Toward 2-Thiophyne: ketocarbene versus hetaryne intermediates from 2-(Trimethylsilyl)thiophen-3-yl Triflate

Toward 2‑Thiophyne: Ketocarbene versus Hetaryne Intermediates from 2‑(Trimethylsilyl)thiophen-3-yl Triflate Iago Pozo, Agustín Cobas, Diego Pena, Enrique Guitián, and Dolores Pérez* Cite This: Org. Lett. 2021, 23, 7376−7380 Read Online ACCESS Metrics & More Article Recommendations * sıSupporting Information ABSTRACT: The reaction of 2-(trimethylsilyl)thiophen-3-yl triflate with CsF in the presence of 2,3,4,5-tetraphenylcyclopentadienone affords 4,5,6,7tetraphenylbenzo[b]thiophene, as it would be expected from the hypothesized generation and trapping of 2-thiophyne. However, a detailed experimental and computational study discards the intermediacy of this elusive 5-membered hetaryne. Instead, a complex mechanism involving the generation of an intermediate ketocarbene, which adds to the cyclopentadienone to give an isolable tricyclic intermediate, followed by thermal rearrangements, is proposed. Around 120 years ago, Stormer and Kahlert postulated, for the first time, the generation of a didehydroaromatic intermediate, 2,3-didehydrobenzofuran, 1 although the general acceptance of arynes was not firmly established until the 1950s. 2 Since then, a large number of arynes have been proposed, including carbocyclic 3 and heterocyclic 4 species. While the existence of six-membered arynes has been firmly established and even proved by STM/AFM imaging, 5 the formation of most 5-membered heterocyclic arynes, 6−8 and particularly, 2,3-didehydrothiophene (2-thiophyne, 1,see Figure 1), 9 has been a matter of debate. In fact, although metal complexes of η2-2-thiophyne are well-known, 10 the existence and reactivity of the free hetaryne species has not been unambiguously proven. Pionering work on the attempted generation and trapping of 2-thiophyne (1) was performed by Wittig and Rings, who heated the organomercuric derivative 2in the presence of cyclopentadienone 3, isolating benzothiophene 4(see Figure 2). 11a Although this product was the one expected from the cycloaddition of the hetaryne 1to diene 3, followed by cheletropic extrusion of CO from adduct 5a, additional experimental evidence led the authors to suggest an alternative mechanism involving the cycloaddition of cyclopentadienone 3 to the C2−C3 double bond of 3-iodothiophene leading to intermediate 6a. 11b Some years later, Reinecke and co-workers studied the flash vacuum pyrolysis (FVP) of anhydride 7in the presence of dienes such as thiophene, obtaining benzothiophene 8. 12 Their detailed study concluded that the best explanation for the results is the one based on the involvement of 2-thiophyne (1) and adduct 5b, although the direct reaction of the diene with anhydride 7(to give 6b) or with some decomposition product of 7, must also be considered. Further attempts to unambiguously demonstrate the generation of 2Received: July 31, 2021 Published: September 13, 2021 Figure 1. 2,3-Didehydrothiophene or 2-thiophyne (1). Figure 2. Previous attempts to generate and trap 2-thiophyne (1). Letterpubs.acs.org/OrgLett © 2021 The Authors. Published by American Chemical Society 7376 https://doi.org/10.1021/acs.orglett.1c02552 Org. Lett. 2021, 23, 7376−7380 Downloaded via UNIV DE SANTIAGO DE COMPOSTELA on July 8, 2022 at 11:15:05 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. thiophyne (1) from anhydride 7were also inconclusive. 13 More recently, the generation of a 2-thiophyne by treatment of a 2-thiophenyltriflate with base was claimed, 14 but the detailed study of this transformation has been not reported. Although the aforementioned unsuccessful results were attributed to the high strain and the lack of stability of 2thiophyne (1), recent computational work identified this hetaryne intermediate as synthetically accessible. 15 This prospect, and our long-term experience in aryne chemistry, led us to explore the possibility to generate 1from a Kobayashi-type precursor, 16 the previously undescribed 2- (trimethylsilyl)thiophen-3-yl triflate (9). For the synthesis of triflate 9, depicted in Scheme 1, (thiophen-3-yl)boronic acid (10) was treated with hydrogen peroxide to afford thiophen-3-ol (11), 17 which was reacted in situ with DABCO and isopropyl isocyanate to give carbamate 12 in 40% yield. Then, the o-lithiation/silylation protocol described by Hoppe and coworkers 18 for N-silylated O-aryl Nisopropylcarbamates was used to obtain compound 13 in 66% yield. A subsequent one-pot deprotection/triflation procedure, previously utilized by Houk and Garg for the synthesis of other hetaryne precursors, 4b,19 afforded silyl triflate 9in 47% yield. The ability of triflate 9as precursor of 2-thiophyne (1) was tested by trapping experiments with different dienes. While treatment of 9with CsF in the presence of furan, 1,3diphenylisobenzofuran, or anthracene did not afford the expected adducts, the reaction with 2,3,4,5-tetraphenylcyclopentadienone (3) at room temperature in THF/ACN, followed by heating under reflux for 16 h, successfully allowed us to detect and isolate 4,5,6,7-tetraphenylbenzo[b]thiophene (4), albeit in low yield (<5%). Although this result was consistent with the expected generation of 2-thiophyne (1) and its trapping as the Diels−Alder adduct 5a, which should lead to 4by cheletropic extrusion of CO upon heating, alternative nonaryne pathways such as the one involving intermediate 14 (Scheme 2) could not be ruled out, particularly considering the precedents discussed above (see Figure 2). To shed light on the reaction mechanism, a careful experimental study was performed, focusing on the identification of intermediate species such as the hypothesized adducts 5a or 14. Thus, we monitored the reaction of triflate 9 with CsF in the presence of 3, performed this time at room temperature, and stopped the reaction once the starting triflate 9was consumed. After workup and chromatographic purification, we isolated a major product that proved to be NMRand IR-data-compatible with 5a, but showed a mass spectrum whose molecular ion peak was 16 mass units larger than expected. Fortunately, we were able to grow single crystals of this new compound, thus allowing us to perform X-ray diffraction (XRD) analysis that unambiguously revealed the totally unexpected structure 15 (Scheme 3 and Figure 3; see the Supporting Information for details). Remarkably, when a solution of 15 in o-dichlorobenzene was heated at 180 °C for a week, benzo[b]thiophene 4was isolated in quantitative yield, proving that 15 is a real intermediate in the formation of 4. Furthermore, stopping this reaction before complete conversion allowed us to isolate a new intermediate which was tentatively identified as 16. This new compound was also quantitatively converted into 4by refluxing in odichlorobenzene (Scheme 3). These results and, particularly, the isolation and unambiguous characterization of the tricyclic intermediate 15, suggest that benzothiophene 4was formed through a complex Scheme 1. Synthesis of 2-(Trimethylsilyl)thiophen-3-yl Triflate (9) Scheme 2. Hypothesized Pathways for the Reaction of Triflate 9 with CsF and Cyclopentadienone 3 Scheme 3. Experimentally Detected Intermediate Species in the Formation of Benzo[b]thiophene 4 from Triflate 9, CsF, and 3 Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.1c02552 Org. Lett. 2021, 23, 7376−7380 7377 mechanism not involving hetaryne 1. We decided to study this reaction computationally and, thus, we first performed B3LYP/ 6-31++G(d,p) calculations 20 on the decomposition of triflate 9 (see the Supporting Information for details). Assuming that the anionic intermediate 17 is formed from 9, 21 several pathways can be envisaged, as depicted in Scheme 4. Calculations show that elimination of the triflate to afford the aryne (2-thiophyne, 1) is a barrierless process, endergonic by 11.7 kcal/mol. 22 An alternative anionic thia-Fries rearrangement, which has been observed in some attempts of aryne generation from aryl triflates, 23 is also unlikely to happen, because of the relatively high activation barrier for the formation of 19 (16.8 kcal mol−1). Surprisingly, we found that the most kinetically favorable process, with an activation barrier of 8.5 kcal mol−1, is the formation of the ketocarbene 18 (see the Supporting Information) by cleavage of an O−S bond of the triflate groups. Interestingly, the unexpectedly found ketocarbene 18 could reasonably explain the formation of the previously isolated tricyclic intermediate 15 and, thus, we computed the reaction of 18 with cyclopentadienone 3, as shown in Scheme 5. One possible mechanistic pathway could involve the [2 + 1] cycloaddition of the carbene to one of the double bonds of 3, leading to the spirocompounds 20 and/or 21. In fact, we could find transition states for the formation of both isomers, given that the barriers (18.6 and 18.7 kcal mol−1) and the reaction energies (−39.1 and −40.8 kcal mol−1, respectively) were quite similar, and also found a transition state for the oxavinylcyclopropane rearrangement 24 of isomer 20 to give the isolated compound 15 (barrier = 23 kcal mol−1). However, the study showed that the alternative pathway that leads directly to 15 through a concerted formal 1,3-dipolar addition is more favorable. This reaction would proceed through a very asynchronous transition state, with a barrier of 16 kcal mol−1 (2.6 kcal mol−1lower than the barrier for the cyclopropanation reaction). Note that the alternative regioisomeric adduct 22 resulted to be lightly less stable than 15, and the barrier for its formation is substantially higher (32.4 kcal/mol). Once the viability of the generation of ketocarbene 18 and its reasonable reaction with cyclopentadienone 3to afford the fully characterized compound 15 were demonstrated, we focused our attention on the transformation of this intermediate product to the final benzothiophene 4. As previously mentioned, 15 is thermally converted to 4, with the loss of CO2, by prolonged heating in refluxing odichlorobenzene. To gain insight into this transformation, we performed a density functional theory (DFT) study (see the Supporting Information) that led us to propose the mechanism outlined in Scheme 6. Thus, compound 15 can suffer a rearrangement to give spirane 20, which might be a key intermediate in this transformation, since DFT calculations show that it easily undergoes ring-opening to give ketene 23. A subsequent 8πelectrocyclization would generate compound 16, which evolves with the loss of CO2to afford benzo[b]- thiophene 4. 25 To summarize, 2-(trimethylsilyl)thiophen-3-yl triflate has been synthesized as a potential Kobayashi-type precursor of the elusive five-membered hetaryne 2-thiophyne (1). Although the reaction of this triflate with 1,2,3,4-tetraphenylcyclopentadienone under aryne forming conditions afforded the expected trapping product, computational and experimental studies, including the isolation and characterization of unexpected intermediate products, ruled out the formation of the hetaryne. Instead, our results revealed an unprecedented mechanism Figure 3. Structure and ORTEP drawing of intermediate 15. Scheme 4. Computed Energy Profiles (ΔG, kcal mol−1) for the Evolution Pathways of Intermediate 17 Scheme 5. Energy Profile (ΔG, kcal mol−1) for the Reaction Ketocarbene 18 with Cyclopentadienone 3 Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.1c02552 Org. Lett. 2021, 23, 7376−7380 7378 involving the generation and subsequent reaction of a ketocarbene intermediate. ■ASSOCIATED CONTENT * sıSupporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c02552. Experimental procedures, characterization of new compounds, including NMR spectra, computational methods and results, including Cartesian coordinates (PDF) Accession Codes CCDC 1837531 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,orbyemailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. ■AUTHOR INFORMATION Corresponding Author Dolores Pérez −Centro Singular de InvestigaciónenQuímica Biolóxica e Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; orcid.org/0000-0003-0877-5938; Email: [email protected] Authors Iago Pozo −Centro Singular de InvestigaciónenQuímica Biolóxica e Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain Agustín Cobas −Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain Diego Pena−Centro Singular de InvestigaciónenQuímica Biolóxica e Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; orcid.org/0000-0003-3814-589X Enrique Guitián −Centro Singular de Investigaciónen Química Biolóxica e Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain Complete contact information is available at: https://pubs.acs.org/10.1021/acs.orglett.1c02552 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ■ACKNOWLEDGMENTS Financial support from the Spanish Agencia Estatal de Investigación (Nos. PID2019-110037GB-I00 and PCI2019111933-2), the European Union’s Horizon 2020 (FET-Open project, Grant No. 863098), the Xunta de Galicia (No. ED431C 2020/22 and Centro Singular de Investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development FundERDF, is gratefully acknowledged. The authors thank the Centro de Supercomputación de Galicia (CESGA) for generous allocation of computer time. I.P. thanks Xunta de Galicia and the European Union (European Social Fund, ESF) for the award of a predoctoral fellowship. ■REFERENCES (1) Störmer, R.; Kahlert, B. Uber das 1und 2-Bromcumaron. Ber. Dtsch. Chem. Ges. 1902,35, 1633−1640. (2) Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. 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