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

Article abstract of DOI:10.1039/c5dt00921a

The stoichiometric reaction of para-methoxyanilines and B(C₆F₅)₃ under H₂ results in reduction of the N-bound phenyl ring(s), and subsequent transannular ring closure with elimination of methanol, affording the respective 7-azabicyclo[2.2.1]heptane derivatives.

Full text of DOI:10.1039/c5dt00921a

Dalton
Transactions
COMMUNICATION
B(C6F5)3 mediated arene hydrogenation/
transannulation of para-methoxyanilines†
Lauren E. Longobardi,‡a Tayseer Mahdi‡a and Douglas W. Stephan*a,b
Cite this: Dalton Trans., 2015, 44,
7114
Received 4th February 2015,
Accepted 9th March 2015
DOI: 10.1039/c5dt00921a
www.rsc.org/dalton
The stoichiometric reaction of para-methoxyanilines and B(C6F5)3
under H2 results in reduction of the N-bound phenyl ring(s),
and subsequent transannular ring closure with elimination of
methanol, affording the respective 7-azabicyclo[2.2.1]heptane
derivatives.
Table 1 Hydrogenation and transannulation reactions of para-methoxy-
anilines
Frustrated Lewis pair (FLP) chemistry has seen considerable
growth since its discovery,1 particularly in the fields of H2 acti-
vation 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 hydro-
genation and intramolecular cyclization with B(C6F5)3, present-
ing 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 crystal-
line product 1 was isolated in 87% yield (Table 1, entry 1).
Entry
1
Starting material
Product
Isolated yield
1: 87%
2
3
2: 51% (N–C)
63% (NvC)
3: 36% (Ph)
63% (Cy)
1
Indeed, the H NMR spectrum indicated loss of aromatic reso-
nances, 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 spec-
trum revealed a doublet (J = 88 Hz) at −25 ppm, and reson-
ances 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).
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
†Electronic supplementary information (ESI) available: Spectroscopic and pre-
parative 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”.
7114 | Dalton Trans., 2015, 44, 7114–7117
This journal is © The Royal Society of Chemistry 2015

Dalton Transactions
Communication
Scheme 1 Synthesis of compounds 4–7.
[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 hydro-
genation of the N-bound aromatic ring was observed affording
Fig. 1 POV-ray depiction of the cations of (a) 1, (b) 2, (c) 3 (N, blue; H,
gray; C, black).
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
the
cyclohexylammonium
salts
[p-EtOC6H10NH2(iPr)]-
1
(Table 1, entry 2). In this case, the H 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
[HB(C6F5)3] 6 and [p-PhOC6H10NH2(iPr)] [HB(C6F5)3] 7, respect-
ively (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
at 65.2 and 64.7 ppm, respectively. In addition, the 11B and 19
F
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-CH3OC6H4NvC(CH3)Ph (Table 1, entry 2).
Under analogous conditions, the bis-aryl substrate
p-CH3OC6H4NHPh yielded the bicyclic product 3 in 40% iso-
lated 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 CH3OC6H4NvCy 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]-
1
prompted release of H2 as evidenced by the H NMR signal at
4.5 ppm. Furthermore, after heating at 110 °C for 12 h com-
pound 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 intermolecu-
lar protonation of the methoxy group but rather that trans-
annular 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 con-
This journal is © The Royal Society of Chemistry 2015
Dalton Trans., 2015, 44, 7114–7117 | 7115

Communication
Dalton Transactions
troscopy 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-tetramethyl-
piperidine and B(C6F5)3. Additionally, Ashley et al.11 have
recently proposed that metal-free carbonyl reduction of alde-
hydes 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 pre-
vious 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 interest-
ing however that ketone hydrogenation to alcohol has been
recently achieved by both our group and that of Ashley employ-
ing 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 proto-
nates the oxygen of the anion en route to 1.
Scheme 2 Reactions
[XB(C6F5)3] (X = C6F5 8a; H 8b) (top) and trans-4-CH3OC6H10NHiPr
(bottom).
of
trans-[4-CH3OC6H10NH2CH(CH3)Ph]-
sistent 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).
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 ele-
vated temperatures this is reversible allowing the borane to
activate the methoxy substituent and induce transannulation
(Scheme 3). Subsequent conversion of the generated
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 H2 1a
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 acti-
vation with the amine (Scheme 2, bottom). 1H NMR spec-
Fig. 2 POV-ray depiction of 1a. (B, yellow-green; O, red; F, deep pink;
Scheme 3 Overall proposed mechanism for the formation of 7-azabi-
N, blue; H, gray; C, black).
cyclo[2.2.1] heptane derivatives.
7116 | Dalton Trans., 2015, 44, 7114–7117
This journal is © The Royal Society of Chemistry 2015

Dalton Transactions
Communication
methoxy-borate anion to the hydridoborate anion proceeds
under H2.
4 P. A. Chase, G. C. Welch, T. Jurca and D. W. Stephan,
Angew. Chem., Int. Ed., 2007, 46, 8050–8053.
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-azabi-
cyclo[2.2.1]heptane derivatives. Traditional synthetic methods
to 7-azabicyclo[2.2.1]heptanes include Diels–Alder cyclo-
addition of pyrroles and alkenes or alkynes, or multi-step
intramolecular cyclizations of 4-aminocyclohexane deriva-
tives.18 These traditional methods are typically low-yielding or
require several protecting group manipulations.
5 (a) H. D. Wang, R. Fröhlich, G. Kehr and G. Erker, Chem.
Commun., 2008, 5966–5968; (b) S. Wei and H. Du, J. Am.
Chem. Soc., 2014, 136, 12261–12264.
6 (a) S. J. Geier, P. A. Chase and D. W. Stephan, Chem.
Commun., 2010, 46, 4884–4886; (b) Y. Liu and H. Du, J. Am.
Chem. Soc., 2013, 135, 12968–12971.
7 (a) L. Greb, C. G. Daniliuc, K. Bergander and J. Paradies,
Angew. Chem., Int. Ed., 2013, 52, 5876–5879; (b) L. Greb,
P. Oña-Burgos, B. Schirmer, S. Grimme, D. W. Stephan and
J. Paradies, Angew. Chem., Int. Ed., 2012, 51, 10164–10168;
(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.
Conclusions
In summary, heating the combination of para-methoxy substi-
tuted anilines and B(C6F5)3 under H2 provides a one-pot
tandem arene hydrogenation-transannular ring closure reac-
tion affording 7-azabicyclo[2.2.1]heptane ammonium salts.
Although the oxophilic B(C6F5)3 facilitates this reaction by
8 Y. Segawa and D. W. Stephan, Chem. Commun., 2012, 48,
11963–11965.
9 K. Chernichenko, Á. Madarász, I. Pápai, M. Nieger,
M. Leskelä and T. Repo, Nat. Chem., 2013, 5, 718–723.
abstracting methoxide, subsequent reaction with H2 affords 10 T. Mahdi and D. W. Stephan, J. Am. Chem. Soc., 2014, 136,
methanol and the hydridoborate anion. Research is continuing 15809–15812.
to design and develop application of this and other tandem 11 D. J. Scott, M. J. Fuchter and A. E. Ashley, J. Am. Chem. Soc.,
FLP-mediated transformations. 2014, 136, 15813–15816.
NSERC of Canada is thanked for financial support. DWS 12 T. Mahdi, Z. M. Heiden, S. Grimme and D. W. Stephan,
is grateful for the award of a Canada Research Chair. T.M. and J. Am. Chem. Soc., 2012, 134, 4088–4091.
L.E.L. are grateful for the award of NSERC postgraduate scho- 13 T. Mahdi, J. N. del Castillo and D. W. Stephan, Organo-
larships. L.E.L. also thanks the Walter C. Sumner foundation
for a fellowship.
metallics, 2013, 32, 1971–1978.
14 A. E. Ashley, A. L. Thompson and D. O’Hare, Angew. Chem.,
Int. Ed., 2009, 48, 9839–9843.
15 (a) P. Spies, G. Erker, G. Kehr, K. Bergander, R. Fröhlich,
S. Grimme and D. W. Stephan, Chem. Commun., 2007,
5072–5074; (b) B.-H. Xu, R. Yanez, H. Nakatsuka,
M. Kitamura, R. Fröhlich, G. Kehr and G. Erker, Chem. –
Asian J., 2012, 7, 1347–1356.
Notes and references
1 D. W. Stephan and G. Erker, Angew. Chem., Int. Ed., 2010,
49, 46–76.
2 (a) D. W. Stephan, Org. Biomol. Chem., 2012, 10, 5740–5746; 16 (a) V. Sumerin, F. Schulz, M. Nieger, M. Leskelä, T. Repo
(b) D. W. Stephan and G. Erker, Top. Curr. Chem., 2013,
332, 85–110; (c) D. W. Stephan, S. Greenberg,
T. W. Graham, P. Chase, J. J. Hastie, S. J. Geier,
and B. Rieger, Angew. Chem., Int. Ed., 2008, 47, 6001–6003;
(b) M. Lindqvist, N. Sarnela, V. Sumerin, K. Chernichenko,
M. Leskelä and T. Repo, Dalton Trans., 2012, 41, 4310–4312.
J. M. Farrell, C. C. Brown, Z. M. Heiden, G. C. Welch and 17 L. E. Longobardi, C. Tang and D. W. Stephan, Dalton
M. Ullrich, Inorg. Chem., 2011, 50, 12338–12348.
Trans., 2014, 43, 15723–15726.
3 Y. Liu and H. Du, J. Am. Chem. Soc., 2013, 135, 6810–6813.
18 Z. Chen and M. L. Trudell, Chem. Rev., 1996, 96, 1179.
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