Synthesis with Perfect Atom Economy: Generation of Furan Derivatives by 1,3-Dipolar Cycloaddition of Acetylenedicarboxylates at Cyclooctynes

Abstract

Cyclooctyne and cycloocten-5-yne undergo, at room temperature, a 1,3-dipolar cycloaddition with dialkyl acetylenedicarboxylates 1a,b to generate furan-derived short-lived intermediates 2, which can be trapped by two additional equivalents of 1a,b or alternatively by methanol, phenol, water or aldehydes to yield polycyclic products 3b–d, orthoesters 4a–c, ketones 5 or epoxides 6a,b, respectively. Treatment of bis(trimethylsilyl) acetylenedicarboxylate (1c) with cyclooctyne leads to the ketone 7 via retro-Brook rearrangement of the dipolar intermediate 2c. In all cases, the products are formed with perfect atom economy.

1. Introduction

Esters of acetylene dicarboxylic acid and especially dimethyl acetylenedicarboxylate (DMAD, 1a) are highly versatile tools for organic chemists [1,2,3,4,5,6,7]. These compounds are successfully utilized as dienophiles in Diels–Alder reactions, as dipolarophiles in 1,3-dipolar cycloadditions and also as components in [2 + 2] or other cycloaddition reactions. Furthermore, they can be used as powerful Michael acceptors, and in several cases, nucleophilic addition and formation of zwitterions are combined with other addition or (formal) cycloaddition steps to yield a variety of products by multicomponent reactions [1].

Tetramerization of 1a, that has been performed by storing the neat substance at room temperature for several years or by heating it neatly or in solution, indicates an unusual reaction course of acetylenedicarboxylates (Scheme 1) [8,9,10]. Formation of the crystalline product 3a was explained by a dimerization step, in which 1a functions as dipolarophile and, also, as 1,3-dipole [8,10,11]. The resulting carbene intermediate 2a is trapped by a third molecule of 1a, and, finally, Diels–Alder reaction of the furan unit with a fourth molecule of 1a leads to 3a. The structure of this tetramer was confirmed by X-ray single crystal structure analysis [10,12]. The compound 3a has been utilized in several transformations, such as thermal retro-Diels–Alder reactions [9,13] or [4 + 2]-cycloaddition in the presence of cyclopentadienes [14], as well as photolysis [8,9] or treatment with triphenylphosphine [10]. The tetramer of diethyl acetylenedicarboxylate has also been prepared by a procedure, which is analogous to the synthesis of 3a [9]. However, formation of products with structures similar to that of 3a is very limited when 1a was heated with other alkynes or alkenes [13,15]. For example, the carbene intermediate 2a can also be trapped in the presence of electron-poor dimethyl fumarate to generate the cyclopropane-derived compound dihydro-3a, but with an excess of tolane, the corresponding interception product was obtained only in trace amounts. This is remarkable because it is well known that carbenes, which were produced by photolysis of methyl aryl(diazo)acetate, react with acceptor-substituted and also electron-rich π-systems to form three-membered rings [16]. In a rhodium-catalyzed transformation, 1a and terminal alkenes led to cyclopropane derivatives that might be explained by trapping of carbene 2a with the help of the olefin [17,18]. However, such a mechanism was left out of consideration.

Scheme 1. Tetramerization of dimethyl acetylenedicarboxylate (1a).

Scheme 1. Tetramerization of dimethyl acetylenedicarboxylate (1a).

2. Results and Discussion

We accidentally found that the alkynes 1a and cyclooctyne [19] undergo an exothermic reaction at room temperature [20,21,22,23]. Thus, the transformation was conveniently performed in dichloromethane (20 h/20 °C) and led to the crystalline product 3b with 79% yield (Scheme 2). The structure of 3b was confirmed not only by NMR spectroscopic data but also by single crystal X-ray diffraction analysis (Figure 1). Obviously, the 1,3-dipolar cycloaddition of 1a at the ring-strained dipolarophile cyclooctyne to generate the intermediate 2b is much more rapid than the dimerization of 1a to produce 2a. This allows the synthesis of the interception product 3b without heating or long reaction times and also formation of several other trapping products of 2b.

Scheme 2. Reaction of 1a with cyclooctyne in the absence or in the presence of other reagents.

Scheme 2. Reaction of 1a with cyclooctyne in the absence or in the presence of other reagents.

Figure 1. ORTEP representation (50% probability level) of the molecular structures of products 3b (left) and 4a (right); hydrogen atoms are omitted for clarity.

Figure 1. ORTEP representation (50% probability level) of the molecular structures of products 3b (left) and 4a (right); hydrogen atoms are omitted for clarity.

After treatment of cyclooctyne with 1a in methanol instead of dichloromethane, the orthoester 4a was isolated in 60% yield. The surprising structure and especially the stereochemistry of this product were proved by spectroscopic data and X-ray diffraction analysis (Figure 1). When 1a and cyclooctyne were analogously reacted in an excess of deuterated methanol (CD₃OD), the product 4b, which indicated the selective incorporation of exactly one equivalent of the deuterated reagent, was obtained with 62% yield. In the presence of phenol instead of methanol, the conversion of 1a and cyclooctyne only led to a low yield (10%) of the corresponding orthoester 4c. We did not get any orthoester trapping product with a structure similar to that of 4 after heating 1a alone in pure methanol (up to 80 °C) because addition of the solvent at the C≡C bond to form dimethyl 2-methoxybut-2-enedioates dominated.

In the case of 4a–c, we exclusively isolated the depicted (E)-stereoisomer, whereas a mixture of (E)-5 and (Z)-5 resulted after exposure of cyclooctyne to 1a in aqueous tetrahydrofuran. The latter products were separated by chromatography to yield (E)-5 (21%) and (Z)-5 (20%), which were assigned with the help of NOE-NMR experiments. The genesis of 5 can be explained through interception of dipolar intermediate 2b by water. The product of this step is similar to orthoesters 4 but includes the substructure of a cyclic hemiacetal, which is transformed into 5 by ring opening followed by tautomerism.

When aldehydes such as acetaldehyde or benzaldehyde were used as solvents for the reaction of cyclooctyne with 1a, epoxides 6a and 6b, respectively, were formed (Scheme 2). In the case of 6a, the ¹H-NMR spectrum of the crude reaction mixture indicated the generation of two diastereomers in a ratio of about 3.5:1 although four diastereomers are possible. Only the main product, however, could be isolated by chromatography (22% yield), and the relative configurations of its stereocenters were determined by single crystal X-ray diffraction analysis (Figure 2). The epoxide 6b was obtained in 21% yield as a mixture of two diastereomers, which could be separated by chromatography.

Figure 2. ORTEP representation (30% probability level) of the molecular structure of 6a; hydrogen atoms are omitted for clarity; only one of the two enantiomers of the asymmetric unit is shown.

Figure 2. ORTEP representation (30% probability level) of the molecular structure of 6a; hydrogen atoms are omitted for clarity; only one of the two enantiomers of the asymmetric unit is shown.

The synthesis of 3b from 1a and cyclooctyne can be transferred to other acetylenedicarboxylates and cycloalkynes. Thus, 1a underwent a similar cascade of cycloaddition reactions in the presence of cycloocten-5-yne [24,25,26] to afford the product 3c in 37% yield (Scheme 3). On the other hand, diethyl acetylenedicarboxylate (1b) reacted only slightly slower than 1a with cyclooctyne to give the polycycle 3d with 61% yield. We attempted to perform the analogous transformation with di-tert-butyl acetylenedicarboxylate, however, not any characterizable product was obtained, even on heating the reaction mixture to 40 °C or on utilizing methanol as solvent. We assume that the sterically hindered diester is not able to enter into the rate-determining first step, which prevents not only the generation of the intermediate 2 but also the formation of products of type 3 or 4. However, treatment of bis(trimethylsilyl) acetylenedicarboxylate (1c) with cyclooctyne in anhydrous dichloromethane at 40 °C led to the oily 1:1 adduct 7 (85% yield). The ¹³C, ¹H long-range correlation 2D-NMR spectra and especially the ²⁹Si-NMR data indicated that the structure of 7 includes an oxygen-bound trimethylsilyl group and also such a group directly connected with carbon (Scheme 3). The genesis of 7 is easily explained by a 1,3-dipolar cycloaddition of the substrates and subsequent retro-Brook rearrangement of the intermediate 2c. This means that the corresponding vinylic carbon atom of 2c should possess nucleophilic properties to allow an intramolecular attack at silicon. Thus, the question arises whether intermediates of type 2 have to be generally described by dipolar resonance structures such as 2b and 2c or by carbene structures like 2a and 2b'. The formation of the three-membered ring in the products 3a–d and 6a,b, respectively, can be interpreted via nucleophilic attack of the negatively charged carbon atom of 2 at the π-system of 1 or the aldehydes followed by ring closure of the resulting dipolar species or alternatively by a cheletropic reaction of the carbene version of 2 [27]. Furthermore, generation of orthoesters 4a–c is possible through trapping of dipole 2b and is less easily explained via carbene 2b'. Finally, the retro-Brook rearrangement 2c→7 and also the fact that interception of 2 to prepare products with three-membered rings is successful only in case of electron-poor π-systems but not with simple alkenes or alkynes, are strong arguments to prefer the dipolar resonance structure of intermediates 2 [28,29,30,31,32].

Scheme 3. Furan derivatives from acetylenedicarboxylates and cyclooctynes.

Scheme 3. Furan derivatives from acetylenedicarboxylates and cyclooctynes.

3. Experimental

3.1. General Information

Melting points were determined with a Pentakon Dresden Boetius apparatus. FTIR spectra were recorded with a Nicolet iS5 spectrophotometer (Thermo Scientific) and solutions in KBr cuvettes. Alternatively, a FTS-165 spectrometer (BioRad) was used. ¹H-NMR spectra were recorded with a Unity Inova 400 spectrometer operating at 400 MHz. By using the same spectrometer, ¹³C-NMR data were recorded at 100.6 MHz, ²H-NMR spectra were measured at 61.4 MHz and ²⁹Si-NMR spectra at 79.5 MHz. NMR signals were referenced to TMS (δ = 0) or solvent signals and recalculated relative to TMS. The multiplicities of ¹³C-NMR signals were determined with the aid of DEPT135 experiments. HRMS (ESI) spectra were recorded with a Bruker micrOTOF-QII spectrometer. Elemental analyses were performed with a Vario Micro Cube from Elementar. HPLC was carried out with HPLC Pump 64 and Variable Wavelength Monitor (Knauer). TLC was performed with Macherey-Nagel Polygram SIL G/UV₂₅₄ polyester sheets. Diffraction data for 3b, 4a and 6a were collected with an Oxford Gemini S diffractometer, with graphite-monochromated Mo Kα radiation (λ = 0.71073 Å) (3b) or Cu Kα radiation (λ = 1.54184 Å) (4a, 6a). The structures were solved by direct methods and refined by full-matrix least-squares procedures on F² [33,34]. Graphics of the molecular structures have been created by using ORTEP [35]. All non-hydrogen atoms were refined anisotropically, and a riding model was employed in the treatment of the hydrogen atom positions.

3.2. Synthesis of Trimethyl 3-[2-Methoxy-3,4-bis(methoxycarbonyl)-5,6,7,8,9,10-hexahydro-2H-2,4a-epoxybenzo[8]annulen-1-yl]cycloprop-1-ene-1,2,3-tricarboxylate (3b)

To a solution of 1a (1.00 g, 7.04 mmol, freshly distilled) in anhydrous CH₂Cl₂ (2.5 mL), cyclooctyne (189 mg, 1.75 mmol) was added with stirring at 0 °C. After 20 h at ambient temperature, the solvent and the excess of 1a were removed at reduced pressure (finally 1 h at 40 °C and 0.1 mbar), and the residue was purified by flash chromatography (SiO₂, CHCl₃/ethyl acetate 15:1) to give 3b (0.74 g, 79%) as a pale yellow solid, which was repeatedly crystallized from cyclohexane to yield colorless crystals with m.p. 90 °C that are appropriate for X-ray diffraction analysis. ¹H-NMR (CDCl₃): δ = 1.15–1.55 (m, 4H), 1.58–1.82 (m, 4H), 1.97–2.08 (m, 2H, 10'-H or 5'-H), 2.42‒2.62 (m, 2H, 10'-H or 5'-H), 3.52 (s, 3H, O-C-OCH₃), 3.64 (s, 3H, OCH₃), 3.75 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃). ¹³C-NMR (CDCl₃): δ = 23.12 (t), 23.26 (t, 2C), 25.33 (t), 25.61 (t), 29.03 (t), 32.27 (s, C-3), 52.15 (q, 2C, OCH₃), 52.75 (q, OCH₃), 53.14 (q, OCH₃), 53.17 (q, OCH₃), 54.87 (q, O-C-OCH₃), 89.42 (s, C-4a'), 114.19 (s), 115.65 (s, O-C-OCH₃), 116.49 (s), 140.36 (s), 150.82 (s), 157.01 (s), 157.12 (s), 157.36 (s), 160.62 (s), 163.23 (s), 164.18 (s), 170.19 (s). IR (CDCl₃): = 2954 (m), 1732 (s), 1268 (s) cm⁻¹. Elemental Analysis calcd. for C₂₆H₃₀O₁₂: C: 58.42%, H: 5.66%. Found: C: 58.45%, H: 5.63%.

Crystal Data for 3b: C₂₆H₃₀O₁₂, M = 534.50 g·mol⁻¹, monoclinic, C2/c, λ = 0.71073 Å, a = 31.6876 (13) Å, b = 10.1200 (3) Å, c = 16.1580 (6) Å, β = 101.909 (4) °, V = 5070.0 (3) (4) ų, Z = 8, ρ_calcd = 1.400 Mg∙m⁻³, μ = 0.112 mm⁻¹, T = 100 (2) K, θ range 3.23°–25.00°, 9688 reflections collected, 4448 independent reflections (R_int = 0.0204), R1 = 0.0462, wR2 = 0.0865 (I > 2σ(I)).

3.3. Synthesis of Trimethyl 3-[2-Methoxy-3,4-bis(methoxycarbonyl)-5,6,9,10-tetrahydro-2H-2,4a-epoxybenzo[8]annulen-1-yl]cycloprop-1-ene-1,2,3-tricarboxylate (3c)

To cycloocten-5-yne (74 mg, 0.70 mmol) in CDCl₃ (0.7 mL), 1a (400 mg, 2.79 mmol) was added. The mixture was allowed to stand at room temperature for 20 h. After removal of the solvent at reduced pressure, the residue was purified by chromatography (silica gel, dichloromethane/ethyl acetate 15:1) to give 3c (138 mg, 37%) as a slightly yellow oil. ¹H-NMR (CDCl₃): δ = 1.99–2.32 (m, 4H, CH₂), 2.64–2.94 (m, 4H, CH₂), 3.45 (s, 3H, O-C-OCH₃), 3.61 (s, 3H, OCH₃), 3.73 (s, 3H, OCH₃), 3.77 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 5.47–5.54 (m, 2H, CH=CH). ¹³C-NMR (CDCl₃): δ = 24.03 (t), 24.07 (t), 27.55 (t), 27.64 (t), 31.53 (s), 52.03 (q, OCH₃), 52.16 (q, OCH₃), 52.63 (q, OCH₃), 52.96 (q, OCH₃), 53.07 (q, OCH₃), 54.62 (q, O-C-OCH₃), 91.06 (s, C-4a'), 113.51 (s), 115.23 (s, O-C-OCH₃), 115.47 (s), 128.18 (d, CH=CH), 129.35 (d, CH=CH), 142.64 (s), 150.62 (s), 156.81 (s), 156.90 (s), 157.25 (s), 159.43 (s), 162.99 (s), 164.16 (s), 170.07 (s). IR (CDCl₃): = 2954 (m), 1732 (s), 1270 (s) cm⁻¹. HRMS: m/z calcd. for C₂₆H₂₈O₁₂ ([M+H]⁺): 533.1659, found: 533.1592; calcd. for ([M+Na]⁺): 555.1478, found: 555.1470; calcd. for ([M+K]⁺): 571.1218, found: 571.1169.

3.4. Synthesis of Triethoxy 3-[2-Ethoxy-3,4-bis(ethoxycarbonyl)-5,6,7,8,9,10-hexahydro-2H-2,4a-epoxybenzo[8]annulen-1-yl]cycloprop-1-ene-1,2,3-tricarboxylate (3d)

To cyclooctyne (20 mg, 0.19 mmol) in CDCl₃ (0.7 mL), 1b (0.13 g, 0.74 mmol) was added. The mixture was allowed to stand at room temperature for 20 h. After removal of the solvent at reduced pressure, the residue was purified by chromatography (silica gel, dichloromethane/ethyl acetate 15:1) to give 3d (70 mg, 61%) as a slightly yellow oil. ¹H-NMR (CDCl₃): δ = 1.13–1.20 (m, 6H, CH₃), 1.25–1.35 (m, 12H, CH₃), 1.39–1.83 (m, 8H, CH₂), 2.01–2.12 (m, 2H, CH₂), 2.48–2.67 (m, 2H, CH₂), 3.70–3.78 (m, 1H, OCH₂), 3.84–3.91 (m, 1H, OCH₂), 3.99–4.08 (m, 1H, OCH₂), 4.11–4.25 (m, 5H, OCH₂), 4.27–4.36 (m, 4H, OCH₂). ¹³C-NMR (CDCl₃): δ = 13.99 (q, 2 C, CH₃), 13.94 (q, CH₃), 13.98 (q, CH₃), 14.07 (q, CH₃), 15.02 (q, CH₃), 23.27 (t, CH₂), 23.31 (t, CH₂), 23.33 (t, CH₂), 25.46 (t, CH₂), 25.68 (t, CH₂), 29.02 (t, CH₂), 32.36 (s, C-3), 61.01 (t, OCH₂), 61.08 (t, OCH₂), 61.53 (t, OCH₂), 62.22 (t, OCH₂), 62.37 (t, OCH₂), 63.59 (t, OCH₂), 89.29 (s, C-4a'), 114.65 (s), 115.40 (s), 116.20 (s), 140.68 (s), 151.17 (s), 156.87 (s), 156.91 (s), 157.17 (s), 160.07 (s), 162.96 (s), 163.91 (s), 169.68 (s). IR (CDCl₃): = 2984 (m), 1727 (s), 1260 (s) cm⁻¹. HRMS: m/z calcd. for C₃₂H₄₂O₁₂ ([M+H]⁺): 619.2755, found: 619.2697; calcd. for ([M+Na]⁺): 641.2574, found: 641.2608; calcd. for ([M+K]⁺): 657.2313, found: 657.2263.

3.5. Synthesis of Methyl (E)-2-(2,2-Dimethoxy-4,5,6,7,8,9-hexahydrocycloocta[b]furan-3(2H)-ylidene)acetate (4a)

To cyclooctyne (271 mg, 2.51 mmol) in anhydrous MeOH (2.5 mL), 1a (1.40 g, 9.85 mmol) was added. The mixture was stirred at room temperature for 20 h. After removal of the solvent at reduced pressure, the residue was purified by chromatography (silica gel, cyclohexane/tert-butyl methyl ether 14:1) to give 4a (426 mg, 60%) as a colorless solid with m.p. 60–61 °C (from cyclohexane/tert-butyl methyl ether). ¹H-NMR (CDCl₃): δ = 1.39–1.46 (m, 2H, 6'-CH₂), 1.49–1.57 (m, 2H, 7'-CH₂), 1.61–1.69 (m, 2H, 5'-CH₂), 1.68–1.75 (m, 2H, 8'-CH₂), 2.46 (m, 2H, 9'-CH₂), 2.73 (t, J = 6.3, 2H, 4'-CH₂), 3.33 (s, 6H, 2'-(OCH₃)₂), 3.69 (s, 3H, CO₂CH₃), 5.50 (s, 1H, 2-CH). ¹³C-NMR (CDCl₃): δ = 22.2 (t, C-4'), 25.6 (t, C-6'), 26.5 (t, C-7'), 27.1 (t, C-9'), 28.7 (t, C-8'), 29.3 (t, C-5'), 51.0 (q, 1-OCH₃), 51.3 (q, 2'-(OCH₃)₂), 106.3 (d, C-2), 112.5 (s, C-3a'), 121.7 (s, C-2'), 152.1 (s, C-3'), 166.3 (s, C-1), 170.3 (s, C-9a'). IR (film): = 2928 (s), 2853 (m), 1718 (s), 1642 (m), 1595 (s), 1458 (m), 1441 (m), 1353 (m), 1324 (m), 1277 (s), 1226 (s), 1167 (s), 1126 (s), 1086 (m), 1050 (s), 1022 (m), 1009 (m), 969 (m), 931 (m), 911 (m), 886 (w), 843 (m), 778 (w) cm⁻¹. HRMS: m/z calcd. for C₁₅H₂₂O₅ ([M+H]⁺): 283.1521, found: 283.1540; calcd. for ([M+Na]⁺): 305.1360, found: 305.1359. Elemental Analysis calcd. for C₁₅H₂₂O₅: C: 63.81%, H: 7.85%, found: C: 63.82%, H: 7.90%.

Crystal Data for 4a: C₁₅H₂₂O₅, M = 282.32 g·mol⁻¹, monoclinic, I2/a, λ = 1.54184 Å, a = 18.1382 (3) Å, b = 11.3690 (2) Å, c = 15.9193 (4) Å, β = 118.261 (2) °, V = 2891.44(12) ų, Z = 8, ρ_calcd = 1.297 Mg∙m⁻³, μ = 0.798 mm⁻¹, T = 110 (2) K, θ range 3.10°–61.986°, 4314 reflections collected, 2243 independent reflections (R_int = 0.0233), R1 = 0.0452, wR2 = 0.1172 (I > 2σ(I)).

3.6. Synthesis of Methyl d4-(E)-2-(2,2-Dimethoxy-4,5,6,7,8,9-hexahydrocycloocta[b]furan-3(2H)-ylidene)acetate (4b)

As described for 4a, cyclooctyne was analogously treated with CD₃OD and 1a, and workup led to 4b (447 mg, 62%) as a colorless solid with m.p. 63–64 °C (from cyclohexane/tert-butyl methyl ether). ¹H-NMR (CDCl₃): δ = 1.35–1.42 (m, 2H, 6'-CH₂), 1.46–1.53 (m, 2H, 7'-CH₂), 1.57–1.65 (m, 2H, 5'-CH₂), 1.64–1.71 (m , 2H, 8'-CH₂), 2.42 (m, 2H, 9'-CH₂), 2.69 (t, J = 6.3, 2H, 4'-CH₂), 3.27 (s, 3H, 2'-OCH₃), 3.63 (s, 3H, CO₂CH₃). ²H-NMR (CHCl₃:CDCl₃ = 9:1): δ = 3.30 (s, 3D, 2'-OCD₃), 5.53 (s, 1D, 2-CD). ¹³C-NMR (CDCl₃): δ = 22.0 (t, C-4'), 25.5 (t, C-6'), 26.4 (t, C-7'), 26.9 (t, C-9'), 28.6 (t, C-8'), 29.2 (t, C-5'), 50.4 (s (DEPT), sept with ¹J_CD = 22.0, 2'-OCD₃), 50.9 (q, OCH₃), 51.1 (q, OCH₃), 105.8 (s (DEPT), t with ¹J_CD = 24.5, C-2), 112.4 (s, C-3a'), 121.6 (s, C-2'), 152.0 (s, C-3'), 166.1 (s, C-1), 170.2 (s, C-9a'). HRMS: m/z calcd. for C₁₅H₁₈D₄O₅ ([M+H]⁺): 287.1791, found: 287.1772; calcd. for ([M+Na]⁺): 309.1611, found: 309.1633; calcd. for ([M+K]⁺): 325.1350, found: 325.1367.

3.7. Synthesis of Methyl (E)-2-(2-methoxy-2-phenoxy-4,5,6,7,8,9-hexahydrocycloocta[b]furan-3(2H)-ylidene)acetate (4c)

To a solution of phenol (3.00 g, 31.9 mmol) and cyclooctyne (0.40 g, 3.7 mmol) in anhydrous THF (4 mL), 1a (1.05 g, 7.4 mmol) was added with the help of a syringe within 2 h. Thereafter, the mixture, which changed its color to deep red, was stirred at ambient temperature for 16 h. After removal of the solvent at reduced pressure, the residue was dissolved in Et₂O (40 mL) and washed with aqueous sodium hydroxide (10%, 2 L). After drying of the organic phase (MgSO₄) and removal of the solvent, the residue was purified by chromatography (first SiO₂, CH₂Cl₂, then basic Al₂O₃, CH₂Cl₂) to furnish a green oil that was treated with hexane. This led to the precipitation of a colorless solid, which was removed by filtration. After removal of the solvent, 4c (247 mg, 10%) was obtained as a green oil that can be further purified by HPLC (LiChrospher Si 60 (5μ), 20 × 2 cm, CH₂Cl₂, 20 mL/min). ¹H-NMR (CDCl₃, relaxation delay d₁ = 15 s): δ = 1.00–1.72 (m, 8H), 2.38–2.41 (m, 2H), 2.53–2.60 (m, 1H), 2.77–2.83 (m, 1H), 3.44 (s, 3H, 2'-OCH₃), 3.70 (s, 3H, CO₂CH₃), 5.74 (s, 1H, 2-H), 7.06–7.25 (m, 5H, O-Ph). ¹³C-NMR (CDCl₃): δ = 22.0 (t, C-4'), 25.1 (t, C-6'), 26.2 (t, C-7'), 26.9 (t, C-9'), 28.3 (t, C-8'), 29.1 (t, C-5'), 51.1 (q, 1-OCH₃), 51.5 (q, 2'-OCH₃), 107.5 (d, C-2), 112.7 (s, C-3a'), 121.1 (d, Ph), 122.3 (s, C-2'), 124.4 (d, Ph), 128.8 (d, Ph), 152.3 (s, C-3'), 152.4 (s, Ph), 166.2 (s, C-1), 169.7 (s, C-9a'). IR (CDCl₃): = 2931 (s), 1705 (s, C=O) 1506 (s), 1490 (s) cm⁻¹.

3.8. Synthesis of Dimethyl (E)-2-(2-oxocyclooctylidene)succinate [(E)-5] and Dimethyl (Z)-2-(2-oxocyclooctylidene)succinate [(Z)-5]

To THF (2 mL) and water (1 mL), cyclooctyne (0.41 g, 3.84 mmol) and 1a (0.56 g, 3.94 mmol) were added with stirring at 0 °C. Thereafter, the mixture was stirred at ambient temperature for 21 h. This led to the formation of an inhomogeneous mixture, which was diluted with diethyl ether (50 mL) and dried (MgSO₄). After removal of the solvent under reduced pressure, the resulting yellow liquid was analyzed by ¹H-NMR, which indicated a 5:1 ratio of (E)-5 and (Z)-5. By using flash chromatography (SiO₂, Et₂O/hexane 1:2), (E)-5 (0.22 g, 21%) and (Z)-5 (0.20 g, 20%) were isolated as colorless liquids.

(E)-5: ¹H-NMR (CDCl₃): δ = 1.42‒1.48 (m, 2H), 1.52‒1.58 (m, 2H), 1.61‒1.68 (m, 2H), 1.78‒1.86 (m, 2H), 2.46‒2.51 (m, 2H, 8'-H), 2.72‒2.76 (m, 2H, 3'-H), 3.25 (s, 2H, 3-H), 3.64 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃). ¹³C-NMR (CDCl₃): δ = 23.64 (t, CH₂), 25.51 (t, CH₂), 25.77 (t, CH₂), 27.56 (t, CH₂), 32.44 (t, C-8'), 36.04 (t, C-3), 43.46 (t, C-3'), 52.03 (q), 52.14 (q), 122.34 (s), 154.13 (s), 167.33 (s), 170.79 (s), 212.43 (s, C-2'). IR (CCl₄): = 1745 (s) cm⁻¹. Elemental Analysis calcd. for C₁₄H₂₀O₅: C: 62.67%, H: 7.51%. found: C: 62.37%, H: 7.46%.

(Z)-5: ¹H-NMR (CDCl₃): δ = 1.44–1.63 (m, 6H), 1.75‒1.82 (m, 2H), 2.40‒2.44 (m, 2H, 8'-H), 2.62‒2.66 (m, 2H, 3'-H) 3.38 (s, 2H, 3-H), 3.68 (s, 6H, 2 × OCH₃). ¹³C-NMR (CDCl₃): δ = 23.62 (t, CH₂), 25.49 (t, CH₂), 25.74 (t, CH₂), 27.53 (t, CH₂), 32.40 (t, C-8'), 36.00 (t, C-3), 43.43 (t, C-3'), 51.99 (q, OCH₃), 52.09 (q, OCH₃), 122.32 (s), 154.08 (s), 167.28 (s), 170.74 (s), 212.36 (s, C-2'). IR (CCl₄): = 1745 (s) cm^‒1. Elemental Analysis calcd. for C₁₄H₂₀O₅: C: 62.67%, H: 7.51%, found: C: 62.43%, H: 7.36%.

3.9. Synthesis of Dimethyl 2-Methoxy-1-[(2-methoxycarbonyl)-3-methyloxiran-2-yl]-5,6,7,8,9,10-hexahydro-2H-2,4a-epoxybenzo[8]annulene-3,4-dicarboxylate (6a)

To a solution of cyclooctyne (410 mg, 3.79 mmol) in acetaldehyde (3 mL, freshly distilled), a solution of 1a (540 mg, 3.79 mmol) in anhydrous THF (2 mL) was added with the help of a syringe within 2 h. The yellow mixture was stirred at room temperature overnight. Thereafter, the solvent and the excess of acetaldehyde were removed at reduced pressure, and the resulting yellow oil was purified by flash chromatography (SiO₂, Et₂O/hexane 1:1). The oily product was recrystallized twice from Et₂O/hexane (1:3) to give 6a (180 mg, 22%) as colorless crystals with m.p. 66–67 °C. Single crystals, which were appropriate for X-ray diffraction analysis, were obtained by slow evaporation of a solution of 6a in cyclohexane. ¹H-NMR (CDCl₃): δ = 1.38 (d, ³J = 5.6, 3H, C–CH₃), 1.25–1.91 (m, 8H), 2.11 (m, 2H, 5-H), 2.51 (ddd, ³J_{10-H(a),9-H(a)} = 15, ²J_{10-H(a),10-H(b)} = 13.2, ³J_{10-H(a),9-H(b)} = 4.8, 1H, 10-H(a)), 2.66 (dt, ²J_{10-H(a),10-H(b)} = 13.2, ³J_{10-H(b),9-H(a)} = 4, ³J_{10-H(b),9-H(b)} = 4, 1H, 10-H(b)), 3.61 (s, 3H, OCH₃), 3.68 (q, ³J_3'-H,CH3 = 5.6, 1 H, 3'-H), 3.73 (s, 3H, OCH₃), 3.779 (s, 3H, OCH₃), 3.783 (s, 3H, OCH₃). ¹³C-NMR (CDCl₃): δ = 13.74 (q, CH₃), 23.01 (t, CH₂), 23.21 (t, CH₂), 23.37 (t, CH₂), 25.13 (t, CH₂), 25.58 (t, CH₂), 29.60 (t, CH₂), 52.24 (q, 2 OCH₃), 52.54 (q, OCH₃), 55.01 (q, OCH₃), 57.60 (s, C-2'), 57.86 (d, C-3'), 89.53 (s, C-4a), 115.48 (s, C-2), 139.33 (s), 150.29 (s), 156.52 (s), 163.22 (s), 163.91 (s), 164.18 (s), 168.35 (s). IR (CCl₄): = 1709 (s) cm⁻¹. Elemental Analysis calcd. for C₂₂H₂₈O₉: C: 60.54%, H: 6.47%. found: C: 60.55%, H: 6.45%.

Crystal Data for 6a: C₂₂H₂₈O₉, M = 436.44 g∙mol⁻¹, monoclinic, P2₁/c, λ = 1.54184 Å, a = 8.8577 (4) Å, b = 28.5456 (16) Å, c = 17.3589 (9) Å, β = 90.063 (4) °, V = 4389.2 (4) ų, Z = 8, ρ_calcd = 1.321 Mg∙m⁻³, μ = 0.863 mm⁻¹, T = 100 (2) K, θ range 3.10°−61.77°, 28823 reflections collected, 6811 independent reflections (R_int = 0.0557), R1 = 0.0548, wR2 = 0.1478 (I > 2σ (I)).

3.10. Synthesis of Dimethyl 2-Methoxy-1-[(2-methoxycarbonyl)-3-phenyloxiran-2-yl]-5,6,7,8,9,10-hexahydro-2H-2,4a-epoxybenzo[8]annulene-3,4-dicarboxylate (6b)

To a solution of cyclooctyne (270 mg, 2.53 mmol) in benzaldehyde (4 mL, freshly distilled), a solution of 1a (1.10 g, 7.58 mmol) in anhydrous THF (2 mL) was added with the help of a syringe within 2 h. The orange mixture was stirred overnight at room temperature. Thereafter, the solvent was evaporated and the excess of benzaldehyde was removed at 50 °C and 9 × 10⁻² mbar. The resulting yellow oil was purified by flash chromatography (SiO₂, Et₂O/hexane 1:1). The oily product was crystallized from Et₂O/hexane (ratio 1:3) to give 6b (260 mg, 21%) as colorless crystals. ¹H NMR data indicated that the substance consisted of two diastereomers in a 4:1 ratio. IR (mixture of isomers): = 1711 (s) cm⁻¹. Elemental Analysis (mixture of isomers) calcd. for C₂₇H₃₀O₉: C: 65.05%, H: 6.07%, found: C: 64.77%, H: 6.02%. The diastereomers of 6b were (partly) separated by flash chromatography (SiO₂, CH₂Cl₂); the minor isomer was eluted before the main isomer.

Minor isomer: ¹H-NMR (CDCl₃): δ = 1.25–2.10 (m, 8H), 2.18 (m, 2H, 5-H), 2.54 (ddd, ³J_{10-H(a),9-H(a)} = 15.2, ²J_{10-H(a),10-H(b)} = 13, ³J_{10-H(a),9-H(b)} = 4.8, 1H, 10-H(a)), 2.72 (dt, ²J_{10-H(a),10-H(b)} = 13, ³J_{10-H(b), 9-H(a)} = 4, ³J_{10-H(b),9-H(b)} = 4, 1H, 10-H(b)), 3.39 (s, 3H, OCH₃), 3.75 (s, 3H), 3.779 (s, 3H), 3.783 (s, 3H), 4.32 (s, 1H, 3'-H), 7.28–7.41 (m, 5 H, Ph). ¹³C-NMR (CDCl₃): δ = 23.05 (t, CH₂), 23.44 (t, CH₂), 23.69 (t, CH₂), 25.37 (t, CH₂), 25.77 (t, CH₂), 30.11 (t, CH₂), 52.08 (q, CH₃), 52.24 (q, 2C), 55.40 (q, CH₃), 60.66 (s, C-2'), 63.11 (d, C-3'), 89.18 (s, C-4a), 115.82 (s, C-2), 126.51 (d, 2C), 128.00 (d, 2C), 128.29 (d, CH), 133.07 (s), 139.82 (s), 150.77 (s), 157.34 (s), 162.24 (s), 163.01 (s), 164.35 (s), 166.51 (s).

Major isomer: M.p. 116–118 °C. ¹H-NMR (CDCl₃): δ = 1.31–2.22 (m, 10 H), 2.55 (ddd, ³J_{10-H(a),9-H(a)} = 15.2, ²J_{10-H(a),10-H(b)} = 13, ³J_{10-H(a),9-H(b)} = 4.8, 1 H, 10-H(a)), 2.85 (dt, ²J_{10-H(a),10-H(b)} = 13, ³J_{10-H(b),9-H(a)} = 4, ³J_{10-H(b),9-H(b)} = 4, 1H, 10-H(b)), 3.42 (s, 3H, OCH₃), 3.70 (s, 3H), 3.79 (s, 6H), 4.71 (s, 1H, 3'-H), 7.28–7.41 (m, 5H, Ph). ¹³C-NMR (CDCl₃): δ = 22.94 (t, CH₂), 23.20 (t, CH₂), 23.45 (t, CH₂), 25.08 (t, CH₂), 25.72 (t, CH₂), 29.82 (t, CH₂), 52.16 (q, CH₃), 52.28 (q, 2C), 55.10 (q, CH₃), 60.54 (s, C-2'), 61.89 (d, C-3'), 89.67 (s, C-4a), 115.54 (s, C-2), 126.28 (d, 2C), 128.06 (d, 2C), 128.34 (d, CH), 133.25 (s), 138.99 (s), 150.43 (s), 156.48 (s), 163.21 (s), 163.80 (s), 165.26 (s), 166.65 (s).

3.11. Synthesis of (Z)-Trimethylsilyl 2-(2-Oxo-4,5,6,7,8,9-hexahydrocycloocta[b]furan-3(2H)-ylidene)-2-(trimethylsilyl)acetate (7)

To a solution of bis(trimethylsilyl) but-2-ynedioate (0.10 g, 0.37 mmol) in anhydrous methylene chloride (2 mL), cyclooctyne (0.06 g, 0.55 mmol) was added under nitrogen atmosphere. The mixture was stirred for 48 h at 40 °C. The solvent and the excess of cyclooctyne were evaporated under reduced pressure to give 0.17 g (85%) of an unstable yellow oil. ¹H-NMR (CDCl₃): δ = 0.23 (s, 9H, CSi(CH₃)₃), 0.30 (s, 9H, CO₂Si(CH₃)₃), 1.44–1.60 (m, 6H, CH₂), 1.69–1.75 (m, 2 H, CH₂), 2.31 (t, J = 6.4, 2 H, CH₂), 2.48 (t, J = 7.1, 2 H, CH₂). ¹³C-NMR(CDCl₃): δ = −1.48 (q, CSi(CH₃)₃), −0.23 (q, OSi(CH₃)₃), 21.11 (t, CH₂), 25.30 (t, CH₂), 25.85 (t, CH₂), 26.00 (t, CH₂), 27.02 (t, CH₂), 28.15 (t, CH₂), 114.48 (s, C-3a'), 133.46 (s, C=C-COOC), 146.84 (s, C=CCOOC), 158.85 (s, C-9a'), 168.35 (s, CO), 171.09 (s, CO). Signal assignment and determination of the stereochemistry were supported by HMBC and NOESY experiments, respectively. ²⁹Si-NMR (CDCl₃): δ = −3.86 (CSi(CH₃)₃), 25.59 (OSi(CH₃)₃). IR (CCl₄): = 3010 (w), 2933 (s), 1785 (s), 1688 (s), 1249 (s) cm⁻¹. HRMS: m/z calcd. for: C₁₈H₃₀O₄Si₂ ([M+Na]⁺): 389.1580, found: 389.1643.

4. Conclusions

In summary, it was shown in this study that cyclooctynes and acetylenedicarboxylates react under mild conditions to generate short-lived dipolar intermediates of type 2 via an unusual 1,3-dipolar cycloaddition. These intermediates can be trapped by molecules with electron-deficient π-systems to give complex polycyclic products through a cascade of cycloaddition reactions. On the other hand, interception of 2 in the presence of protic reaction partners leads to 2,3-dihydrofuran derivatives with the rare substitution pattern of an orthoester functionality and a 3-methylidene group [36,37,38]. In all cases, the products are formed with perfect atom economy, that means that all atoms of the substrate molecules are found in the product.

Currently, we investigate scope and limitations of the presented method to prepare furan derivatives and whether acetylenedicarboxylates can be substituted by prop-2-ynoic esters with different electron-withdrawing substituents in 3-position or by the analogous amides to generate intermediates similar to 2 and the corresponding subsequent products.