Consecutive reactions to construct tricarbonyl compounds and synthetic applications thereof

Abstract

Lithium anions derived from O-carbonate-protected cyanohydrins undergo conjugate addition to cycloalkenones with the concomitant transfer of the alkoxycarbonyl group to produce tricarbonyl compounds. These products offer numerous possibilities for further elaboration. The synthetic potential of the cascade products was demonstrated by forming bicyclic and tricyclic systems through intramolecular condensation reactions.

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Introduction

Since the pioneering work by Stork et al.,¹ O-protected cyanohydrins have become recognized as valuable acyl anion synthons.^2,3 Over the years, this approach has been widely used^4a–k to achieve the chemical synthesis of organic molecules with diverse architectures (Scheme 1).

Scheme 1 Pioneering work of Stork and Maldonado to use protected cyanohydrins as acyl anion equivalents.

Among the different groups used to protect the hydroxyl group in cyanohydrins, carbonates^5a–c display a moderately electrophilic carbon atom. This reactivity can be exploited to perform subsequent transformations to the anions' reaction with electrophiles (i.e., transfer of an acyl group), thus enabling consecutive reactions. Consecutive reactions, also known as cascade or domino reactions,⁶ are a practical strategy to form multiple bonds sequentially, simplifying the construction of organic molecules.

A recent paper⁷ demonstrated that anions derived from O-carbonate-protected cyanohydrins undergo conjugate addition to cyclohexenone with concomitant transfer of the alkoxycarbonyl group to produce β-keto-β′-acylcycloalkanecarboxylic acid esters; however, these were isolated as the enol acetate derivatives.

Tricarbonyl compounds have been used for the synthesis of functionalized biphenyls via an oxidative aromatization with iodine^8a and for the formal synthesis of (±)-cochlearol A.^8b The oxidation of tricarbonyl compounds has been used for the preparation of propellanes, compounds showing a broad spectra of biological and pharmacological activities,^8c as well as for the synthesis of heterocycles.^8d

Considering the tremendous synthetic utility of the functionalities present in the putative intermediate products namely β-keto ester,^9a–f gamma-keto ester,^9g and 1,4-dione,¹⁰ we attempted to directly obtain these intermediates by modifying Le Lagadec's procedure.⁷

Herein, we present a procedure to construct synthetically valuable tricarbonyl cyclic compounds featuring consecutive Michael–Claisen reactions of lithium anions derived from O-carbonate-protected cyanohydrins with 5, 6, and 7-membered cycloalkenones. The functionalities introduced into the cycloalkenones was exploited by annulation of a five-membered ring onto the olefin of the original cycloalkenone.

Results and discussion

Our strategy is shown in Scheme 2, consisting of the preparation of cyanocarbonates 6 from aldehydes 1 according to literature procedures (Scheme 2A). Deprotonation with a suitable base (2 equiv.), followed by conjugate addition of the corresponding anions onto cyclic enones 7 (Scheme 2B) and subsequent reaction of the tricarbonyl product 9 (as an enolate) with electrophiles would afford highly functionalized products 10 (Scheme 2C).

Scheme 2 (A and B) Synthetic strategy for the construction of tricarbonyl compounds using consecutive reactions. (B and C) Plausible mechanism for the consecutive reactions illustrated for the formation of 10.

The preparation of some cyanocarbonates 6 was achieved using the two-phase reaction system procedure reported by Kolis et al.¹¹ (Table 1, Method A). In other cases, higher yields were obtained using ethyl carbonocyanidate (CNCOOEt) in the presence of DMAP and CH₃CN as the solvent (Table 1, Method B).^5c A total of 23 cyanocarbonates were prepared and satisfactorily characterized.

Table 1 Preparation of cyanocarbonates

a (Boc)₂O was used instead of ClCOOMe.b The reaction was heated at 40 °C.

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To evaluate the deprotonation ease of the NC-C–H bond, its pK_a was determined using a direct approach,¹² in which free energies are calculated directly in THF solution at −78 °C (Table 2). Calculations were carried out using the ωB97XD DFT hybrid functional,¹³ the 6-311++G(d,p) basis set, and the D2 Grimme dispersion correction¹⁴ as implemented in the Gaussian 16 suite.¹⁵ The solvent was described implicitly using the SMD method.¹⁶ This methodology has been used before to determine pK_a in several systems.^12,17 Fig. 1 shows that the obtained pK_a values highly correlate with the Hammett constants¹⁸ (σ) of the phenyl substituent for compounds 6a, 6d, 6e, and 6f, for which it was obtained pK_a = 37.503–11.527σ and R² = 0.931. Therefore, the deprotonation ease of these compounds increases with the electron-withdrawing properties of the substituents, which results in the stabilization of the corresponding carbanion. Similar correlations are observed with other molecular parameters and also for compounds 7. The relatively large pK_a values indicated the use of a strong base would be required to obtain the corresponding carbanion efficiently.

Table 2 Scope of the cascade reactions between cyanocarbonates 6 and 7 with 2-cyclohexen-1-one

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Fig. 1 Correlation of pK_a with the Hammett constant of the phenyl substituent for compounds 6a, 6d, 6e, 6f.

To test our hypothesis and standardize the reaction conditions, we selected cyanocarbonate 6a as the carbanion source and commercially available LiHMDS as the base. The base was added dropwise to a solution of 6a in THF at −78 °C. After 15 min, cyclohex-2-en-1-one was added, and the course of the reaction was monitored by TLC.

To investigate the scope of the cascade process under the optimized conditions described above, the anions of cyanocarbonates 6 and 7 were added to cyclohexanone. The results of those experiments are summarized in Table 2. A total 15 of tricarbonyl compounds (8a–o and 9a–c) were obtained in moderate yields. All the products were successfully characterized.

Next, we investigated the use of 2-cyclopenten-1-one, 2-cyclohepten-1-one, and 3-methyl-2-cyclohexen-1-one as the enone component for the cascade process to further explore the scope of the methodology. The results are presented in Table 3. For 2-cylopenten-1-one, the tricarbonyl compound 9a was obtained in 80% yield, whereas for 2-cyclohepten-1-one the desired product 9b was obtained in 50% yield. In the case of 3-methyl-2-cyclohexen-1-one, 9c was obtained in 38% yield. This lower yield was attributed to the steric hindrance caused by the methyl group at C-3 of the cycloalkenone. This assumption is supported by the failure to obtain the cascade product when the more sterically hindered 4,4-dimethyl-2-cyclohexen-1-one was used as the substrate.

Table 3 Use of different cycloalkenones to explore the scope of the process

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Interestingly, ¹H NMR spectra for all the cascade products obtained from 2-cyclohexen-1-one and 3-methyl-2-cyclohexen-1-one were isolated as a mixture of keto and enol tautomers. In contrast only a single keto tautomer or the keto diastereomers were observed by ¹H NMR for the adducts derived from 2-cyclopenten-1-one and 2-cyclohepten-1-one (i.e., 9a and 9b). Computational results indicate that the keto-tautomer of compounds 9a and 9b is 1.365 and 1.366 kcal mol⁻¹, respectively, more stable than the corresponding enol-tautomer. On the contrary, for compound 8a, the enol-tautomer is only 0.274 kcal mol⁻¹ more stable than the corresponding keto-tautomer. This small energy difference could explain the reason to observe this product as a mixture of tautomers. Further investigation on the tautomeric behavior of these systems is currently underway. Clearly, the cascade process can occur for 5, 6, and 7-membered cycloalkenones, even enones showing moderate steric hindrance.

After proving the efficiency of the cascade process, we investigated the possibility of performing annulations via intramolecular condensation reactions. Thus, when 14b was treated with NaH in THF at rt, followed by the addition of triphenylvinylphosphonium bromide (Schweizer's reagent)¹⁹ no reaction was observed. If the reaction mixture was heated under reflux, several spots are observed on TLC. However, when DBU was used as the base (in CH₃CN), 39% of intramolecular Wittig product 10 was obtained after purification, along with unreacted starting material and traces of two unknown compounds. Treatment of 8b with methylvinyl ketone and cyclopentenone as the Michael acceptors in the presence of DBU (in CH₃CN at room temperature), afforded cyclic products 11 and 12 in 88 and 32% yield, respectively (Table 4). It is noteworthy that decarboxylation occurred during the formation of 11 and 12.

Table 4 Further transformations of cascade product 8b

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The preparation of annulated products 10, 11, and 12 nicely exemplifies the synthetic potential of β-keto-β′-acylcycloalkanecarboxylic acid esters 8 as scaffolds to obtain products with increased structural complexity. With some adjustments, we believe that compounds 8 can be used to obtain diverse molecules such as the core of pacifigorgianes²⁰ 13, the sesquiterpenoid cyperolone²¹ 14, indanones²² 15, furans²³ pyrroles and thiophenes 16, 1,2-azoles 17, pyrimidines 18 and 1,2-diazines 19 (Fig. 2).

Fig. 2 Potential use of tricarbonyl compounds 8 to generate structural diversity.

Experimental

General information

All experiments involving air and/or moisture-sensitive compounds were conducted in an oven dried round-bottom flask capped with a rubber septum under a positive pressure of nitrogen. Air- and moisture-sensitive liquids were transferred via syringe or stainless-steel cannula. Low temperature baths were ice/water (0 °C), CO₂(s)/acetone (−78 °C). Unless otherwise noted, reaction temperatures refer to that of the bath. Concentration refers to removal of volatiles on a rotary evaporator below 35 °C. Analytical thin-layer chromatography (TLC) was performed using glass plates pre-coated with silica gel (0.25 mm, 60 Å pore size, 230–400 mesh, Merck) impregnated with a fluorescent indicator (254 nm). Materials on TLC plates were visualized under an ultraviolet lamp (254 nm) and/or by submersion of the plate in a solution of phosphomolybdic acid (5%) containing a trace of ceric sulfate in aqueous sulfuric acid (5% v/v) followed by charring on a hot plate. Flash column chromatography (FCC) was performed according to Still et al. with silica gel 60 (40–63 μm). All mixed solvent eluents are reported as v/v solutions. Unless otherwise noted, all reported compounds were homogeneous by thin layer chromatography (TLC) and by ¹H NMR.

Materials and methods

All the reagents were purchased from Sigma-Aldrich and were used as received unless other thing stated. Solvents were distilled prior to use. Anhydrous solvents were distilled under nitrogen atmosphere. THF and diethyl ether were distilled on sodium benzophenone ketyl; MeOH on magnesium activated with 5% iodine. Et₃N, CH₃CN dichloroethane and DMF were distilled on CaH₂.

Proton nuclear magnetic resonance (¹H NMR) spectra and carbon nuclear magnetic resonance (¹³C NMR) spectra were recorded on Agilent-Inova-300 and Varian VNMRS-400 NMR spectrometers. Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to tetramethylsilane (TMS: 0.0). Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to tetramethylsilane (TMS: 0.0). For compounds 6e, 7e, 7f, 7h, 7p, 8g, and 8n, CDCl₃ was used as a standard. This information is included in the ESI.† Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets, ddd = doublet of doublets of doublets, ddt = doublet of doublets of triplets, dqd = doublet of quartets of doublets, m = multiplet, br = broad, app = apparent), integration, and coupling constant (J) in Hertz (Hz).

IR spectra were recorded on a PerkinElmer Spectrum 400 FT-IR/FIR spectrometer with ATR. Mass spectra were carried out on a JEOL SMX-102a spectrometer.

Method A

A 2 M aqueous solution of NaCN (4.8 mL) was added dropwise to a mixture of the aldehyde (5 mmol), ClCOOMe (0.43 mL, 5.5 mmol) and (nBu)₄NBr (160 mg, 0.5 mmol) in CH₂Cl₂ (6.25 mL) at ambient temperature. The resultant mixture was vigorously stirred overnight, the two phases were separated, and the organic layer was washed with sat. NaCl dried on anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO₂).

Method B

CNCOOEt (0.108 mL, 1.1 mmol) was slowly added to a mixture of aldehyde (1 mmol) and DMAP (6 mg, 0.05 mmol) in CH₃CN (2 mL) under nitrogen atmosphere at ambient temperature. When all the starting material has been consumed (TLC) the reaction mixture is poured on sat NaCl (5 mL) and extracted with EtOAc (3 × 20 mL). The organic extracts were combined and dried on anhydrous Na₂SO₄, the solvent evaporated in vacuo and the residue purified by column chromatography.

Cyano(phenyl)methyl methyl carbonate (6a). Prepared following Method A. The residue was purified by column chromatography (hexanes/EtOAc 95 : 5) to obtain 755 mg (79%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 3.87 (s, 3H, OCH₃), 6.27 (s, 1H, CHCN), 7.47–7.48 (m, 3H, m,p-C₆H₅), 7.53–7.56 (m, 2H, o-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 56.0, 66.7, 115.8, 128.0, 129.4, 130.8, 131.3, 154.2 ppm. APCI: m/z calculated for C₈H₈NO₄ [M + H]⁺ = 192.0661; found: 192.0703.

Cyano(furan-2-yl)methyl methyl carbonate (6b). Prepared following Method A. The residue was purified by column chromatography (hexanes/EtOAc 95 : 5) to obtain 729 mg (80%) of a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 3.86 (s, 3H, OCH₃), 6.34 (s, 1H, CHCN), 6.44–6.45 (dd, 1H, J = 1.8, 3.2 Hz, 3-C₄H₃O), 6.72–6.73 (d, 1H, J = 3.2 Hz, 4-C₄H₃O), 7.51–7.52 (d, 1H, J = 1.8 Hz, 5-C₄H₃O). ¹³C NMR (400 MHz, CDCl₃) δ: 56.1, 59.5, 111.3, 113.3, 113.8, 143.6, 145.4, 154.0 ppm. APCI: m/z calculated for C₈H₈NO₄ [M + H]⁺ = 182.0453; found: 182.0502.

tert-Butyl (cyano(phenyl)methyl)carbonate (6c). A 2 M aqueous solution of NaCN (4.8 mL) was added dropwise to a mixture of benzaldehyde (5 mmol), Boc₂O (1.2 g, 5.5 mmol) and (nBu)₄NBr (16 mg, 0.05 mmol) in CH₂Cl₂ (6.25 mL) at ambient temperature. The resulting mixture was stirred overnight, the two phases were separated, and the organic layer was washed with sat NaCl, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 845 mg (72%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.44 (s, 9H, Ot-Bu), 6.14 (s, 1H, CHCN), 7.34–7.36 (m, 3H, m,p-C₆H₅), 7.43–7.45 (m, 2H, o-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 27.7, 65.8, 85.0, 116.2, 128.0, 129.3, 130.6, 131.7, 151.7 ppm. APCI: m/z calculated for C₁₃H₁₆NO₃ [M + H]⁺ = 234.1130; found: 234.1124.

Cyano(4-methoxyphenyl)methyl methyl carbonate (6d). Prepared according to Method A with the following modification: the reaction mixture was stirred at 40 °C for 12 h. The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 700 mg (63%) of a pale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 3.82 (s, 3H, COOCH₃), 3.84 (s, 3H, OCH₃), 6.20 (s, 1H, CHCN), 6.95 (m, 2H m-C₆H₄OMe), 7.47 (m, 2H, o-C₆H₄OMe) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 55.5, 55.9, 66.5, 114.7, 116.0, 123.4, 129.9, 154.2, 161.5 ppm. APCI: m/z calculated for C₁₁H₁₂NO₄ [M + H]⁺ = 222.0766; found: 222.0769.

(2-Bromophenyl)(cyano)methyl methyl carbonate (6e). Prepared following Method A. The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 1.23 g (91%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 3.89 (s, 3H, OCH₃), 6.57 (s, 1H, CHCN), 7.61–7.64 (m, 1H, m-C₆H₄Br), 7.73–7.76 (m, 1H, m-C₆H₄Br), 7.87–7.89 (m, 1H, p-C₆H₄Br), 8.14–7.16 (m, 1H, o-C₆H₄Br) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 56.4, 63.0, 114.7, 126.0, 126.9, 129.3, 131.6, 134.9, 146.9, 153.6 ppm. ESI⁺: m/z calculated for C₁₀H₉BrNO₃ [M + H]⁺ = 269.9766, found: 269.9775.

Cyano(2-nitrophenyl)methyl methyl carbonate (6f). Prepared following Method A. The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 1.16 g (93%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 3.89 (s, 3H, OCH₃), 7.01 (s, 1H, CHCN), 7.67–7.71 (m, 1H, m-C₆H₄NO₂), 7.79–7.83 (m, 1H, m-C₆H₄NO₂), 7.94–7.96 (m, 1H, p-C₆H₄NO₂), 8.21–8.24 (m, 1H, o-C₆H₄NO₂) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 56.4, 63.0, 114.7, 126.0.127.0, 129.3, 131.7, 134.9, 146.9, 153.6 ppm. ESI⁺: m/z calculated for C₁₀H₉N₂O₅ [M + H]⁺ = 237.0511, found: 237.0510.

(6-Bromobenzo[d][1,3]dioxol-5-yl)(cyano)methyl methyl carbonate (6g). Prepared according to Method A with the following modification: the reaction mixture was stirred at 40 °C for 12 h. The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 1.32 g (84%) of a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 3.88 (s, 3H, OCH₃), 6.04 (s, 2H, OCH₂O), 6.51 (s, 1H, CHCN), 7.04 (s, 1H, m-C₆H₂Br), 7.16 (s, 1H, o-C₆H₂Br) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 56.2, 66.2, 102.8, 109.3, 113.3, 114.9, 115.3, 123.8, 148.3, 150.5, 153.9 ppm. ESI⁺: m/z calculated for C₁₁H₉BrNO₅ [M + H]⁺ = 313.9664, found: 313.9658.

Cyano(phenyl)methyl ethyl carbonate (7a). Prepared according to Method B (reaction time 8 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 203 mg (99%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.32 (t, 3H, J = 7.2 Hz, OCH₂CH₃), 4.21–4.33 (m, 2H, OCH₂CH₃), 6.26 (s, 1H, CHCN), 7.44–7.45 (m, 3H, m,p-C₆H₅), 7.52–7.54 (m, 2H, o-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 65.7, 66.5, 115.9, 128.0, 129.4, 130.7, 131.4, 153.5 ppm. APCI: m/z calculated for C₁₁H₁₂NO₃ [M + H]⁺ = 206.0817; found: 206.0849.

Cyano(furan-2-yl)methyl ethyl carbonate (7b). Prepared according to Method B (reaction time 8 h). The residue was purified by column chromatography (hexanes/EtOAc 95 : 5) to obtain 190 mg (97%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.32 (t, 3H, J = 7.1 Hz, OCH₂CH₃), 4.22–4.33 (m, 2H, OCH₂CH₃), 6.32 (s, 1H, CHCN), 6.43 (dd, 1H, J = 1.8, 3.2 Hz, 3-C₄H₃O), 6.71 (d, 1H, J = 3.2 Hz, 4-C₄H₃O), 7.5 (d, 1H, J = 1.8 Hz, 5-C₄H₃O) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 59.3, 65.9, 111.3, 113.1, 113.9, 143.8, 145.4, 153.3 ppm. APCI: m/z calculated for C₉H₁₀NO₄ [M + H]⁺ = 196.0610; found: 196.0626.

Cyano(thiophen-2-yl)methyl ethyl carbonate (7c). Prepared according to Method B (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 195 mg (92%) of a brown oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.33 (t, 3H, J = 7.16 Hz, OCH₂CH₃), 4.25–4.32 (m, 2H, OCH₂CH₃), 6.48 (s, 1H, CHCN), 7.04–7.05 (m, 1H, 4-C₄H₃S), 7.36–7.38 (m, 1H, 3-C₄H₃S), 7.46–7.47 (m, 1H, 5-C₄H₃S) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.1, 61.5, 65.8, 115.0, 127.3, 129.4, 130.0, 132.7, 153.2 ppm. APCI: m/z calculated for C₉H₁₀NO₃S [M + H]⁺ = 212.0381; found: 212.0395.

tert-Butyl 2-(cyano((ethoxycarbonyl)oxy)methyl)-1H-pyrrole-1-carboxylate (7d). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 70 : 30) to obtain 248 mg (84%) of a translucent orange oil ¹H NMR (400 MHz, CDCl₃) δ: 1.33 (t, 3H, J = 7.13 Hz, OCH₂CH₃), 1.58 (s, 9H, Ot-Bu), 4.22–4.33 (m, 2H, OCH₂CH₃), 6.18–6.20 (t, 1H, J = 3.4 Hz, 4-C₄H₃N), 6.70–6.71 (m, 1H, 3-C₄H₃N), 6.81 (s, 1H, CHCN), 7.31–7.32 (m, 1H, 5-C₄H₃N) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.3, 28.0, 60.3, 65.5, 85.7, 110.7, 115.4, 117.6, 123.5, 124.7, 148.4, 153.5 ppm. APCI: m/z calculated for C₁₄H₁₉N₂O₅ [M + H]⁺ = 295.1294; found: 295.1214.

Cyano(pyridin-2-yl)methyl ethyl carbonate (7e). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 190 mg (92%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.35 (t, 3H, J = 7.15 Hz, OCH₂CH₃), 4.27–4.35 (m, 2H, OCH₂CH₃), 6.37 (s, 1H, CHCN), 7.37–7.39 (m, 1H, 5-C₅H₄N), 7.58–7.60 (m, 1H, 3-C₅H₄N), 7.80–7.83 (m, 1H, 4-C₅H₄N), 8.66–8.67 (m, 1H, 6-C₅H₄N) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 66.0, 67.2, 115.3, 121.9, 125.0, 137.8, 150.3, 150.7, 153.4 ppm. APCI: m/z calculated for C₁₃H₁₄NO₅ [M + H]⁺ = 207.0770, found: 207.0797.

Cyano(pyridin-3-yl)methyl ethyl carbonate (7f). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 197 mg (96%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.32 (t, 3H, J = 7.13 Hz, OCH₂CH₃), 4.23–4.33 (m, 2H, OCH₂CH₃), 6.30 (s, 1H, CHCN), 7.40–7.42 (m, 1H, 5-C₅H₄N), 7.89–7.91 (m, 1H, 4-C₅H₄N), 8.70–8.71 (m, 1H, 6-C₅H₄N), 8.76–8.77 (m, 1H, 2-C₅H₄N) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 64.3, 66.1, 115.1, 124.1, 127.6, 135.6, 149.2, 152.0, 153.3 ppm. APCI: m/z calculated for C₁₃H₁₄NO₅ [M + H]⁺ = 207.0770, found: 207.0797.

Cyano(pyridin-4-yl)methyl ethyl carbonate (7g). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 190 mg (92%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl3) δ: 1.29 (t, 3H, J = 7.14 Hz, OCH₂CH₃), 4.22–4.29 (m, 2H, OCH₂CH₃), 6.22 (s, 1H, CHCN), 7.40 (d, 2H, J = 6.19 Hz, 3,5-C₅H₄N), 8.68 (d, 2H, J = 6.19 Hz, 2,6-C₅H₄N) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 64.8, 66.2, 114.8, 121.6, 139.8, 150.9, 153.3 ppm. APCI: m/z calculated for C₁₃H₁₄NO₅ [M + H]⁺ = 207.0770, found: 207.0809.

Cyano(2-nitrophenyl)methyl ethyl carbonate (7h). Prepared according to Method B (reaction time 2 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 245 mg (98%) of colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.35 (t, 3H, J = 7.15 Hz, OCH₂CH₃), 4.26–4.34 (m, 2H, OCH₂CH₃), 7.00 (s, 1H, CHCN), 7.67–7.70 (m, 1H, m-C₆H₄NO₂), 7.79–7.83 (m, 1H, m-C₆H₄NO₂), 7.94–7.96 (m, 1H, p-C₆H₄NO₂), 8.21–8.23 (m, 1H, o-C₆H₄NO₂) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 62.8, 66.2, 114.8, 126.0, 127.1, 129.3, 131.6, 134.9, 146.9, 153.0 ppm. APCI: m/z calculated for C₁₁H₁₁N₂O₅ [M + H]⁺ = 251.0668; found: 251.0599.

Benzofuran-2-yl(cyano)methyl ethyl carbonate (7i). Prepared according to Method B (reaction time 5 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 216 mg (88%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.36 (t, 3H, J = 7.15 Hz, OCH₂CH₃), 4.29–4.37 (m, 2H, OCH₂CH₃), 6.49 (s, 1H, CHCN), 7.10 (s, 1H, 3-C₈H₅O), 7.28–7.32 (m, 1H, 6-C₈H₅O), 7.38–7.42 (m, 1H, 5-C₈H₅O), 7.52–7.54 (m, 1H, 7-C₈H₅O), 7.62–7.64 (m, 1H, 4-C₈H₅O) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 59.9, 66.1, 109.5, 112.0, 113.7, 122.2, 123.9, 126.6, 127.0, 145.8, 153.3, 155.9 ppm. APCI: m/z calculated for C₁₃H₁₂NO₄ [M + H]⁺ = 246.0766, found: 246.0770.

Benzo[b]thiophen-2-yl(cyano)methyl ethyl carbonate (7j). Prepared according to Method B (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 226 mg (86%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.36 (t, 3H, J = 7.14 Hz, OCH₂CH₃), 4.28–4.36 (m, 2H, OCH₂CH₃), 6.58 (s, 1H, CHCN), 7.41–7.44 (m, 2H, 5,6-C₈H₅S), 7.62–7.63 (m, 1H, 3-C₈H₅S), 7.81–7.86 (m, 2H, 4,7-C₈H₅S) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 62.4, 66.0, 114.8, 122.7, 124.8, 125.2, 126.2, 126.8, 133.3, 138.4, 140.9, 153.3 ppm. APCI: m/z calculated for C₁₃H₁₃NO₄ [M − OEt]⁺ = 216.0119, found: 216.0106.

tert-Butyl 2-(cyano((ethoxycarbonyl)oxy)methyl)-1H-indole-1-carboxylate (7k). Prepared according to Method B (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 70 : 30) to obtain 275 mg (80%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.36 (t, 3H, J = 7.10 Hz, OCH₂CH₃), 1.70 (s, 9H, Ot-Bu), 4.30–4.35 (m, 2H, OCH₂CH₃), 6.99 (s, 1H, CHCN), 7.08–7.09 (m, 1H, 3-C₈H₅N), 7.25–7.29 (m, 1H, 5-C₈H₅N), 7.35–7.39 (m, 1H, 6-C₈H₅N), 7.57–7.59 (m, 1H, 4-C₈H₅N), 8.06–8.09 (m, 1H, 7-C₈H₅N) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.3, 28.2, 61.6, 65.7, 86.1, 112.6, 115.3, 116.0, 121.7, 123.6, 126.2, 127.8, 129.3, 137.0, 149.8, 153.4 ppm. APCI: m/z calculated for C₁₈H₂₁N₂O₅ [M + H]⁺ = 345.1450, found: 245.1482.

Methyl 2-(cyano((ethoxycarbonyl)oxy)methyl)benzoate (7l). Prepared according to Method B (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 232 mg (88%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.33 (t, J = 7.11 Hz, 3H, OCH₂CH₃), 3.93 (s, 3H, OMe), 4.25–4.33 (m, 2H, OCH₂CH₃), 7.28 (s, 1H, CHCN), 7.51–7.55 (m, 1H, m-C₆H₄CO₂Me), 7.63–7.67 (m, 1H m-C₆H₄CO₂Me), 7.83–7.86 (m, 1H, p-C₆H₄CO₂Me), 8.05–8.10 (m, 1H, o-C₆H₄CO₂Me) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.1, 52.7, 63.6, 65.6, 115.9, 128.1, 128.2, 130.2, 131.5, 132.8, 133.4, 153.2, 166.2 ppm. APCI: m/z calculated for C₁₃H₁₄NO₅ [M + H]⁺ = 264.0872, found: 264.0841.

(2-Bromophenyl)(cyano)methyl ethyl carbonate (7m). Prepared according to Method B (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 270 mg (95%) of translucent oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.34 (t, 3H, J = 7.15 Hz, OCH₂CH₃), 4.27–4.33 (m, 2H, OCH₂CH₃), 6.57 (s, 1H, CHCN), 7.30–7.34 (m, 1H, m-C₆H₄Br), 7.40–7.45 (m, 1H, m-C₆H₄Br), 7.61–7.64 (m, 1H, p-C₆H₄Br), 7.71–7.74 (m, 1H, o-C₆H₄Br) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.1, 65.8 (×2), 115.1, 123.1, 128.3, 129.6, 130.7, 132.0, 133.5, 153.1 ppm. ESI⁺: m/z calculated for C₁₁H₁₁BrNO₃ [M + H]⁺ = 283.9922, found: 283.9927.

Cyano(2-methoxyphenyl)methyl ethyl carbonate (7n). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 212 mg (90%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.33 (t, J = 7.12 Hz, 3H, OCH₂CH₃), 3.88 (s, 3H, OMe), 4.24–4.32 (m, 2H, OCH₂CH₃), 6.58 (s, 1H, CHCN), 6.92–6.95 (m, 1H, o-C₆H₄OMe), 7.00–7.05 (m, 1H, p-C₆H₄OMe), 7.40–7.44 (m, 1H, m-C₆H₄OMe), 7.56–7.58 (m, 1H m-C₆H₄OMe) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.1, 55.7, 61.7, 65.4, 111.1, 115.9, 119.5, 120.9, 128.9, 132.0, 153.5, 156.7 ppm. APCI: m/z calculated for C₁₂H₁₄NO₄ [M + H]⁺ = 236.0923, found: 236.0930.

Cyano(3-methoxyphenyl)methyl ethyl carbonate (7o). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 222 mg (94%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.33 (t, J = 7.12 Hz, 3H, OCH₂CH₃), 3.83 (s, 3H, OMe), 4.24–4.32 (m, 2H, OCH₂CH₃), 6.22 (s, 1H, CHCN), 6.97–7.00 (m, 1H, o-C₆H₄OMe), 7.04–7.05 (m, 1H, o-C₆H₄OMe), 7.09–7.11 (m, 1H p-C₆H₄OMe), 7.33–7.37 (m, 1H, m-C₆H₄OMe) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.1, 55.4, 65.6, 66.2, 113.0, 116.4, 116.5, 120.0, 130.4, 132.5, 153.4, 160.1 ppm. APCI: m/z calculated for C₁₂H₁₄NO₄ [M + H]⁺ = 236.0923, found: 236.0955.

Cyano(cyclohexyl)methyl ethyl carbonate (7p). Prepared according to Method B (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 180 mg (85%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.15–1.29 (m, 5H), 1.33 (t, 3H, J = 7.13 Hz, OCH₂CH₃), 1.68–1.93 (m, 6H), 4.21–4.31 (m, 2H OCH₂CH₃), 5.03 (d, J = 5.88 Hz, 1H, CHCN) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 25.3, 25.8, 28.1, 40.3, 65.5, 69.4. APCI: m/z calculated for C₁₁H₁₈NO₃ [M + H]⁺ = 212.1287, found: 212.1255.

General procedure for conjugate additions

1 M LiHMDS (THF) (750 μL, 0.75 mmol) was slowly added to a solution of cyanocarbonate (0.5 mmol) in THF (2.5 mL) at −78 °C under nitrogen atmosphere, and the resultant mixture stirred at this temperature for 15 min. Then, the enone (0.75 mmol) was added dropwise, and after the addition was completed, the mixture was allowed to reach ambient temperature. When the starting material has been consumed (TLC), the reaction was quenched by the slow addition of sat NH₄Cl (5 mL). The mixture was diluted with water and extracted with EtOAc (3 × 20 mL); the organics were combined, dried (anh Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂).

Methyl 6-benzoyl-2-hydroxycyclohex-1-ene-1-carboxylate (8a). Prepared following the general procedure (reaction time 2 h). The residue was purified by column chromatography (hexanes/EtOAc 95 : 5) to obtain 103 mg (79%) of a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.65–1.95 (m, 4H, CH₂CH₂CH₂CH), 2.17–2.44 (m, 2H, COHCH₂CH₂), 3.55 (s, 3H, OMe), 4.48–4.50 (m, 1H, CH), 7.44–7.46 (m, 2H, m-C₆H₅), 7.47–7.48 (m, 1H, p-C₆H₅), 7.95–7.98 (m, 2H, o-C₆H₅), 12.34 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 18.5, 26.1, 28.9, 41.0, 51.5, 97.2, 128.3, 128.7, 132.9, 133.7, 172.0, 174.5, 201.7 ppm. IR (cm⁻¹): 3334, 1738, 1714, 1673, 1333. APCI: m/z calculated for C₁₅H₁₇O₄ [M + H]⁺ = 261.1127, found: 261.1064.

Ethyl 6-benzoyl-2-hydroxycyclohex-1-ene-1-carboxylate (8b). Prepared following the general procedure (reaction time 2 h). The residue was purified by column chromatography (hexanes/EtOAc 95 : 5) to obtain 103 mg (75%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 0.97 (t, 3H, J = 7.12 Hz, OCH₂CH₃), 1.67–1.94 (m, 4H, CH₂CH₂CH₂CH), 2.32–2.39 (m, 2H, COHCH₂CH₂), 4.01–4.06 (m, 2H, OCH₂CH₃), 4.50–4.53 (m, 1H, CH), 7.46–7.49 (m, 2H, m-C₆H₅), 7.55–7.57 (m, 1H, p-C₆H₅), 7.96–8.01 (m, 2H, o-C₆H₅), 12.37 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 13.9, 18.8, 26.3, 29.0, 41.0, 60.5, 97.6, 128.4, 128.7, 132.9, 136.6, 171.7, 174.5, 202.1 ppm. IR (cm⁻¹): 3448, 1740, 1682, 1651, 1334. APCI: m/z calculated for C₁₆H₁₉O₄ [M + H]⁺ = 275.1283; found: 275.1242.

tert-Butyl 6-benzoyl-2-hydroxycyclohex-1-ene-1-carboxylate (8c). Prepared following the general procedure (reaction time 5 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 94 mg (62%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.21 (s, 9H, Ot-Bu), 1.63–1.74 (m, 4H, CH₂CH₂CH₂CH), 2.30–2.34 (m, 2H, COHCH₂CH₂), 4.43–4.47 (m, 1H, CH), 7.43–7.53 (m, 2H, p-C₆H₅), 7.49–7.55 (m, 1H, m-C₆H₅), 7.94–8.01 (m, 2H, o-C₆H₅), 12.55 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl3) δ: 19.0, 26.3, 28.1, 29.1, 41.3, 81.9, 98.8, 128.4, 128.7, 132.9, 133.6, 168.4, 173.8, 202.0 ppm. IR (cm⁻¹): 3061, 1716, 1683, 1648, 1317. APCI: m/z calculated for C₁₄H₁₃O₃ [M + H]⁺ = 303.1596; found: 303.1594.

Methyl 6-(furan-2-carbonyl)-2-hydroxycyclohex-1-ene-1-carboxylate (8d). Prepared following the general procedure (reaction time 2 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 102 mg (82%) of a light brown oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.60–1.67 (m, 2H, CH₂CH₂CH₂), 1.83–1.92 (m, 2H, CH₂CH₂CH), 2.27–2.32 (m, 2H, COHCH₂CH₂), 3.55 (s, 3H, OMe), 4.22–4.23 (m, 1H, CH), 6.51–6.53 (m, 1H, 4-C₄H₃O), 7.19–7.20 (m, 1H, 3-C₄H₃O), 7.57–7.59 (m, 1H, 5-C₄H₃O), 12.33 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 18.6, 26.4, 28.9, 41.8, 51.6, 96.5, 112.3, 117.3, 146.4, 147.1, 172.0, 174.9, 190.8 ppm. IR (cm⁻¹): 3321, 1732, 1715, 1666, 1328. APCI: m/z calculated for C₁₃H₁₅O₅ [M + H]⁺ = 251.0919; found: 251.0824.

tert-Butyl 2-(3-hydroxy-2-(methoxycarbonyl)cyclohex-2-ene-1-carbonyl)-1H-pyrrole-1-carboxylate (8e). Prepared following the general procedure (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 70 : 30) to obtain 128 mg (70%) of a light brown oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.09 (t, 3H, J = 7.13 Hz, OCH₂CH₃), 1.56 (s, 9H, Ot-Bu), 1.80–1.93 (m, 4H, CH₂CH₂CH₂CH), 2.32–2.37 (m, 3H, COHCH₂CH₂), 3.93–4.15 (m, 3H, OCH₂CH₃, CH), 6.16–6.20 (m, 1H, 4-C₄H₃N), 6.98–6.99 (m, 1H, 3-C₄H₃N), 7.37–7.38 (m, 1H, 5-C₄H₃N), 12.42 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.0, 18.8, 26.0, 27.7, 29.1, 50.8, 60.6, 84.9, 97.1, 109.7, 121.4, 128.7, 133.3, 149.2, 169.2, 174.7, 192.0 ppm. IR (cm⁻¹): 3476, 1744, 1717, 1673, 1619, 1310. APCI: m/z calculated for C₁₉H₂₅NO₆ [M + H]⁺ = 364.1760; found: 364.1737.

Methyl 6-(thiophen-2-carbonyl)-2-hydroxycyclohex-1-ene-1-carboxylate (8f). Prepared following the general procedure (reaction time 2 h). The residue was purified by column chromatography (hexanes/EtOAc 95 : 5) to obtain 97 mg (69%) of a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 0.93 (t, 3H, J = 7.15 Hz, OCH₂CH₃), 1.84–1.9 (m, 4H, CH₂CH₂CH₂CH), 2.30–2.34 (m, 2H, COHCH₂CH₂), 3.96–4.02 (m, 2H, OCH₂CH₃), 4.24–4.27 (m, 1H, CH), 7.10–7.12 (m, 1H, 4-C₄H₃S), 7.59–7.61 (m, 1H, 3-C₄H₃S), 7.62–7.77 (m, 1H, 5-C₄H₃S), 12.36 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 13.7, 19.0, 26.9, 29.0, 43.0, 60.5, 97.4, 128.1, 131.7, 133.4, 143.3, 171.6, 174.7, 195.0 ppm. IR (cm⁻¹): 3091, 1737, 1715, 1652, 1333, 1216. APCI: m/z calculated for C₁₄H₁₇O₄S [M + H]⁺ = 281.0848; found: 281.0838.

Methyl 6-(2-bromobenzoyl)-2-hydroxycyclohex-1-ene-1-carboxylate (8g). Prepared following the general procedure (reaction time 1 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 143 mg (84%) of a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.68–1.77 (m, 4H, CH₂CH₂CH₂CH), 2.31–2.45 (m, 2H, COHCH₂CH₂), 3.70 (s, 3H, OMe), 4.22–4.24 (m, 1H, CH), 7.26–7.31 (m, 1H, m-C₆H₄Br), 7.36–7.40 (m, 1H, m-C₆H₄Br), 7.52–7.54 (m, 1H, p-C₆H₄Br), 7.60–7.64 (m, 1H, o-C₆H₄Br), 12.36 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 18.5, 24.4, 29.0, 45.3, 51.7, 96.6, 119.9, 127.3, 128.5, 131.6, 134.1, 141.2, 172.1, 174.9, 203.6 ppm. IR (cm⁻¹): 3440, 1742, 1702, 1655, 1333, 1087. APCI: m/z calculated for C₁₅H₁₆BrO₄ [M + H]⁺ = 339.0232; found: 239.0232.

Ethyl 6-(2-bromobenzoyl)-2-hydroxycyclohex-1-ene-1-carboxylate (8h). Prepared following the general procedure (reaction time 5 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 153 mg (87%) of a colorless oil (mp = 92–94 °C, EtOAc). ¹H NMR (400 MHz, CDCl₃) δ: 1.20 (t, 3H, J = 7.17 Hz OCH₂CH₃), 1.63–1.81 (m, 4H, CH₂CH₂CH₂CH) 2.32–2.44 (m, 2H, COHCH₂CH₂), 4.13–4.19 (m, 2H, 7.38) (m, 1H, m-C₆H₄Br), 7.54–7.56 (m, 1H, p-C₆H₄Br), 7.59–7.76 (m, 1H, o-C₆H₄Br), 12.46 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.2, 18.3, 24.1, 28.9, 45.2, 60.6, 96.5, 119.8, 127.1, 128.3, 131.5, 133.9, 141.1, 169.4, 174.8, 203.4 ppm. IR (cm⁻¹): 3064, 1703, 1651, 1617, 1304, 1086. APCI: m/z calculated for C₁₆H₁₈BrO₃ [M + H]⁺ = 353.0388; found: 353.0352.

Methyl 2-hydroxy-6-(2-nitrobenzoyl)cyclohex-1-ene-1-carboxylate (8i). Prepared following the general procedure (reaction time 30 min). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 132 mg (86%) of a light-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.61–1.71 (m, 4H, CH₂CH₂CH₂CH), 2.26–2.30 (m, 2H, COHCH₂CH₂), 3.63 (s, 3H, OMe), 4.16–4.17 (m, 1H, CH), 7.20–7.24 (m, 1H, m-C₆H₄NO₂), 7.30–7.33 (m, 1H m-C₆H₄NO₂), 7.46–7.48 (m, 1H, p-C₆H₄NO₂), 7.55–7.57 (m, 1H, o-C₆H₄NO₂), 12.30 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 18.5, 24.3, 28.9, 45.3, 51.6, 96.6, 119.8, 127.3, 128.4, 131.6, 134.0, 141.1, 172.0, 174.9, 203.6 ppm. IR (cm⁻¹): 3001, 1742, 1702, 1657, 1440. APCI: m/z calculated for C₁₅H₁₆NO₆ [M − CO₂Me]⁺ = 247.0845; found: 247.0862.

Methyl 2-hydroxy-6-(3-methoxybenzoyl)cyclohex-1-ene-1-carboxylate (8j). Prepared following the general procedure (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 77 mg (50%) of a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 0.98 (t, 3H, J = 7.13 Hz, OCH₂CH₃), 1.62–1.79 (m, 4H, CH₂CH₂CH₂CH), 2.31–2.37 (m, 2H, COHCH₂CH₂), 3.85 (s, 3H, OMe), 4.01–4.02 (m, 2H, OCH₂CH₃), 4.46–4.48 (m, 1H, CH), 7.08–7.11 (m, 1H, o-C₆H₄), 7.35–7.39 (m, 1H, o-C₆H₄), 7.49–7.50 (m, 1H, m-C₆H₄), 7.56–7.58 (m, 1H, p-C₆H₄), 12.42 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 13.8, 18.6, 26.1, 28.8, 41.0, 55.4, 60.4, 97.5, 112.9, 119.0, 120.7, 129.5, 137.8, 159.8, 171.6, 174.3, 201.8 ppm. IR (cm⁻¹): 3074, 1738, 1716, 1682, 1329. APCI: m/z calculated for C₁₇H₂₁O₅ [M + H]⁺ = 305.1389; found: 305.1392.

Ethyl 2-hydroxy-6-picolinoylcyclohex-1-ene-1-carboxylate (8k). Prepared following the general procedure (reaction time 10 h). The residue was purified by column chromatography (hexanes/EtOAc 70 : 30) to obtain 84 mg (61%) of a brown oil. ¹H NMR (400 MHz, CDCl3) δ: 0.88 (t, 3H, J = 7.17 Hz, OCH₂CH₃), 1.68–1.77 (m, 4H, CH₂CH₂CH₂CH), 2.33–2.36 (m, 2H, COHCH₂CH₂), 3.96–4.01 (m, 2H, OCH₂CH₃), 5.12–5.15 (m, 1H, CH), 7.47–7.49 (m, 1H, 5-C₅H₄N), 7.82–7.84 (m, 1H, 3-C₅H₄N), 8.05–8.06 (m, 1H, 4-C₅H₄N), 8.69–8.71 (m, 1H, 6-C₅H₄N), 12.35 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 13.6, 19.0, 25.9, 29.0, 39.2, 60.2, 97.7, 122.3, 126.9, 136.9, 148.8, 152.7, 169.2, 174.2, 202.8 ppm. IR (cm⁻¹): 3054.9, 1739, 1695, 1652, 1583, 1347. APCI: m/z calculated for C₁₅H₁₈NO₄ [M + H]⁺ = 276.1236, found: 276.1200.

Ethyl 2-hydroxy-6-nicotinoylcyclohex-1-ene-1-carboxylate (8l). Prepared following the general procedure (reaction time 1.5 h). The residue was purified by column chromatography (hexanes/EtOAc 70 : 30) to obtain 105 mg (76%) of a light-yellow oil. ¹H NMR (400 MHz, DMSO) δ: 0.91 (t, 3H, J = 7.12 Hz, OCH₂CH₃), 1.55–1.72 (m, 4H, CH₂CH₂CH₂CH), 2.25–2.43 (m, 2H, COHCH₂CH₂), 3.97–4.13 (m, 2H, OCH₂CH₃), 4.41–4.43 (m, 1H, CH), 7.22–7.39 (m, 1H, 5-C₅H₄N), 8.19–8.21 (m, 1H, 4-C₅H₄N), 8.72–8.73 (m, 1H, 6-C₅H₄N), 9.12–9.16 (m, 1H, 2-C₅H₄N), 12.29 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, DMSO) δ: 14.0, 18.7, 25.9, 28.8, 48.4, 60.7, 97.6, 124.5, 131.5, 136.2, 149.7, 153.9, 171.5, 174.5, 201.7 ppm. IR (cm⁻¹): 3048, 1737, 1716, 1784, 1584, 1331. APCI: m/z calculated for C₁₅H₁₈NO₄ [M + H]⁺ = 276.1236; found: 276.1204.

Methyl 2-hydroxy-6-(4-methoxybenzoyl)cyclohex-1-ene-1-carboxylate (8m). Prepared following the general procedure (reaction time 12 h). The residue was purified by column chromatography (hexanes/EtOAc 90 : 10) to obtain 77 mg (53%) of a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 1.61–1.93 (m, 4H, CH₂CH₂CH₂CH), 2.28–2.40 (m, 2H, COHCH₂CH₂), 3.57 (s, 3H, CO₂Me), 3.88 (s, 3H, OMe), 4.45–4.48 (m, 1H, CH), 6.93–6.98 (m, 2H, m-C₆H₄OMe), 7.94–8.00 (m, 2H, o-C₆H₄OMe), 12.35 (bs, 1H, OH) ppm. RMN ¹³C NMR (400 MHz, CDCl₃) δ: 18.7, 26.6, 29.0, 40.7, 48.3, 58.7, 97.5, 113.9, 130.8, 163.5, 170.0, 174.6, 198.3 ppm. IR (cm⁻¹): 3328, 1742, 1714, 1662, 1334. APCI: m/z calculated for C₁₆H₁₉NO₅ [M + H]⁺ = 291.1232; found: 291.1251.

Methyl 6-(6-bromobenzo[d][1,3]dioxole-5-carbonyl)-2-hydroxycyclohex-1-ene-1-carboxylate (8n). Prepared following the general procedure (reaction time 3 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 150 mg (78%) of a white solid (mp = 92–94 °C AcOEt) ¹H NMR (400 MHz, CDCl₃) δ: 1.66–1.76 (m, 4H, CH₂CH₂CH₂CH), 2.02–2.35 (m, 2H, COHCH₂CH₂), 3.69 (s, 3H, OMe), 4.15–4.17 (m, 1H, CH), 6.03 (s, 2H, OCH₂O), 7.03 (s, 1H, m-C₆H₂Br), 7.05 (s, 1H, o-C₆H₂Br), 12.32 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 18.5, 24.6, 29.0, 45.0, 51.7, 96.7, 102.5, 108.5, 112.0, 114.2, 134.0, 147.3, 150.0, 172.0, 174.9, 202.5 ppm. IR (cm⁻¹): 3384, 1716, 1699, 1662, 1328, 1037. APCI: m/z calculated for C₁₆H₁₆BrO₆ [M + H]⁺ = 383.0130; found: 383.0155.

tert-Butyl 2-(3-hydroxy-2-(methoxycarbonyl)cyclohex-2-ene-1-carbonyl)-1H-indole-1-carboxylate (8o). Prepared following the general procedure (reaction time 6 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 123 mg (60%) of a brown oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.05 (t, 3H, J = 7.13 Hz, OCH₂CH₃), 1.60 (s, 9H, Ot-Bu), 1.89–1.99 (m, 4H, CH₂CH₂CH₂CH), 2.34–2.37 (m, 2H, COHCH₂CH₂), 3.99–4.14 (m, 2H, OCH₂CH₃), 4.28–4.30 (m, 1H, CH), 7.23–7.27 (m, 1H, 5-C₈H₅N), 7.30 (s, 1H, 3-C₈H₅N) 7.37–7.44 (m, 1H, 6-C₈H₅N), 7.62–7.65 (m, 1H, 4-C₈H₅N), 7.98–8.01 (m, 1H, 7-C₈H₅N), 12.45 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.0, 18.7, 25.8, 27.9, 29.0, 43.4, 60.5, 84.5, 96.7, 114.5, 115.7, 117.0, 122.5, 123.1, 127.3, 137.5, 138.9, 149.6, 169.2, 174.8, 193.5 ppm. IR (cm⁻¹): 3053, 1736, 1679, 1652, 1613, 1321. APCI: m/z calculated for C₁₅H₁₈NO₄ [M + H]⁺ = 414.1917; found: 414.1865.

Methyl 2-benzoyl-5-oxocyclopentane-1-carboxylate (9a). Prepared following the general procedure (reaction time 5 h). The residue was purified by column chromatography (hexanes/EtOAc 70 : 30) to obtain 99 mg (80%) of a translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.94–1.99 (m, 1H, CH₂CH₂CH), 2.44–2.58 (m, 3H, COCH₂CH₂CH), 3.75 (s, 3H, OMe), 3.89–3.92 (d, 1H, J = 9.39 Hz, COCHCO), 4.50–5.57 (m, 1H, CH₂CHCO), 7.49–7.60 (m, 2H, m-C₆H₅), 7.61–7.62 (m, 1H, p-C₆H₅), 8.02–8.05 (m, 2H, o-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 25.9, 37.9, 47.2, 53.0, 57.1, 128.8, 129.1, 134.0, 135.4, 168.6, 199.0, 209.1 ppm. IR (cm⁻¹): 3053, 1748, 1724, 1678, 1321. APCI: m/z calculated for C₁₃H₁₁O₃ [M + H]⁺ = 247.0970; found: 247.1008.

Methyl 2-benzoyl-7-oxocycloheptane-1-carboxylate (9b). Prepared following the general procedure (reaction time 5 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 68 mg (50%) of a pale-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.49–1.62 (m, 2H, CH₂CH₂CH₂CH), 1.95–2.70 (m, 4H, CH₂CH₂CH₂CH), 2.63–2.73 (m, 2H, COCH₂CH₂), 3.64 (s, 3H, OMe), 4.01–4.03 (m, 1H, COCHCO), 4.39–4.41 (d, 1H, J = 10.18 Hz, CH₂CHCO), 7.45–7.49 (m, 2H, m-C₆H₅), 7.56–7.57 (m, 1H, p-C₆H₅), 7.95–7.97 (m, 2H, o-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 24.1, 26.9, 31.7, 43.2, 45.5, 52.6, 59.9, 128.6, 128.9, 133.5, 135.5, 170.0, 201.1, 207.6 ppm. IR (cm⁻¹): 3061, 1742, 1702, 1679, 1322. APCI: m/z calculated for C₁₆H₁₉O₄ [M + H]⁺ = 275.1283; found: 275.1294.

Methyl 6-benzoyl-2-hydroxy-6-methylcyclohex-1-ene-1-carboxylate (9c). Prepared following the general procedure (reaction time 24 h). The residue was purified by column chromatography (hexanes/EtOAc 80 : 20) to obtain 52 mg (38%) of a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.51 (s, 3H, OCH₃), 1.70–1.74 (m, 1H, CH₂CH₂C), 1.90–1.94 (m, 2H, CH₂CH₂CH₂), 2.12–2.18 (m, 1H, CH₂CH₂C), 2.48–2.54 (m, 2H, COHCH₂CH₂), 3.39 (s, 3H, OMe), 7.32–7.36 (m, 2H, m-C₆H₅), 7.40–7.45 (m, 1H, p-C₆H₅), 7.81–7.83 (m, 2H, o-C₆H₅), 12.61 (bs, 1H, OH) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 18.1, 24.9, 29.6, 34.8, 48.2, 51.1, 104.7, 128.3 (×2), 131.7, 136.7, 172.1, 172.8, 203.9 ppm. 3056, 1717, 1678, 1650, 1308. APCI: m/z calculated for C₁₅H₁₅O₃ [M + H]⁺ = 275.1283; found: 275.1240.

Ethyl 4-oxo-1-phenyl-3,4,5,6,7,7a-hexahydro-3aH-indene-3a-carboxylate (10). DBU (109 μL, 0.73 mmol) was added to a solution of 30 (100 mg, 0.37 mmol) in acetonitrile (3.7 mL) at 0 °C under nitrogen atmosphere. After stirring the mixture at this temperature for 15 min, triphenylvinylphosphonium bromide (202 mg, 546 mmol) was added portion wise. After the addition was completed, the mixture was stirring for 12 h at room temperature. The reaction was quenched by the addition of H₂O (10 mL) and extracted with EtOAc (3 × 20 mL); the organics were combined, dried (anh Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂) (hexanes/EtOAc 70 : 30) to obtain 40 mg (39%) of translucent yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.25 (t, 3H, J = 3.17 Hz, OCH₂CH₃), 1.56–1.78 (m, 4H, CH₂CH₂CH₂CH), 2.11–2.14 (m, 1H, COHCH₂CH₂), 2.46–2.50 (m, 1H, COHCH₂CH₂), 2.52–2.54 (m, 1H, CCH₂CH), 3.06–3.07 (m, 1H, CCH₂CH), 3.984.00 (m, 1H, CH), 4.02–4.22 (m, 2H, OCH₂CH₃), 5.93–5.95 (m, 1H, CCHCH₂), 7.31–7.35 (m, 5H, C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 14.1, 21.5, 26.3, 38.3, 39.3, 51.5, 61.7, 65.8, 125.0, 126.3, 127.4, 128.4, 135.3, 144.4, 172.1, 208.7. IR (cm⁻¹): 2945, 1709, 1676, 1315. APCI: m/z calculated for C₁₈H₂₁O₃ [M + H]⁺ = 285.1491; found: 285.1467.

2-Acetyl-1-phenyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one (11). DBU (82 μL, 0.55 mmol) was added to a solution of 30 (100 mg, 0.37 mmol) in acetonitrile (1.2 mL) at 0 °C under nitrogen atmosphere. After stirring the mixture at this temperature for 15 min, methyl vinyl ketone (35 μL, 401 mmol) was added dropwise. After the addition was completed, the mixture was stirring for 12 h at 80 °C. The reaction was quenched by the addition of H₂O (5 mL). The mixture was diluted with water and extracted with EtOAc (3 × 20 mL); the organics were combined, dried (anh Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂) (hexanes/EtOAc 80 : 20) to obtain 82 mg (88%) of translucent oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.40–1.44 (m, 1H, CH₂CH₂CH₂), 1.62–1.74 (m, 1H, CH₂CH₂CH₂), 1.75–1.77 (m, 2H, CH₂CH₂CH), 1.81 (s, 3H, COCH₃), 2.36–2.39 (m, 2H, COCH₂CH₂), 2.84–2.85 (m, 1H, CHCH₂C), 2.97–2.99 (m, 1H, CHCH₂C), 3.12–3.15 (m, 1H, CH), 3.48–3.50 (m, 1H, CH), 7.12–7.15 (m, 2H, m-C₆H₅), 7.32–7.37 (m, 3H, o,p-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 22.4, 26.2, 29.8, 35.3, 39.4, 48.7, 53.7, 127.8, 128.4, 128.6, 136.2, 138.4, 155.1, 198.8, 212.4 ppm. IR (cm⁻¹): 1348, 1682, 1704, 1720, 2939. APCI: m/z calculated for C₁₇H₁₉O₂ [M + H]⁺ = 255.1385; found: 255.1379.

8-Phenyl-2,3,3a,3b,5,6,7,7a-octahydrocyclopenta[a]indene-1,4-dione (12). DBU (82 μL, 0.55 mmol) was added to a solution of 30 (100 mg, 0.37 mmol) in acetonitrile (1.2 mL) at 0 °C under nitrogen atmosphere. After stirring the mixture at this temperature for 15 min, 2-cyclopenten-1-one (34 μL, 401 mmol) was added dropwise. After the addition was completed, the mixture was stirring for 24 h at room temperature. The reaction was quenched by the addition of H₂O (5 mL). The mixture was diluted with water and extracted with EtOAc (3 × 20 mL); the organics were combined, dried (anh Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂) (hexanes/EtOAc 80 : 20) to obtain 31 mg (32%) of translucent oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.51–1.61 (m, 1H), 1.71–1.80 (m, 2H), 2.02–2.10 (m, 2H), 2.24–2.37 (m, 1H), 2.47–2.50 (m, 2H), 2.61–2.65 (m, 2H), 2.84–2.89 (m, 1H), 3.63–3.70 (m, 1H, CH), 3.88–3.94 (m, 1H, CH), 7.39–7.43 (m, 2H, m-C₆H₅), 7.99–8.02 (m, 3H, o,p-C₆H₅) ppm. ¹³C NMR (400 MHz, CDCl₃) δ: 24.0, 27.8, 28.9, 39.1, 44.7, 53.3, 54.9, 59.3, 128.5, 129.5, 130.5, 132.1, 137.6, 151.2, 200.5, 212.3 ppm. IR (cm⁻¹): 1335, 1590, 1686, 2951. APCI: m/z calculated for C₁₇H₁₉O₂ [M + H]⁺ = 267.1385; found: 267.1349.

Conclusions

We utilized a cascade process to obtain tricarbonyl compounds by adding anions of cyanocarbonates derived from aromatic aldehydes onto 5, 6, and 7-membered cycloalkenones. During the process, we exploited the dual role of cyanocarbonates: as “latent” acylcarbanions and as acylating reagents. The synthetic potential of the cascade products obtained was successfully demonstrated by forming bicyclic and tricyclic systems through intramolecular condensation reactions. These results suggest that tricarbonyl compounds can be used as scaffolds to generate structural diversity. The investigation of further transformations is currently underway and will be published in due course.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank Facultad de Química, UNAM for financial support (Grant PAIP 50009062). We thank Professor D. E. Ward for revising the manuscript, and for helpful suggestions. We also thank Rosa Isela del Villar, Nayeli López, Georgina Duarte, and Marisela Gutierrez for recording NMR, MS, and IR spectra. DM thanks CONACYT for Graduate Scholarship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra05187c

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