Highly enantioselective intermolecular hydroamination of allylic amines with chiral aldehydes as tethering catalysts

Article abstract of DOI:10.1002/chem.201203462

Chirally LinkedIn: Chiral aldehydes are effective tethering catalysts for enantioselective intermolecular hydroamination, which provides access to vicinal diamine motifs in good yields and excellent enantioselectivities (see scheme). This work highlights simple chiral α-oxygenated aldehydes as effective organocatalysts capable of efficiently inducing asymmetry through transient intramolecularity. Copyright

Full text of DOI:10.1002/chem.201203462

COMMUNICATION
DOI: 10.1002/chem.201203462
Highly Enantioselective Intermolecular Hydroamination of Allylic Amines
with Chiral Aldehydes as Tethering Catalysts
Melissa J. MacDonald,[a] Colin R. Hesp,[a] Derek J. Schipper,[a] Marc Pesant,[b] and
Andrꢀ M. Beauchemin*[a]
Asymmetric catalysis is of enormous academic and indus-
trial importance as a highly efficient approach to enantioen-
riched organic molecules. Enzymes and bifunctional cata-
lysts are among the most efficient systems available to per-
form difficult intermolecular reactions with nearly perfect
stereocontrol. This efficiency stems from their ability to per-
form substrate activation while favoring substrate preassoci-
ation and preorganization. However, highly efficient asym-
metric catalysis does not require both activation methods.
Many asymmetric catalysts achieve high enantioselectivities
by performing substrate activation in a chiral environment
alone. In contrast, and despite the possibility of accelerating
intermolecular reactions by a factor of 104 to 108 through
substrate preassociation,[1] catalytic reactions relying exclu-
sively on temporary intramolecularity are rare, and highly
efficient examples of such asymmetric catalysis have not
been reported.[2] Herein, we show that chiral aldehydes are
capable tethering asymmetric catalysts, leading to highly
enantioenriched vicinal diamine motifs through temporary
intramolecularity alone.
ble by means of tethering catalysis, we embarked on a sys-
tematic survey of chiral aldehyde catalysts and reaction con-
ditions (selected data shown in Table 1).
In a previous communication, we had shown that com-
mercially available (R)-glyceraldehyde acetonide (1a) led to
Table 1. Representative results of chiral aldehyde screening[a]
Recently, we reported that aldehydes catalyze intermolec-
ular Cope-type hydroaminations of allylic amines via the
formation of a temporary tether [(Eq. (1)].[3,4] In contrast to
common tethering strategies,[5] which rely on the stepwise
assembly and cleavage of a tether, this approach uses alde-
hydes as catalysts to access a transient mixed aminal in situ
and thus allow a facile “intramolecular” hydroamination.
Although encouraging enantioselectivities suggested that
transfer of stereochemical information from chiral aldehydes
was possible (4 examples, 47–87% ee), initial efforts were
thwarted by catalyst epimerization and reproducibility
issues. Seeking to develop an enantioselective hydroamina-
tion[6,7] approach to synthetically useful vicinal diamines[8]
and to establish that highly efficient stereoinduction is possi-
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1 f
1g
1h
1b
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
C6F6
C6F6
C6F6
93
91
16
12
5
16
51
41
34
54
46
91
75
88
37
9
3
9
À85
À94
8[d]
10
11
12
À94[d]
À93[e]
97[d]
[a] M. J. MacDonald, C. R. Hesp, D. J. Schipper, Prof. A. M. Beauchemin
Centre for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
10 Marie-Curie, Ottawa, ON K1N 6N5 (Canada)
E-mail: andre.beauchemin@uottawa.ca
[a] Performed with hydroxylamine (1 equiv), allylamine (1.5 equiv), and
catalyst 1a–h (0.2 equiv) in a solvent (1m) under argon, for 24 h at room
temperature. [b] Determined by 1H NMR spectroscopy with 1,4-dime-
thoxybenzene as internal standard. [c] Determined by chiral HPLC anal-
ysis of derivatized products (see the Supporting Information). [d] Cata-
lyst was added to the reaction mixture last. [e] At 10 mol%, catalyst 1h
gave 89% ee with a 43% NMR yield in 72 h.
[b] M. Pesant
Boehringer Ingelheim (Canada) Ltd
2100 Cunard Street, Laval, QC, H7S 2G5 (Canada)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203462.
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Table 2. Scope of asymmetric hydroamination with chiral aldehydes[a]
enantioenriched products with moderate enantiocontrol (3
examples, 45–78% ee; Table 1, entry 1). However, this alde-
hyde is notorious for its ready epimerization, and prelimina-
ry efforts thus focused on the identification of a more robust
aldehyde. Increased enantioselectivity was observed with
the more easily handled diphenyl analogue 1b (88% ee;
Table 1, entry 2), but an early screening of the substrate
scope showed that this procedure was not general and was
plagued by some catalyst epimerization. Unfortunately, the
Ley aldehyde[9] (1c), the Garner aldehyde[10] (1d), and an al-
dehyde lacking an a proton (1e) led to poor reactivity and
enantiocontrol (Table 1, entries 3–5). The low yields ob-
tained with these aldehyde catalysts suggest that their steric
bulk has a negative impact on the preassociation step, which
involves the formation of the mixed aminal I. However, the
acyclic aldehyde 1 f also showed poor reactivity (Table 1,
entry 6), which highlights the benefits associated with the
cyclic structures present in 1a and 1b. It is also worth noting
that catalysts 1a–d and 1 f had the common problem that
epimerization (via enamine formation, for example) would
lead to catalyst racemization. In contrast, the bicyclic alde-
hydes 1g and 1h possess several stereocenters embedded in
a rigid bicyclic structure that could help prevent epimeriza-
tion and help ensure retention of the original chirality.[11]
Encouragingly, high enantioselectivities were observed with
both the 6- and 5-membered bicyclic aldehydes 1g (85% ee;
Table 1, entry 7) and 1h (94% ee; Table 1, entry 9). Catalyst
1h showed remarkable stability as the reaction proceeds in
72 h with high selectivity. In addition, these catalysts led to
the R enantiomer of the diamine, which complements the
ability of catalyst 1b to provide access to the S enantiomer.
Fortunately, two additional observations were made during
this screening process that led to higher enantioselectivities
with catalyst 1b. We found that addition of the catalyst last
proved optimal, and higher enantioselectivities were ob-
tained with C6F6 as solvent. By following this revised proce-
dure, catalyst 1b afforded the S enantiomer in 97% ee
(Table 1, entry 11)!
Entry
Product
Catalyst
Yield
[%][b]
ee
[%][c]
1
2
3
4
R3 =H (2a)
R3 =H (2a)
R3 =Cl (2b)
R3 =OMe (2c)
1b
1h
1b
1b
91
79
81
86
97
À88
94
92
5
6
7
8
9
R1 =3,5-(CF3)2Bn (2d)
R1 =3,5-(CF3)2Bn (2d)
R1 =iPr (2e)
1b
1h
1b
1b
1h
82
74
60
63
60
82
À92
60
R1 =(CH2)3Ph (2 f)
R1 =(CH2)3Ph (2 f)
71
À77
10
11
12
13
14
15
16
17
18
19
20
R2 =Me (2g)
1b
1b
1h
1b
1b
1b
1h
1b
1h
1b
1h
91
85
76
83
81
62
51
75
71
73
66
56
82
R2 =allyl (2h)
R2 =allyl (2h)
R2 =p-NO2Bn (2i)
R2 =BrBn (2j)
À88
95
90
60
R2 =CH2CH
R2 =CH2CH
U
À88
R2 =CH2CO2Et (2l)
R2 =CH2CO2Et (2l)
R2 =(CH2)CO2Me (2m)
R2 =(CH2)CO2Me (2m)
72
À91
82
À90
[a] Performed with hydroxylamine (1 equiv), allylamine (1.5 equiv), and
catalyst (0.2 equiv) in solvent (1m) under argon, for 24 h with catalyst 1b
(and 72 h with 1h) at room temperature. [b] Yields of the isolated prod-
uct. [c] Determined by chiral HPLC analysis of derivatized products (see
the Supporting Information).
With efficient conditions giving access to either enantiom-
er of the diamine motifs with catalysts 1b and 1h,[12] the ap-
plicability of this enantioselective reaction was evaluated
(Table 2). Electron-rich and electron-poor benzylic hydrox-
ylamines displayed excellent enantioselectivity with benzyl-
allylamine as substrate (Table 2, entries 1–6). In contrast, re-
duced enantioselectivity was seen with two aliphatic hydrox-
ylamines (Table 2, entries 7–9). To determine if this effect
was steric or electronic in nature, the reaction of benzylhy-
droxylamine and methylallylamine was also performed. This
reaction led to reduced enantioselectivity (56% ee; Table 2,
entry 10), which suggests that the size of the allylic amine is
important for high enantioselectivity. Additionally, the lower
enantioselectivity could result from reduced diastereoselec-
tivity in the formation of the mixed aminal I or from an
amine-catalyzed aldehyde epimerization process (see
below). To probe this, many secondary allylic amines were
reacted with benzylhydroxylamine and catalysts 1b and 1h
(Table 2, entries 11–20). Collectively, these results reveal
that the enantioselectivities obtained with catalyst 1b are
quite sensitive to the structure of the allylic amine (Table 2,
entries 10, 11, 13, 15, 17, and 19), and that the lowest enan-
tioselectivities are observed with the least nucleophilic
amines (60–95% ee; Table 2, entries 15 and 17 vs. 19). In
contrast, 1h afforded the enantiomeric products reliably in
high enantioselectivities (88–91% ee; Table 2, entries 12, 16,
18, and 20). Overall, the enantioselectivities obtained are, in
many cases, the highest obtained for intermolecular hydroa-
minations of unactivated alkenes by any method[7i,j] (includ-
ing metal-catalyzed reactions) and clearly validate the teth-
ering strategy as an effective method in asymmetric organo-
catalysis.
The enantioselectivity trend highlighted above for alde-
hyde 1b suggests that catalyst epimerization occurs under
the reaction conditions. To probe this, the aldehyde was sep-
arately exposed to catalytic amounts of each reagent and
the enantiopurity of the catalyst was determined after 24 h
(Figure 1). Both experiments showed significant epimeriza-
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Hydroamination of Allylic Amines with Chiral Aldehyde Catalysts
COMMUNICATION
oxyacetaldehyde, the latter step was shown to be rate deter-
mining.[14] Thus it is not clear if, in this system, the stereoin-
duction results from the stereoselective formation of aminal
I because of a preference for one of the two diastereomeric
transition states for the Cope-type hydroamination, or from
the synergy between these two steps. Experiments are un-
derway to determine the origin of enantioinduction in this
system.
In summary, we have shown that aldehydes catalyze the
intermolecular hydroamination of unactivated alkenes in
high enantiomeric excess. Both enantiomers of the hydro-
amination products containing the 1,2-diamine motif can be
synthesized in high enantioselectivity by using two different
chiral aldehydes catalysts. This work highlights the fact that
simple chiral a-oxygenated aldehydes are effective organo-
catalysts capable of efficiently inducing asymmetry through
temporary intramolecularity. Advanced scope, further cata-
lyst design, and mechanistic insights will be presented in due
course.
Figure 1. Probing the source of epimerization for catalyst 1b.
tion, with benzylallylamine (25 mol%) leading to almost
complete
racemization
and
benzylhydroxylamine
(25 mol%) leading to recovered aldehyde in 66% ee. Con-
trol experiments also showed that no epimerization of the
catalyst occurred simply upon stirring in benzene or hexa-
fluorobenzene. In agreement with this, the highest enantio-
selectivities observed with catalyst 1b involve the fastest re-
actions.[13]
With less nucleophilic amines, catalyst racemization is a
competing side reaction, leading to formation of the desired
adduct in 60 and 72% ee (Table 2, entries 15 and 17). Be-
cause aldehyde 1b epimerizes over time, even if stored neat
under argon at reduced temperatures (7–14 d, depending on
the batch), oxidation of the commercially available alcohol
precursor prior to each reaction proved a reliable experi-
mental procedure. In contrast, catalyst 1h is more robust,
because of its bicyclic nature, and affords the enantiomeric
products in high ee (Table 2, entries 16 and 18). In agree-
ment with this observation, the nitrone derived from 1h
proved remarkably stable toward epimerization in the pres-
ence of either excess hydroxyla-
Experimental Section
A round-bottom flask (5 mL) was charged with a stirring bar, hydroxyla-
mine (1 equiv; typically 1 mmol), degassed solvent (1.0m with respect to
hydroxylamine), amine (1.5 equiv), and lastly, catalyst (0.2 equiv). The re-
action was stirred at room temperature for 24–72 h. The crude reaction
mixture was concentrated under reduced pressure and purified by flash
column chromatography to give the corresponding N,N-dialkylhydroxyl-
amine products. To determine the ee, the hydroamination product (2a–
2m; 1 equiv) was dissolved in CH2Cl2 (0.5m) then 1,1’-carbonyldiimida-
zole (CDI; 1.5–2.5 equiv) was added and the reaction stirred for 3–24 h.
After completion, the reaction mixture was concentrated under reduced
pressure, purified by column chromatography and analyzed by HPLC
with an appropriate chiral column. See the Supporting Information for
details.
mine or amine (NMR spectra
are provided in Figure S1 of the
Supporting Information).
The proposed mechanism is
presented in Figure 2, and has
been thoroughly examined for
the related racemic reactions
involving a-benzyloxyacetalde-
hyde.[14] Condensation of the
hydroxylamine and the alde-
hyde precatalyst affords a ni-
trone, which is rapidly attacked
by an allylic amine to form a
transient, chiral mixed aminal I
(likely with high stereocontrol).
This stereocenter is then effi-
ciently transferred[5,15] through
the bicyclic transition state as-
sociated with a Cope-type hy-
Figure 2. Enantioselective hydroamination by temporary intramolecularity, with stereocontrol originating from
droamination. With a-benzyl- a transient stereocenter formed by a stereoselective 1,2-addition reaction.
Chem. Eur. J. 2013, 00, 0 – 0
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A. M. Beauchemin et al.
Chem. 2008, 120, 1432–1435; Angew. Chem. Int. Ed. 2008, 47, 1410–
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Acknowledgements
Support from NSERC, the University of Ottawa, the Canadian Founda-
tion for Innovation and the Ontario Ministry of Research and Innovation
is gratefully acknowledged. The donors of The American Chemical Soci-
ety Petroleum Research Fund are also acknowledged for support of re-
lated research efforts. D.J.S. thanks NSERC for postgraduate scholar-
ships. M.J.M. thanks Boehringer Ingelheim (Canada) Ltd. for a collabora-
tive graduate scholarship.
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Keywords: asymmetric catalysis
·
hydroamination
·
hydroxylamines · tethered reactions · vicinal diamines
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reverse Cope cyclizations or reverse Cope eliminations in the litera-
ture). Intermolecular variants of this reaction are scarce. For exam-
ples with alkenes, see: e) A. M. Beauchemin, J. Moran, M.-E.
Lebrun, C. Sꢂguin, E. Dimitrijevic, L. Zhang, S. I. Gorelsky, Angew.
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Hydroamination of Allylic Amines with Chiral Aldehyde Catalysts
COMMUNICATION
[14] N. Guimond, M. J. MacDonald, V. Lemieux, A. M. Beauchemin, J.
Am. Chem. Soc. 2012, 134, 16571–16577.
1996, 35, 2708–2748; for a review of reactions with chiral tethers,
see: b) T. Sugimura, Eur. J. Org. Chem. 2004, 1185–1192.
[15] For a leading review, see: a) D. Seebach, A. R. Sting, M. Hoffman,
Angew. Chem. 1996, 108, 2881–2921; Angew. Chem. Int. Ed. Engl.
Received: September 28, 2012
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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A. M. Beauchemin et al.
Chirally LinkedIn: Chiral aldehydes
are effective tethering catalysts for
enantioselective intermolecular hydro-
amination, which provides access to
vicinal diamine motifs in good yields
and excellent enantioselectivities (see
scheme). This work highlights simple
chiral a-oxygenated aldehydes as
effective organocatalysts capable of
efficiently inducing asymmetry through
transient intramolecularity.
Organocatalyzed Hydroamination
M. J. MacDonald, C. R. Hesp,
D. J. Schipper, M. Pesant,
A. M. Beauchemin* ............ &&& — &&&
Highly Enantioselective Intermolec-
ular Hydroamination of Allylic
Amines with Chiral Aldehydes as
Tethering Catalysts
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!