Metal-free catalytic hydrogenation

Article abstract of DOI:10.1002/anie.200702908

(Chemical Equation Presented) Phosphonium borates of the form R ₂PH-(C₆F₄)BH(C₆F₅) ₂ are shown to be metalfree hydrogenation catalysts (see scheme) that effect reduction of sterically hindered imines and aziridines, as well as B(C₆F₅)₃-protected unhindered imines and nitriles, at relatively low H₂ pressures and temperatures.

Full text of DOI:10.1002/anie.200702908

Communications
DOI: 10.1002/anie.200702908
H2 Activation
Metal-Free Catalytic Hydrogenation**
Preston A. Chase, Gregory C. Welch, Titel Jurca, and Douglas W. Stephan*
Hydrogenation is the addition of hydrogen to unsaturated
organic compounds. Such reactions are used for the produc-
tion of a myriad of chemical products worldwide, from large-
scale operations including the upgrading of crude oil and the
production of bulk commodity materials to the synthesis of a
variety of fine chemicals used in the food, agricultural, and
pharmaceutical industries.[1] The process of hydrogen addition
to unsaturated precursors is mediated by either homogeneous
or heterogeneous transition-metal-based catalysts.[1] Blaser et
al.[2] place the importance of this chemistry in context, stating
that “hydrogen is the cleanest reducing agent and hydro-
genation is arguably the most important catalytic method in
synthetic organic chemistry both on the laboratory and the
production scale”. Historically, hydrogenation began with
Sabatierꢀs 1897 discovery that traces of nickel could mediate
the catalytic hydrogenation of olefins and culminated in a
share of the 1912 Nobel Prize with Grignard. In the 1960s, the
advent of organometallic chemistry gave rise to homogeneous
transition-metal-based hydrogenation catalysts for a variety
of substrates. The operation of these catalysts hinges on the
key step of oxidative addition of hydrogen.[3] More recently,
transition-metal systems that effect heterolytic cleavage of
hydrogen at a metal center have been uncovered. In these
cases, a metal hydride is formed with concurrent protonation
of an amido ligand.[4,5]
adducts.[13] Mixtures of “frustrated” phosphines and boranes
can heterolytically cleave H2, forming phosphonium borates
of the form [R3PH][BHR’3].[14] In very recent work, Bertrand
and co-workers have demonstrated that selected carbenes
exhibit transition-metal-like reactivity and cleave hydrogen
or ammonia to effect a formal oxidative addition of the
carbene C atom.[15] Last year, we reported the only nonmetal
system known to reversibly activate and liberate H2. The
phosphonium borate (2,4,6-Me3C6H2)2PH(C6F4)BH(C6F5)2
(1) is formed by reaction of the phosphine–borane species
(2,4,6-Me3C6H2)2P(C6F4)B(C6F5)2 (3) with H2 while heating of
the zwitterion 1 above 1008C liberates hydrogen and regen-
erates the phosphine–borane 3.[16] Herein, we demonstrate
that this system and a related system provide the first metal-
free hydrogenation catalysts that effect the addition of
molecular H2 to imines, nitriles, and aziridines to produce
primary and secondary amines in high yields under relatively
mild reaction conditions.
The reduction of imines and nitriles is one of the best
synthetic methods to generate secondary and primary amines,
and has found tremendous importance in the pharmaceutical
and fine chemicals industry.[17–20] The air- and moisture-stable
phosphonium borates (R2PH)(C6F4)BH(C6F5)2 (R = 2,4,6-
Me3C6H2 (1)[16] and tB u 2()[13]) are active catalysts for the
À
hydrogenation of C N multiple bonds with H2. For example,
Non-transition-metal catalysts for hydrogenation reac-
tions are all but unknown. KOtBu has been shown to act as a
catalyst effecting the addition of H2 to benzophenone under
forcing conditions of 2008C and greater than 100 bar H2.[6]
Organocatalysts have been developed for hydrogenations of
enones and imines; however, such systems do not employ H2
directly but rather a surrogate such as a Hantzsch ester as the
stoichiometric source of hydrogen.[7–11] The development of
nonmetal hydrogenation catalysts hinges on the discovery of
systems that react cleanly with H2, but few are known. Power
and co-workers reported the hydrogenation of Ge2–alkyne
analogues to give a mixture of Ge2 and primary germane
products.[12] Recently we have introduced the concept of
“frustrated Lewis pairs”, bulky Lewis acids and bases which
are sterically precluded from forming simple Lewis
imines are reduced in toluene to the corresponding amines
cleanly and in high yield at slightly elevated temperatures
(80–1408C) and H2 pressures (1–5 atm) in sealed glass bombs
(Table 1, entries 1–6). The amine products are readily sepa-
rated from residual catalyst by filtration through a plug of
silica gel; no other side products are observed in the NMR
spectra of the crude reaction mixtures. In the case of a
sterically less demanding imine (Table 1, entry 6) no catalytic
turnover was noted. Similarly, nitriles are not catalytically
reduced, as these donors intervene in the catalytic cycle by
binding strongly to the Bcenter of the catalyst. Sequestering
=
the N lone pair by coordination of Ph(H)C NCH2Ph to
B(C6F5)3 (Table 1, entry 7) allowed catalytic imine reduction
to proceed. In a similar fashion, by employing the more active
2 as the catalyst, alkyl and aryl B(C6F5)3-bound nitriles are
also successfully reduced and isolated as the corresponding
primary amine–borane adducts (Table 1, entries 8–10).[21] In
these cases, partial reduction of nitriles to the corresponding
imines can not be intercepted or observed. It is noteworthy
that the bis-borane adduct of adiponitrile is also fully reduced
under similar conditions to give the bis-borane adduct of 1,6-
diaminohexane (Table 1, entry 10). Attempts to reduce
similar B(C6F5)3–isonitrile adducts were unsuccessful. How-
ever, catalytic reductive ring opening of an unactivated N-aryl
aziridine functionality is achieved under similar conditions
(Table 1, entry 11).
[*] P. A. Chase, G. C. Welch, T. Jurca, Prof. Dr. D. W. Stephan
Department of Chemistry and Biochemistry
University of Windsor
Windsor, Ontario, N9B 3P4 (Canada)
Fax: (+1)519-973-7098
E-mail: stephan@uwindsor.ca
[**] Financial support from NSERC of Canada is acknowledged. G.C.W.
is grateful for an NSERC scholarship.
Supporting information for this article, including preparative details
for B(C6F5)3–imine and B(C6F5)3–amine adducts as well as for 6 and
7, is available on the WWW under http://www.angewandte.org or
from the author.
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Chemie
Table 1: Hydrogenations catalyzed by 1 or 2.[a]
tBuNHCH2Ph. Similarly, the corre-
sponding reaction of imine with 1
gives an orange solution which
exhibits NMR parameters charac-
teristic of the phosphine–borane 3
(Scheme 1).
Given that we have independ-
ently established that 4 reacts with
H2 to re-form 2, the stoichiometric
Entry Substrate
Catalyst T [8C] t [h] Yield [%] Product
1
Ph(H)C NtBu
1[b]
2[b]
1
80
80
1
1
79
98
PhCH2NHtBu
PhCH2NHtBu
PhCH2NHSO2Ph
=
=
2
Ph(H)C NtBu
=
3
Ph(H)C NSO2Ph
120
120
140
120
120
120
120
120
120
10.5 97
=
4
Ph(H)C NSO2Ph
2
1
1
1
1
1
16
1
87
88
PhCH2NHSO2Ph
PhPhCH2NHCHPh2
PhCH2NHCH2Ph
PhCH2NHCH2Ph(B(C6F5)3)
MeCH2NH2B(C6F5)3
PhCH2NH2B(C6F5)3
(CH2CH2CH2NH2B(C6F5)3)2
PhCH2CHPhNHPh
=
5
Ph(H)C NCHPh2
6
Ph(H)C NCH2Ph
48
46
24
24
48
5[c]
=
=
7
Ph(H)C NCH2Ph(B(C6F5)3)
57
75
84
99
8
MeCNB(C6F5)3
=
reaction mixture of 2 and tBuN
9
PhCNB(C6F5)3
CPh(H) was treated with H2 pres-
sure and subsequently heated to
808C for 2 h, which discharged the
yellow color and afforded the ion
10
11
(CH2CH2CNB(C6F5)3)2
PhCHCHPhNPh
1[d]
1[d]
1.5 98
[a] Standard conditions: 5 mol% catalyst, 4 mL toluene, ca. 5 atm H2. [b] 1 atm H2. [c] Determined by
1H NMR spectroscopy. [d] 10 mol% catalyst.
pair
[tBuNH2CH2Ph]
(5,
[tBu2PC6F4BH(C6F5)2]
The relative rates of imine reductions shed some light on
the mechanism of catalytic reduction. The sterically encum-
Scheme 1). This product is consistent with addition of H2 to
4; however, the greater basicity of the amine tBuNHCH2Ph
over the phosphine center in 5 triggers proton transfer.
Although it is possible that 5 is generated by the direct
reaction of tBuNHCH2Ph and 4, the linked systems 3 and 4
react at a much greater rate with H2 (10 min) than the
unlinked PR3/BR’3 systems (12–24 h), suggesting that H2 is
cleaved by 4 initially. Addition of excess imine to this mixture
under a H2 atmosphere prompts smooth reduction to the
corresponding amine, thus demonstrating that 5 acts as a
living imine reduction catalyst. In a similar fashion, following
=
bered and electron-rich imine tBuN CPh(H) is reduced in
one hour under 1 atm H2 pressure at 808C in toluene with
both catalysts 1 and 2 (Table 1, entries 1 and 2) whereas
=
reduction of the electron-poor imine PhSO2N CPh(H)
requires significantly longer reaction times (10.5–16 h),
higher H2 pressure, and higher temperature (Table 1, entries 3
and 4). As these bulky imines and the corresponding amines
do not form strong adducts with B(C6F5)3,[22] the relative rates
of these reactions suggest that it is the basicity of the N center
rather than the steric demand of the substituents that
determines the rate of reduction. This observation indicates
that imine reduction is initiated by proton transfer from P to
N rather than by borohydride attack of the imine carbon
center. To further address this question, stoichiometric
=
complete reduction of PhSO2N CPh(H) with 5 mol% 1
(Table 1, entry 3), addition of another 20 equivalents of
substrate prompted the continuation of imine reduction
with no changes in reaction rate. A similar observation was
made with the substrate 1,2,3-triphenylaziridine.
[13]
reaction of the phosphonium borate Cy3P(C6F4)BH(C6F5)2
These data support a mechanism for hydrogenation of
imines that is initiated by imine protonation[23] from the
phosphonium borate zwitterion to give the iminium salt,
which then undergoes nucleophilic attack by the borohydride
anion, transferring hydride and affording the amine. Disso-
ciation of the amine from the boron atom liberates the
phosphine–borane, which then reacts with H2 to regenerate
the phosphonium borate (Scheme 2). Similar proton initiation
was found to be important for the B(C6F5)3-catalyzed ring
opening of aziridines.[24–26]
An important aspect of the mechanism involves suppres-
sion of catalyst inhibition by amine–borane adduct formation.
In some cases, amine dissociation can be encour-
aged by the incorporation of sterically demanding
substituents on the substrate that disfavor tight
adduct formation. As well, elevated temperatures
between 80–1208C promote amine dissociation
and speed catalytic reduction. In contrast, while
stoichiometric reductions are complete within
5 minutes at room temperature, catalysis is
blocked by amine–borane adduct formation.
Related steric effects have also been noted in
the rates of imine hydrosilation catalyzed by
B(C6F5)3.[22] In the case of the imine substrate
=
with the imine tBuN CPh(H) was performed. This resulted in
no reaction even after heating to 1208C for 24 h, implying that
catalysis is indeed initiated by imine protonation.
Additional mechanistic insight was gleaned from stoi-
chiometric reactions of imines with 1 or 2. In an NMR tube, a
=
1:1 mixture of tBuN CPh(H) and 2 in CD2Cl2 immediately
gives a yellow solution with a 31P NMR signal at d = 22 ppm
À
(compared to 35 ppm in 2), loss of the B H resonance in the
11BNMR spectrum, and a 19F NMR spectrum indicative of
the formation of the neutral phosphine–borane 4 (Scheme 1).
Species 4 forms a very weak adduct with the amine
=
PhCH2N CPh(H) (Table 1, entry 5) amine–
borane adduct formation inhibits reduction,
thereby allowing only stoichiometric reduction.
Scheme 1. Stoichiometric reaction of imines with 1 or 2 with H2 in toluene.
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Scheme 4. Stoichiometric reactions of benzaldehyde with 1 or 2 in
CH2Cl2.
as a result of the lower basicity of the O versus N atom.
Nonetheless, efforts to achieve catalytic metal-free hydro-
genation of carbonyl funationalities through the judicious
design of related catalysts with both reduced Lewis acidity at
boron and lowered basicity at phosphorus are in progress.
This study demonstrates new and readily accessible metal-
free catalyst systems for the reduction by H2 of imines, nitriles,
and aziridines. These findings foreshadow a new battery of
catalytic tools available for applications both in academic
organic laboratories and in industry, allowing stoichiometric
reductions mediated by NaBH4 or LiAlH4 to be performed in
a catalytic fashion and greatly reducing subsequent waste
production. Moreover, this approach could replace expensive
precious-metal catalysts, thus offering the potential benefit of
lower cost and diminished environmental impact from heavy-
metal pollutants.
Scheme 2. Catalytic cycle for reduction of imines.
The resulting amine (PhCH2)2NH coordinates strongly to the
boron center of 4, as evidenced by NMR spectroscopy, even at
elevated temperatures. However, sequestering the N-based
[27–29]
lone pair by coordination to the Lewis acid B(C6F5)3
liberates the phosphine–boranes R2PC6F4B(C6F5)2 to activate
H2, allowing the catalytic cycle to turnover and provide the
amine–B(C6F5)3 species in reasonable yields. This protection
strategy is based on our previous report demonstrating that
B(C6F5)3 is a better Lewis acid than the species R2PC6F4B-
(C6F5)2 (R = 2,4,6-Me3C6H2, tBu).[13] It is also important to
note that coordination of the substrate to B(C6F5)3 prompts a
mechanistic alteration. The reduction is initiated by hydride
transfer from 1 or 2 to the imine carbon atom of the activated
imine–borane adduct, in which B(C6F5)3 acts as a Lewis acid
promoter, and is completed by proton transfer from the
phosphonium center to the intermediate amido borate anion
(Scheme 3).
Experimental Section
All experiments were performed on double-manifold N2(H2)/vacuum
lines or in a N2-filled MBraun 130-BG glove box. Toluene was dried
by passage through alumina and molecular sieves in a commercially
available solvent-purification system. H2 gas (Praxair) was dried by
passage through a column of 50:50 activated molecular sieves and
Dririte. NMR experiments were performed on a Bruker Avance-300
1
spectrometer at 300 K unless otherwise noted. H and 13C{1H} NMR
spectra are referenced to SiMe4 using the residual proton peak of the
given solvent. 31P, 11B, and 19F NMR spectra were referenced to 85%
H3PO4, B F(OEt2), and CFCl3, respectively. Combustion analyses
3
were performed in house employing a Perkin Elmer CHN analyzer.
All imines, nitriles, and 1,2,3-triphenylaziridine were purchased from
Aldrich and used without further purification.
Typical catalysis procedure: Each catalytic run was performed in
duplicate, and the yields reported are the averages between the two
runs. The reactions were monitored periodically by 1H NMR
spectroscopy until complete. In all cases, the crude mixtures of the
completed reactions were pure to the limits of NMR spectroscopy.
a) In a glove box, a 100-mL glass bomb equipped with a small stir bar
and a teflon screw tap was charged with imine (1 mmol), catalyst
(0.05 mmol, 5 mol%), and dry toluene (4 mL). The reaction was
transferred to the vacuum/H2 line and was degassed three times with a
freeze–pump–thaw cycle. The reaction flask was cooled to À1968C,
1 atm of H2 was introduced, and the flask then sealed and warmed to
room temperature. The reaction was placed in a preheated oil bath
and stirred at 500 rpm; at 1208C, this gave an H2 pressure of about
5 atm. To take aliquots, the reaction was cooled rapidly in an ice bath,
vented to release the H2 pressure, and taken into a glove box. b) In a
glove box, the catalyst (0.05 mmol) was weighed into a 50-mL round-
bottom Schlenk flask and slurried in toluene (2 mL). The reaction was
attached to a vacuum/H2 line and subjected to three freeze–pump–
thaw cycles. The slurry was then allowed to equilibrate at the desired
temperature under an atmosphere of H2 with rapid stirring (500 rpm).
A solution of substrate (1.0 mmol) in toluene (2 mL) was added by
Scheme 3. Catalytic cycle for reduction of B(C6F5)3-protected imines.
While imines, nitriles, and aziridines are efficiently
reduced in a catalytic manner, aldehydes react only in a
stoichiometric fashion. For example, reaction of benzalde-
hyde with 1 or 2 occurs rapidly upon mixing at room
=
temperature with reduction of the C O double bond, but
the NMR spectra of the final product are consistent with the
zwitterionic formulation R2PHC6F4B(C6F5)2OCH2Ph (R =
2,4,6-Me3C6H2 (6) and tB u (7); Scheme 4). It is perhaps not
surprising that proton transfer from the phosphonium center
to the O atom does not occur, in contrast to imine reductions,
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syringe. Aliquots were taken periodically by syringe. After reaction
was complete, all volatiles were removed in vacuo, and the product
was purified by trap-to-trap vacuum distillation or filtration through a
small plug of silica (ca. 30 cm) with hexanes/ethylacetate (3:1,
200 mL) eluent to remove residual catalyst. The B(C6F5)3-protected
amines were not purified from residual catalyst.
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Received: June 30, 2007
Published online: August 15, 2007
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Keywords: boron · dihydrogen · homogeneous catalysis ·
hydrogenation · phosphorus
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