional isomer was isolated and characterized. Rf = 0.40 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.98 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.57 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 6.52–6.45 (m, 1H), 6.36 (br, 1H), 6.04 (d, J = 4.6 Hz, 1H), 5.98–5.92 (m, 1H), 3.88–3.73 (m, 2H), 3.08 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 154.9, 154.7, 133.1, 131.7, 131.4, 131.3, 128.8, 128.1, 127.6, 126.9, 126.5, 125.6, 123.3, 121.5, 54.0, 26.9, 25.4. IR (ATR, neat, cm⁻¹): 3053 (w), 1760 (m), 1684 (s), 1478 (m), 763 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₇H₁₄N₃O₂ [M−2H + H]⁺ calc.: 292.1086; found: 292.1081.

4.2.13. 4-Methyl-1-(6-phenyl-1,4-dihydronaphthalen-1-yl)-1,2,4-triazolidine-3,5-dione (7k)

Following General Procedure B, the crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 97:3) to provide 7k as an off-white solid (47 mg, 0.15 mmol, 30 %, r.r. > 20:1). Rf = 0.40 (CH₂Cl₂: MeOH = 95:5, KMnO₄). ¹H NMR (600 MHz, CDCl₃): δ 7.59–7.55 (m, 2H), 7.50–7.43 (m, 4H), 7.43–7.41 (m, 1H), 7.39–7.34 (m, 1H), 6.41–6.35 (m, 1H), 6.27 (br, 1H), 5.97–5.87 (m, 2H), 3.58 (dd, J = 22.3, 3.0 Hz, 1H), 3.48 (d, J = 22.3 Hz, 1H), 3.11 (s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 155.05, 155.04, 141.4, 140.5, 136.2, 132.0, 129.7, 129.0, 128.8, 127.78, 127.77, 127.4, 127.3, 127.1, 126.3, 122.2, 53.4, 29.8, 25.5. IR (ATR, neat, cm⁻¹): 2923 (w), 1759 (w), 1697 (s), 1481 (m), 761 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₉H₁₆N₃O₂ [M−2H + H]⁺ calc.: 318.1243; found: 318.1239.

4.2.14. 1-(2,3-dimethyl-5,8-dihydroquinoxalin-5-yl)-4-methyl-1,2,4-triazolidine-3,5-dione (7l)

Following General Procedure B and using SPhos (20.5 mg, 0.050 mmol, 10 mol%) as ligand, 7l was obtained as an off-white solid after extraction. The yield was determined by ¹H NMR with 0.167 mmol of nitromethane as internal standard, due to instability during column chromatography (0.29 mmol, 58 %). An analytically pure sample was obtained by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 97:3), albeit with low mass recovery. Rf = 0.45 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 6.89 (br, 1H), 6.29 (dtd, J = 10.2, 3.6, 2.1 Hz, 1H), 5.97–5.90 (m, 1H), 5.87 (dp, J = 5.6, 2.6 Hz, 1H), 3.59–3.52 (m, 2H), 3.12 (s, 3H), 2.50 (s, 3H), 2.44 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 156.9, 155.8, 152.3, 151.2, 146.4, 142.0, 130.4, 123.2, 56.5, 32.1, 25.5, 22.2, 22.0. IR (ATR, neat, cm⁻¹): 3153 (w), 3042 (w), 1771 (w), 1698 (s), 1477 (m), 1404 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₃H₁₆N₅O₂ [M+H]⁺ calc.: 274.1304; found: 274.1299.

4.2.15. 4-Methyl-1-(2-methyl-5,8-dihydroquinolin-8-yl)-1,2,4-triazolidine-3,5-dione (7m)

Following General Procedure B and using DavePhos (19.7 mg, 0.050 mmol, 10 mol%) as ligand, the crude residue was triturated in diethyl ether and the resulting suspension was filtered to provide 7m as an off-white solid (41 mg, 0.16 mmol, 32 %, r.r. > 20:1). ¹H NMR (500 MHz, CDCl₃): δ 7.39 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.44 (br, 1H), 6.24 (dtd, J = 9.9, 3.6, 2.1 Hz, 1H), 6.01–5.94 (m, 1H), 5.77 (tt, J = 5.2, 2.7 Hz, 1H), 3.49–3.35 (m, 2H), 3.14 (s, 3H), 2.46 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 157.0, 156.9, 156.1, 149.1, 136.8, 129.7, 127.1, 123.8, 123.0, 56.2, 29.2, 25.4, 24.3. IR (ATR, neat, cm⁻¹): 2922 (w), 1765 (w), 1701 (s), 1476 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₃H₁₅N₄O₂ [M+H]⁺ calc.: 259.1195; found: 259.1191.

4.2.16. 1-(2,3-dihydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-4-methyl-1,2,4-triazolidine-3,5-dione (9)

Olefin 7i (114 mg, 0.469 mmol, 1 equiv.) and anhydrous citric acid (135 mg, 0.703 mmol, 1.5 equiv.) were dissolved in MeCN, water, and tert-butanol (2:1:1, 3.74 mL, 0.125 M) under ambient atmosphere, then N-methylmorpholine N-oxide (60 mg, 0.52 mmol, 1.1 equiv.) was added while stirring. Osmium tetroxide (0.12 mL, 0.2 M in MeCN, 0.023 mmol, 5 mol%) was added dropwise, and the solution was stirred at room temperature for 3 h. Upon completion, aq. sodium thiosulfate (2 mL, 10 % w/v) was added, and the reaction mixture was concentrated under reduced pressure. The ratio of diastereomers was determined by ¹H NMR of the resulting residue. The residue was condensed onto Celite and purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 10:1) to provide 9 as a white solid (62 mg, 0.22 mmol, 48 %, d.r. > 20:1). Rf = 0.20 (CH₂Cl₂:MeOH = 10:1, KMnO₄). ¹H NMR (500 MHz, methanol-d₄): δ 7.26–7.14 (m, 4H), 5.51 (d, J = 9.8 Hz, 1H), 4.29 (q, J = 3.1 Hz, 1H), 4.11 (dd, J = 9.8, 2.2 Hz, 1H), 3.20–3.14 (m, 1H), 3.10 (s, 3H), 3.00 (dd, J = 17.5, 3.1 Hz, 1H). ¹³C NMR (126 MHz, methanol-d₄): δ 157.2, 156.0, 135.7, 133.4, 130.6, 129.1, 127.6, 127.5, 71.4, 70.7, 59.7, 37.1, 25.4. IR (ATR, neat, cm⁻¹): 3346 (br), 2925 (w), 1755 (w), 1684 (s), 1489 (m), 757 (w). HRMS (ESI-TOF, m/z): calcd. for C₁₃H₁₆N₃O₄ [M+H]⁺ calc.: 278.1141; found: 278.1137.

4.2.17. 2,3-Dihydroxy-3,4-dihydronaphthalen-1(2H)-one (10)

Diol 9 (32 mg, 0.12 mmol, 1 equiv.) was dissolved in MeCN (2.3 mL, 0.05 M) under ambient atmosphere, and aq. sodium hypochlorite (0.67 mL, 6 wt%, 0.58 mmol, 5 equiv.) was added quickly dropwise. The suspension was stirred at room temperature for 1 min, then quenched immediately with aq. sodium thiosulfate (1 mL, 10 % w/v). The reaction mixture was diluted with EtOAc (3 mL) and water (3 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 × 3 mL), and the combined organic extracts were washed with brine (5 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, n-hexane:EtOAc = 1:1) to provide 10 as a white solid (4.6 mg, 0.03 mmol, 22 %). Rf = 0.15 (n-hexane:EtOAc = 1:1, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J = 7.5 Hz, 1H), 7.57 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 4.64 (q, J = 2.8 Hz, 1H), 4.49 (d, J = 2.8 Hz, 1H), 4.09 (br, 1H), 3.40–3.27 (m, 2H), 2.46 (br, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 198.2, 140.2, 135.0, 130.2, 129.9, 127.2, 127.1, 76.4, 70.9, 34.0. IR (ATR, neat, cm⁻¹): 3424 (br), 2917 (w), 1690 (s), 1603 (m), 1096 (m), 988 (m), 758 (w). HRMS (EI, m/z): calcd. for C₁₀H₁₀O₃ [M]⁺ calc.: 178.0630; found: 178.0635.

Acetonide 11 (50 mg, 0.16 mmol, 1 equiv.) was dissolved in MeCN and water (1:1, 1.6 mL, 0.1 M) under ambient atmosphere, then AcOH (0.27 mL, 4.8 mmol, 30 equiv.) was added and the solution was cooled to 0 °C. Freshly prepared ^tBuOCl [24] (36 μL, 0.32 mmol, 2 equiv.) was added dropwise, and the resulting solution was stirred at 0 °C for 5 min, then quenched immediately with aq. sodium thiosulfate (1 mL, 10 % w/v). The reaction mixture was diluted with diethyl ether (3 mL) and water (3 mL), and the organic phase was separated. The aqueous phase was extracted with diethyl ether (3 × 3 mL), and the combined organic extracts were washed with brine (5 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, n-hexane:EtOAc = 1:1) to provide 10 as a white solid (5.0 mg, 0.03 mmol, 18 %).

4.2.18. 1-(2,2-dimethyl-3a,4,9,9a-tetrahydronaphtho[2,3-d][1,3]dioxol-4-yl)-4-methyl-1,2,4-triazolidine-3,5-dione (11)

Diol 9 (200 mg, 0.72 mmol, 1 equiv.) was dissolved in CH₂Cl₂ and 2,2-dimethoxypropane (1:1, 6.0 mL, 0.12 M) under ambient atmosphere. p-Toluenesulfonic acid (856 mg, 4.50 mmol, 6.4 equiv.) was added, and the resulting mixture was stirred at room temperature for 16 h. Upon completion, sat. aq. K₂CO₃ (5 mL) was added, and the reaction mixture was diluted with CH₂Cl₂ (5 mL) and water (5 mL). The organic phase was drained and discarded, and the aqueous phase (pH ~ 9) was acidified using aq. citric acid (1.0 M) to pH ~ 4, followed by extraction with CH₂Cl₂ (5 × 10 mL). The organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 97:3) to provide 11 as a white solid (189 mg, 0.60 mmol, 83 %). Rf = 0.30 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.30–7.21 (m, 3H), 7.16–7.12 (m, 1H), 5.17 (d, J = 7.7 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.42 (t, J = 7.7 Hz, 1H), 3.29 (dd, J = 15.2, 6.8 Hz, 1H), 3.13 (s, 3H), 2.87 (dd, J = 15.2, 6.8 Hz, 1H), 1.43 (s, 3H), 1.34 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 155.8, 155.6, 134.6, 132.7, 129.0, 128.6, 127.5, 124.6, 110.3, 75.3, 72.5, 60.4, 34.1, 27.1, 25.6, 25.1. IR (ATR, neat, cm⁻¹): 2987 (w), 2935 (w), 1771 (w), 1694 (s), 1481 (m), 1382 (w), 1212 (m), 1162 (w), 1064 (m), 733 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₆H₂₀N₃O₄ [M+H]⁺ calc.: 318.1454; found: 318.1456.

4.2.19. 4-Methyl-1-(1a,2,7,7a-tetrahydro-1H-cyclopropa[b]naphthalen-2-yl)-1,2,4-triazolidine-3,5-dione (12)

Diethylzinc (0.96 mL, 1.0 M in n-hexane, 0.96 mmol, 2 equiv.) was mixed with CH₂Cl₂ (2 mL) and cooled to 0 °C. ICH₂Cl (140 μL, 1.92 mmol, 4 equiv.) was added dropwise, and the resulting solution was stirred at 0 °C for 15 min. Upon completion, olefin 7i (117 mg, 0.48 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (2.8 mL, 0.1 M overall) and this solution was added dropwise to reaction vessel at 0 °C. The resulting mixture was stirred at room temperature for 48 h. Upon completion, sat. aq. K₂CO₃ (5 mL) was added, and the reaction mixture was diluted with CH₂Cl₂ (5 mL) and water (5 mL). The organic phase was drained and discarded, and the aqueous phase (pH ~ 9) was acidified using aq. citric acid (1.0 M) to pH ~ 4, followed by extraction with CH₂Cl₂ (5 × 10 mL). The organic extracts were combined, dried over MgSO₄, and concentrated under reduced pressure. The ratio of diastereomers was determined by ¹H NMR of the resulting residue. The crude residue was purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 98:2) to provide 12 as a white solid (44 mg, 0.17 mmol, 36 %, d.r. > 20:1). Rf = 0.40 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.21 (dt, J = 6.0, 2.4 Hz, 2H), 7.13–7.09 (m, 1H), 7.00 (dd, J = 6.6, 2.9 Hz, 1H), 5.77 (d, J = 3.2 Hz, 1H), 3.17 (s, 3H), 3.08 (d, J = 9.0 Hz, 1H), 3.03 (d, J = 16.8 Hz, 1H), 1.46–1.40 (m, 2H), 0.58 (td, J = 8.1, 5.1 Hz, 1H), 0.41 (q, J = 5.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 154.9, 154.3, 134.6, 130.4, 129.9, 128.2, 127.2, 124.9, 54.3, 29.0, 25.5, 13.4, 8.3, 3.3. IR (ATR, neat, cm⁻¹): 2925 (w), 1767 (w), 1693 (s), 1481 (m), 763 (w), 745 (w), 720 (w). HRMS (ESI-TOF, m/z): calcd. for C₁₄H₁₆N₃O₂ [M+H]⁺ calc.: 258.1243; found: 258.1241.

4.2.20. 4-Methyl-1-(2-oxo-2-phenylethyl)-2-(1a,2,7,7a-tetrahydro-1H-cyclopropa[b]naphthalen-2-yl)-1,2,4-triazolidine-3,5-dione (13)

Cyclopropane 12 (44 mg, 0.17 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (1.7 mL, 0.1 M), and K₂CO₃ (119 mg, 0.86 mmol, 5 equiv.) and 2-bromoacetophenone (103 mg, 0.52 mmol, 3 equiv.) were added. The resulting suspension was stirred at room temperature for 12 h. Upon completion, sat. aq. NaHCO₃ (3 mL) was added, and the organic phase was separated. The aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL), and the combined organic extracts were washed with brine (5 mL), dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO₂, n-hexane:EtOAc = 3:1) to provide 13 as a white solid (49 mg, 0.13 mmol, 76 %). Rf = 0.45 (n-hexane:EtOAc = 1:1, KMnO₄). ¹H NMR (500 MHz, CDCl₃): δ 7.67–7.62 (m, 2H), 7.60–7.54 (m, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 1H), 7.01 (m, 2H), 6.66 (t, J = 7.5 Hz, 1H), 5.89 (d, J = 4.6 Hz, 1H), 4.99 (d, J = 18.2 Hz, 1H), 4.39 (d, J = 18.2 Hz, 1H), 3.29 (s, 3H), 3.09–2.99 (m, 2H), 1.51–1.43 (m, 1H), 1.33 (tt, J = 8.5, 4.6 Hz, 1H), 0.65 (td, J = 8.5, 5.2 Hz, 1H), 0.39 (q, J = 5.2 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 192.6, 157.5, 156.8, 134.4, 134.2, 134.0, 132.1, 129.5, 128.9, 127.9, 127.8, 126.8, 125.1, 56.8, 53.4, 29.1, 26.1, 13.9, 9.0, 4.3. IR (ATR, neat, cm⁻¹): 3067 (w), 3021 (w), 2989 (w), 1772 (m), 1710 (s), 1694 (s), 1474 (m), 1227 (m), 738 (w). HRMS (ESI-TOF, m/z): calcd. for C₂₂H₂₁N₃O₃Na [M+Na]⁺ calc.: 398.1481; found: 398.1483.

4.2.21. 1-Methyl-3-(1a,2,7,7a-tetrahydro-1H-cyclopropa[b]naphthalen-2-yl)urea (14)

Cyclopropane 13 (42 mg, 0.11 mmol, 1 equiv.) was dissolved in EtOH (1.1 mL, 0.1 M). KOH (0.17 mL, 50 % w/v aqueous, 2.2 mmol, 20 equiv.) was added, and the solution was immediately sparged with nitrogen under sonication for 3 min. The resulting solution was stirred at 80 °C for 24 h. Upon completion, the reaction mixture was condensed onto Celite and purified by flash chromatography (SiO₂, CH₂Cl₂:MeOH = 99:1) to provide 14 as a white solid (9.9 mg, 0.046 mmol, 41 %). Rf = 0.25 (CH₂Cl₂:MeOH = 95:5, KMnO₄). ¹H NMR (500 MHz, methanol-d₄): δ 7.22 (d, J = 7.2 Hz, 1H), 7.19–7.10 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 5.20 (d, J = 4.1 Hz, 1H), 3.11 (dd, J = 16.2, 4.3 Hz, 1H), 2.99 (dd, J = 16.2, 2.1 Hz, 1H), 2.79 (s, 3H), 1.45 (tt, J = 8.3, 4.1 Hz, 1H), 1.42–1.34 (m, 1H), 0.36 (td, J = 8.3, 5.0 Hz, 1H), 0.12 (q, J = 5.0 Hz, 1H). ¹³C NMR (126 MHz, methanol-d₄): δ 160.5, 135.6, 133.5, 128.3, 126.6, 126.1, 125.2, 47.1, 28.6, 25.6, 16.2, 8.9, 0.7. IR (ATR, neat, cm⁻¹): 3339 (br), 2924 (w), 1634 (s), 1568 (s), 1489 (w), 1454 (w), 1258 (w), 742 (m). HRMS (ESI-TOF, m/z): calcd. for C₁₃H₁₇N₂O [M+H]⁺ calc.: 217.1341; found: 217.1338.

Data availability

No data was used for the research described in the article.