A catalytic tethering strategy: Simple aldehydes catalyze intermolecular alkene hydroaminations

Article abstract of DOI:10.1021/ja208867g

Herein we describe a catalytic tethering strategy in which simple aldehyde precatalysts enable, through temporary intramolecularity, room-temperature intermolecular hydroamination reactivity and the synthesis of vicinal diamines. The catalyst allows the formation of a mixed aminal from an allylic amine and a hydroxylamine, resulting in a facile intramolecular hydroamination event. The promising enantioselectivities obtained with a chiral aldehyde also highlight the potential of this catalytic tethering approach in asymmetric catalysis and demonstrate that efficient enantioinduction relying only on temporary intramolecularity is possible.

Full text of DOI:10.1021/ja208867g

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A Catalytic Tethering Strategy: Simple Aldehydes Catalyze
Intermolecular Alkene Hydroaminations
Melissa J. MacDonald,† Derek J. Schipper,† Peter J. Ng, Joseph Moran, and Andrꢀe M. Beauchemin*
Center for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
S Supporting Information
b
ABSTRACT: Herein we describe a catalytic tethering strat-
egy in which simple aldehyde precatalysts enable, through
temporary intramolecularity, room-temperature intermolecu-
lar hydroamination reactivity and the synthesis of vicinal
diamines. The catalyst allows the formation of a mixed aminal
from an allylic amine and a hydroxylamine, resulting in a facile
intramolecular hydroamination event. The promising en-
antioselectivities obtained with a chiral aldehyde also highlight
the potential of this catalytic tethering approach in asym-
metric catalysis and demonstrate that efficient enantioinduc-
tion relying only on temporary intramolecularity is possible.
atalysis of intermolecular reactions is at the basis of chemical
reactivity. Bifunctional catalysts performing both substrate
C
Figure 1. Prototypical catalytic tethering strategy: activation only
through temporary intramolecularity.
activation and substrate preassociation—thus offsetting the nega-
tive reaction entropy—are particularly effective in achieving high
catalytic activities for intermolecular reactions. In addition, the
preorganization that results from substrate preassociation usually
leads to increased control in reactions where multiple products
can be formed (regio-, chemo-, or stereoselectivity).1 Recently,
several strategies to incorporate a “preassociation domain” on
catalysts or ligands have been reported, thus allowing increased
efficiency through temporary intramolecularity.2 However, most
catalysis still operate by performing the activation of one or both
substrates. Incontrast, thecatalysis of intermolecularreactionsonly
through temporary intramolecularity has received less attention
from the synthetic community.2a,3 Indeed, simple catalysts oper-
ating only through this pathway are rare and achieve relatively
simple synthetic transformations,4 and efficient examples of
enantioselective catalysis have not been reported. In contrast,
the inherent increased reactivity and control associated with tem-
porary intramolecularity has typically been used in stepwise ap-
proaches involving the formation of “temporary” tethers.5 Despite
being applicable to a wide variety of chemical transformations,
such tethering strategies are unfortunately not catalytic and
generally involve two or three additional steps required for tether
assembly and cleavage. Catalytic variants of this reactivity are
critically needed since they would allow tethered reactivity to be
possible in one step and would avoid the inherent inefficiency and
byproduct formation that are associated with stepwise approaches.
Herein we show that simple activated aldehydes display catalytic
tethering activity and demonstrate that such organocatalysis can
lead to the formation of enantioenriched molecules through
efficient transfer of stereochemical information.
reversibly from alcohols or amines under mild conditions. How-
ever, the necessity of favoring substrate preassociation and forma-
tion of the mixed tether (over unproductive homodimers) along
with the issue of catalyst turnover have been serious obstacles to
overcome for the development of a prototypical catalytic system
(Figure 1). In our efforts to develop metal-free Cope-type hydro-
aminations,6,7 we had noted the stark difference between the
excellent intramolecular reactivity in five-membered-ring systems7
and the forcing conditions required for limited intermolecular
reactivity. Thus, we speculated that notoriously difficult intermo-
lecular alkene hydroaminations could be achieved provided that a
mixed aminal such as I (eq 1), and thus temporary intramolecu-
larity, could be accessed reversibly in the presence of a tethering
catalyst. Herein we report that aldehyde-based organocatalysts
form a temporary tether between hydroxylamines and allylic
amines in situ, thus enabling room-temperature directed intermol-
ecular metal-free hydroaminations (eq 1). We also demonstrate
the potentialof this approach in asymmetric catalysis, showingthat
a readily available α-chiral aldehyde catalyst leads to the synthesis
of enantioenriched vicinal diamines with high stereocontrol.
Aldehydes offer an opportunity to develop a catalytic tethering
reactivity because of their propensity to form acetals or aminals
Received: September 20, 2011
Published: November 18, 2011
r
2011 American Chemical Society
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Table 1. Representative Reactivity and Optimization Dataa
Figure 2. (A) A stoichiometric system leading to hydroamination
products through a transient hydroxylamine (Knight and co-workers,
ref 11). (B) Proposed catalytic cycle for a catalytic variant in which an
aldehyde is used as the tethering precatalyst (this work).
Intermolecular alkene hydroamination stands out as a simple
and desirable reaction for which no general solution currently
exists. While progress has been achieved using transition-metal
catalysts to overcome the high activation energy associated with
the addition of an NÀH bond across electron-rich alkenes,8
reactions of unbiased alkenes typically require catalysis at high
temperatures and have limited synthetic applicability. Enantio-
selective variants are also severely underdeveloped despite the
industrial importance of chiral amines.9 Furthermore, a conse-
quence of the near-thermoneutral profile of the hydroamination
reaction and its negative entropy is that ideally the temperature
should be as low as possible to maximize the yield and minimize
reversibility.10 Surprisingly, directed or tethered intermolecular
reactions are rare in the hydroamination literature.
To address this issue, we sought to validate the catalytic tether-
ing strategy described above to achieve intermolecular Cope-type
hydroaminations of allylic amines (eq 1). This reaction required
the formation of a mixed aminal intermediate (I) with selective
tethering of the hydroxylamine through the nitrogen atom (since
an O-linkage would prevent a further Cope-type hydroamination
step). In this context, the work of Knight and co-workers11 on the
reaction of nitrones with allylic amines provided strongsupport for
the formation of a transient hydroxylamine displaying the desired
hydroamination reactivity (Figure 2A). In this system, nitrones
are used as reagents and become incorporated into the product
through an aminal formation/hydroamination/ring-opening/
ring-closing sequence. Indirectly, this work also suggested that a
catalytic version (Figure 2B) would be possible provided that the
formation of a cyclic intermediate such as II could be avoided (or
be reversible) and that an aldehyde precatalyst possessing the
desired ability to promote the formation of the mixed aminal and
allow catalyst turnover could be identified.
a Conditions: Hydroxylamine (1 equiv), allylamine (1.5 equiv), alde-
hyde (20 mol %), and C6H6 (1 mL) were charged into a vial and stirred
at room temperature for 24 h. b Determined using 1,4-dimethoxyben-
zene as an internal standard.
aldehydes bearing electron-withdrawing substituents (Table 1, en-
tries 6 and 8). Our working hypothesis is that inductively destabi-
lized aldehydes favor the formation of aminal I kinetically and
thermodynamically, thus helping to offset the negative reaction
entropy associated with formation of this mixed aminal intermediate.
We were delighted to see that catalytic turnover is indeed possible
with aldehydes containing an α-heteroatom, with α-benzyloxyace-
taldehyde (A) being optimal (entries 6 and 8). Further optimization
of the conditions revealed that the reaction can be carried out at
room temperature with 20 mol % catalyst and that both benzene and
chloroform are competent solvents (see Tables S2ÀS4).
With the optimized reaction conditions in hand, we probed
the reaction scope, and the results are presented in Table 2. The
organocatalytic reaction is compatible with allylamine (entry 1)
as well as N-substituted allylamines (entries 2À12). Both allyl
and benzyl substituents are tolerated, allowing the synthesis of
orthogonally protected vicinal diamines. Hydroxylamines bear-
ing benzylic (entries 1À10) and aliphatic (entries 11À12)
substituents are also suitable substrates. Tolerance of the steric
hindrance associated with N-cyclohexylhydroxylamine (entry
12) is also noteworthy. However, attempts to use this tethering
catalyst with disubstituted allylic amines and homoallylic amines
led to minimal product formation. Typically, related intramole-
cular hydroaminations proceed efficiently but require heating
at temperatures in the 60À100 °C range.7,11b Preliminary data
suggested that irreversible formation of the cyclic 1,2,5-oxadiazi-
nane II (see Figure 2A) results in catalyst inhibition and limited
substrate scope with catalyst A. Efforts to expand the scope of this
transformation are ongoing.
Our work began with an extensive screening of aldehydes and
ketones that could potentially act as tethering organocatalysts [see
Table S1 in the Supporting Information (SI)].12 Representative
reactivity and optimization data are presented in Table 1. In a
departure from this work, optimal reactivity was observed for
One of the hallmarks of successful organocatalytic activation
modes is that access to enantioenriched products is possible
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Table 2. Aldehyde-Catalyzed Intermolecular Cope-Type
Hydroaminationa
Table 3. Asymmetric Catalysis Using (R)-Glyceraldehyde
Ketals as Chiral Catalystsa
a Conditions: Hydroxylamine (1 equiv), allylamine (1.5 equiv), catalyst
(20 mol %), and C6H6 (1 mL) were charged into a vial and stirred at
room temperature for 24 h. b Isolated yields. c Determined by chiral
HPLC analysis (see the SI).
sense of induction is consistent with formation of the tem-
porary stereocenter present in the tether via a FelkinÀAnh-
controlled addition of the allylamine to the chiral nitrone18 followed
by efficient transposition of chirality19 through the rigid bicyclic
transition state associated with Cope-type hydroaminations.7 Ef-
forts to identify a highly enantioselective catalyst(s) and expand the
substrate scope are ongoing and will be reported in due course.
Our proposed catalytic cycle (Figure 2B) first involves the
condensation of the hydroxylamine onto the aldehyde to form a
nitrone (this nitrone was observed by 1H NMR spectroscopy).
Attack on this nitrone by the allylamine leads to an aminal
intermediate that undergoes a facile intramolecular Cope-type
hydroamination. The resulting charged intermediate favors
aminal cleavage to yield an iminium ion. Finally, condensation
of a second molecule of hydroxylamine completes the catalytic
cycle and releases the product, which is the result of a formal
intermolecular hydroamination process. Current experiments
are directed at probing this mechanistic scenario, preventing
catalyst inhibition (via irreversible formation of intermediate II),
and determining the rate-limiting step to allow subsequent
improvement of this catalytic system.
In conclusion, we have reported the validation of a catalytic
tethering strategy to achieve challenging intermolecular Cope-
type hydroaminations under mild and metal-free conditions.
This new paradigm in organocatalysis is also applicable in
asymmetric synthesis, and this work highlights the fact that
simple molecules such as chiral α-oxygenated aldehydes are
capable of efficiently inducing asymmetry only through tempor-
ary intramolecularity. Therefore, we expect this advance will
prompt the investigation and development of a broad range of
transformations using this concept.
a Conditions: Hydroxylamine (1 equiv), allylamine (1.5 equiv), catalyst
A (20 mol %), and solvent (1 mL) were charged into a vial and stirred
at room temperature for 24 h [except for entries 5 (48 h), 6 (96 h), 7
(46 h), and 10 (29 h)]. b Isolated yields. c 1:1 mixture of diastereo-
isomers. d At 60 °C.
through asymmetric catalysis.13 Encouraged by the success of
this catalytic tethering strategy and the importance of the chiral
1,2-diamine motif,14 we sought to validate this approach in the
context of enantioselective catalysis.15 Gratifyingly, encouraging
enantiomeric excess (ee) was observed in the reactions of several
secondary allylic amines with N-benzylhydroxylamine using com-
mercially available (R)-glyceraldehyde acetonide (B) as the
catalyst (Table 3, entries 1À3). Higher yields were also obtained
using this catalyst rather than A (Table 2, entries 2À4 vs Table 3).
Optimization efforts were pursued with the related, more easily
handled catalyst C (see the SI), and improved enantioselectivity
was observed for the formation of 1d (87% ee; entry 4).
Importantly, the enantioselectivities obtained for 1c and 1d
(75 and 87% ee; entries 3 and 4) validate this tethering approach
as an effective strategy in asymmetric catalysis. To the best of our
knowledge, this enantioselectivity is the highest obtained for
intermolecular hydroaminations of unactivated alkenes by any
method, including metal-catalyzed reactions.16,17 The observed
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and characterization, catalyst identification and optimization
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COMMUNICATION
data, assignment of absolute configuration, and NMR and HPLC
spectra. This material is available free of charge via the Internet at
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’ AUTHOR INFORMATION
Corresponding Author
andre.beauchemin@uottawa.ca
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Author Contributions
†These authors contributed equally.
’ ACKNOWLEDGMENT
This communication is dedicated to the memory of Professor
Keith Fagnou. This work was initiated through support of an
Enantioselective Synthesis Grant (sponsored by the Canadian
Society for Chemistry, AstraZeneca Canada, Boehringer Ingelheim
(Canada) 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 is also gratefully acknowledged. Acknowledgment is
also made to the donors of The American Chemical Society
Petroleum Research Fund for support of related research efforts.
D.J.S. and J.M. thank NSERC for postgraduate scholarships.
M.J.M. thanks Boehringer Ingelheim (Canada) Ltd. for a collabo-
rative graduate scholarship. We also thank Marc Pesant for
stimulating discussions.
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