A Flow Microreactor Approach to a Highly Efficient Diels–Alder Reaction with an Electrogenerated o-Quinone

Published as part of the Cluster Electrochemical Synthesis and Catalysis

Abstract

We have demonstrated a Diels–Alder reaction of an o-quinone generated in an electrochemical flow microreactor. In the flow microreactor system, 4-tert-butyl-o-benzoquinone was easily electrogenerated from 4-tert-butylpyrocatechol in the absence of chemical oxidants and then rapidly used, without decomposing, in a subsequent Diels–Adler reaction with various fulvenes to give the desired products efficiently.

The Diels–Alder reaction is one of the most powerful tool for the construction of six-membered rings through the formation of two C–C bonds, and it has been successfully used for the synthesis of many natural or biologically active products.[1] Because p-quinones are excellent dienophiles, their Diels–Alder reactivity has been extensively investigated.[1`] [c] [d] In contrast, however, the reactivity profile of o-quinones has received less attention due to their instability and inaccessibility.[2] Although o-quinones can be easily prepared from the corresponding catechols by treatment with a stoichiometric amount of a chemical oxidant such as Ag₂CO₃ or NaIO₄,[3] they frequently undergo decomposition, isomerization, or polymerization during storage.[4] Therefore, these o-quinones are usually prepared in situ by the oxidation of the catechols in the presence of a coupling partner for the Diels–Alder reaction. However, the presence of the partners can, through competing oxidation, prevent the desired oxidation of the catechol, and hence the range of suitable partners is limited.[5] To overcome these problems, the development of more-elegant and more-efficient methods for the Diels–Alder reactions of o-quinones was highly desirable.

The flow microreactor is a new and attractive reaction system in synthetic organic chemistry.[6] The key advantages of the system are precise temperature control, high-speed mixing, and a large specific interfacial area. Moreover, the microreactor permits the rapid generation and consumption of unstable species.[7] We have developed various electrosynthetic processes by using a flow microreactor.[8] In particular, we previously reported that a flow microreactor is extremely useful in controlling Michael addition reactions involving an unstable electrogenerated o-quinone.[9]

With this background, and to expand the utility of o-quinones, we have demonstrated the electrogeneration of an o-quinone in an electrochemical flow microreactor and its subsequent efficient Diels–Alder reaction with fulvenes.

The flow system fabricated for the model reaction consisted of two parts (Figure [1]): an electrolysis part for the generation of the o-quinone (in this case, 4-tert-butyl-o-benzoquinone) and a chemical-reaction part for the rapid Diels–Alder reaction of the o-quinone with a fulvene. Because 4-tert-butyl-o-benzoquinone is produced by electrochemical oxidation of 4-tert-butyl-pyrocatechol, this method does not require the use of a chemical oxidant that might complicate the downstream Diels–Alder reaction.

First, we recorded linear sweep voltammograms for the oxidation of 4-tert-butylpyrocatechol (1) and 6,6-dimethylfulvene (3) at a graphite disk electrode in a conventional undivided cell. As shown in Figure [2], the onset oxidation potentials of 1 and 3 were relatively close to one another. Therefore, competing oxidation of 1 and 3 would be unavoidable in a conventional batch-type reactor.

Next, we examined the model Diels–Alder reaction of catechol 1, with fulvene 3 in a batch-type reactor and in a flow microreactor.[10] In the batch-type reactor, the desired Diels–Alder cycloadduct 4 was obtained in low yield (Table [1], entry 1).[11] In contrast, the yield of 4 was markedly improved to 75% in the flow microreactor (Table [1], entry 2). This result suggests that the o-quinone 2 can be generated effectively, without interference by oxidation of fulvene 3 and, moreover, the generated o-quinone can be used rapidly, without decomposition, in a reaction with the fulvene.

Table 1 Diels–Alder Reaction between 4-tert-Butylpyrocatechol (1) with 6,6-Dimethylfulvene (3) in a Batch-Type Reactor and the Flow Microreactor^a

Entry	Reactor type	Yieldc
1	Batch-type reactor	13
2	Flow microreactorb	75

^a Experimental conditions: Anode, graphite plate; Cathode, Pt plate; Current density, 1.5 mA cm^–2; Solvent, MeCN; Substrate, 4-tert-butylpyrocatechol (10 mM); Coupling partner for Diels–Alder reaction, 6,6-dimethylfulvene (200 mM); Supporting electrolyte: NaClO₄ (100 mM).

^b Solvent for Diels–Alder reaction: CH₂Cl₂; electrode distance, 80 μm; flow rate, 6.0 mL h^–1.

^c Determined by HPLC.

The anode material can play an important role in controlling the efficiency of an anodic oxidation process. We therefore investigated the effect of the anode material [graphite, glassy carbon (GC), or platinum (Pt)] of the flow microreactor on the yield of adduct 4 (Figure [3]).

Among the anode materials examined, the graphite electrode gave the best results. To evaluate the efficiency of o-quinone generation on all the tested anode materials, we performed linear sweep voltammetry measurements (Figure [4]). The voltammograms for the catechol oxidation indicated that the graphite electrode has a lower overpotential for the oxidation of 4-tert-butylpyrocatechol compared with GC or Pt electrodes. It is known that graphite electrodes have large specific superficial areas, which should reduce the current density required to oxidize the catechol. These features might improve the efficiency of the catechol oxidation.

Next, we examined the effect of the flow rate and the electrode distance on the model reaction in the flow microreactor (Table [2]). The yield of adduct 4 increased with increasing flow rate, and the highest value was obtained at 6.0 mL h^–1 (Table [2], entries 1–3). At lower flow rates, black precipitates were observed on the electrode surfaces. These might have been formed by decomposition and overoxidation of 4-tert-butyl-o-benzoquinone due its long residence time in the microreactor. On the other hand, when the flow rate was increased to 7.5 mL h^–1, the yield decreased again (entry 4). This can be explained by insufficient bulk conversion due to the higher flow rate. At electrode distances of 20 and 50 μm, the yields were lower than that obtained at 80 μm (entries 5 and 6). This might be due to reduction of 4-tert-butyl-o-benzoquinone at the counter-electrode (cathode), due to the smaller electrode distances. In addition, the yield obtained at an electrode separation of 100 µm was also lower than that obtained at 80 µm (entry 7). This can be explained by insufficient bulk conversion due to the greater electrode distance.

Finally, to demonstrate the general applicability of this electrosynthetic system, we carried out Diels–Alder reactions of 4-tert-butyl-o-benzoquinone (2) with various fulvenes by using a flow microreactor (Table [3]). The reaction of electrogenerated o-quinone 2 with fulvene 5 provided the desired cycloadduct 6 in 47% yield (Table [3], entry 2). The Diels–Alder reaction of o-quinone 2 with fulvene 7 similarly gave product 8 in moderate yield (entry 3), whereas fulvene 9 gave a low yield of cycloadduct 10 (entry 4). Because only about 10% of 4-tert-butylpyrocatechol (1) was recovered in all entries, the oxidation of 1 effectively proceeded to give the corresponding o-quinone. Therefore, it can be stated that the product yield depends largely on the reactivity of the fulvene. These general experiments suggest that this system has potential to be applied in efficient Diels–Alder reactions involving unstable o-quinones.

Table 3 Electrochemical Reactions of 4-tert-Butylpyrocatechol (1) with Various Fulvenes in a Flow Microreactor^a

Entry	Fulvene	Product	Yieldb (%)
1			75
2			47
3			43
4			31

^a Reaction conditions: Anode, graphite plate; Cathode, Pt plate; Current density, 1.5 mA cm^–2; Solvent for electrolysis, MeCN; Solvent for Diels–­Alder reaction, CH₂Cl₂; Substrate, 4-tert-butylpyrocatechol (100 mM); Coupling partner for Diels–Alder reaction, fulvene (200 mM); Supporting electrolyte, NaClO₄ (100 mM).

^b Determined by HPLC.

In summary, we have successfully demonstrated a highly efficient Diels–Alder reaction of an o-quinone by using a flow microreactor. 4-tert-Butyl-o-benzoquinone, smoothly electrogenerated from the corresponding catechol in the flow reactor without a stoichiometric amount of oxidant, reacted rapidly with fulvenes downstream of the reactor to give the desired Diels–Alder cycloadducts in moderate to excellent yields. This reaction system permits selective oxidation of the catechol, although its oxidation potential is close to that of fulvenes, whereas a model Diels–Alder reaction in a batch-type reactor gave the product in a low yield due to nonselective oxidation. We hope that this novel Diels–Alder reaction system will highlight the utility of flow microreactors in optimizing reactions involving unstable o-quinones.

• References and Notes

• 1a Diels O, Alder K. Justus Liebigs Ann. Chem. 1928; 460: 98 ; For reviews on Diels–Alder reactions, see for example:
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• 1b Nicolaou KC, Snyder SA, Montagnon T, Vassilikogiannakis G. Angew. Chem. Int. Ed. 2002; 41: 1668
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• 1c Takao K.-i, Munakata R, Tadano K.-i. Chem. Rev. 2005; 105: 4779
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• 1d Nawrat CC, Moody CJ. Angew. Chem. Int. Ed. 2014; 53: 2056
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• 2a Nair V, Menon RS, Bijub AT, Abhilashc KG. Chem. Soc. Rev. 2012; 41: 1050
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• 2b Nair V, Kumar S. Synlett 1996; 1143
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• 2c Nair V, Kumar S, Williard PG. Tetrahedron Lett. 1995; 36: 1605
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• 2d Allmann R, Debaerdemaeker T, Friedrichsen W, Jürgens HJ, Betz M. Tetrahedron 1976; 32: 147
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• 2e Kaicharla T, Bhojgude SS, Biju AT. Org. Lett. 2012; 14: 6238
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• 2f Xu D, Chiaroni A, Largeron M. Org. Lett. 2005; 7: 5273
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• 3a Takata T, Tajima R, Ando W. J. Org. Chem. 1983; 48: 4764
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• 3b Nair V, Sethumadhavan D, Nair SM, Rath NP, Eigendorf GK. J. Org. Chem. 2002; 67: 7533
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• 3c Nair V, Mathew B, Radhakrishnan KV, Rath NP. Tetrahedron 1999; 55: 11017
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• 3d Nair V, Anilkumar G, Radhakrishnan KV, Sheela KC, Rath NP. Tetrahedron 1997; 53: 17361
  CrossrefSearch in Google Scholar
• 4a Sagawa Y, Kobayashi S, Mukaiyama T. Chem. Lett. 1988; 17: 1105
  CrossrefSearch in Google Scholar
• 4b Chiba K, Tada M. J. Chem. Soc., Chem. Commun. 1994; 0: 2485
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• 5a Jung ME, Perez F. Org. Lett. 2009; 11: 2165
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• 5b Wanzlick HW, Lehmann-Horchler M, Mohrmann S, Gritzky R, Heidepriem H, Pankow B. Angew. Chem. Int. Ed. 1964; 3: 401
  CrossrefSearch in Google Scholar
• 5c Zhang N.-T, Gao X.-G, Zeng C.-C, Hu L.-M, Tian H.-Y, She Y.-B. RSC Adv. 2012; 2: 298
  CrossrefSearch in Google Scholar
• 5d Gao X.-G, Zhang N.-T, Zenga C.-C, Liu Y.-D, Hu L.-M, Tian H.-Y. Curr. Org. Synth. 2014; 11: 141
  CrossrefSearch in Google Scholar
• 6a Atobe M, Tateno H, Matsumura Y. Chem. Rev. 2018; 118: 4541
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• 6b Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
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• 6c Hardwick T, Ahmed N. RSC Adv. 2018; 8: 22233
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• 7a Yoshida J.-i, Takahashi Y, Nagaki A. Chem. Commun. 2013; 49: 9896
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• 7b Yoshida J.-i, Nagaki A, Yamada T. Chem. Eur. J. 2008; 14: 7450
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• 8a Qu Y, Tsuneishi C, Tateno H, Matsumura Y, Atobe M. React. Chem. Eng. 2017; 2: 871
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• 8b Mizuno M, Tateno H, Matsumura Y, Atobe M. React. Chem. Eng. 2017; 2: 642
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• 8c Matsumura Y, Yamaji Y, Tateno H, Kashiwagi T, Atobe M. Chem. Lett. 2016; 45: 816
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• 8d Arai T, Tateno H, Nakabayashi K, Kashiwagi T, Atobe M. Chem. Commun. 2015; 51: 4891
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• 8e Tateno H, Matsumura Y, Nakabayashi K, Senboku H, Atobe M. RSC Adv. 2015; 5: 98721
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• 9a Kashiwagi T, Amemiya F, Fuchigami T, Atobe M. Chem. Commun. 2012; 48: 2806
  CrossrefPubMedSearch in Google Scholar
• 9b Kashiwagi T, Amemiya F, Fuchigami T, Atobe M. J. Flow Chem. 2012; 3: 17
  Search in Google Scholar
• 10 Electrochemical Reaction in a Batch-Type Reactor The reaction of 4-tert-butylpyrocatechol (1; 10 mM) with 6,6-dimethylfulvene (3; 200 mM) was performed by using a graphite plate anode (working electrode; 2 × 2 cm²) and a Pt plate cathode (counter-electrode, 2 × 2 cm²) in a 100 mM solution of NaClO₄ in MeCN (10 mL). A constant current (1.5 mA cm^–2) was applied during the electrolysis. After the electrolysis was complete, the mixture was analyzed by HPLC to determine the yield of the Diels–Alder cycloadduct 4. Electrochemical Reactions in the Flow Microreactor; General Procedure A 10 mM solution of 4-tert-butylpyrocatechol in a 100 mM solution of NaClO₄ in MeCN was introduced into the reactor from a syringe pump (Model 100; KD Scientific, Holliston, MA: see Figs. S1 and S2 in the Supporting Information). Constant-current electrolysis was performed at 1.5 mA cm^–2 by using the electrochemical flow microreactor. The electrolyzed solution emerging from the microreactor was poured into CH₂Cl₂ containing the appropriate fulvene (200 mM), and the mixture was stirred for 8 h. The mixture was then analyzed by HPLC to determine the yield of the Diels–Alder cycloadduct. (3aR*,4S*,7R*,7aS*)-6-(tert-Butyl)-1-(1-methylethylidene)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoindene-8,9-dione (4) Yellow solid; yield: 75%; mp 97.7 °C. IR (KBr): 2964, 1732, 1508, 1473, 1458, 1363, 1099, 812 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.42 (dd, J = 5.7, 1.9 Hz, 1 H), 5.86 (ddd, J = 6.6, 2.2, 0.6 Hz, 1 H), 5.58 (dd, J = 5.7, 2.5 Hz, 1 H), 3.70 (dd, J = 3.0, 2.4 Hz, 1 H), 3.61 (dd, J = 6.8, 2.7 Hz, 1 H), 3.56 (d, J = 7.9 Hz, 1 H), 3.31 (d, J = 7.9 Hz, 1 H), 1.80 (s, 3 H), 1.77 (s, 3 H), 1.00 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 191.5, 191.2, 151.8, 139.4, 135.6, 132.2, 125.2, 118.3, 54.1, 50.5, 46.4, 40.6, 35.3, 28.3, 21.7, 21.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₂₂NaO₂: 293.1512; found: 293.1498. (3aR*,4S*,7R*,7aS*)-6-tert-Butyl-1-(1-methylhexylidene)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoindene-8,9-dione (6) Yellow solid; yield: 47%; mp 101.1 °C. IR (KBr): 2966, 2870, 1735, 1463, 1365, 1161, 813 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.44 (dd, J = 5.7, 1.9 Hz, 1 H), 5.84 (dd, J = 6.5, 2.1, 1 H), 5.60 (dd, J = 5.7, 2.5 Hz, 1 H), 3.69 (m, 1 H), 3.57 (dd, J = 6.8, 2.7 Hz, 1 H), 3.53 (m, 1 H), 3.34 (dd, J = 7.9, 2.5 Hz, 1 H), 2.10 (q, J = 7.04 Hz, 4 H), 1.48–1.55 (m, 1 H), 1.30–1.46 (m, 3 H) 1.00 (s, 9 H), 0.95 (t, J = 7.41 Hz, 3 H), 0.86 (t, J = 7.41 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 191.2, 191.2, 151.6, 139.9, 135.5, 134.0, 132.3, 118.1, 53.8, 51.1, 46.0, 40.0, 35.0, 34.5, 33.9, 28.1, 22.1, 21.6, 14.2, 13.9. HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₃₁O₂; 327.2309; found: 327.2319.
• 11 Nair V, Kumar S. Tetrahedron 1996; 52: 4029
  CrossrefSearch in Google Scholar

• References and Notes

• 1a Diels O, Alder K. Justus Liebigs Ann. Chem. 1928; 460: 98 ; For reviews on Diels–Alder reactions, see for example:
  CrossrefSearch in Google Scholar
• 1b Nicolaou KC, Snyder SA, Montagnon T, Vassilikogiannakis G. Angew. Chem. Int. Ed. 2002; 41: 1668
  CrossrefPubMedSearch in Google Scholar
• 1c Takao K.-i, Munakata R, Tadano K.-i. Chem. Rev. 2005; 105: 4779
  CrossrefPubMedSearch in Google Scholar
• 1d Nawrat CC, Moody CJ. Angew. Chem. Int. Ed. 2014; 53: 2056
  CrossrefPubMedSearch in Google Scholar
• 2a Nair V, Menon RS, Bijub AT, Abhilashc KG. Chem. Soc. Rev. 2012; 41: 1050
  CrossrefPubMedSearch in Google Scholar
• 2b Nair V, Kumar S. Synlett 1996; 1143
  Thieme Connect
• 2c Nair V, Kumar S, Williard PG. Tetrahedron Lett. 1995; 36: 1605
  CrossrefSearch in Google Scholar
• 2d Allmann R, Debaerdemaeker T, Friedrichsen W, Jürgens HJ, Betz M. Tetrahedron 1976; 32: 147
  CrossrefSearch in Google Scholar
• 2e Kaicharla T, Bhojgude SS, Biju AT. Org. Lett. 2012; 14: 6238
  CrossrefPubMedSearch in Google Scholar
• 2f Xu D, Chiaroni A, Largeron M. Org. Lett. 2005; 7: 5273
  CrossrefPubMedSearch in Google Scholar
• 3a Takata T, Tajima R, Ando W. J. Org. Chem. 1983; 48: 4764
  CrossrefSearch in Google Scholar
• 3b Nair V, Sethumadhavan D, Nair SM, Rath NP, Eigendorf GK. J. Org. Chem. 2002; 67: 7533
  CrossrefPubMedSearch in Google Scholar
• 3c Nair V, Mathew B, Radhakrishnan KV, Rath NP. Tetrahedron 1999; 55: 11017
  CrossrefSearch in Google Scholar
• 3d Nair V, Anilkumar G, Radhakrishnan KV, Sheela KC, Rath NP. Tetrahedron 1997; 53: 17361
  CrossrefSearch in Google Scholar
• 4a Sagawa Y, Kobayashi S, Mukaiyama T. Chem. Lett. 1988; 17: 1105
  CrossrefSearch in Google Scholar
• 4b Chiba K, Tada M. J. Chem. Soc., Chem. Commun. 1994; 0: 2485
  CrossrefSearch in Google Scholar
• 5a Jung ME, Perez F. Org. Lett. 2009; 11: 2165
  CrossrefPubMedSearch in Google Scholar
• 5b Wanzlick HW, Lehmann-Horchler M, Mohrmann S, Gritzky R, Heidepriem H, Pankow B. Angew. Chem. Int. Ed. 1964; 3: 401
  CrossrefSearch in Google Scholar
• 5c Zhang N.-T, Gao X.-G, Zeng C.-C, Hu L.-M, Tian H.-Y, She Y.-B. RSC Adv. 2012; 2: 298
  CrossrefSearch in Google Scholar
• 5d Gao X.-G, Zhang N.-T, Zenga C.-C, Liu Y.-D, Hu L.-M, Tian H.-Y. Curr. Org. Synth. 2014; 11: 141
  CrossrefSearch in Google Scholar
• 6a Atobe M, Tateno H, Matsumura Y. Chem. Rev. 2018; 118: 4541
  CrossrefPubMedSearch in Google Scholar
• 6b Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
  CrossrefPubMedSearch in Google Scholar
• 6c Hardwick T, Ahmed N. RSC Adv. 2018; 8: 22233
  CrossrefPubMedSearch in Google Scholar
• 7a Yoshida J.-i, Takahashi Y, Nagaki A. Chem. Commun. 2013; 49: 9896
  CrossrefPubMedSearch in Google Scholar
• 7b Yoshida J.-i, Nagaki A, Yamada T. Chem. Eur. J. 2008; 14: 7450
  CrossrefPubMedSearch in Google Scholar
• 8a Qu Y, Tsuneishi C, Tateno H, Matsumura Y, Atobe M. React. Chem. Eng. 2017; 2: 871
  CrossrefSearch in Google Scholar
• 8b Mizuno M, Tateno H, Matsumura Y, Atobe M. React. Chem. Eng. 2017; 2: 642
  CrossrefSearch in Google Scholar
• 8c Matsumura Y, Yamaji Y, Tateno H, Kashiwagi T, Atobe M. Chem. Lett. 2016; 45: 816
  CrossrefSearch in Google Scholar
• 8d Arai T, Tateno H, Nakabayashi K, Kashiwagi T, Atobe M. Chem. Commun. 2015; 51: 4891
  CrossrefPubMedSearch in Google Scholar
• 8e Tateno H, Matsumura Y, Nakabayashi K, Senboku H, Atobe M. RSC Adv. 2015; 5: 98721
  CrossrefSearch in Google Scholar
• 9a Kashiwagi T, Amemiya F, Fuchigami T, Atobe M. Chem. Commun. 2012; 48: 2806
  CrossrefPubMedSearch in Google Scholar
• 9b Kashiwagi T, Amemiya F, Fuchigami T, Atobe M. J. Flow Chem. 2012; 3: 17
  Search in Google Scholar
• 10 Electrochemical Reaction in a Batch-Type Reactor The reaction of 4-tert-butylpyrocatechol (1; 10 mM) with 6,6-dimethylfulvene (3; 200 mM) was performed by using a graphite plate anode (working electrode; 2 × 2 cm²) and a Pt plate cathode (counter-electrode, 2 × 2 cm²) in a 100 mM solution of NaClO₄ in MeCN (10 mL). A constant current (1.5 mA cm^–2) was applied during the electrolysis. After the electrolysis was complete, the mixture was analyzed by HPLC to determine the yield of the Diels–Alder cycloadduct 4. Electrochemical Reactions in the Flow Microreactor; General Procedure A 10 mM solution of 4-tert-butylpyrocatechol in a 100 mM solution of NaClO₄ in MeCN was introduced into the reactor from a syringe pump (Model 100; KD Scientific, Holliston, MA: see Figs. S1 and S2 in the Supporting Information). Constant-current electrolysis was performed at 1.5 mA cm^–2 by using the electrochemical flow microreactor. The electrolyzed solution emerging from the microreactor was poured into CH₂Cl₂ containing the appropriate fulvene (200 mM), and the mixture was stirred for 8 h. The mixture was then analyzed by HPLC to determine the yield of the Diels–Alder cycloadduct. (3aR*,4S*,7R*,7aS*)-6-(tert-Butyl)-1-(1-methylethylidene)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoindene-8,9-dione (4) Yellow solid; yield: 75%; mp 97.7 °C. IR (KBr): 2964, 1732, 1508, 1473, 1458, 1363, 1099, 812 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.42 (dd, J = 5.7, 1.9 Hz, 1 H), 5.86 (ddd, J = 6.6, 2.2, 0.6 Hz, 1 H), 5.58 (dd, J = 5.7, 2.5 Hz, 1 H), 3.70 (dd, J = 3.0, 2.4 Hz, 1 H), 3.61 (dd, J = 6.8, 2.7 Hz, 1 H), 3.56 (d, J = 7.9 Hz, 1 H), 3.31 (d, J = 7.9 Hz, 1 H), 1.80 (s, 3 H), 1.77 (s, 3 H), 1.00 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 191.5, 191.2, 151.8, 139.4, 135.6, 132.2, 125.2, 118.3, 54.1, 50.5, 46.4, 40.6, 35.3, 28.3, 21.7, 21.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₂₂NaO₂: 293.1512; found: 293.1498. (3aR*,4S*,7R*,7aS*)-6-tert-Butyl-1-(1-methylhexylidene)-3a,4,7,7a-tetrahydro-1H-4,7-ethanoindene-8,9-dione (6) Yellow solid; yield: 47%; mp 101.1 °C. IR (KBr): 2966, 2870, 1735, 1463, 1365, 1161, 813 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.44 (dd, J = 5.7, 1.9 Hz, 1 H), 5.84 (dd, J = 6.5, 2.1, 1 H), 5.60 (dd, J = 5.7, 2.5 Hz, 1 H), 3.69 (m, 1 H), 3.57 (dd, J = 6.8, 2.7 Hz, 1 H), 3.53 (m, 1 H), 3.34 (dd, J = 7.9, 2.5 Hz, 1 H), 2.10 (q, J = 7.04 Hz, 4 H), 1.48–1.55 (m, 1 H), 1.30–1.46 (m, 3 H) 1.00 (s, 9 H), 0.95 (t, J = 7.41 Hz, 3 H), 0.86 (t, J = 7.41 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 191.2, 191.2, 151.6, 139.9, 135.5, 134.0, 132.3, 118.1, 53.8, 51.1, 46.0, 40.0, 35.0, 34.5, 33.9, 28.1, 22.1, 21.6, 14.2, 13.9. HRMS (ESI) m/z [M + H]⁺ calcd for C₂₂H₃₁O₂; 327.2309; found: 327.2319.
• 11 Nair V, Kumar S. Tetrahedron 1996; 52: 4029
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• Supplementary Material