Formaldehyde as Tethering Organocatalyst: Highly Diastereoselective Hydroaminations of Allylic Amines

Article abstract of DOI:10.1021/acs.orglett.5b02675

Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations

Full text of DOI:10.1021/acs.orglett.5b02675

Letter
pubs.acs.org/OrgLett
Formaldehyde as Tethering Organocatalyst: Highly
Diastereoselective Hydroaminations of Allylic Amines
†
,§
†,§
†
†
†
Colin R. Hesp, Melissa J. MacDonald, M. Mehdi Zahedi, Didier A. Bilodeau, Shu-Bin Zhao,
‡
,†
́
Marc Pesant, and Andre M. Beauchemin*
†Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada
‡Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, QC H7S 2G5, Canada
*
S Supporting Information
ABSTRACT: Catalysts possessing sufficient activity to achieve
intermolecular alkene hydroaminations under mild conditions are
rare, and this likely accounts for the scarcity of asymmetric variants
of this reaction. Herein, highly diastereoselective hydroaminations
of allylic amines utilizing hydroxylamines as reagents and
formaldehyde as catalyst are reported. This catalyst induces
temporary intramolecularity, which results in high rate acceler-
ations, and high diastereocontrol with either chiral allylic amines or
chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to
form complex vicinal diamines.
fficient stereoselective C−N bond forming reactions are of
Scheme 1. Temporary Intramolecularity Now Allows
Diastereoselective Hydroaminations
E
high interest due to the importance of chiral nitrogen-
containing molecules. While many asymmetric reactions have
been developed to form chiral amines, asymmetric alkene
hydroaminations suffer from narrow applicability, despite
1
intense efforts toward enantioselective variants. Asymmetric
intramolecular reactions are often limited to five-membered
ring cyclizations of biased substrates (Thorpe−Ingold activa-
tion or terminal alkenes). Until recently, highly enantioselective
(
>80% ee) intermolecular reactions had only been reported for
three alkene types: strained alkenes, styrenes, and cyclic
1
,2
dienes. Highly diastereoselective variants are even more
3
rare, especially catalytic intermolecular examples. We were
thus drawn to this issue as part of our efforts on the catalysis of
4
difficult reactions via temporary intramolecularity. Indeed, a
catalytic tethering strategy should allow for high diastereocon-
trol through temporary intramolecularity. In addition, this
would circumvent the additional steps of tether formation and
tether cleavage that are inherent to stoichiometric diaster-
5
eoselective tethered reactions. Herein, we report a remarkably
that its activity and minimal size could tolerate the increased
substitution inherently required for a diastereoselective variant.
To perform reaction development, a less reactive internal
alkene was used with the goal to control alkene facial selectivity
simple catalytic system that allows a highly stereocontrolled
synthesis of vicinal diamines in which either reagent controls
the stereochemical outcome of the reaction.
We have recently reported that aldehydes catalyze metal-free
Cope-type hydroaminations via transient formation of an
aminal intermediate (I), in which temporary intramolecularity
9
using N-(1-phenylethyl)hydroxylamine. Encouragingly, we
observed and improved a rare example of an asymmetric
intermolecular hydroamination reaction in which the amine
reagent controls the stereochemical outcome (Table 1).
Optimization began with N-(1-phenylethyl)hydroxylamine
since this chiral reagent can be reliably obtained in optically
6
,7
is achieved. Notably, chiral aldehydes were efficient organo-
catalysts and provided the 1,2-diamine motif in up to 97% ee
(Scheme 1). Although the use of unbiased alkenes was achieved
and selectivity was high, this reactivity was limited to terminal
allylamines and sensitive to steric hindrance.
Given that our recent mechanistic studies identified form-
aldehyde as a superior preassociation catalyst, we speculated
Received: September 15, 2015
8
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Formaldehyde-Catalyzed
Asymmetric Intermolecular Hydroamination
Table 2. Diastereoselective Hydroamination Using a Chiral
Hydroxylamine
a
a
b
entry catalyst (x mol %) temp (°C) time (h) yield (%)
dr
1
2
3
4
5
6
10
10
10
10
5
30
50
50
80
50
50
24
24
48
24
24
24
10
58
42
41
39
0
>20:1
>20:1
>20:1
>20:1
>20:1

c
0
a
Conditions: Hydroxylamine (1 equiv), allylic amine (1.0 equiv),
formaldehyde (x mol %, from 37 wt % aqueous solution; see
Supporting Information), in t-BuOH (1 M) under Ar. H NMR yield,
b
1
c
determined using 1,4-dimethoxybenzene as internal standard. Product
degradation was observed.
9
pure form by the method of Fukuyama. We speculated that a
chiral center on the periphery of the bicyclic Cope-type
hydroamination transition state could allow stereocontrol.
Initial efforts rapidly identified t-BuOH as an ideal solvent to
a
8
Conditions: Hydroxylamine (1 equiv), allylic amine (1.5 equiv),
ensure solubility of aqueous formaldehyde. The diastereose-
formaldehyde (10 mol %, from 37 wt % aqueous solution, see
lectivity was greater than 20:1; however, the conversions
obtained were quite low (Table 1, entry 1). Increasing the
temperature to facilitate the hydroamination step greatly
increased the yield without impacting the selectivity (entry
Supporting Information), in t-BuOH (1 M) under Ar, at 30 °C, 24 h.
b
c
1
Isolated yields (mixture of diastereoisomers). Determined by H
d
NMR of unpurified reaction mixture. Stereochemistry of major
diastereomer assigned by X-ray analysis. Performed at 50 °C.
e
2). A moderate conversion and diastereomeric ratio were
observed with only 5 mol % of catalyst (entry 5), and no
background reaction was detected in the absence of form-
aldehyde (entry 6). With optimized conditions in hand (entry
2
2
), the scope of this hydroamination was investigated (Table
).
N-(1-Phenylethyl)hydroxylamine was reacted with several
secondary allylic amines (Table 2). We observed that terminal
Figure 1. Rationale for stereoinduction: proposed transition state
models for diastereoselective Cope-type hydroaminations.
alkenes react with moderate to good yields (47−85%, entries
1
−4) and consistent diastereoselectivity (ca. 5−6:1 dr).
Electron-rich allylic amines likely favor the formation of the
mixed aminal intermediate I, thus leading to an increased yield
(
>20:1, entry 1). The overall reaction was very tolerant to
8
steric hindrance α to the amine, with little effect on the
reactivity (entries 5−8). Of note is the chemoselectivity
observed with the diene substrate (entry 3) and the
compatibility with heterocyclic substituents (entries 6−7).
Higher yields could be obtained with N-methyl as opposed to
the N-benzyl substrates. This is likely due to steric hindrance
affecting the initial addition onto the formaldehyde-derived
nitrone as well as steric destabilization present in the tether and
(
entry 1 vs 2; 3 vs 4). The reactions of internal alkenes showed
very high diastereoselectivity (>20:1 dr, entries 5−6). The
favored anti stereochemistry was confirmed with an X-ray
structure (1a) and proves to be consistent with the proposed
transition state model (see Figure 1 below). Overall, these
results show that the use of a chiral hydroamination reagent can
lead to high diastereocontrol in the formation of 1,2-diamine
motifs.
1
3
transition state model (interaction between R and R ; see
Figure 1). A limitation of this catalytic approach was
substitution on the alkene; however, this could be overcome
We then sought to explore if the chirality present on the
allylic amine could be used to achieve stereoinduction in the
synthesis of vicinal diamine motifs. A similar but stoichiometric
approach had been previously investigated by Knight and co-
workers, using nitrones and allylic amines as reagents to form
six-membered heterocycles via an aminal formation/hydro-
11
by using stoichiometric amounts of formaldehyde (eq 1).
10,11
amination/ring-opening/ring-closing sequence.
Excellent
diastereoselectivities were observed and suggested that a
catalytic variant could be very effective. Again using form-
aldehyde as a catalyst, intermolecular hydroaminations were
performed using N-benzylhydroxylamine with several chiral
allylic amines (Table 3).
Encouragingly, using N-benzylbut-3-en-2-amine 2a as a
substrate, near perfect diastereoselectivity was observed
1
0b
Such cyclic derivatives were also produced by Knight and
converted into other diamine motifs.
1
0c
In our hands,
hydrolysis of 2j was challenging; an improved procedure to
B
DOI: 10.1021/acs.orglett.5b02675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Diastereoselective Hydroamination of Chiral Allylic
a
Amines
diastereocontrol (>20:1) and displayed a similar stereochemical
outcome to the reaction directed via hydrogen bonding.
As the prevalence and utility of 1,2 diamines continue to
grow in pharmaceutical targets and chiral ligands, the ability to
14
achieve diastereocontrolled hydroaminations is significant.
Consequently, the products obtained were derivatized into
diverse useful structures (Scheme 2). To this end, differentially
Scheme 2. Diamine Motifs: Derivatization Reactions
a
b
c
1
Conditions: see Table 2. Isolated yields. Determined by H NMR.
Performed at 50 °C.
protected diamine precursor 2i was used, it was prepared on
gram scale (Table 3, entry 9 was performed on a 10 mmol scale
to afford 2.36 g of 2i). The N−O bond could be cleaved easily
under mild conditions to yield diamine 4a. This diamine could
be selectively debenzylated to afford diamine 4c. Diamine 4c
was then converted into imidazolidinone 4d upon reaction with
d
convert such cyclic derivatives to the parent amino-hydroxyl-
amine was developed using NH OH·HCl (see Supporting
2
Information).
1
,1′-carbonyldiimidazole (CDI). Alternatively, these diamine
The selectivity for these diastereoselective transformations
originates from the rigid cis-bicyclic 5,5-transition state
structure for the concerted hydroamination event, presented
in the models below (Figure 1). In both models the benzylic
substituent on the hydroxylamine is in a pseudoaxial
orientation, with its C−H bond positioned to avoid
destabilizing syn-pentane interactions with the tether (i.e.,
motifs could also be cyclized with CDI to yield six-membered
heterocycles, which could also be performed after a selective
6
debenzylation in the presence of the hydroxylamine and PMB
groups (4b).
In conclusion we have developed an efficient approach to
,2-diamine motifs via highly diastereoselective intermolecular
1
Cope-type hydroaminations of allylamines using hydroxyl-
amines. Using formaldehyde as an efficient tethering organo-
catalyst, this reaction can proceed with high diastereoselectivity
using either chiral allylic amines or chiral hydroxylamines.
These results demonstrate that high diastereocontrol can be
achieved using tethering catalysis and, more broadly, illustrate
the synthetic efficiency that can be achieved by catalysts
operating only via temporary intramolecularity. Expansion of
the scope of this directed hydroamination methodology and
applications of aldehyde catalysis to other transformations are
ongoing and will be reported in due course.
1
C−H is eclipsed with C−NR ). For reactions of chiral
hydroxylamines, the large substituent on the stereocenter (RL
=
Ph) is oriented opposite to the forming C−N bond, to
minimize steric interactions between the pseudoaxial sub-
stituent (RM = Me) and the incoming alkene. In the model
proposed for chiral allylic amines, the R substituent is adopting
3
a pseudoequatorial position. This orients the tethered
hydroxylamine so that C−N bond formation occurs opposite
3
to this R substituent.
We were also interested in probing the efficiency of this
12
catalytic directed reaction procedure. Toward this, we
performed a double hydroamination cascade with N-benzyl-
hexa-1,5-dien-3-amine under our standard conditions (eq 2).
We had previously achieved this cascade using a hydrogen-
bonding approach, which yielded the product in 62% yield over
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02675.
1
3
7
days at 80 °C (in the absence of solvent). Utilizing
formaldehyde as a catalyst the sequence worked in solution, at a
lower temperature, and with a significantly shortened reaction
time. The pyrrolidine N-oxide 3 was synthesized with excellent
Complete experimental procedures, characterization, and
NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.5b02675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Author
■
(m) Reznichenko, A. L.; Hultzsch, K. C. Organometallics 2013, 32,
*
E-mail: andre.beauchemin@uottawa.ca.
1394. (n) Manna, K.; Everett, W. C.; Schoendorff, G.; Ellern, A.;
Windus, T. L.; Sadow, A. D. J. Am. Chem. Soc. 2013, 135, 7235.
Author Contributions
(o) McGhee, A.; Cochran, B. M.; Stenmark, T. A.; Michael, F. E.
§
C.R.H. and M.J.M. contributed equally.
Chem. Commun. 2013, 49, 6800. (p) Nguyen, T. M.; Nicewicz, D. A. J.
Am. Chem. Soc. 2013, 135, 9588.
Notes
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The authors declare no competing financial interest.
8
(
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DOI: 10.1021/acs.orglett.5b02675
Org. Lett. XXXX, XXX, XXX−XXX