Base-catalyzed bifunctional addition to amides and imides at low temperature. A new pathway for carbonyl hydrogenation

Article abstract of DOI:10.1021/ja401294q

Mono- or dideprotonation at the N-H groups of the Noyori ketone hydrogenation catalyst trans-[RuH₂((R)-BINAP)((R,R)-dpen)] (1a) yields trans-M[RuH₂((R,R)-HNCH(Ph)CH(Ph)NH₂)((R)-BINAP)], where M = K⁺(8-K) or Li⁺ (8-Li), or trans-M ₂[RuH₂((R,R)-HNCH(Ph)CH(Ph)NH)((R)-BINAP)], where M = Li⁺ (8-M′₂), which have unprecedented activity toward the hydrogenation of amide and imide carbonyls at low temperatures in THF-d₈. Details of the origins of the enantioselection for the desymmetrization of meso-cyclic imides by hydrogenation with 8-K are also described herein.

Full text of DOI:10.1021/ja401294q

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Article
Base-Catalyzed Bifunctional Addition to Amides and Imides at
Low Temperature. A New Pathway for Carbonyl Hydrogenation
Jeremy Michael John, Satoshi Takebayashi, Nupur Dabral, Mark Miskolzie, and Steven Herbert Bergens
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401294q • Publication Date (Web): 20 May 2013
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Journal of the American Chemical Society
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Base-Catalyzed Bifunctional Addition to Amides and Imides at
Low Temperature. A New Pathway for Carbonyl Hydrogena-
tion.
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Jeremy M. John, Satoshi Takebayashi,† Nupur Dabral, Mark Miskolzie and Steven H. Bergens*
Department of Chemistry University of Alberta, Edmonton, Alberta, Canada, T6G 2G2
ABSTRACT: Monoꢀ or diꢀdeprotonation at the NꢀH groups of the Noyori ketone hydrogenation catalyst transꢀ[RuH2((R)ꢀ
BINAP)((R,R)ꢀdpen)] (1a) yields transꢀM[RuH2((R,R)ꢀHNCHPhCHPhNH2)((R)ꢀBINAP)], where M = K+ (8-K) or Li+ (8-Li), or
transꢀM2[RuH2((R,R)ꢀHNCHPhCHPhNH)((R)ꢀBINAP)] where M = Li+ (8-M’2) that have unprecedented activity towards the hyꢀ
drogenation of amide and imide carbonyls at low temperatures in THFꢀd8. Details into the origins of the enantioselection for the
desymmetrization of mesoꢀcyclic imides by hydrogenation with 8-K are also described herein.
NMR study that shows that the bifunctional addition of an
arylꢀalkylꢀketone to transꢀ[RuH2((R)ꢀBINAP)((R,R)ꢀdpen)],
(1a) [BINAP: 2,2'ꢀbis(diphenylꢀphosphino)ꢀ1,1'ꢀbinaphthyl,
dpen: 1,2ꢀdiphenylꢀethylenediamine] forms the rutheniumꢀ
alkoxide, 3, without formation of product alcohol and the corꢀ
INTRODUCTION
The catalytic hydrogenation of carboxylic acid derivatives
such as imides, esters, and amides is a key, emerging class of
sustainable chemistry. These hydrogenations will likely
replace the use of stoichiometric, wasteful aluminumꢀ and
boronꢀhydrides for industrialꢀscale carbonyl reductions
because they typically produce only the desired product and
excess hydrogen gas that can simply be recycled, or burned to
provide energy and water.1 Hydrogenations of imides, esters,
and amides have historically required impractical
temperatures, pressures, times, and catalyst loadings to
overcome the low reactivity of their carbonyl groups.2 There
is, however, a revolution underway in catalytic hydrogenation.
Within the last decade, there have been numerous reports of
catalysts that hydrogenate esters,2b, 3 imides,4 imines,5 nitriles,6
responding Ruꢀamide as intermediates upon thawing at −80°C
15
.
This experiment was biased towards scrambling of the free
Ruꢀamide 2 and alcohol, even in a solvent cage on timescales
faster than NMR, as such, it is strong evidence that they are
not the products of this addition under these conditions. An
analogous Osꢀalkoxide was isolated by Bertoli et al,10e and
alkoxides were observed or proposed to form with other biꢀ
functional systems.16 Our group has also observed analogous
Ruꢀalkoxides as products for rapid addition reactions between
1a and ketones,17 and lactones at low temperatures.3e Based on
the unexpected result from our intramolecular trapping study,
we proposed a transition state that contains a partial RuꢀO
bond rather than a partial Ru=N bond as described in the origꢀ
inal mechanism (Scheme 1, bottom).15 A recent computational
study on the addition of acetophenone to the catalyst model
transꢀ[RuH2(1,2ꢀbis(phosphino)ethane)(ethylenediamine)]
concluded that the reaction proceeds via a stepwise pathway,
with a rateꢀlimiting hydride transfer from Ru to the hydrogen
bonded carbonyl to form a metalꢀalkoxide ion pair with the
alkoxide hydrogen bonded to a NꢀH group in the Ru cation
(ꢁG°‡ for the addition = 11.5 kcal/mol, ꢁH°‡ = ꢀ3.5 kcal/mol)
(Scheme 1, middle). This species then either undergoes proton
transfer from a NꢀH group to the alkoxide to form 2 and the
alcohol, or the alkoxide undergoes a simple rotation to form
the model coordinated alkoxide 3.14n The pathway forming 3 is
consistent with our experimental observations on the catalyst
system. Similar results were obtained from a computational
study on the addition of acetone or acetophenone to (S)ꢀ[RuH
and even amides3d, with high turnover numbers and rates
7
under practical conditions. Curiously, the reported systems
tend to be most active in THF solvent and often in the
presence of high ratios of base to catalyst. A handful of
systems are active in the absence of base in THF.2b, 3b, 8 Most
of these catalysts operate by the ligandꢀassisted bifunctional
addition.
Noyori’s discovery of the bifunctional addition to ketones is a
landmark moment in the history of asymmetric catalysis
because it made available the first practical methodology to
enantioselectively hydrogenate ketones in high yields for use
in synthesis of pharmaceuticals, insecticides, flavors, and
fragrances.9 The parent system for bifunctional ketone
hydrogenations
are
mixtures
of
transꢀ
[RuCl2(diamine)(diphosphine)] and base that react to form
transꢀdihydrides, such as 1 (Scheme 1), as the active catalyst.
The ligandꢀassisted bifunctional addition was first proposed to
proceed with a nucleophilic hydride on ruthenium, and a
protic hydrogen on nitrogen, that add in a concerted manner to
the carbon and oxygen of the carbonyl group to form the
product alcohol and the Ruꢀamide, 2 (Scheme 1, top).
((R,R)ꢀOCH(Ph)CH(Ph)NH2)(η6ꢀC6H6)] and (S)ꢀ[RuH(η6
ꢀ
(CH3)3C6H3)((R,R)ꢀTsdpen)] [Tsdpen: (1R,2R)ꢀ(ꢀ)ꢀNꢀ(4ꢀ
toluenesulfonyl)ꢀ1,2ꢀdiphenylethylenediamine].14o More reꢀ
fined experiments and calculations will provide further inꢀ
sights into the mechanism of these additions.
The pathways for these bifunctional additions have been heavꢀ
ily studied with model systems,10 isotope studies,11 productꢀ
forming kinetics,12 trapping experiments,13 and calculations.14
We recently reported a solventꢀcage, intramolecular trapping
Aided by mechanistic understandings,17 we recently developed
the first enantioselective desymmetrization of mesoꢀcyclic
imides via monohydrogenation (eq. 1).4c For example, the
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tigation on this desymmetrization that uncovers a new, highly
facile base-catalyzed bifunctional addition to imideꢀ and amꢀ
ideꢀcarbonyl groups at low temperatures.
monohydrogenation of the endo mesoꢀcyclic imide 4 by 1a
formed the transꢀhydroxy lactam 5 with five new stereogenic
centres in 96% ee (eq. 1). We now report a mechanistic invesꢀ
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Scheme 1. Proposed mechanisms for the Bifunctional Addition
There are no prior reports of a base-catalyzed bifunctional
addition. This is the first observed instance of base promotꢀ
ing the activity of the fully hydrogenated catalyst in a carꢀ
bonyl reduction. To investigate this unexpected phenomeꢀ
non, we reacted 1 equiv. of anhydrous KOH with the imide 4
at −80°C, but observed, no net reaction.18 Similarly, no net
reaction was observed between 1a and either KOH, or exꢀ
cess KN[Si(CH3)3]2 (>1.0 equiv. relative to Ru), in the presꢀ
ence of the conjugate acid HN[Si(CH3)3]2 at −80°C. Further,
the reaction between KN[Si(CH3)3]2 and 4 lead to mixtures
of unidentified species that also did not react with 1a at
−80°C.
RESULTS AND DISCUSSION
We prepared the Ruꢀdihydride 1a in the rigorous absence of
water and excess inorganic base by reacting mixtures of
transꢀ[RuH(L)((R)ꢀBINAP)((R,R)ꢀdpen)]BF4 (L=η2ꢀH2 or
THFꢀd8) with 0.9 equiv. of KN[Si(CH3)3]2 or KOtꢀBu as base
under H2 (~2 atm) at −78°C in THFꢀd8.17b All the reactions
reported in this paper are carried out in THFꢀd8, unless reꢀ
ported otherwise. Less than 1 equiv. of base was used to
ensure that no residual base remained after the formation of
1a. These preparations form mixtures of 1a, the conjugate
acids HN[Si(CH3)3]2 or HOtꢀBu (depending on which base
was used), and KBF4 (0.9 equiv. each).
These observations do not exclude a reversible reaction beꢀ
tween 1a and base that lies to the side of the dihydride. To
explore this possibility, we employed a variant of Schlossꢀ
er’s base,19 prepared by reacting a mixture of 1a, HOtꢀBu,
and KBF4 with a mixture of nꢀBuLi and KOtꢀBu (2.5 and 1.0
equiv. respectively) to form a new intermediate, the transꢀ
Ruꢀdihydride amidate, 8 (Figure 1) in 84% yield at −60°C
(eq. 3). This is the first experimental observation of such a
species in a carbonyl hydrogenation. The Ruꢀamidate (8)
resulted from the deprotonation of one of the protic NꢀH
groups in the dpen ligand. 8 was not isolatable, but was fully
The stoichiometric addition reaction between 1a and the
mesoꢀcyclic imide 4 only formed small amounts of what
appeared to be catalyst decomposition after ~ 3.3 h at
−60°C. Further warming resulted in more decomposition. To
our surprise, the addition between 1a and 4 does occur in the
presence of catalytic amounts of KOH (0.2 equiv. relative to
Ru and imide substrate) at −80°C to give the alkoxide 7 as
the major product in 78% yield after 3 h (eq. 2).
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characterized at −80°C in anhydrous THFꢀd8 using 1H,
iments show a negative ROE correlation between the signals
31P{1H}, 1Hꢀ1H gCOSY, 1Hꢀ13C gHSQC, TOSCY and
TROESY NMR experiments. The signals for all three NꢀH’s
at δ –6.1 ppm for the hydride and at δ 0.2 ppm for the Nꢀ
Hamidate. Thus, the signal at δ –6.1 ppm is definitively from
the Ruꢀhydride adjacent to the NꢀHamidate, and it is very likely
that the amidate NꢀH in 8-K is axially oriented in the deproꢀ
tonated dpen moiety. We had previously reported evidence
that KOtꢀBu forms a hydrogen bond with the NꢀHequatorial of
the Ruꢀalkoxide transꢀ[RuH(2ꢀPrO)((R)ꢀBINAP)((R,R)ꢀ
dpen)].17b Therefore, these observations combined, suggest
that the equatorial NꢀH’s in coordinated dpen are either more
accessible and/or more acidic than the axial NꢀH’s.
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were identified in the H NMR spectrum, with the NꢀHamidate
at δ 0.22 ppm, NꢀHaxial at δ 2.8 ppm, and NꢀHequatorial at δ 2.9
ppm. The amidate ligand is best described as singlyꢀbonded
to the coordinatively saturated ruthenium center in 8, with
the lone pair on nitrogen in an equatorial disposition and
coordinated to the cation, which is likely potassium i.e. 8-
K.20 Based upon kinetic studies, Chen et al proposed in 2001
that a similar species forms during ketone hydrogenations.
Specifically, they proposed that an axial, cationꢀselective
binding site (e.g. K+ over Li+) allows deprotonation of an
axial NꢀH in 1a to form 8ꢀKaxial, which differs from the
equatorial disposition we observe in 8-K. In a manner relatꢀ
ed to the original pathway for the bifunctional addition, the
addition of a ketone to 8ꢀKaxial was proposed to form the
product alkoxide ionically bonded to K+ which was also
bonded to the nitrogen in the Ruꢀamide (2). This species
would react with H2 to regenerate 8ꢀKaxial and the product
alcohol faster than 2 reacts with H2 to form 1a.21 Subsequent
studies were unable to confirm this pathway.10b, 12a It is unꢀ
likely that activation of hydrogen is the slow step in imide or
amide hydrogenations.
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Figure 1. Comparison of the δ 0.5 to δ −7 ppm 1H (left) and
δ 90 to δ 75 ppm 31P{1H} (right) NMR spectra for the transꢀ
Ruꢀdihydrides 1a (bottom), 8-K (middle) and 8-Li (top)
The Ruꢀhydride signals in 8-Li are slightly shifted from
those of 8-K. The upfield signal for the Ruꢀhydride adjacent
to the NꢀHamidate in 8-Li was comparable to that of 8-K.
However, the Ruꢀhydride next to the NH2 group in 8-Li is at
–5.5 ppm, ~0.5 ppm upfield from those in the neutral dihyꢀ
dride, 1a. These subtle differences in 1H NMR show that Li+
is coordinated to the lone pair on the NꢀHamidate in 8-Li. Unꢀ
like, 8-K, however, no ROE correlations could be observed
between the NꢀHamidate adjacent to the Ruꢀhydride in 8-Li.
Thus, the orientation of the NꢀHamidate could not be unambigꢀ
Although detectable amounts of 8-K were not observed in
the NMR of a mixture of 1a with KN[Si(CH3)3]2 and HN[Si
(CH3)3]2 (1.5 and 1.0 equiv. respectively), we reasoned that
the lithium salt, LiN[Si(CH3)3]2 would deprotonate 1a to a
further extent, as the conjugate base 8 would be stabilized by
the coordination of lithium to the free lone pair in the amiꢀ
date ligand. Indeed, reacting a 1:1:1 mixture of 1a,
HN[Si(CH3)3]2, and LiBF4 with 2.0 equiv. LiN[Si(CH3)3]2
forms the lithium adduct 8-Li in 90% yield at −20°C (eq. 4).
This compound was also not isolatable, but was fully characꢀ
terized in solution at −20°C with the same NMR experiꢀ
ments used to characterize 8-K.
1
uously assigned. Similarities between the H and 31P{1H}
NMR data of 8-K and 8-Li, and the smaller size of Li+ comꢀ
pared to that of K+, lead us to propose that the NꢀHamidate in 8-
Li is axial. Although there are several reports of neutral, 18ꢀ
electron compounds containing singlyꢀbonded amide ligands
(i.e. RuꢀNH2) in the literature,22 compounds 8-K and 8-Li
are to our knowledge, the first characterized examples of late
transitionꢀmetal singlyꢀbonded Kꢀ and Liꢀamidates.
Remarkably, we found that adding 2 equiv. nꢀBuLi to 8-K at
−60°C resulted in a second deprotonation, to form the transꢀ
dihydrideꢀdiamidate (8-M’2, M’ = K or Li) in quantitative
yield (eq. 5, Figure 2).
1
The H NMR signals for the amidate, axial, and equatorial
NꢀH’s of 8-Li at −20°C were δ −0.2 ppm, δ 2.5 ppm, and δ
2.6 ppm respectively. Figure 1 compares the most significant
1
regions of the H and 31P{1H} NMR spectra for the transꢀ
Ruꢀdihydrides 1a, 8-K, and 8-Li. There are two signals for
the inequivalent phosphorous centers in the 31P{1H} NMR of
8-K and 8-Li. Each species has one signal with a chemical
shift similar to that of 1a, and another shifted upfield by 7.0ꢀ
9.0 ppm. One of the hydride signals in transꢀRuꢀamidate 8-
K overlaps with the Ruꢀhydride signal of 1a, while the other
is shifted upfield by 1.1 ppm to δ –6.1 ppm. TROESY experꢀ
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NH(CH(Ph))2NH2)((R)ꢀBINAP)], 2a, and the potassium
alkoxide of the cisꢀhydroxy lactam, 6a (eq. 6). This is a hithꢀ
erto unobserved, active pathway for the bifunctional addiꢀ
tion. We believe that 8-K is dramatically more active than 1a
because the amidate group increases the electron density at
the Ruꢀcenter, making the hydride ligand more nucleophilic
towards the imide carbonyl group.
This compound was fully characterized in solution at −50°C
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using the same NMR experiments used to characterize 8-K
and 8-Li. The 31P{1H} NMR of 8-M’2 consisted of a singlet
at δ 76.8 ppm. The C2ꢀdissymmetrical nature of the comꢀ
pound resulted in equivalent hydride, NꢀHamidate and CH(Ph)
signals located respectively at δ −6.6 ppm, δ −0.15 ppm and
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δ 2.9 ppm in the H NMR. TROESY NMR experiments
showed significant ROE correlations between the Ruꢀ
hydrides and amidate NꢀH’s, and CH(Ph) signals. Thus, the
amidate NꢀH’s in 8-M’2 are axially oriented with respect to
the Ruꢀhydride, and the coordinating metals occupy equatoꢀ
rial positions (Figure 2). We could not unambiguously assign
the identity of M’. We propose that the coordinating metal is
Li+ due to its higher stoichiometric ratio and its stronger
Lewis acidity.
We utilized 1Hꢀ15N HSQC NMR to gather information on the
different nitrogen environments in these compounds in an
attempt to identify the cation in 8-M’2. The 15NH2 and 15N–H
chemical shifts for 8-K were 11.8 and 34.6 ppm at –40°C,
respectively, while those for 8-Li were 11.2 and 22.2 ppm at
–20°C. The 15N data for 8-M’2 was 22.8 ppm at –50°C. The
similarity between the 15N–H chemical shifts in 8-Li and 8-
M’2 support the assignment of M’2 as Li+.23
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We reported previously that the additions of ketones and
lactones to 1a generate the corresponding Ruꢀalkoxide, as
does the KOHꢀcatalyzed addition of 4 to 1a at −80°C (vide
supra). We also showed that the Ruꢀ2ꢀpropoxide, transꢀ[Ru
H(2ꢀPrO)((R)ꢀBINAP)((R,R)ꢀdpen)], and related compounds
are inactive towards ketone hydrogenations in the absence of
base under our conditions.17b These Ruꢀalkoxide compounds
do, however, undergo a base-assisted elimination reaction
where, an NꢀH group in the dpen ligand is deprotonated, and
2ꢀpropoxide is eliminated to generate the Ruꢀamide, 2a. If
the product of the addition of 4 to 8-K is the Ruꢀalkoxide
corresponding to those we observed for the additions of keꢀ
tones and esters to 1,17b such a species would be predisposed
to undergo this elimination to form the alkoxide 6a and 2a
(Scheme 2, top). If the addition proceeds by rapid hydride
transfer to form the corresponding alkoxide ion pair, 9,
(Scheme 2, middle) this species presumably can also elimiꢀ
nate the alkoxide 6a to form 2a. Alternatively, the alkoxide
in 9 can deprotonate the NꢀH group to form the alcohol and
the potassium amide 2a-K (Scheme 2, bottom). Proton transꢀ
fer forms the observed product mixture. These additions
could also proceed with K+ directly involved in the bifuncꢀ
tional addition, as proposed by Chen and coꢀworkers for the
addition of ketones to 8-Kaxial (via 8-K rearrangement). A
sequence of steps analogous to those in Scheme 2 would
form the observed products.
Figure 2. Comparison of the δ 0.5 to δ −7 ppm 1H (left) and
δ 90 to δ 75 ppm 31P{1H} (right) NMR spectra for the transꢀ
Ruꢀdihydrides 1a (bottom), and 8-M’2 (top)
Unlike the slow decomposition reaction between the mesoꢀ
cyclic imide 4 and the neutral dihydride 1a, the addition of 4
to 8-K was complete on mixing at −80°C. Unexpectedly, the
products of the addition were the Ruꢀamide [RuH((R,R)ꢀ
Scheme 2. Possible pathways for the formation of 2a and 6a from 8-K
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some decomposition of 4. It is well established that Li+
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The addition of the imide 4 to 8-Li is slower than the correꢀ
forms stronger adducts to Nꢀcontaining bases than K+. Thus
the Ru center in 8-K is more electron rich, and thereby the
hydride ligands are more nucleophilic than those in 8-Li.
sponding potassium analogue, 8-K, but still forms the Ruꢀ
amide 2a and the lithium alkoxide of the cisꢀhydroxy lactam
(6b) in ~8% yield after 15 min at −60°C. The excess
LiN[Si(CH3)3]2 (2.0 equiv. relative to 1a) also resulted in
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Scheme 3. Mechanism for the formation of 7 from 1a catalyzed by KOH
sistent with our previous observations, the transꢀRuꢀ
dihydrideꢀamidate, 8-Li was somewhat less reactive towards
10 than 8-K, undergoing the addition starting at −60°C.
The KOHꢀcatalyzed addition of 4 to 1a likely proceeds by
the reaction of 4 with small amounts of 8-K that would be
present in solutions of 1a and KOH. This addition forms the
Ruꢀamide, 2a, and the potassium salt of the monoꢀreduced
product 6a. 6a would then react with the conjugate acid
(H2O) to form the transꢀhydroxy lactam 5 and regenerate
KOH (Scheme 2). To complete the pathway, we carried out
control experiments that showed that the transꢀhydroxy lacꢀ
tam 5 adds on mixing at −80°C to the Ruꢀamide 2a to form
the transꢀRuꢀalkoxide (7), which is the product of the KOHꢀ
catalyzed addition.
We note that the kinetic product of the hydrogenation is the
cisꢀhydroxy lactam (6) formed by addition to the leastꢀ
hindered, convex face of the imide carbonyl in 4. The transꢀ
alcohol 5, however, is the favored thermodynamic product.
We carried out control experiments that show the rapid cisꢀ
(6) to transꢀ(5) isomerization is catalyzed by KOH in THFꢀd8
at −80°C, thereby explaining the formation of the transꢀ
alkoxide, 7 as the observed product from the addition of 4 to
1a catalyzed by KOH (eq. 7, Scheme 3).
We reported that the catalytic desymmetrizationꢀ
hydrogenation of 4 by 1a (0.1 mol% Ru, 1.0 mol% KOtꢀBu,
0°C, 50 atm, 17 h) generates the transꢀhydroxy lactam 5 in
96% ee and 98% yield under mild conditions (eq. 1)].4c Our
control experiments show that KOtꢀBu catalyzes the addition
of 4 to 1a at −80°C, but also undergoes a slow decomposiꢀ
tion reaction with the substrate 4 shown above with Kꢀ and
LiꢀN[Si(CH3)3]2. Thus, during the catalytic desymmetrizaꢀ
tionꢀhydrogenation, a portion of the KOtꢀBu is consumed by
reaction with 4, and some is converted into KOH by reaction
with the residual H2O in the system. The KOH then acts as
the coꢀcatalyst for the hydrogenation. To confirm this scenarꢀ
io, we carried out control experiments that showed that the
ee and absolute configuration of the stoichiometric addition
of 4 to 1a, carried out in the presence of added trace water,
were the same as the catalytic hydrogenation reaction.
Upon further investigation of this new pathway for the biꢀ
functional addition, we found, remarkably, that 8-K underꢀ
went the addition reaction with the amide, N, N′ꢀdiphenylꢀ2ꢀ
phenoxypropionamide (10) starting at −80°C in THFꢀd8 (eq.
8). The net products of the addition were the neutral dihyꢀ
dride 1a (formed by the reaction of the Ruꢀamide, 2a, with
excess H2) and a mixture of organic potassium salts. Hydrolꢀ
ysis of these salts with excess 2ꢀpropanolꢀd8 forms the prodꢀ
uct alcohol and amine from the complete reduction of the αꢀ
chiral amide via CꢀN cleavage.24 It is noteworthy that no
deuterium incorporation was observed in the αꢀposition of
the product alcohol, showing that 8-K did not simply deproꢀ
tonate the amide 10 to form 1a under our conditions. Conꢀ
We determined the absolute configuration of the major enanꢀ
tiomer of 5 with Xꢀray crystallography. This determination
shows that the major enantiomer of the hydrogenation results
from addition to the convex face of the Sꢀside enantiotopic
carbonyl (all stereogenic centres on the norbornene backꢀ
bone adopt the S configuration upon reduction) of 4, as
shown in Figure 3. The unique combination of the structural
and conformational rigidity of 4 and 1a, the requirement for
addition to the convex face of the enantiotopic Sꢀside carꢀ
bonyl, and the published studies of the enantioselection of
aryl ketones to 1a, make the origins of enantioselection for
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Journal of the American Chemical Society
Page 6 of 7
these hydrogenations readily apparent. Specifically, the new hydrogenation of less reactive carboxylic acid and carbonic
1
2
3
4
5
6
reaction pathway proceeds through bonding interactions
between the carbonyl, RuꢀH, and the axially orientated Nꢀ
Hamidate of the transꢀdeprotonated dihydride (8-M where M =
K+ or Li+). Figure 3 represents the stereoelectronic conseꢀ
quences for this addition to the convex faces of the Sꢀside
(TSA) and Rꢀside (TSB) carbonyls of 4.
acid derivatives.
EXPERIMENTAL SECTION
Stoichiometric Reactions. Experimental details are found in
the Supporting Information.
Inspection of molecular models shows that the Nꢀphenyl
group projects deeply into the spatial domain of the BINAP
ligand, resulting in strong steric repulsions in TSB (Figure 3).
The endo-geometry of 4, and the addition to the convex face
of the Sꢀside carbonyl, result in no appreciable steric crowdꢀ
ing in TSA. Further, the geometry of TSA allows for the staꢀ
bilizing NHequitorialꢀπ attraction, by lone equatorial NꢀH in the
deprotonated dpen moiety.25 This simple, wellꢀdefined modꢀ
el thereby explains the high preference for addition to the Sꢀ
side of 4. Addition to the other RuꢀH in 8 is also possible,
which would replace the NꢀHꢀπ interaction by a NꢀK+ꢀπ inꢀ
teraction, but the same steric forces would form the same
major enantiomer.
7
8
9
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and chaꢀ
raterization of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*EꢀMail: steve.bergens@ualberta.ca
Present Addresses
†Department of Organic Chemistry, The Weizmann Institute of
Science, Rehovot 76100, Israel
Funding Sources
O
This work was supported in part by the Natural Sciences and
Engineering Research Council of Canada (NSERC) and the
University of Alberta.
Top view:
repulsion Ph2P
PPh2
Ph2P
PPh2
N
C
O
C
N
O
O
KHN
NH2
KHN
NH2
ACKNOWLEDGMENTS
We thank R. J. Hamilton and R. Loorthuraja for their advice and
experimental assistance during the course of the mechanistic
investigation. The University of Alberta’s Department of Chemꢀ
istry is thanked for the R.A. awarded to J.M.J.
O
O
N
N
repulsion
O
O
H
Side view:
H
H
?
?
H
REFERENCES
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H
H
δ
δ
N
Ru N
N
Ru N
δ
δ
K
K
H
H
H
H
TSA (favoured)
TSB (unfavoured)
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CONCLUSIONS
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These studies revealed the first intermediates in the hydroꢀ
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baseꢀcatalyzed pathway for the bifunctional addition mechaꢀ
nism to unreactive carbonyls. Deprotonation of the dihydride
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(and others with high base to catalyst ratios) and will in prinꢀ
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ligand. The high enantioselectivity of the desymmetrization
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the results of these investigations. A combination of NMR
rate measurements (to obtain activation parameters), isotope
labeling, and trapping studies, with computational studies
will provide further insights into the mechanism of these
additions. We are currently exploring such experimental
studies and the use of the variants of 8 as catalysts for the
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Journal of the American Chemical Society
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7
lithium species in the reaction mixture. The Li{1H} NMR of 8-Li,
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(24) Aldehyde was not observed in the workedꢀup reaction mixꢀ
ture. We attribute this to its facile reduction by the Ruꢀdihydride,
1a, at higher temperatures.
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