Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis, Isolation, and Characterization of Mono- and Bisnorbornene-Annulated Biarylamines through Pseudo-Catellani Intermediates Pratheepkumar Annamalai,† Huan-Chang Hsiao,† Selvam Raju,† Yi-Hsuan Fu,‡ Pei-Ling Chen,‡ Jia-Cherng Horng,‡ Yi-Hung Liu,§ and Shih-Ching Chuang*,† †
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan Department of Chemistry, National Tsing Hua University, Hsinchu 30010, Taiwan § Instrumentation Center, National Taiwan University, Taipei 10617, Taiwan
Downloaded via STOCKHOLM UNIV on February 4, 2019 at 17:20:47 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
ABSTRACT: A palladium-catalyzed C−H functionalization of an external ring of N-acyl 2-aminobiaryl with bicyclo[2.2.1]hept-2-ene (norbornene) via multiple C−H bond activations was developed. This study is the first report of the formation of bis-norbornene annulated biarylamines isomers (syn-3a′/anti3a′ = 36:64) from multiple C−H bond functionalizations. Additionally, nondirected C−H bond functionalization at the C-4′ position with alkenes rendered complete C−H functionalization of five C−H bonds that formed a stable hexasubstituted benzene ring.
I
Scheme 1. Previous Work and Our Findings
n recent years, C−H functionalization has become a popular research topic in organometallic chemistry and catalysis.1 Site-selective activation and functionalization of inert C−H bonds through regioselective and stereoselective processes have been the foci of relevant studies.2 In 1997, Catellani demonstrated palladium-catalyzed Heck-type ipso and ortho aryl carbon functionalization in which norbornene was used as a transient mediator.3 Subsequently, the Catellani strategy was utilized to prepare arenes with diverse functional moieties in both ipso and ortho positions.2f,4 The Catellani reaction was also applied to prepare natural products and medicinal molecules such as (+)-linoxepin,5 rhazinal,6 goniomitine, and aspidospermidine7 and various classes of condensed heterocyclic compounds as well as polycyclic and polyheterocyclic aromatic hydrocarbons.2a,f,8 Expanding the scope of the Catellani reaction, Zhou et al. demonstrated Heck−Catellani reactions involving aryl halide and norbornene to produce strained norbornene-annulated arenes by using palladium as a catalyst and PtBu3 as a ligand (Scheme 1a).9 Jiang et al. described C−H bond activation and oxidative cyclization of acetanilide with norbornene to produce indolines (Scheme 1b).10 Yu et al. reported site-selective ligand-enabled direct meta C−H functionalization using norbornene as a transient mediator, which provided a new pathway for siteselective meta C−H functionalization with a wide variety of functional groups such as aryls, amines, alkyls, and alkynes (Scheme 1c).11 Protected and unprotected amino-containing groups in aromatic and aliphatic substrates are potential directing moieties and have been utilized in the synthesis of various nitrogen-containing heterocycles ranging from bioactive molecules to material science applications.2f,7,12 In numerous studies, free amines or N-substituted amines have © XXXX American Chemical Society
been used as directing groups under various metal catalysts such as Pd, Rh, Ru, Co, Cu, and Ir.13 In this context, our research group demonstrated palladium-catalyzed C2′−H activation of N-tosyl 2-aminobiaryls followed by the insertion of [60]fullerene and CO to yield fullerobenzoazepines14 and phenanthridinones, respectively.15 We also achieved the aromatic homologation of N-acyl 2-aminobiaryls through oxidative ortho/meta insertion of two diphenyl acetylenes.16 Received: January 10, 2019
A
DOI: 10.1021/acs.orglett.9b00119 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 2. Substrate Scope of Various N-Acylbiarylaminesa
Recently, Yu et al. reported meta-selective C−H arylation of nosyl-protected phenethylamines, benzylamines, and 2-arylanilines.12b Additionally, Ling et al. demonstrated the interannular meta-selective C−H arylations of biaryl-2trifluoroacetamides using Pd(II)/norbornene catalysis.17 It is noteworthy that formation of norbornene-annulated arenes was described as a pitfall in ligand-enabled direct meta C−H functionalization.11b,c,18 Although mononorbornene annulation through a C−H activation process has been described by Yu,12b Takemoto,19 and Hong,20 respectively, their syntheses provided poor yields and limited scopes and were not applicable to double annulations in the biaryl system. However, we perceived that bis-norbornene-annulated biaryls through double C−H activations were previously inaccessible.19,20 The target, a bis-norbornene-annulated arene, can be separated to give chiral auxiliary molecules for possible application in asymmetric catalysis.21 In our study of palladium-catalyzed selective meta functionalization of N-acyl 2-aminobiaryls using activated olefins as a coupling partner and norbornene as a transient mediator, we happened to isolate bulk intermediate products from oxidative cyclization of norbornene with N-acyl 2-aminobiaryls. This indicated that formation of norbornene-annulated arenes through reductive elimination was faster than subsequent reaction with electrophiles toward meta functionalization in the N-acyl 2-aminobiaryl system. Here, we report the isolation and characterization of mono- and bisnorbornene-annulated arenes from direct multiple C−H activations of N-acyl 2-aminobiaryls. The major products, syn-3a′/anti-3a′ = 36:64, were formed when two norbornenes underwent insertion/reductive elimination, and minor products were formed with the mononorbornene functionalization under palladium catalysis using Cu(OAc)2/O2 as oxidants at 120 °C for 24 h (Scheme 1d). The absolute configurations of syn-3a′/anti-3a′ products were determined using single-crystal X-ray diffraction and circular dichroism measurements after separation of diastereomers and enantiomers. The substrate scope of various bicyclic alkenes was also studied. Additionally, nondirected C−H bond functionalization at the C-4′ position with alkenes rendered complete C−H functionalization of five C−H bonds that formed a stable hexasubstituted benzene ring system. We first evaluated condition optimization for preparation of 3a′ and 3a (see the Table S1). Scheme 2 summarizes the reaction scope study of multiple C−H bond activation and norbornene insertion followed by reductive elimination that rendered formation of the major bis-norbornene annulated compounds syn-3′/anti-3′ and the minor mononorborneneannulated compound 3. The bis-norbornene annulated compounds contained syn-3′ and anti-3′. The anti-isomer anti-3a′ exhibited a pair of chiral enantiomers, (R)-anti-3a′ and (S)-anti-3a′, due to its chiral axis. These isomers were practically separated using chiral high-performance liquid chromatography (HPLC), and the isomers syn-3a′, (R)-anti3a′, and (S)-anti-3a′ were characterized using single-crystal Xray diffraction with CuKα as a source. To study the scope of mononorbornene annulation, we used substrates with different electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) in the C-3′ position of N-acyl 2-aminobiarylamines. The reactivity of the studied substrates was highly dependent on the electronic effect exerted by the substitutions on the aryl moieties of N-acyl 2-aminobiaryls and the structural moiety of bicyclic alkenes. Substrates containing EDGs on the
a
All reactions were conducted using 1 (0.30 mmol), 2a (0.9 mmol), NaOAc (1.0 equiv), Pd(OAc)2 (10 mol %), and Cu(OAc)2 (1.0 equiv)/O2 (1 atm) in 2 mL DMF at 120 °C for 24 h. bNaOPiv (1.0 equiv) was used instead of NaOAc.
bottom ring underwent smooth dual C−H bond activation and coupling with a norbornene, resulting in moderate to good yields (Scheme 2, 3b−h, 67−84%). This result is likely attributable to the enhanced reactivity of the bottom ring toward C−H bond activation and reductive annulation promoted by the EDGs. Substrates containing an EWG exhibited relatively poor reactivity toward C−H bond activation or coupling with norbornene, and they had moderate yields (3i−k, 48−58%). The sterically bulky 1naphthyl group exhibited coupling, but it enabled formation of diastereomers syn-3l/anti-3l and syn-3m/anti-3m isomers in a 50:50 ratio (78−88% yields). Additionally, the substrate with the 3′-position bearing EWG such as the Cl, Br, and I (1n−p) moiety underwent oxidative annulation to produce the doublenorbornene annulated product 3a′ (35−52%) and mononorbornene-annulation products 3a and 3n,o (15−28%). In the case of iodo-substitution, only trace mononorborneneannulated product was observed. Substrates with a C-4 Me or C-4′ Me group also had high yields through quadruple bond C−H activation products and corresponding mononorbornene annulation products (3q′,r′ and 3q,r, 76−77%), with diastereometric ratios of 32:68 and 48:52, respectively. Furthermore, substrates without meta protection on the bottom aryl moiety and with EWGs, such as 4-F and 4-Cl groups, on their top rings provided moderate yields through quadruple bond C−H activation and corresponding monoannulation products (3s′,t′ and 3s,t, 62−78%), with diastereometric ratios of 34:66 and 33:67, respectively. We also studied the norbornene annulation toward the bicyclic alkenes 2b−f (Scheme 3). In the case with norbornadiene 2b, the yield was low at 16% (85% based on converted reactants) (Scheme 3, 3u); this was likely due to its B
DOI: 10.1021/acs.orglett.9b00119 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Substrate Scope of Various Bicyclic Alkenesa
alkenylation to give 6e′ with a yield of 50% (syn-6e′/anti-6e′ = 40:60). The reactants, 3t′ and 3s′, also underwent alkenylation to provide 6f′ and 6g′ with yields of 76 and 60%, respectively. Figure 1 represents the Oak Ridge Thermal Ellipsoid Plot solid-state structures of pure syn-3a′, (R)-anti-3a′, and (S)-
a
All reactions were conducted using 1 (0.10 mmol), 2a (0.3 mmol), NaOPiv (1.0 equiv), Pd(OAc)2 (10 mol %), and Cu(OAc)2 (1.0 equiv)/O2 (1 atm) in 2 mL DMF at 120 °C for 36 h. b1a (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2 (10 mol %), and AgOAc (3.0 equiv) under N2 at 120 °C for 24 h.
coordinative effect on palladium.19 By contrast, electrondeficient bicyclic alkenes (2c,d) with EDG- and EWGsubstituted N-acyl biarylamine underwent annulation with moderate yields (3v−y, 47−68%). Reactions with N-Boc-7azabenzonorbornadiene (2e) produced 3z with a yield of 51%; however, the reaction with 7-oxabenzonorbornene did not give the desired product. Interestingly, reactions with cyclopentadiene dimer 2f provided moderate yields of inseparable isomers (3za, 76:24), and their regiochemistry could not be exactly determined. Other biaryl systems, namely 2-phenylazoles and 2-phenylpyridine, were also tested, but only 2phenylazole provided norbornene-annulated product 3zab with a yield of 24% under the optimized conditions. The plausible catalytic cycle, kinetic isotopic effect study (KIE), circular dichroism (CD) of (R)-anti-3a′ and (S)-anti3a′, and 1H NMR plots of all isomers were studied (see descriptions in Schemes S1 and S2 and Figures S1 and S2). Scheme 4 summarizes the reaction scope study of nondirected
Figure 1. Solid-state structure of (a) syn-3a′, (b) (R)-anti-3a′, and (c) (S)-anti-3a′.
anti-3a′ isomers drawn with 50% probability, with hydrogens omitted for clarity. These isomers were practically separated through HPLC on a CHIRALPAK IG column with hexanes/2propanol (v/v 70/30) as eluents. These single crystals in the form of thin white needles can be prepared from their hexane solutions through slow evaporation at room temperature. Isomers syn-3a′, (R)-anti-3a′, and (S)-anti-3a′ crystallized in space groups P212121 (orthorhombic), P21 (monoclinic), and P21 (monoclinic), respectively. The isomer syn-3a′ was achiral due to the plane of symmetry, and the isomers (R)-anti-3a′ and (S)-anti-3a′ were a mutual pair of enantiomers. For isomer syn-3a′, the NHAc moiety rested on a less hindered side that is on a different face compared to that of the [2.2.1] bicyclooctane ring. The typical dihedral angles φC31C36C37C54, φC54C53C52C56, and φC38C39C40C55 were 57.8(5)°, 58.8(4)°, and −58.0(4)°, respectively. For chiral (R)-anti3a′, the typical dihedral an gles φC8C7 C6C11, φC5C20C21C22, and φC11C12C13C24 were 69.0(3)°, −58.8(2)°, and −56.2(2)°, respectively. The typical bond angles around the annulated norbornene moiety ∠C12C11C18 and ∠C11C12C17 were 93.7(2)° and 86.0(1)°, respectively. For chiral (S)-anti-3a′, the typical dihedral angles φC8C7C6C5, φC5C4C3C22, and φC11C18C17C19 were −151.7(2)°, −57.9(2)°, and −59.0(2)°, respectively. The versatility of the developed strategy was systematically examined in various control experiments (Scheme 5). The stepwise oxidative coupling of 3a with norbornene was confirmed to produce 3a′ with a yield of 66% (Scheme 5a). Compound 3a underwent intramolecular oxidative C−N coupling to produce carbazole with a yield of 70% (Scheme 5b). Aromatic homologation of 3a with diphenylacetylene produced isomer syn-5ab and anti-5ab (1:1) with a yield of 86% (Scheme 5c). Compound 3ab underwent oxidative coupling with norbornene to give a moderate yield of syn5ab and anti-5ab (1:1) (Scheme 5d). Oxidative coupling of 3a
Scheme 4. Nondirected C−H Bond Functionalization
C−H bond activation and oxidative insertion of various activated olefins followed by reductive elimination to form syn6a′/anti-6a′. We examined the reaction scope with substituted olefins (4a−d). The reaction of 3a′ (a mixture of syn-3a′ and anti-3a′) with acrylate 4a produced C-4′-activated product 6a′ with a yield of 64% (syn-6a′/anti-6a′ = 37:63). Similarly, reactions with phenyl vinyl sulfone 4b produced 6b′ with a yield of 54% (syn-6b′/anti-6b′ = 26:74). The reaction with diethylvinyl phosphonate 4c also provided the selective product 6c′ (syn-6c′/anti-6c′ = 40:60), but the yield was 40%. Substrate acrylonitrile 4d was also tolerated in this alkenylation and produced 6d′ (syn-6d′/anti-6d′ = 28:72) with a yield of 45%. The reactant 3r′ also underwent C
DOI: 10.1021/acs.orglett.9b00119 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
Scheme 5. Functionalization of 3a with Versatile Reactivity
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank the Ministry of Science and Technology of Taiwan for supporting this research financially (MOST104-2113-M009-014-MY3 and MOST105-2628-M-009-002-MY3).
■
(1) (a) Han, J.; Zhang, L.; Zhu, Y.; Zheng, Y.; Chen, X.; Huang, Z.B.; Shi, D.-Q.; Zhao, Y. Chem. Commun. 2016, 52, 6903. (b) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518. (c) Li, G.; Wan, L.; Zhang, G.; Leow, D.; Spangler, J.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 4391. (d) Maity, S.; Hoque, E.; Dhawa, U.; Maiti, D. Chem. Commun. 2016, 52, 14003. (e) Wu, Q.-F.; Shen, P.-X.; He, J.; Wang, X.-B.; Zhang, F.; Shao, Q.; Zhu, R.-Y.; Mapelli, C.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Science 2017, 355, 499. (f) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Acc. Chem. Res. 2016, 49, 1389. (2) (a) Catellani, M.; Motti, E.; Baratta, S. Org. Lett. 2001, 3, 3611. (b) Dong, Z.; Dong, G. J. Am. Chem. Soc. 2013, 135, 18350. (c) Han, J.; Wang, N.; Huang, Z.-B.; Zhao, Y.; Shi, D.-Q. Org. Biomol. Chem. 2017, 15, 5112. (d) Rasina, D.; Kahler-Quesada, A.; Ziarelli, S.; Warratz, S.; Cao, H.; Santoro, S.; Ackermann, L.; Vaccaro, L. Green Chem. 2016, 18, 5025. (e) Wang, J.; Zhang, L.; Dong, Z.; Dong, G. Chem. 2016, 1, 520. (f) Ye, J.; Lautens, M. Nat. Chem. 2015, 7, 863. (3) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. (4) Zhang, H.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 10174. (5) Weinstabl, H.; Suhartono, M.; Qureshi, Z.; Lautens, M. Angew. Chem., Int. Ed. 2013, 52, 5305. (6) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem. Soc. 2013, 135, 9318. (7) Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563. (8) Zheng, H.; Zhu, Y.; Shi, Y. Angew. Chem., Int. Ed. 2014, 53, 11280. (9) Wu, X.; Zhou, J. Chem. Commun. 2013, 49, 11035. (10) Gao, Y.; Huang, Y.; Wu, W.; Huang, K.; Jiang, H. Chem. Commun. 2014, 50, 8370. (11) (a) Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137, 5887. (b) Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 9269. (c) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Nature 2015, 519, 334. (12) (a) Shi, H.; Herron, A. N.; Shao, Y.; Shao, Q.; Yu, J.-Q. Nature 2018, 558, 581. (b) Ding, Q.; Ye, S.; Cheng, G.; Wang, P.; Farmer, M. E.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139, 417. (13) (a) Preciado, S.; Mendive-Tapia, L.; Albericio, F.; Lavilla, R. J. Org. Chem. 2013, 78, 8129. (b) Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2013, 15, 3990. (c) Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2015, 17, 1597. (d) Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014, 16, 2892. (e) Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2015, 80, 3242. (14) Rajeshkumar, V.; Chan, F.-W.; Chuang, S.-C. Adv. Synth. Catal. 2012, 354, 2473. (15) Rajeshkumar, V.; Lee, T.-H.; Chuang, S.-C. Org. Lett. 2013, 15, 1468. (16) Annamalai, P.; Chen, W.-Y.; Raju, S.; Hsu, K.-C.; Upadhyay, N. S.; Cheng, C.-H.; Chuang, S.-C. Adv. Synth. Catal. 2016, 358, 3642. (17) Ling, P.-X.; Chen, K.; Shi, B.-F. Chem. Commun. 2017, 53, 2166. (18) Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 11574. (19) Nanjo, T.; Tsukano, C.; Takemoto, Y. Chem. Pharm. Bull. 2016, 64, 1384. (20) Chou, H.-M.; Jhou, J.-N.; Hong, F.-E. J. Organomet. Chem. 2017, 853, 178.
with methyl acrylates resulted in ortho alkenylation, generating inseparable syn-5ac and anti-5ac (1:1) with a yield of 56% (Scheme 5e). Similarly, oxidative coupling of 3a with methyl acrylates followed by Michael addition produced dihydrophenanthridine syn-5ad/anti-5ad (2:1) with a yield of 57% (Scheme 5f). In conclusion, we have demonstrated the approach for the formation of bis-norbornene-annulated biarylamines isomers through dual and quadruple oxidative cyclization of norbornene with N-acyl 2-aminobiaryls via ortho and meta C−H bond activation/insertion/reductive elimination sequences. The versatility and synthetic utility of stepwise C−H bond activation with different reactive functional substrates were demonstrated. Nondirected C−H functionalization at the C-4′ position provided a penta C−H activation product with the complete functionalization of aromatic systems. This finding may represent a new opportunity for the construction of chiral architectures with annulated norbornenes using directinggroup-assisted C−H functionalization.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00119. Detailed experimental procedures, spectral data, and 1H and 13 spectra for compounds (PDF) Accession Codes
CCDC 1848316−1848318, 1848323−1848324, 1849514, and 1858119 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, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jia-Cherng Horng: 0000-0002-9936-5338 Shih-Ching Chuang: 0000-0002-6926-9812 D
DOI: 10.1021/acs.orglett.9b00119 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (21) (a) Murray, S. J.; Ibrahim, H. Chem. Commun. 2015, 51, 2376. (b) Otevrel, J.; Bobal, P. J. J. Org. Chem. 2017, 82, 8342. (c) AlegreRequena, J. V.; Marqués-López, E.; Herrera, R. P. Adv. Synth. Catal. 2016, 358, 1801. (d) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807.
E
DOI: 10.1021/acs.orglett.9b00119 Org. Lett. XXXX, XXX, XXX−XXX
