Catalysis through temporary intramolecularity: Mechanistic investigations on aldehyde-catalyzed cope-type hydroamination lead to the discovery of a more efficient tethering catalyst

Article abstract of DOI:10.1021/ja303320x

Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.

Full text of DOI:10.1021/ja303320x

Article
pubs.acs.org/JACS
Catalysis through Temporary Intramolecularity: Mechanistic
Investigations on Aldehyde-Catalyzed Cope-type Hydroamination
Lead to the Discovery of a More Efficient Tethering Catalyst
Nicolas Guimond, Melissa J. MacDonald, Valerie Lemieux, and Andre M. Beauchemin*
́
́
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario K1N
6N5, Canada
S
* Supporting Information
ABSTRACT: Mechanistic investigations on the aldehyde-
catalyzed intermolecular hydroamination of allylic amines using
N-alkylhydroxylamines are presented. Under the reaction
conditions, the presence of a specific aldehyde catalyst allows
formation of a mixed aminal intermediate, which permits
intramolecular Cope-type hydroamination. The reaction was
determined to be first-order in both the aldehyde catalyst (α-
benzyloxyacetaldehyde) and the allylic amine. However, the
reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights
the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest
that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more
accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5−
10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields
of intermolecular hydroamination products within 24 h at 30 °C.
mainly for hydrolysis reactions, and the original work of
Commeyras et al. on the hydrolysis of α-aminoamides using
formaldehyde is an illustrative example (Figure 1).8 In this
reaction, the amine moiety of an α-aminoamide reacts with
formaldehyde to transiently generate a hemiaminal. The alcohol
portion of this hemiaminal then undergoes an intramolecular
addition onto the amide moiety. Hydrolysis of the resulting
intermediate regenerates the formaldehyde catalyst and yields
the corresponding amino acid. Several related reactions
building on temporary intramolecularity were developed: CO2
and aldehyde promoted ester hydrolysis,9,10 ketone mediated α-
thioamide hydrolysis,11 and ketone and aldehyde catalyzed
nitrile hydration.12 However, common to all these hydrolysis
reactions is the use of stoichiometric amounts of a carbonyl
catalyst, even though turnover should occur according to the
proposed mechanism. This highlights the underdevelopment
and opportunities associated with tethering catalysis: simple
systems achieving high catalytic efficiency (catalyst turnover
number and rates) remain to be established. In addition, highly
stereoselective variants and the application of this strategy to
complex reactions have barely been studied.13
INTRODUCTION
■
Catalysis of intermolecular reactions is necessary to perform a
variety of chemical transformations with high efficiency and
control. Bifunctional catalysts and enzymes are particularly
effective, as they execute this by combining the ability to
perform substrate activation while favoring substrate preasso-
ciation. In many respects, the synthetic catalysts developed so
far attempt to emulate the remarkable efficiency of enzymes in
catalyzing intermolecular reactions (with rate accelerations as
high as 1017).1 To achieve such high activity and control,
enzymes preorganize reagents and consequently induce a
“temporary intramolecularity” that minimizes the entropic
penalty associated with intermolecular reactions. It is generally
accepted that rate accelerations of 104−108 for 1 M reactants
can be obtained for room temperature reactions involving such
temporary intramolecularity.2 From this perspective, it is not
surprising that synthetic chemists have developed multiple
transformations building on preassociation3,4 and that several
families of bifunctional catalysts have emerged.5 In contrast, the
catalysis of chemical transformations only through temporary
intramolecularity or by building high effective concentrations of
reagents has received less attention from the synthetic
community.6 Indeed, simple catalysts operating only through
this pathway are rare, perform relatively simple synthetic
transformations, and highly efficient examples of enantiose-
lective catalysis have not been reported.
Building on these reports and, most importantly, on the work
of Knight et al. on the synthesis of cyclic 1,2-diamine motifs
from nitrones and allylamines (Figure 1),14 we recently
disclosed that simple aldehydes catalyze intermolecular Cope-
type hydroaminations15,16 solely via temporary intramolecular-
A limited number of examples of catalysis induced only
through temporary intramolecularity have been reported using
carbonyl catalysts.6,7 This type of catalysis was developed
Received: April 5, 2012
Published: September 12, 2012
© 2012 American Chemical Society
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the catalytic cycle of this transformation. Herein we present a
complete picture of this catalytic cycle, including information
on the rate-determining step and catalyst inhibition pathways.
We also report a system that builds on this information to
perform hydroamination reactions with higher catalytic
efficiency than previously reported by using only 5 mol % of
paraformaldehyde as precatalyst.
RESULTS AND DISCUSSION
■
Our interest in the development of catalytic tethering reactivity
stems from ongoing efforts directed toward intermolecular
Cope-type hydroamination reactions of alkenes,20 which
typically require forcing conditions and catalysis to occur.
Currently, these reactions show limited applicability: biased
alkenes are generally required and highly enantioselective
variants are rare. As previously observed,20b strained alkenes
and vinylarenes (e.g., norbornene and styrene) require heating
at elevated temperatures (90 and 140 °C, respectively), and
little to no reactivity is detected with unbiased alkenes.
Consequently, our efforts were naturally drawn to systems
where preassociation or temporary intramolecularity could help
to obtain increased reactivity. Indeed, room temperature Cope-
type hydroamination is typically efficient in five-membered ring
systems.15 The challenge thus resided in the identification of a
practical catalytic tethering method.
Figure 1. Selected reports of Commeyras and Knight using
formaldehyde.
Our inspiration toward tethering catalysis was drawn from a
key precedent from Knight et al. involving the reaction of
various nitrones with allylamines.14 In this system, 1,2-
nucleophilic addition of allylic amines triggers a one-pot
sequence featuring Cope-type hydroamination, aminal opening,
and ring closure (Figures 1 and 2). The products of this
sequence were 1,2,5-oxadiazinanes or cyclic derivatives of
vicinal diamines. From this well-developed work, we hypothe-
sized that it would be possible, using a substoichiometric
amount of an appropriate aldehyde, to achieve catalyst turnover
via a transimination step as shown in Figure 2. Encouragingly,
extensive screening of carbonyl compounds revealed that α-
oxygenated aldehydes were competent catalysts for this
transformation (see Table 1 for representative data). Our
working hypothesis is that inductively destabilized aldehydes
favor thermodynamically the formation of aminals, which likely
is an important feature for catalysts operating via temporary
intramolecularity.
Table 1. Selected Examples of Aldehydes Tested for
a
Catalytic Activity
Figure 2. Intermolecular Cope-type hydroamination using aldehydes
as tethering catalysts.
ity. As illustrated in Figure 2, the reaction proceeds via the key
in situ formation of a mixed aminal (II), which allows for a
facile intramolecular hydroamination event.17 As opposed to
more traditional tethering strategies,18 this catalytic method
does not require additional synthetic steps for the installation
and cleavage of the tether. It also allows room temperature
reactivity with a minimal excess of one of the reaction
components. Additionally, it enables the formation of
enantioenriched molecules through efficient transfer of stereo-
chemical information using a chiral aldehyde catalyst.19 Given
the lack of precedence for such complex catalytic tethering
systems (Figure 2) and our desire to achieve higher efficiency
and enantioselectivity, we initiated mechanistic studies to probe
a
Conditions: 1a (1.5 equiv), 2a (1 equiv), catalyst (20 mol %), C6D6,
b
c
rt, 24 h. Used as a 40% solution in water. Used as the hydrate.
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Although the prototypical catalytic cycle was based on
literature precedents from the work of Knight et al.,14 the
catalyst resting state and potential inhibition pathways were still
unknown at this point. Further experiments were thus
conducted to identify the rate-determining and kinetically
significant steps of this process. To do so, the reaction of N-
allylbenzylamine 1b (1.5 equiv) with N-benzylhydroxylamine
2a using α-benzyloxyacetaldehyde 3i (20 mol %) as catalyst was
investigated. The typical reaction conditions employed (1 M in
benzene, room temperature) are the result of a thorough
optimization previously described.17a
concentration that the reaction is approximately first-order in
aldehyde (Figure 3a). This is well in agreement with a catalytic
cycle where only one molecule of aldehyde is involved prior to
or at the rate-determining step. Then, plotting the log of the
initial rate of the reaction versus the log of the initial
allylbenzylamine concentration also revealed a first order-
behavior (Figure 3b). This is again consistent with a single
molecule of allylamine being involved before or at the rate-
limiting step. Next, the order of N-benzylhydroxylamine was
probed. Interestingly, a slope of −0.83, indicative of an inverse
order, was found for this reaction component (Figure 3c). To
gain further insight into the reaction mechanism and explain
this result, the title reaction was conducted in a 1H NMR probe
using C6D6 as solvent (Figure 4). From this experiment, it was
At the outset, the order of every component implicated in the
reaction was evaluated (Figure 3). It was first determined from
the log plots of initial rate versus the initial catalyst
Figure 4. Representative reaction profile over 13 h for a 1 M reaction.
Conditions: 1b (0.75 mmol, 1.5 equiv), 2a (0.5 mmol, 1 equiv), and 3i
(0.1 mmol, 20 mol %) in C6D6 (1 M).
determined that nitrone formation occurs rapidly upon addition
of the reagents. The concentration of this intermediate can
easily be monitored as the reaction proceeds. It proved to be
quite steady while still displaying a very slight increase over
time.21 Of note, the product was formed at a constant rate for
1
the 13 h period monitored (the H NMR yield of product
formation was 45% after 13 h). This suggests that there is little
to no product inhibition under the reaction conditions. This
can also be well-rationalized by the fact that the hydroxylamine
becomes N,N-disubstituted as the alkene undergoes hydro-
amination. Thus, the product cannot interfere with nitrone
formation.
Taken together, these results are consistent with initial
1
formation of nitrone 5a (observed by H NMR) followed by
the competitive addition of either N-benzylhydroxylamine or
N-allylbenzylamine (Figure 5). The addition of N-benzylhy-
droxylamine affords an unreactive aminal (6a).22 This off-cycle
pathway is (fortunately) reversible. On the other hand, the
addition of N-allylbenzylamine leads to the formation of a key
mixed aminal (7a) that can undergo the critical Cope-type
hydroamination step. Of note, the addition of water to the
reaction did not slow down the catalytic process. This rules out
the competitive addition of water on the nitrone (or other
intermediates) as a potential catalyst deactivation pathway(s).
To get a better picture of the association processes displayed
in Figure 5, the equilibrium constants KA and KB were
Figure 3. Initial rate dependence on the concentration of the reaction
components showing (a) first-order dependence in organocatalyst
(3i), (b) first-order dependence in allylbenzylamine (1b), and (c)
inverse-order dependence in benzylhydroxylamine (2a).
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Figure 5. Competing 1,2-addition of 2a and 1b on 5a, which explains
the inverse order behavior in 2a.
measured independently. The value obtained for the reaction of
nitrone 5a with benzylhydroxylamine 2a forming the sym-
metrical adduct 6a is 1.1 (eq 1). This constant suggests that the
Figure 7. Proposed catalytic cycle.
formation of this cyclized product is irreversible, this might
represent an important source of catalyst inhibition. To test
this, the cyclic compound 9a was synthesized according to
Knight’s procedure and utilized as a precatalyst for our
hydroamination reaction (eq 4). Interestingly, only a 10%
yield of 4b was obtained. This observation suggests that this
pathway (IV → V) is hardly reversible and leads to catalyst
inhibition.
equilibrium is slightly shifted toward the symmetrical adduct 6a
under the initial reaction conditions. It also accounts for a
concentration of nitrone a little under 0.1 M during the first
hours of the reaction. Experiments to probe the value of the
equilibrium constant KB were also conducted. Since we needed
to prevent the Cope-type hydroamination, N-benzylethylamine
8a was used in place of 1b. A value of 0.5 was obtained for this
constant (eq 2). Overall, these values are consistent with the
symmetrical adduct 6a being the resting state of the catalyst at
low conversion and the mixed aminal being a thermodynami-
cally disfavored species.23
Deuterium kinetic isotope effect (DKIE) experiments were
also conducted to probe the nature of the rate-determining
step. All exchangeable protons of both starting materials were
replaced by deuterium and the initial rate of the reaction was
measured. As shown in eq 3, a primary DKIE of 2.8 0.9 was
Taking into account the results obtained herein, a more
accurate catalytic cycle can now be drawn (Figure 7). The first
step is a rapid reaction of the aldehyde precatalyst with
benzylhydroxylamine to afford the nitrone catalyst (I). From
this point, either another molecule of benzylhydroxylamine or
the allylamine can effect a 1,2-addition. The reaction of the later
yields a mixed aminal (II) that can then undergo the proposed
rate-determining hydroamination.24 It is believed that the
reason why only a limited number of aldehydes with very
specific electronic properties are competent catalysts can be
explained as follows. If the aldehyde is not inductively
destabilized enough (i.e., most aliphatic aldehydes) or is
stabilized (i.e., aromatic or conjugated aldehydes), the nitrone
is stable, and consequently, the tetrahedral intermediate is only
present in a low concentration. Since the rate of the
hydroamination step (rate-determining step) of the reaction
is function of the concentration of the mixed aminal II, stable
nitrones that disfavor the formation of aminals would be poor
catalysts. On the other hand, if the aldehyde is too destabilized,
it is believed that the aminal could be too stable and thus not
easily returned to the nitrone. Since the formation of
symmetrical aminal VI can compete with the mixed aminal
II, a situation where the symmetrical aminal is formed and
hardly returns to the nitrone could be very detrimental to the
reaction. It is thus important to have a nitrone catalyst that
favors preassociation while also allowing reversibility between
the nitrone and the aminal species. In other words, an ideal
catalyst would allow for a high and renewable concentration of
mixed aminal II via the destabilization of nitrone I.25
obtained for this reaction. If we assume the proton transfer
steps to have a low energy barrier, this result suggests that
hydroamination is the rate-determining step of this catalytic
process.
Toward the turnover-enabling step of the originally proposed
catalytic cycle (Figure 2), two competing reactions can occur.
The first one, which is desired, is a transimination providing the
nitrone catalyst I and the hydroamination product (Figures 2
and 7). The second possibility is to generate adduct V, which
results from a 6-endo-trig addition of the negatively charged
oxygen onto the iminium ion in IV (Figures 2 and 7, off-cycle
straight arrow). The latter gives a 6-membered heterocycle (V)
that has been extensively described by Knight et al.14 If the
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Having a better understanding of the operative catalytic
cycle, we decided to reinvestigate the catalyst design in order to
increase the rate of the reaction and hopefully broaden its
scope. It was initially thought that promoting hydroamination,
the proposed rate-limiting step, would lead to increased
reactivity. To do so, the possibility of using a ketone catalyst
was explored. The rationale was to benefit from a Thorpe-
Ingold effect that would favor the difficult cyclization: this is
well-known for intramolecular hydroaminations16 and for
Cope-type hydroaminations in particular.15
However, intensive screening of electron-deficient ketones
revealed that only poor reactivity could be achieved. The best
results obtained were with the inductively destabilized ketone
3j. In contrast to the results obtained with aldehyde 3i, the
ketone precatalysts seemed to be considerably more sensitive to
steric factors. Hydroamination of a primary allylamine with
benzylhydroxylamine using ketone 3j provided a 1H NMR yield
of 21% over 24 h. The use of methylallylamine (6%) and
benzylallylamine (trace) gave much lower yields (Scheme 1).
Scheme 1. Importance of Steric Factors with a Ketone
a
Precatalyst
Figure 8. Initial rate comparison in DMSO-d6 using 1b (1.5 equiv), 2a
(1 equiv), catalyst 3i or 3k (20 mol %), and DMSO-d6 (1 M), at 25
b
°C. Value obtained after induction period.
Encouraged by this result, we next sought to determine if this
improved reactivity would translate into improved catalytic
activity. Gratifyingly, it was found that the catalyst loading in
“formaldehyde” could be reduced to 5 mol % while still
displaying increased yields compared to reactions using 20 mol
% of α-benzyloxyacetaldehyde (3j). As shown in Table 2,
isolated yields for alkene hydroamination using diverse
secondary allylamines are significantly higher. N-Methyl, N-
allyl, and N-benzyl allylamines provided quantitative, 92%, and
85% yields, respectively (entries 1−3). Using several other
starting materials also gave yield increases compared to the
first-generation conditions, albeit using 10 mol % of catalyst
(entries 4−6). These results not only make for a more efficient
alkene hydroamination method, but also for a more practical
approach to vicinal diamines given that paraformaldehyde is
inexpensive and readily available.
a
Conditions: allylamine (1.5 equiv), 2a (1 equiv), 3j (20 mol %),
C6D6, rt, 24 h.
This data suggests that the added steric hindrance present in
the mixed aminal (increasing with R = H < Me < Bn) leads to
an unfavorable preassociation equilibrium (I ⇆ II) and that this
negative effect is more important than the probable acceleration
of the Cope-type hydroamination step (II ⇆ III). As such, this
observation is related to the concept of tether strain recently
discussed by Krenske et al. in related systems.26 In addition, the
increased stability of ketonitrones relative to aldonitrones
should also result in a disfavored preassociation equilibrium.
Taking these results into account, we aimed at improving the
reaction rate by using a more destabilized nitrone, to provide a
more favorable preassociation equilibrium for the mixed aminal
intermediate. Initial attempts with paraformaldehyde in C6H6
and CHCl3 (i.e., original reaction conditions) resulted in low
conversion. However, polar solvents proved superior, and the
use of either t-BuOH or DMSO led to high yields of the desired
hydroamination products, with slightly better results using t-
BuOH (see the Supporting Information for optimization data).
In order to compare the performance of α-benzyloxyacetalde-
hyde (3i) and formaldehyde (3k), the reaction rates of both
catalytic systems were determined in DMSO-d6. Interestingly,
the rate at low conversion is lower with paraformaldehyde than
with aldehyde 3i, but it becomes ca. 3 times faster after an
induction period (Figure 8). This is presumably due to the slow
depolymerization of the paraformaldehyde precatalyst em-
ployed in this reaction.
Building on these results under anhydrous (but initially
heterogeneous) conditions, we explored the use of a
concentrated aqueous solution of formaldehyde (formalin, in
which formaldehyde is present as a hydrate). Gratifyingly, a
similar result was observed using this convenient precatalyst
(eq 5).
This result again highlights that high catalytic efficiency is
achievable with tethering catalysis. The early development of an
efficient tethering organocatalytic system operating at 5 mol %
despite the presence of two different catalyst inhibition
pathways suggests that this concept will be applicable to
other reactions. Efforts along this path and the development of
a highly enantioselective variant of this tethered hydro-
amination reactivity are ongoing and will be reported in due
course.
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use of 20 mol % of α-benzyloxyacetaldehyde, leading to high
yields of intermolecular hydroamination products within 24 h
at 30 °C in t-BuOH.
Table 2. Comparative Reaction Scope for the Formaldehyde-
Catalyzed Cope-type Hydroamination
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
andre.beauchemin@uottawa.ca
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was initiated through support of an Enantioselective
Synthesis Grant [sponsored by the Canadian Society for
Chemistry, AstraZeneca Canada, Boehringer Ingelheim (Can-
ada) Ltd. and Merck Frosst Canada] and the NSERC
collaborative R & D program. Support from the University of
Ottawa, the Canadian Foundation for Innovation, the Ontario
Ministry of Research and Innovation (Ontario Research Fund
and Early Researcher Award to A.M.B.), NSERC (Discovery
Grant and Discovery Accelerator Supplement to A.M.B.) and
AstraZeneca are also gratefully acknowledged. Acknowledg-
ment is also made to the donors of The American Chemical
Society Petroleum Research Fund for support of related
research efforts. N.G. thanks NSERC for a CGS D scholarship.
M.J.M. thanks Boehringer Ingelheim (Canada) Ltd for a
collaborative graduate scholarship. We also thank Marc Pesant
for stimulating discussions. We also thank Prof. Derek Pratt
(University of Ottawa) and the reviewers for insightful
comments and suggestions.
a
Conditions: 3i catalyzed (red), allylamine (1.5 equiv), hydroxylamine
(1 equiv), 3i (20 mol %), C6H6 or CHCl3 (1 M), 24−96 h; 3k
catalyzed (blue), allylamine (2 equiv), hydroxylamine (1 equiv), 3k (5
mol %), t-BuOH (1 M), 30 °C, 24 h. Using 10 mol % 3k.
b
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■
CONCLUSION
■
In conclusion, the reaction mechanism of the recently
developed aldehyde-catalyzed intermolecular Cope-type hydro-
aminations was investigated. Key observations that should help
the development of tethering catalysis through temporary
intramolecularity were made. As expected, the reaction was
determined to be approximately first-order in both the aldehyde
catalyst (α-benzyloxyacetaldehyde) and the allylic amine.
However, the reaction displays an inverse order behavior in
benzylhydroxylamine, which reveals a significant off-cycle
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(24) The kinetic equation for the proposed catalytic cycle can be
expressed as follows:
kHAKB[1][3]
rate =
1 + KB[1] + KA[2]
See the Supporting Information for more details.
(25) In contrast, a higher concentration of tetrahedral intermediate
obtained by stabilization of the aminal instead of destabilization of the
nitrone could lead to a reduction of the hydroamination rate (kHA).
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For kinetic
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́
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(15) Such reactions are also often called reverse Cope cyclization or
reverse Cope eliminations in the literature. For an excellent review,
see: Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
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̈
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̈
40, 3983. (e) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
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(17) (a) MacDonald, M. J.; Schipper, D. J.; Ng, P.; Moran, J.;
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̌
́
of this work, see: (b) List, B.; Coric, I. Synfacts 2012, 8, 210. (c) Tan,
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achieve increased reactivity and control, see: (a) Diederich, F. S.;
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(19) For a review relating to transfer of chirality, see: Seebach, D.;
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́
(20) (a) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; Seguin, C.;
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