Nonplanar Tub-shaped Benzocyclooctatetraenes via Halogen-Radical Ring Opening of Dihydrobiphenylenes

Nonplanar Tub-Shaped Benzocyclooctatetraenes via HalogenRadical Ring Opening of Dihydrobiphenylenes Jesus Bello-García, Damián Padín, Jesus A. Varela, and Carlos Saá* Cite This: Org. Lett. 2021, 23, 5539−5544 Read Online ACCESS Metrics & More Article Recommendations * sıSupporting Information ABSTRACT: A novel tandem Ru-catalyzed [2+2+2] cycloaddition of arylenynes to dihydrobiphenylenes followed by halogen-radical ring opening has been developed for the construction of tub-shaped halogenated benzocyclooctatetraenes (bCOT’s). Cross-couplings and Diels−Alder reactions of the brominated bCOT’s allow the formation of the corresponding eight-membered ring-fused PAH’s. The halogen-radical ring opening probably occurs via a selective formation of a bis-allyl radical at the 1,3-cyclohexadiene moiety, halogenation at the bridgehead carbon, and finally electrocyclic ring opening. Cyclooctatetraenes (COT) are nonplanar tub-shaped hydrocarbon compounds having a D2dconformation (more stable in its dynamic equilibrium than the planar D4h and delocalized D8hconformations) that have attracted a great deal of interest due to their electronic properties that result from having cyclic conjugated eight-π-electron systems. 1 They are also very useful sterically demanding ligands for metals. 2 These important features triggered an enormous effort throughout the years that aimed to develop and efficient synthesis of these archetypical medium-sized carbocycles 3 with the aim of understanding their aromatic and antiaromatic properties according to Huckel’srules. 4 More recently, nanographenes containing nonhexagonal rings are being considered as ideal models of defective graphene for building new semiconductor materials. 5 In particular, distortion from planarity caused by the presence of eight-membered rings or the introduction of [8]circulene moieties that induce a deep curvature in the aromatic lattice and deeply influence the electronic and optical properties has attracted considerable attention. 6 Consequently, the development of efficient synthetic methods for COT-embedded arenes is greatly significant and in high demand. In this context, synthetic approaches to dbCOT’s, 7 dbCOTP’s, 8 tribCOT’s, 9 and tetraphenylenes 10 are relatively well studied while the simple benzocyclooctatetraenes (bCOT’s) have received significantly less synthetic attention (Scheme 1). 11 The parent benzocyclooctatetraene unit had also been observed in pioneer Gunther’s 12 studies of Birch reduction of biphenylene in which the double protonation of the dianion occurred at the bridgehead position giving 4a,8b-dihydrobiphenylene. 13 This reactive species very rapidly evolved to the more stable benzocyclooctatetraene via thermal electrocyclic ring opening (Scheme 1). On the contrary, a mild and powerful method for assembling 1,3-cyclohexadiene units (dihydrobiphenylene isomers) had been recently developed in our group via Ru(II)-catalyzed [2+2+2] cycloaddition of arylenynes and alkynes. 14 This type of cyclohexadiene has been utilized in efficient synthetic manipulations such as oxidations and Diels−Alder reactions. 15 Moreover, a tandem Ru-catalyzed [2+2+2] cyclization/iodinemediated ring expansion of enediynes led to a straightforward Received: June 7, 2021 Published: July 6, 2021 Scheme 1. COT-Embedded Polycyclic Arenes, Birch Reduction of Biphenylene, and Formation of Cyclooctatetraenes by Halogen-Radical Ring Opening of 1,8b-Dihydrobiphenylenes Letterpubs.acs.org/OrgLett © 2021 American Chemical Society 5539 https://doi.org/10.1021/acs.orglett.1c01881 Org. Lett. 2021, 23, 5539−5544 Downloaded via UNIV DE SANTIAGO DE COMPOSTELA on November 3, 2021 at 07:24:18 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. assembly of benzo-fused bridged ketones. 16 However, to the best our knowledge, the radical opening of benzo-fused cyclohexadienes has not been investigated even though such combined processes have synthetic potential for accessing interesting functionalized scaffolds. Herein, we report an efficient tandem process based on a Ru-catalyzed [2+2+2] cycloaddition of arylenynes 1with alkynes 2to 1,8bdihydrobiphenylenes 3 14 followed by halogen-radical ring opening to benzocyclooctatetraenes 4(Scheme 1). The halogenated (mainly, bromo derivatives) bCOT’s have proved to be privileged functionalized structural units for accessing PAH’s that combine aromatic and antiaromatic properties. 17 Inspired by Gunther’s observations, we began our investigation by examining the well-known Wohl−Ziegler bromination 18 of dihydrobiphenylene 3a. Thus, as a proof of concept, the use of NBS and AIBN as radical initiators in CCl4 at rt promoted the formation of the desired bromobenzocyclooctatetraene 4a, although in low yield (Table 1, entry 1). Gratifyingly, when the reaction temperature is increased at reflux, the yield of 4a increases to 89% (Table 1, entry 2). Other solvents were then tested. The use of chlorinated solvents like CHCl3or CH2Cl2or nonpolar heptane or polar CH3CN afforded 4a but in lower yields (Table 1, entries 3−6). By contrast, polar ethereal or aprotic solvents such as 1,4dioxane or DCE and a nonpolar solvent like benzene gave 4a in fairly good yields (Table 1, entries 7−9). Experimental reaction conditions using CCl4as a solvent were then examined. Thus, performing the reaction in the absence of light led to a lower yield of 4a (Table 1, entry 10) as did not using AIBN as a radical initiator (Table 1, entry 11). In addition, the presence of NBS is mandatory for the consumption of starting product 3a, while the rest gave rise to a complex mixture (Table 1, entry 12). 19 The use of other halogen sources (NIS and NCS) is also feasible, affording the corresponding iodinated (4a′) and chlorinated (4a″) benzocyclooctatetraenes albeit in lower yields (Table 1, entries 13 and 14). With the optimized conditions in hand, we next investigated the scope of the reaction (Scheme 2). For dihydrobiphenylenes 3arising from electron-rich arylalkynes 2and arylenyne 1a (R1= H), either the trialkoxyphenyl 3b,the6methoxynaphthyl 3c, or the heteroaryl 3-thiophene 3d behaves similarly giving fairly good yields of the corresponding bCOT’s 4b−d. Not unexpectedly, the parent phenyl dihydrobiphenylene 3e affords the benzocyclooctatetraene 4e in a moderate yield (48%), probably due to the lower electron richness of the influential aryl ring involved in the electrocyclic opening. 20 Curiously, with an extended conjugated π-system, such as in dihydrobiphenylene 3f, the ring opening was favorably affected giving rise to the biphenyl benzocyclooctatetraene 4f in a fairly good yield. On the contrary, dihydrobiphenylenes 3arising from the electron-rich dialkoxy arylenyne 1b (R1/R1= OCH2O) and electron-rich alkynes 2gave rise to the corresponding benzocyclooctatetraenes 4g−iin moderate to good yields, showing the versatility of combining one or two electron-rich partners. Interestingly, the vinyl substituent on dihydrobiphenylene 3j, derived from Ru-catalyzed dimerization of 1-ethynyl-4-methoxy-2-vinylbenzene 1c, 14 or the ethynyl substituent on 3k [from Ru-catalyzed cycloaddition of 1d (R1= alkynyl) and 2a] remained intact under the radical conditions giving the corresponding styrenic bCOT 4j and acetylenic bCOT 4k in fairly good yields that might be capable of future manipulations. 21 Table 1. Optimization of Halogen-Radical Ring Opening of 1,8b-Dihydrobiphenylene 3a to Halobenzocyclooctatetraenes 4a (X = Br), 4a′(X = I), and 4a″(X = Cl) a entry solvent T(°C) yield of 4a b 1 CCl4rt 30 2 CCl4reflux 85 3 DCM reflux 32 4 CHCl3reflux 38 5 heptane reflux 44 6CH 3CN reflux 40 7 1,4-dioxane reflux 61 8 DCE reflux 66 9 benzene reflux 65 10 CCl4(darkness) reflux 53 11 CCl4(no AIBN) reflux 30 12 CCl4(no NBS) reflux SM (50) 13 c CCl4reflux 77, 4a′ 14 d CCl4reflux 36, 4a″ a Reaction conditions: 3a (0.2−0.3 mmol) in solvent (0.036 M), NBS (1.1 equiv), AIBN (0.11 equiv), 1−1.5 h. b Isolated yield. c NIS. d NCS. Scheme 2. Radical Ring Opening of Dihydrobiphenylenes 3 to bCOT’s4 a a Reaction conditions: 3 (0.2−0.3 mmol) in CCl4(0.036 M), NBS (1.1 equiv), AIBN (0.11 equiv), 1−1.5 h. Isolated yield. The ORTEP drawing of 4a shows ellipsoids at the 50% contour probability level. b The reaction time was 4 h. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.1c01881 Org. Lett. 2021, 23, 5539−5544 5540 Interestingly, the heteroannulated benzocyclooctatetraenes 6a and 6b could be assembled in moderate yields via a one-pot, two-step process from arylenynes 5a and 5b bearing an O and a NTs group as linkers (Scheme 3, eq 1). 16 Double tandem processes were also accessible. Thus, a simple and straightforward entry to the linear benzodiCOT 9(benzo[1,2:4,5]di[8]- annulene), 22 an appealing nonbenzenoid PAH structure with intriguing electronic and aromatic properties, 23 was achieved from 1,4-diethynyl-2,5-divinylbenzene 7. The double Rucatalyzed [2+2+2] cycloaddition of 7with alkyne 2a led to the linear tetrahydro[3]phenylene 8in an excellent 80% yield. The halogen-radical double ring opening of 8with NBS in DCE occurred uneventfully to give the benzodiCOT 9in a satisfactory 62% yield as a mixture of Uand S-shaped conformers in solution, the S-shaped form being 1.2 kcal mol−1 more stable than the U-shaped form as shown by DFT calculations (Scheme 3, eq 2). 24 1H NMR spectra of 9reveal the presence of the two conformers at rt in a 1:2.5 ratio, Uand S-shaped, which could be thermally equilibrated to 1:1.5 ratio at 100 °C. Single crystals of 9suitable for X-ray diffraction analysis were grown from a solution in a hot CHCl3/hexane mixture by slow evaporation of the solvents. 9shows an Sshaped geometry with the bromine atoms on opposite faces with respect to the central benzene plane. In addition, the two eight-membered rings are considerably bent up and down from the plane of the central benzene unit with a large dihedral angle of ∼138°. Similar to COT, the two eight-membered rings adopt a tub-shaped conformation, with large bond length alternation. The bonds of the central six-membered rings are within the typical range of 1.39−1.40 Å, revealing an aromatic benzenoid character. Scaling up was also feasible as shown by performing a tandem process from initial enyne 1a and arylalkyne 2a without the isolation of dihydrobiphenylene 3a. Thus, reaction of 1a (8.1 mmol) and 2a (9.7 mmol) in MeOH under catalytic conditions (as little as 3% Ru) followed by a rapid replacement of the solvent with the apolar DCE to perform the radical reaction allowed us to obtain bCOT 4a (2.1 g) in a 76% overall yield (Scheme 3, eq 3). In an effort to gain further insights into the reaction mechanism, DFT calculations were performed to analyze all possible radical pathways. 24 We began the mechanistic studies by elucidating the selectivity of the initial radical formation because two different radicals can be formed depending on the abstractions of the tertiary hydrogen H1of the cyclobutene moiety or one of the two secondary hydrogens H2on the 1,3cyclohexadiene core. Even though tertiary C−H bonds are weaker than secondary ones, the presence of the cyclobutene moiety dramatically changes the reactivity of the 1,3-cyclohexadiene core, making the formation of the secondary bisallylic radical I4.3 kcal mol−1more favorable than that of the allylic benzylic tertiary radical (Scheme 4). Atomic spin densities were then computed for the more stable allylic/ secondary radical I, showing that, as expected, it is mainly divided among the three carbons of the central six-membered ring. 24 We then evaluate the three possible evolution pathways for the most stable radical I(Figure 1): (a) six-π-electron electrocyclic ring opening followed by trapping of the resulting radical with Br2to afford the observed cyclooctatetraene 4e (ΔG⧧= 39.2 kcal mol−1, red pathway), (b) radical opening of the cyclobutane ring followed trapping with Br2to afford terphenyl II (ΔG⧧= 19.4 kcal mol−1, blue pathway), and (c) the most favorable one (ΔG⧧= 5.7 kcal mol−1, black pathway) that involves direct bromination of the resonance structure of I with the radical into the tertiary, allylic, and benzylic position to give rise to the brominated dihydrobiphenylene III. Once III had been established as the most favorable product of radical bromination of 3e, the observed product 4e would be formed through a six-π-electrocyclic ring opening. 24 The utility of the brominated bCOT’s4was tested in the preparation of valuable COT-embedded PAH’s(Scheme 5). Suzuki cross-coupling between 4a and phenylboronic acid affords the expected phenyl-substituted bCOT 10 in 70% yield (Scheme 5, eq 1). Sonogashira couplings were also satisfactorily carried out under typical reaction conditions. Alkynyl-substituted COT’s11a and 11b were obtained in good to excellent yields using trimethylsilylacetylene 2l and Scheme 3. Heteroannulated bCOT’s 6a and 6b, Linear BenzodiCOT 9, and Scale-Up Synthesis of bCOT 4a a a The ORTEP drawing of 9shows ellipsoids at the 50% contour probability level. Scheme 4. Bond Dissociation Energies (BDE’s) of H1and H2 Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.1c01881 Org. Lett. 2021, 23, 5539−5544 5541 alkynylaniline 2m, respectively (Scheme 5, eq 2). To our delight, an efficient Sonogashira coupling between 4a and alkynylCOT 11a′(from desilylation of 11a)renders uneventfully the interesting bis-COT derivative 11c,as confirmed by X-ray analysis (Scheme 5, eq 3). 25 Finally, treatment of 4a with KOtBu 10 generates a strained cyclic alkyne that could be subsequently trapped as a dienophile with tetraphenylcyclopentadienone in a Diels−Alder reaction affording the π-extended dibenzoCOT 12 in very good yield (Scheme 5, eq 4). Note the higher reactivity of the triple bond in planarized systems containing one benzo-fused eightmembered ring (rt, 25 °C) as compared to the typical dibenzo-fused derivative (Ph2Oreflux, >250 °C). 26 In conclusion, we have developed a general synthetic method for constructing a new class of polycyclic arenes embedded with a brominated (halogenated) COT ring via a tandem Ru-catalyzed [2+2+2] cycloaddition of arylenynes to dihydrobiphenylenes followed by halogen-radical ring opening. The process involves the initial formation of a bis-allylic radical at the 1,3-cyclohexadiene core of the dihydrobiphenylene. Then, halogenation at the bridgehead position of the benzocyclobutene ring followed by a subsequent electrocyclic ring opening renders the observed cyclooctatetraene. This protocol provides a new synthetic approach to polycyclic arenes fused with an eight-membered ring (bCOT), which is expected to be applicable for the synthesis of diverse curved nanocarbons. ■ASSOCIATED CONTENT * sıSupporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c01881. General experimental procedures, X-ray crystallographic data, NMR spectra, and DFT calculations (PDF) Computational details, free energy profile for the isomerization of benzodiCOT 9from the Uto Sshaped conformers, complete free energy profile for the radical bromination of dihydrobiphenylene 3e and six-πelectron electrocyclic ring opening of brominated dihydrobiphenylene III, natural bond orbital analysis, references, and Cartesian coordinates, energy values, and imaginary frequencies for all of the stationary points involved throughout the DFT study (PDF) Accession Codes CCDC 2085992−2085994 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,orby emailing [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 Carlos Saá −Centro Singular de InvestigaciónenQuímica Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; orcid.org/0000-0003-3213-4604; Email: carlos.saa@ usc.es Authors Jesus Bello-García −Centro Singular de Investigaciónen Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain Damián Padín −Centro Singular de InvestigaciónenQuímica Biolóxica e Materiais Moleculares (CiQUS), Departamento Figure 1. Free energy profiles for the radical bromination of 3e. Energies are relative to 3e and are mass balanced. Scheme 5. Synthetic Applications of Brominated bCOT’s a a The ORTEP drawing of 11c shows ellipsoids at the 50% contour probability level. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.1c01881 Org. Lett. 2021, 23, 5539−5544 5542 de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; orcid.org/0000-0002-3841-727X Jesus A. Varela −Centro Singular de InvestigaciónenQuímica Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; orcid.org/0000-0001-8499-4257 Complete contact information is available at: https://pubs.acs.org/10.1021/acs.orglett.1c01881 Notes The authors declare no competing financial interest. ■ACKNOWLEDGMENTS This work has received financial support from MINECO (Project CTQ2017-87939R and ORFEO-CINQA Network RED2018-102387-T), the Xunta de Galicia (Project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03), and the European Union (European Regional Development Fund). J.B.-G. thanks Xunta de Galicia for a predoctoral contract. The authors are also grateful to the CESGA (Xunta de Galicia) for computational time. Dedicated to Prof. K. Peter C. 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For a recent Scholl-based synthetic approach to a perylene-fused benzodiCOT derivative, see: (d) Zou, Y.; Han, Y.; Wu, S.; Hou, X.; Chow,C.H.E.;Wu,J.SchollReactionofPerylene-Based Polyphenylene Precursors under Different Conditions: Formation of Hexagon or Octagon? Angew. Chem., Int. Ed. 2021,DOI: 10.1002/ anie.202105427. (24) See the Supporting Information for computational details. (25) CCDC-2085994, 2085993, and 2085992 contain the supplementary crystallographic data for compounds 4a,9, and 11c, respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (26) Huang, N. Z.; Sondheimer, F. The planar dehydro[8]- annulenes. Acc. Chem. Res. 1982,15,96−102. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.1c01881 Org. Lett. 2021, 23, 5539−5544 5544