B(C₆F₅)₃ mediated arene hydrogenation/transannulation of para-methoxyanilines†

Lauren E. Longobardi‡ ^a, Tayseer Mahdi‡ ^a and Douglas W. Stephan *^ab
aDepartment of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
^bChemistry Department-Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

First published on 13th March 2015

---

---

Frustrated Lewis pair (FLP) chemistry has seen considerable growth since its discovery,¹ particularly in the fields of H₂ activation and hydrogenation.² While initial reports of these metal-free hydrogenations were limited to the reduction of imines,³ protected nitriles, and aziridines,⁴ the scope has broadened dramatically to include enamines, silyl enol ethers,⁵ N-heterocycles,⁶ olefins,⁷ poly-arenes,⁸ alkynes,⁹ ketones,¹⁰ and aldehydes.¹¹ In addition to these catalytic reductions, we have reported the stoichiometric FLP reduction of anilines to afford cyclohexylammonium derivatives.¹² These unique main group-mediated aromatic reductions can be extended to include pyridines and other N-heterocycles.¹³ In an effort to further explore the scope of these remarkable metal-free aromatic reductions, herein we report the finding that para-methoxy substituted anilines undergo tandem hydrogenation and intramolecular cyclization with B(C₆F₅)₃, presenting a unique route to 7-azabicyclo[2.2.1]heptane derivatives.

A toluene solution of B(C₆F₅)₃ and the substituted aniline p-CH₃OC₆H₄NH(iPr) was pressurized with H₂ (4 atm) and heated at 115 °C for 48 h. Upon workup, a new white crystalline product 1 was isolated in 87% yield (Table 1, entry 1). Indeed, the ¹H NMR spectrum indicated loss of aromatic resonances, and showed a diagnostic broad singlet at 4.29 ppm with the corresponding ¹³C{¹H} resonance at 64.7 ppm. These data inferred the presence of two equivalent bridgehead CH groups of the bicyclic ammonium cation. The ¹¹B NMR spectrum revealed a doublet (J = 88 Hz) at −25 ppm, and resonances at −134, −164, and −167 ppm were observed in the ¹⁹F NMR spectrum, consistent with the presence of the [HB(C₆F₅)₃] anion. An X-ray diffraction study confirmed that 1 was indeed the bicyclic product isolated as [C₆H₁₀NH(iPr)][HB(C₆F₅)₃] (Fig. 1a).

---

In a similar fashion, the reaction of p-CH₃OC₆H₄NHCH(CH₃)Ph with B(C₆F₅)₃ under H₂ at 115 °C afforded the product [C₆H₁₀NHCH(CH₃)Ph][HB(C₆F₅)₃]2 in 51% isolated yield (Table 1, entry 2). In this case, the ¹H NMR spectrum showed two inequivalent doublet of doublets at 4.47 and 3.74 ppm that are attributable to the bridgehead protons of the bicyclic cation, with corresponding ¹³C{¹H} NMR resonances observed at 65.2 and 64.7 ppm, respectively. In addition, the ¹¹B and ¹⁹F NMR spectra were consistent with the presence of [HB(C₆F₅)₃] as the counter anion and the formulation was also confirmed by single crystal X-ray crystallography (Fig. 1b). Compound 2 was also isolated in 63% yield from the corresponding reaction of the imine p-CH₃OC₆H₄NC(CH₃)Ph (Table 1, entry 2).

Under analogous conditions, the bis-aryl substrate p-CH₃OC₆H₄NHPh yielded the bicyclic product 3 in 40% isolated yield (Table 1, entry 3). ¹H NMR analysis showed that both N-bound aromatic rings were reduced, resulting in a cyclohexyl-substituted 7-aza-bicyclo[2.2.1]heptane ammonium product [C₆H₁₀NHCy][HB(C₆F₅)₃]. This formulation was also confirmed through a single crystal X-Ray diffraction study (Fig. 1c). The same product was isolated when starting from the imine substrate CH₃OC₆H₄NCy in 56% yield (Table 1, entry 3).

The ortho- and meta-methoxy substituted amines CH₃OC₆H₄NHCH(CH₃)Ph were independently reacted with B(C₆F₅)₃ and H₂ using the above protocol. In both cases, while hydrogenation of the N-bound phenyl group was observed, no transannular attack followed. The ortho-substituted amine gave a mixture of cis and trans-[o-CH₃OC₆H₁₀NH₂CH(CH₃)Ph][HB(C₆F₅)₃] 4 in 92% isolated yield while the meta precursor gave rise to C–O bond cleavage yielding [C₆H₁₁NH₂CH(CH₃)Ph][HB(C₆F₅)₃] 5 in 65% isolated yield (Scheme 1). Similarly, replacement of para-methoxy substituent on the aromatic ring by ethoxy and phenoxy substituents in the precursor anilines did not lead to bicyclic products. In these cases, only hydrogenation of the N-bound aromatic ring was observed affording the cyclohexylammonium salts [p-EtOC₆H₁₀NH₂(iPr)][HB(C₆F₅)₃] 6 and [p-PhOC₆H₁₀NH₂(iPr)] [HB(C₆F₅)₃] 7, respectively (Scheme 1).

The mechanism through which these bicyclic products were formed was further investigated. To this end, a toluene solution of the independently-synthesized ammonium-borate salt [trans-4-CH₃OC₆H₁₀NH₂CH(CH₃)Ph][B(C₆F₅)₄] 8a was heated at 110 °C (Scheme 2, top). No reaction was evidenced by ¹H, ¹¹B and ¹⁹F NMR spectroscopy. However, addition of [trans-4-CH₃OC₆H₁₀NH₂CH(CH₃)Ph][HB(C₆F₅)₃] 8b at 110 °C prompted release of H₂ as evidenced by the ¹H NMR signal at 4.5 ppm. Furthermore, after heating at 110 °C for 12 h compound 1 was isolated (Scheme 2, top). This observation infers that ring closing yielding the 7-azabicyclo[2.2.1]heptane ammonium cation does not proceed by intra- or intermolecular protonation of the methoxy group but rather that transannular attack proceeds via intramolecular nucleophilic attack of the para-carbon by free amine, facilitated by borane capture of the methoxide fragment. To further support this proposed mechanism, the independently synthesized amine trans-4-CH₃OC₆H₁₀NH(iPr) was treated with an equivalent of B(C₆F₅)₃ in the absence of H₂. Interestingly, after heating for 2 h, the reaction resulted in quantitative formation of compound 1 with a borane-methoxide anion [C₆H₁₀NH(iPr)] [CH₃OB(C₆F₅)₃] 1a (Scheme 2, bottom). ¹H NMR spectra showed the diagnostic resonances for the bridgehead CH protons at 4.13 ppm consistent with the formation of the 7-azabicyclo[2.2.1]heptane ammonium cation. A sharp ¹¹B resonance at −2.42 ppm and ¹⁹F resonances at −135, −162 and −166 ppm were consistent with the formation of the borane-methoxide anion [CH₃OB(C₆F₅)₃]. This formulation of 1a was further confirmed by an X-ray diffraction study (Fig. 2).

While heating of 1a for 2 h at 110 °C in the absence of H₂ resulted in amine liberation and rapid degradation of the borane to CH₃OB(C₆F₅)₂ and C₆F₅H, in the presence of H₂1a is transformed to 1 with the liberation of CH₃OH (Scheme 2, bottom). This observation infers that the ammonium cation protonates the methoxide bound to boron, liberating methanol and regenerating B(C₆F₅)₃, which undergoes FLP type H₂ activation with the amine (Scheme 2, bottom). ¹H NMR spectroscopy confirmed the presence of methanol as a reaction product (see ESI†). Interestingly, a similar protonation pathway has been previously proposed by Ashley and O'Hare¹⁴ in the stoichiometric hydrogenation of CO₂ using 2,2,6,6-tetramethylpiperidine and B(C₆F₅)₃. Additionally, Ashley et al.¹¹ have recently proposed that metal-free carbonyl reduction of aldehydes also proceed through protonation of B(C₆F₅)₃-alkoxide bonds.

One can also envision the combination of [CH₃OB(C₆F₅)₃]⁻ and B(C₆F₅)₃ acting as an FLP to activate H₂. To probe this, a toluene solution of [NEt₄][CH₃OB(C₆F₅)₃] and 5 mol% B(C₆F₅)₃ was exposed to H₂ (4 atm) at 110 °C. After heating for 2 h, the ¹H, ¹¹B and ¹⁹F NMR data revealed complete consumption of the [CH₃OB(C₆F₅)₃] anion and the emergence of [NEt₄][HB(C₆F₅)₃] and CH₃OH (see ESI†). This latter mechanism provides an alternative path to the anion of 1.

Regardless of the mechanism of methanol liberation, the cleavage of the B–O bond in this case stands in contrast to previous work from our group⁴ and the groups of Erker,¹⁵ Repo and Rieger¹⁶ where robust B–O bonded products are derived from reactions of oxygen based substrates and FLPs. Indeed, in our own efforts to effect aliphatic ketone reduction in toluene, borinic esters were obtained from the stoichiometric combination of ketones and B(C₆F₅)₃ under H₂.¹⁷ It is interesting however that ketone hydrogenation to alcohol has been recently achieved by both our group and that of Ashley employing ethereal solvents. In these cases, hydrogen bonding of the protonated ketone with the solvent, preclude protonation of the B–C bond of the generated [HB(C₆F₅)₃]. In a similar sense, the intermediate ammonium cation of 1a selectively protonates the oxygen of the anion en route to 1.

Collectively these data infer that compounds 1–3 are formed by initial hydrogenation of the aniline arene ring affording the cyclohexylamine. Although the amine and borane can activation H₂ to give the ammonium salt, at elevated temperatures this is reversible allowing the borane to activate the methoxy substituent and induce transannulation (Scheme 3). Subsequent conversion of the generated methoxy-borate anion to the hydridoborate anion proceeds under H₂.

The formation of 1, 1a, 2 and 3 represent, to the best of our knowledge, the first examples of a one-pot synthesis of 7-azabicyclo[2.2.1]heptane derivatives. Traditional synthetic methods to 7-azabicyclo[2.2.1]heptanes include Diels–Alder cycloaddition of pyrroles and alkenes or alkynes, or multi-step intramolecular cyclizations of 4-aminocyclohexane derivatives.¹⁸ These traditional methods are typically low-yielding or require several protecting group manipulations.

Conclusions

In summary, heating the combination of para-methoxy substituted anilines and B(C₆F₅)₃ under H₂ provides a one-pot tandem arene hydrogenation-transannular ring closure reaction affording 7-azabicyclo[2.2.1]heptane ammonium salts. Although the oxophilic B(C₆F₅)₃ facilitates this reaction by abstracting methoxide, subsequent reaction with H₂ affords methanol and the hydridoborate anion. Research is continuing to design and develop application of this and other tandem FLP-mediated transformations.

NSERC of Canada is thanked for financial support. DWS is grateful for the award of a Canada Research Chair. T.M. and L.E.L. are grateful for the award of NSERC postgraduate scholarships. L.E.L. also thanks the Walter C. Sumner foundation for a fellowship.

Notes and references

1. D. W. Stephan and G. Erker, Angew. Chem., Int. Ed., 2010, 49, 46–76 CrossRef CAS PubMed .
2. (a) D. W. Stephan, Org. Biomol. Chem., 2012, 10, 5740–5746 RSC ; (b) D. W. Stephan and G. Erker, Top. Curr. Chem., 2013, 332, 85–110 CrossRef CAS ; (c) D. W. Stephan, S. Greenberg, T. W. Graham, P. Chase, J. J. Hastie, S. J. Geier, J. M. Farrell, C. C. Brown, Z. M. Heiden, G. C. Welch and M. Ullrich, Inorg. Chem., 2011, 50, 12338–12348 CrossRef CAS PubMed .
3. Y. Liu and H. Du, J. Am. Chem. Soc., 2013, 135, 6810–6813 CrossRef CAS PubMed .
4. P. A. Chase, G. C. Welch, T. Jurca and D. W. Stephan, Angew. Chem., Int. Ed., 2007, 46, 8050–8053 CrossRef CAS PubMed .
5. (a) H. D. Wang, R. Fröhlich, G. Kehr and G. Erker, Chem. Commun., 2008, 5966–5968 RSC ; (b) S. Wei and H. Du, J. Am. Chem. Soc., 2014, 136, 12261–12264 CrossRef CAS PubMed .
6. (a) S. J. Geier, P. A. Chase and D. W. Stephan, Chem. Commun., 2010, 46, 4884–4886 RSC ; (b) Y. Liu and H. Du, J. Am. Chem. Soc., 2013, 135, 12968–12971 CrossRef CAS PubMed .
7. (a) L. Greb, C. G. Daniliuc, K. Bergander and J. Paradies, Angew. Chem., Int. Ed., 2013, 52, 5876–5879 CrossRef CAS PubMed ; (b) L. Greb, P. Oña-Burgos, B. Schirmer, S. Grimme, D. W. Stephan and J. Paradies, Angew. Chem., Int. Ed., 2012, 51, 10164–10168 CrossRef CAS PubMed ; (c) L. Greb, S. Tussing, B. Schirmer, P. Oña-Burgos, K. Kaupmees, M. Lõkov, I. Leito, S. Grimme and J. Paradies, Chem. Sci., 2013, 4, 2788–2796 RSC .
8. Y. Segawa and D. W. Stephan, Chem. Commun., 2012, 48, 11963–11965 RSC .
9. K. Chernichenko, Á. Madarász, I. Pápai, M. Nieger, M. Leskelä and T. Repo, Nat. Chem., 2013, 5, 718–723 CrossRef CAS PubMed .
10. T. Mahdi and D. W. Stephan, J. Am. Chem. Soc., 2014, 136, 15809–15812 CrossRef CAS PubMed .
11. D. J. Scott, M. J. Fuchter and A. E. Ashley, J. Am. Chem. Soc., 2014, 136, 15813–15816 CrossRef CAS PubMed .
12. T. Mahdi, Z. M. Heiden, S. Grimme and D. W. Stephan, J. Am. Chem. Soc., 2012, 134, 4088–4091 CrossRef CAS PubMed .
13. T. Mahdi, J. N. del Castillo and D. W. Stephan, Organometallics, 2013, 32, 1971–1978 CrossRef CAS .
14. A. E. Ashley, A. L. Thompson and D. O'Hare, Angew. Chem., Int. Ed., 2009, 48, 9839–9843 CrossRef CAS PubMed .
15. (a) P. Spies, G. Erker, G. Kehr, K. Bergander, R. Fröhlich, S. Grimme and D. W. Stephan, Chem. Commun., 2007, 5072–5074 RSC ; (b) B.-H. Xu, R. Yanez, H. Nakatsuka, M. Kitamura, R. Fröhlich, G. Kehr and G. Erker, Chem. – Asian J., 2012, 7, 1347–1356 CrossRef CAS PubMed .
16. (a) V. Sumerin, F. Schulz, M. Nieger, M. Leskelä, T. Repo and B. Rieger, Angew. Chem., Int. Ed., 2008, 47, 6001–6003 CrossRef CAS PubMed ; (b) M. Lindqvist, N. Sarnela, V. Sumerin, K. Chernichenko, M. Leskelä and T. Repo, Dalton Trans., 2012, 41, 4310–4312 RSC .
17. L. E. Longobardi, C. Tang and D. W. Stephan, Dalton Trans., 2014, 43, 15723–15726 RSC .
18. Z. Chen and M. L. Trudell, Chem. Rev., 1996, 96, 1179 CrossRef CAS PubMed .

---

Footnotes

† Electronic supplementary information (ESI) available: Spectroscopic and preparative details have been deposited. Crystallographic data have been deposited see: CCDC 1046629-1046633. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5dt00921a

‡ These authors contributed equally and should be both deemed “first author”.

This journal is © The Royal Society of Chemistry 2015