Lewis acid-catalyzed hydrogenation: B(C6F5) 3-mediated reduction of imines and nitriles with H2

Article abstract of DOI:10.1039/b718598g

The Lewis acid B(C₆F₅)₃ has been found to be an efficient catalyst for the direct hydrogenation of imines and the reductive ring-opening of aziridines with H₂ under mild conditions; addition of a bulky phosphine allows for the reduction of protected nitriles. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718598g

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Lewis acid-catalyzed hydrogenation: B(C6F5)3-mediated reduction of
imines and nitriles with H2wz
Preston A. Chase, Titel Jurca and Douglas W. Stephan*y
Received (in Cambridge, UK) 3rd December 2007, Accepted 15th February 2008
First published as an Advance Article on the web 6th March 2008
DOI: 10.1039/b718598g
The Lewis acid B(C6F5)3 has been found to be an efficient
catalyst for the direct hydrogenation of imines and the reductive
ring-opening of aziridines with H2 under mild conditions; addi-
tion of a bulky phosphine allows for the reduction of protected
nitriles.
amino alkyl carbenes.15 We have recently reported that H2 can
be heterolytically cleaved under ambient conditions by a
reaction with a combination of bulky boranes and phos-
phines.16 Such sterically ‘‘frustrated Lewis pairs’’ (FLPs)
provide unquenched acceptor and donor abilities to the acid
and base, respectively, opening new modes of reactivity.16–18
Such FLPs furnished the first main group system (1a, Scheme
1) that reversibly reacts with H2.19 Moreover, FLP mixtures of
B(C6F5)3 and PR3 have been shown to react with alkenes,20
while compounds 1 have recently been shown to catalyze the
reduction of imines and nitriles under H2.21 Herein, we show
that simple combinations of the commercially available Lewis
Hydrogenation is one of the most utilized and important
reactions in chemistry. Typically, the hydrogenation of organic
substrates using H2 directly is mediated by a transition metal
catalyst.1 Alternatively, main group hydrides such as NaBH4
and LiAlH42 afford stoichiometric reductions, with complemen-
tary chemo- and regioselectivity to metal catalysis. For these
reagents in industrial scale reduction processes, cost, chemical
efficacy and waste disposal are significant concerns. Thus,
catalytic hydrogenations employing transition metal-free cata-
lysts could address the cost and waste remediation issues
associated with main group hydrides, as well as avoid the
expense and potentially toxic nature of precious metal catalysts.
A number of transition metal-free hydrogenation reactions
are known within the realm of organocatalysis.3–7 These
systems do not use H2 directly but rather a surrogate, such
as a Hantzsch ester, as a source of H2. Alternatively, as H2 is
known to react directly with trialkylboranes to give R2BH and
RH, a hydrogenation cycle by successive hydroboration/
hydrogenolysis reactions can be used to effect the reduction
of alkenes. However, the required conditions are rather for-
cing (4200 1C, 15 atm).8–11 Similarly, Berkessel et al. reported
the catalytic reduction of benzophenone using KOtBu/H2,
although the conditions were again quite harsh (180 1C, 50
bar).12 The key to developing main group hydrogenation
catalysis utilizing H2 has been the discovery of main group
compounds that react directly with H2.13 Power and co-work-
ers reported the addition of H2 to a germyne,14 and Bertrand
et al. demonstrated the addition of H2 and NH3 to certain
22
acid B(C6F5)3 with sterically demanding aldimines and
ketimines constitute FLPs that react with H2, affording direct
and catalytic reduction to amines. In addition, aziridines are
shown to undergo reductive ring-opening, while protected
nitriles are also reduced, although in the latter case, addition
of a bulky phosphine Lewis base is required.
The direct hydrogenation of a number of aldimines and
ketimines23,24 catalyzed by B(C6F5)3 is shown in Table 1.w In
accordance with the results of imine hydrogenation with 1, the
bulkier, more basic aldimines (Table 1, E1 and E2) were
hydrogenated more rapidly than an electron poor system
(Table 1, E3) (vide infra). Indeed, reactions E1 and E2
proceeded in similar times to the hydrogenations catalyzed
by 1. Ketimines (Table 1, E4 and E5) are also efficiently
reduced under these conditions, with one exception (Table 1
E6), which does not show any reactivity due to the steric bulk
at the imine C. cis-Triphenylaziridine (Table 1, E7) is reduc-
tively ring opened to racemic N-(1,2-diphenylethyl)aniline.
Notably in E1, reduction continues after the addition of an
extra equivalent of tBuNQCPh(H) to the completed reaction,
demonstrating the living nature of the catalysis.
The above catalysis supports the view that the splitting of
H2 occurs by the action of an FLP, generated by the combina-
tion of the N-Lewis base and B(C6F5)3, in a similar fashion to
that previously described for P-donors.16,19 The ability of an
imine and an amine to act as the basic FLP partner was
established unambiguously as follows. The stoichiometric
Department of Chemistry and Biochemistry, University of Windsor,
401 Sunset Ave. Windsor, Ontario, Canada N9B 3P4. E-mail:
dstephan@chem.utoronto.ca
w Electronic supplementary information (ESI) available: Catalysis
procedures and full experimental data for 2–4. See DOI: 10.1039/
b718598g
z Crystallographic data for 3: space group monoclinic, P21/n, a =
10.2932(10), b = 13.9127(14), c = 20.747(2) A, b = 104.0340(10)1, V
= 2882.4(5) A3, Z = 4, m = 0.159 mmꢀ1, measured reflections =
5088, independent reflections = 3004, parameters = 427, Rint
=
0.0440, R = 0.869, Rw = 0.1228, GOF = 0.996. CCDC 669400. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b718598g
y Current address: Department of Chemistry, University of Toronto,
80 St. George St., Toronto, Ontario, Canada, M5S 3H6.
Scheme 1 Reactivity of H2 with R2PC6F4B(C6F5)2 (R = C6H2Me3
(1a) and tBu (1b)) (note: the reaction is reversible for 1a).
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Table 1 Catalytic hydrogenations by B(C6F5)3 and H2
Entry
E1
Substrate
Time/h
2a
Yield (%) Product
89
Scheme 2 Synthesis of 2–4.
signals (d ꢀ132.9, ꢀ162.7 and ꢀ166.0) are indicative of the
E2
E3
E4
E5
E6
E7
1
99
94
98
94
0
1
formation of the [HB(C6F5)3]ꢀ anion. In the H NMR spec-
trum, signals for the NH (d 10.50) and BH (d 3.85) groups are
readily apparent. The formation and isolation of 4 suggests
that the steric bulk about the iminium cation precludes hydride
transfer from the borate to the iminium carbon, allowing
observation of this mechanistically relevant intermediate.
Thus, the isolation of 2–4 permit the formulation of a
catalytic cycle (Scheme 3). As none of the imines in Table 1,
E1–E6 form an adduct with B(C6F5)3,26 the first step involves
heterolytic H2 splitting by the imine/borane FLP to generate
an iminium hydridoborate ion pair analogous to 4. The
protonated imine is activated to nucleophilic attack of the
iminium carbon by the BH unit of the borohydride, collapsing
the ion pair to an amine–borane adduct. Dissociation of the
B–N bond releases the product amine and regenerates the free
borane to re-enter the cycle. It appears that this latter step of
amine dissociation is rate-determining. This mechanism also
accounts qualitatively for the observed relative rates. The
elongated reaction time necessary in Table 1, E3 is consistent
with the diminished basicity of the imine N slowing down the
H2 cleavage, whereas hydrogenation of more basic imines
proceeds more quickly due to facile reactions with H2. This
mechanism has direct parallels with that proposed by Piers
and co-workers for the B(C6F5)3-catalyzed hydrosilylation of
imines,26 ketones,27,28 enones and silyl enol ethers,29 in which
borane activation of the silane reagent generates a silylium-
activated substrate and [HB(C6F5)3]ꢀ. Similar Lewis acid-
catalyzed main group hydride additions to alkenes,30,31 al-
kynes32 and allenes33 have been described by Gevorgyan et al.
The sluggish reduction of PhSO2NQCPh(H) (Table 1, E3)
stands in contrast to the corresponding reduction of this imine
41
1
8
48
2
95
a
Alternate conditions: 80 1C, 1 atm. H2. Dipp = 2,6-(Me2CH)C6H3.
reaction between imine tBuNQCPh(H) and B(C6F5)3 with H2
at room temperature gave the amine–borane adduct
tBu(PhCH2)NHꢂB(C6F5)3 (2) by reduction of the CQN bond
(Scheme 2). Heating of the adduct (80 1C) for 1 h under
H2 (4–5 atm) resulted in thermal dissociation of the B–N
dative bond and hydrogen splitting to generate the salt
[tBuNH2(CH2Ph)][HB(C6F5)3] (3), which was identified by
NMR spectroscopy. Furthermore, an X-ray crystal structure
of 3 confirmed the proposed formulation (Fig. 1).z The
structural parameters are unexceptional, although it is noted
that the refined NH2 and BH hydrogens display a B–Hꢂ ꢂ ꢂH–N
close contact of 1.87(3) A, consistent with a non-traditional
proton–hydride hydrogen bond25 between one of the NH2
protons and the B–H hydride. Similar protic–hydridic hydro-
gen bonding was also observed in the X-ray crystal structure
of [tBu3PH][HB(C6F5)3].16 In addition, the analogous reaction
of the ketimine DippNQCMe(tBu) with B(C6F5)3 under H2
afforded the ion pair [DippN(H)QCMe(tBu)][HB(C6F5)3]
(4, Scheme 2), as evidenced by multinuclear NMR spectro-
scopy. The 11B NMR (d ꢀ24.4, 1JBH = 80 Hz) and 19F NMR
Fig. 1 ORTEP drawing of 3. 30% probability thermal ellipsoids are
shown; all protons are omitted for clarity, except the BH and NH2
groups.
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nitriles cannot act as proton acceptors to facilitate H2 clea-
vage. However, the addition of phosphine expedites H2 activa-
tion and consequently reduction catalysis. The proposed
mechanism is depicted in Scheme 4. We have previously
reported analogous reductions employing 1b as a catalyst.21
In conclusion, the combination of basic, sterically-hindered
imines and the Lewis acid B(C6F5)3 act as a ‘‘frustrated Lewis
pair’’ to activate H2, which facilitates the catalytic hydrogena-
tion of sterically-hindered imines directly with H2. In addition,
B(C6F5)3 and the additional base P(C6H2Me3)3 were found to
catalyze the reduction of electron poor imines and protected
nitriles.
Scheme 3 Proposed mechanism of the hydrogenation of imines.
Table 2 Catalytic hydrogenations by B(C6F5)3/P(C6H2Me3)3 and H2
Notes and references
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mol% P(C6H2Me3)3 to the present reaction greatly increased
the reaction rate (see Table 2, E8). The rate acceleration was
presumably due to the rapid reaction of P(C6H2Me3)3/
B(C6F5)3 with H2, giving [(C6H2Me3)3PH][HB(C6F5)3],16
which reduces the imine. In a similar fashion, the reaction of
MeCN–B(C6F5)3 or PhCN–B(C6F5)3 with 5 mol% B(C6F5)3
and H2 alone gave no reduction. However, the addition of 5
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Scheme 4 Proposed mechanism of the hydrogenation of protected
nitriles.
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