Metal-free aromatic hydrogenation: Aniline to cyclohexyl-amine derivatives

Article abstract of DOI:10.1021/ja300228a

Hydrogenation of the N-bound phenyl rings of amines, imines, and aziridine is achieved in the presence of H₂ and B(C₆F ₅)₃, affording the corresponding N-cyclohexylammonium hydridoborate salts.

Full text of DOI:10.1021/ja300228a

Communication
pubs.acs.org/JACS
Metal-Free Aromatic Hydrogenation: Aniline to Cyclohexyl-amine
Derivatives
Tayseer Mahdi,† Zachariah M. Heiden,† Stefan Grimme,*,‡ and Douglas W. Stephan*,†
†
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6
‡ Mulliken Center for Theoretical Chemistry, Institut fuer Physikalische und Theoretische Chemie, Universitaet Bonn, Beringstrasse
4, D-53115 Bonn, Germany
S
* Supporting Information
tions are stoichiometric, these reactions represent rare examples
of homogeneous aromatic reductions that are metal-free and
performed under comparatively mild conditions.
ABSTRACT: Hydrogenation of the N-bound phenyl
rings of amines, imines, and aziridine is achieved in the
presence of H2 and B(C6F5)3, affording the corresponding
N-cyclohexylammonium hydridoborate salts.
The combination of the amine tBuNHPh with an equivalent
of B(C6F5)3 in C6D5Br or pentane solutions initially results in
no apparent reaction. However, following the exposure of this
solution to H2 (4 atm.) at 25 °C, the gradual precipitation of a
solid was observed. After standing for 12 h, the white product 1
can be isolated in 82% yield. NMR data for 1 obtained in
C6D5Br revealed a 11B NMR resonance at −24.0 ppm
exhibiting one bond B−H coupling of 78 Hz.15 These data,
together with the resonances in the 19F NMR observed at
−133.5, −161.3, and −165.0 ppm were consistent with the
ydrogenation is a conceptually simple reaction in which
H
molecular hydrogen is added to an unsaturated organic
molecule. Such reactions are used in a diverse range of
applications, including the upgrading of crude oil paper
production and the generation of commodity and fine
chemicals for the food, agricultural, and pharmaceutical
industries.1 The atom economy and cleanliness of the
transformation makes hydrogenation “arguably the most
important catalytic method in synthetic organic chemistry
both on the laboratory and the production scale”.2 It was early
in the 20th century when Sabatier discovered that amorphous
metals could catalyze the hydrogenation of olefins. In the
1960s, the advent of organometallic chemistry led Wilkinson
and others to uncover homogeneous ruthenium and rhodium
based hydrogenation catalysts3 that operate via oxidative
addition of H2 to transition metal centers.4 Further advance-
ments in hydrogenations came in the 1980s with the
development of asymmetric hydrogenation catalysts by Noyori5
and Knowles.6
11a
1
presence of the anion [HB(C6F5)3]−. The H NMR data
showed a broad resonance at 7.15 ppm attributable to an NH2
fragment, integrating to two protons, as well as the signals
assignable to the phenyl and tbutyl groups. These data were
consistent with the formulation of 1 as [tBuNH2Ph][HB-
(C6F5)3].
In contrast, repetition of the above reaction in toluene with
heating to 110 °C for 96 h led to the formation of a new
product 2. Subsequent workup and characterization by NMR
spectroscopy revealed the presence of the anion [HB(C6F5)3]−.
1
The H NMR data displayed a broad resonance at 5.07 ppm
attributed to an NH2 moiety while aromatic resonances were
no longer observed. Instead, multiplets at 2.72, 1.55, 1.45, 1.31,
1.17, and 0.90 ppm, along with a sharp singlet at 0.91 ppm,
were observed. These data were consistent with the identity of
2 as [tBuNH2Cy][HB(C6F5)3] (Scheme 1).
Despite these advancements in hydrogenation catalysis, over
the last century, catalytic reduction of aromatic rings remains
challenging. This is typically attributed to the inherent stability
resulting from aromaticity. While a tantalum-based homoge-
neous catalyst system has been described by Rothwell et al.,7 a
majority of catalysts used for hydrogenation of aromatic
substrates are heterogeneous cobalt or nickel catalysts on
oxide supports, used at temperatures greater than 200 °C and
1
Monitoring the reaction by H NMR spectroscopy showed
the gradual growth of methylene resonances with the
corresponding disappearance of the aromatic signals. After 48
h, the cyclohexylamine product constituted approximately 81%
of the reduced product in solution although it was obtained in
30% isolated yield.
H pressures on the order of 200 atm.8 Koster and co-workers
̈
2
In an analogous fashion, treatment of iPrNHPh with an
equivalent of B(C6F5)3 in toluene under H2 (4 atm) at 110 °C
for 36 h resulted in reduction of the aromatic ring affording the
salt [iPrNH2Cy][HB(C6F5)3] 3 in 93% yield. Similar treatment
of PhCyNH or Ph2NH afforded [Cy2NH2][HB(C6F5)3] 4 in
yields of 88 and 65%, respectively. In addition to the NMR
spectroscopy data, the formulations of 3 and 4 were
unambiguously confirmed crystallographically (Figure 1).16
have demonstrated that hydroboration and subsequent hydro-
genolysis effects the conversion of naphthalenes to tetralins9
and anthracenes to coronenes10 at 170−200 °C and 25−100
atm of hydrogen. More recently, we have reported metal-free
systems capable of reversible heterolytic activation of H2.11 On
the basis of these “frustrated Lewis pairs” (FLPs),12 we12b,13
and others,14 have developed metal-free hydrogenation catalysts
for a variety of imines, enamines, silylenol ethers, diimines, and
N-heterocyclic compounds. In this communication, we describe
metal-free hydrogenation of N-bound aromatic rings to the
corresponding cyclohexylamine derivatives. While these reduc-
Received: January 14, 2012
Published: February 15, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of Compounds 1 and 2
Table 1. Reductions of N-Phenyl Substrates to N-
Cyclohexylammonium Salts
Figure 1. POV-ray drawings of (left) 3 and (right) 4. C, black; F, pink;
N, blue-green; B, yellow-green; H, gray. Hydrogen atoms except for
NH and BH groups are omitted for clarity.
Additional substrates explored in analogous reductions
included, iPrNH(2-MeC6H4), iPrNH(4-RC6H4) (R = Me,
OMe), iPrNH(3-MeC6H4), and iPrNH(3,5-Me2C6H3). afford-
ing the arene-reduced products [iPrNH2(2-MeC6H10)][HB-
(C6F5)3] 5, [iPrNH2(4-RC6H10)][HB(C6F5)3] (R = Me 6,
OMe 7), [iPrNH2(3-MeC6H10)][HB(C6F5)3] 8, and
[iPrNH2(3,5-Me2C6H9)][HB(C6F5)3] 9 in yields of 77, 73,
61, 82, and 48%, respectively (Table 1). In cases where
reduction affords a chiral center, mixtures of diastereomers
were observed.
We have previously reported the catalytic hydrogenative ring-
opening of cis-1,2,3-triphenylazirdine using 5 mol % B(C6F5)3
to give PhNHCHPhCH2Ph.13d However, employing 1 equiv of
B(C6F5)3 at 110 °C for 96 h resulted in the reduction of the N-
bound phenyl ring yielding the salt [CyNH2CHPhCH2Ph]-
theoretical level denoted as PWP95-D3/def2-TZVPP//TPSS-
D3/def-TZVP provides reaction energies with an estimated
accuracy of about 1−2 kcal/mol. Solvation effects of toluene
were considered using the COSMO-RS continuum solvation
model (for details see Supporting Information). The optimized
structures, computed relative energies, free enthalpies G (298
K) of 1 and 2, important intermediates and the H2-addition
transition state (TS) are shown in Figure 2. The theoretical
results support a mechanism initiated by the dissociation of the
weak amine-borane adducts. FLP activation of H2 yields the salt
1 which is computed to be 9.7 kcal/mol lower in energy but the
free enthalpy difference is close to zero. Hence, under
equilibrium conditions, it can be considered as a resting state
of the reaction. Rotation of the amine such that the arene para-
position is oriented towards the boron atom afford a van der
Waals complex (Figure 2, vdW-complex) which benefits from
significant pi-stacking stabilization. Similar to the reaction of
classical FLPs,18 this pairing can effect H2-splitting in the
’cavity’ formed by the borane and the arene ring with a
relatively low energy barrier of 8.7 kcal/mol. The effective free
activation enthalpy (i.e., relative to the resting state) is
computed to be 21.2 kcal/mol which is in agreement with
the experimentally observed reactivity at elevated temperatures.
1
[HB(C6F5)3] 10. The H NMR data were in keeping with the
formulation of the cation with the notable presence of
resonances at 5.88 and 4.61 ppm, ascribed to the NH2 and
methine fragments, respectively, in addition to the phenyl,
cyclohexyl, methylene, and BH signals. 19F and 11B NMR
spectra displayed the characteristic resonances of the anion
[HB(C6F5)3]−.
Reduction of the imine PhNCMePh, to the corresponding
amine, has also been previously reported to occur upon
exposure of the imine to H2 using 10 mol % B(C6F5)3.13c
However, on heating the substrate to 110 °C for 96 h under H2
(4 atm) and in the presence of 1 equiv of B(C6F5)3, reduction
of the N-bound aromatic ring is also observed, affording the
species[CyNH2PhCH(Me)][HB(C6F5)3] 11. The reduction of
(Me2CN)2C6H4 was observed on heating for 72 h, in the
presence of 2 equiv of B(C6F5)3, yielding 64% of the product
[(iPrNH2)2C6H10][HB(C6F5)3]2 12 (Table 1).
The mechanism of these reductions is the subject of ongoing
study. To this end, quantum chemical calculations were
performed at the dispersion-corrected meta-double hybrid
level (PW6P95 functional), employing large triple-ζ type
basis sets, and TPSS-D3 optimized geometries.17 This final
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Communication
to yield the corresponding cyclohexylamine derivatives under
mild conditions. In these reactions, the borane mediates uptake
of 4 equiv of H2, terminating with a final FLP activation of H2
affording the cyclohexylammonium salts. These results
represent the first stoichiometric, homogeneous, metal-free
hydrogenations of aromatic rings. We are actively studying a
broadening range of substrates for arene hydrogenations and
the application of this new methodology in targeted syntheses.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental, computational, and crystallographic data are
deposited. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
dstephan@chem.utoronto.ca
■
Figure 2. Optimized structures, energies (in parentheses), and free
enthalpies G (298K) are relative to FLP + H2 (all data are in kcal/mol)
for the first step of the reaction mechanism. Computations refer to the
PWP95-D3/def2-TZVPP//TPSS-D3/def-TZVP level of theory (for
details see Supporting Information).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.W.S. gratefully acknowledges the financial support of NSERC
of Canada, the award of a Canada Research Chair and a Killam
Research Fellowship. T.M. is grateful for the support of an
NSERC Scholarship.
The H−H distance in the TS structure is about 0.97 Å,
significantly longer than that seen for P/B based FLPs (0.78−
0.8 Å) indicating a somewhat ’later’ TS. The corresponding H−
H and C−H covalent Wiberg bond orders are 0.33 and 0.41 Å,
respectively, while the B−H bond order is 0.63 Å, indicating
approximately half-broken and half-formed bonds in the TS.
The transient intermediate product (Figure 2, CH-intermedi-
ate) of the reaction is an ion pair of [tBuNHC6H6][HB-
(C6F5)3] showing a completely rehybridized carbon atom in the
para-position and an almost planar NHRC unit in the cation.
This species has similar energy and free enthalpy to the vdW-
complex. While the anticipated complexity of subsequent
hydrogenation steps to 2 has limited further computations, it is
clear that access to the arene−B(C6F5)3 vdW-complex is key in
initiating the arene reduction.
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Cyclohexylammonium Salts
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