A dual-catalysis/anion-binding approach to the kinetic resolution of allylic amines

Article abstract of DOI:10.1021/ol200712b

Chemical equations presented. A dual-catalysis approach enables the small-molecule catalyzed kinetic resolution of allylic amines by acylation. By employing 2 mol % of each 4-(pyrrolidino)pyridine (PPY) and a readily available chiral hydrogen-bonding coca

Full text of DOI:10.1021/ol200712b

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2464–2467
A Dual-Catalysis/Anion-Binding Approach
to the Kinetic Resolution of Allylic Amines
Eric G. Klauber, Nisha Mittal, Tejas K. Shah, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New
Jersey, Piscataway, New Jersey 08854, United States
seidel@rutchem.rutgers.edu
Received March 16, 2011
ABSTRACT
A dual-catalysis approach enables the small-molecule catalyzed kinetic resolution of allylic amines by acylation. By employing 2 mol % of each
4-(pyrrolidino)pyridine (PPY) and a readily available chiral hydrogen-bonding cocatalyst, the first nonenzymatic kinetic resolution of allylic amines
was accomplished with s factors of up to 20.
Allylic amines are useful building blocks for the synth-
esis of amino acids,1 alkaloids,2 and therapeutic agents.3
Enantioenriched allylic amines4 have been prepared via
aza-Claisen rearrangement,1d,5 allylic amination,1a,c,e,6 vi-
nylation of protected imines,7 and aza-BaylisÀHillman
reaction,8 in addition to other methods.9 Many of these
approaches produce secondary or tertiary allylic amines.
Access to enantioenriched primary allylic amines may be
achieved via kinetic resolution of the corresponding race-
mic amines, but this process has remained elusive. This is
despite considerable efforts that have been devoted to the
kinetic resolution of allylic alcohols.10 Here we report the
kinetic resolution of allylic amines via a dual-catalyst
approach.
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r
10.1021/ol200712b
Published on Web 04/08/2011
2011 American Chemical Society

concentrations than achiral ion pair I. This favors a
scenario in which amines preferentially react with chiral
ion pair II over achiral ion pair I or unmodified acylating
reagent, thereby allowing for kinetic resolution.
Scheme 1. Anion-Binding Concept for Asymmetric Nucleophi-
lic Catalysis
Table 1. Evaluation of Reaction Parametersa
The high nucleophilicity of many primary amines poses
a significant challenge for their kinetic resolution by
acylation, specifically in the context of small-molecule
catalysis.11 Several elegant approaches to the kinetic reso-
lution of certain amines and some of their less nucleophilic
derivatives have been reported,12 but there is still no
general solution that is applicable to a broad range of
unmodified and highly reactive amines, including primary
allylic amines. We haverecently reported a new concept for
asymmetric nucleophilic catalysis,13 along with its applica-
tion to the kinetic resolution of benzylic13a and propargylic
amines.13b This concept is outlined in Scheme 1. Upon
combining a simple nucleophilic catalyst14 such as DMAP
with an acylating reagent, an equilibrium is set up in which
achiral ion pair I is formed. The addition of a chiral
catalyst, capable of binding to the anion of ion pair I via
hydrogen-bonding (HB) interactions, establishes a second
equilibrium that results in the formation of chiral ion pair
II.15À17 On the basis of our previous studies, it appears that
chiral ion pair II is more reactive and/or present in higher
HB catalyst
(mol %)
Nu catalyst
(mol %)
conversion
(%)
s
entry
factor
1
2
1a (5)
1a (5)
1a (5)
none
DMAP (5)
DMAP NO (5)
PPY (5)
none
55
57
55
8
12
12
3
14
4
N/A
N/A
N/A
N/A
N/A
N/A
13
5
none
DMAP (5)
PPY (5)
none
8
6
none
8
7b
8b
9b
10b
11b
12b
13
14
15
16
17
18
none
<2
<2
<2
55
33
29
56
53
55
58
55
58
none
DMAP (5)
PPY (5)
PPY (5)
DMAP (5)
none
none
1a (5)
1a (5)
1a (5)
1a (2)
1a (1)
1b (5)
1c (5)
1d (5)
2 (5)
9.5
1.6
14
(11) Enzymatic preparations of nonracemic amines: (a) Paetzold, J.;
€
Backvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620. (b) Turner, N. J. Nat.
PPY (2)
PPY (1)
PPY (5)
PPY (5)
PPY (5)
PPY (5)
Chem. Biol. 2009, 5, 568. (c) Hohne, M.; Bornscheuer, U. T. Chem-
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J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman,
G. W.; Hughes, G. J. Science 2010, 329, 305.
12
4.5
3.5
8.1
8.4
a Reactions were performed on a 0.2 mmol scale. The s factors were
determined by HPLC analysis; see the Supporting Information for
details. b Reactions were run for 30 min.
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Org. Lett., Vol. 13, No. 9, 2011
2465

Specifically, the combination of 5 mol % of each of the
two catalysts, 1a and DMAP, in addition to 0.6 equiv of
benzoic anhydride, resulted in the kinetic resolution
of amine 3a with an s factor18 of 12 at 55% conversion
(Table 1, entry 1). Other achiral nucleophilic cocatalysts
were subsequently evaluated. Interestingly, DMAP N-oxide
gave virtually identical results (entry 2), whereas the
more nucleophilic PPY led to an improved s factor of 14
(entry 3). Reactions in the absence of any catalyst or with
DMAP or PPY as the only catalyst under otherwise
identical conditions led to 8% conversion after 2 h. This
observation indicates that allylic amines are more nucleo-
philic than benzylic or propargylic amines, as the latter two
substrates typically give less than 2% conversion under the
same conditions.13
still observed. Other HB catalysts were also evaluated but
found to give poorer results (entries 15À18).
Table 2. Evaluation of Different Anhydridesa
entry
anhydride
conversion (%)
s factor
1
2
3
4
4a (R = H)
55
54
18
53
14
16
4b (R = Me)
4c (R = OMe)
4d (R = tBu)
9.2
5.6
a Reactions were performed on a 0.2 mmol scale. The s factors were
determined by HPLC analysis; see the Supporting Information for
details.
In order to better understand background rates and how
they affect selectivities, we performed a number of experi-
ments in which the reaction time was reduced from 2 h to
30 min (entries 7À12). Under these conditions, in the
absence of any catalyst or with DMAP or PPY as the only
catalyst, less than 2% conversion was observed. The
superiority of PPY over DMAP becomes apparent when
entries 10 and 11 are compared.19 In combination with
catalyst 1a, PPY led to 55% conversion and an s factor of
13, whereas DMAP only gave 33% conversion (s factor =
9.5). Consistent with our previous studies, catalyst 1a was
capable of catalyzing the reaction by itself, presumably
through direct activation of benzoic anhydride via HB.
However, this process was unselective (s factor = 1.6,
entry 12).
We hypothesized that a reduction in background rate
may be achieved by employing a less reactive acylating
reagent. To this end, several modified benzoic anhydrides
were tested under the optimized conditions (Table 2).
Indeed, the use of the more electron-rich anhydride 4b
led to an increased s factor of 16 (entry 2). However, a
further reduction in reactivity by using p-MeO-benzoic
anhydride led to lower conversion and selectivity (entry 3).
The bulkier tert-butyl-substituted anhydride 4d also gave a
lower s factor, although the reactivity remained high for
this acylating reagent.
Attempts to lower catalysts loadings in an effort to
increase the overall efficiency of the resolution were met
with success. The use of 2 mol % of each 1a and PPY
produced results similar to those obtained at 5 mol %
catalyst loadings (entry 13). The efficiency decreased
slightly when only 1 mol % of both catalysts was used
(entry 14). Nevertheless, a respectable s factor of 12 was
Scheme 2. Scope of the Resolution with Anhydride 4ba
(17) For other examples of chiral anion catalysis, see: (a) Alper, H.;
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Hebbe- Viton, V. Chem. Soc. Rev. 2003, 32, 373. (d) Carter, C.; Fletcher,
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(18) s factor = rate of faster reacting enantiomer/rate of slower
reacting enantiomer. s factors were calculated according to: Kagan,
H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249 See the Supporting
Information for details.
a Reactions were performed on a 0.25 mmol scale. The s factors are
averages of two runs (determined by HPLC analysis; see the Supporting
Information for details).
Given the improved results obtained with anhydride 4b
over benzoic anhydride (4a), we initially used 4b to explore
the scope of the allylic amine resolution. Some results of
this survey are shown in Scheme 2. Whereas in some cases
better s factors were indeed obtained with 4b than with 4a,
this trend proved not to be general. In many cases, con-
versions were low with 4b, and more importantly, selectiv-
ities also suffered.
(19) For kinetic studies with DMAP and derivatives, see: (a) Hofle,
G.; Steglich, W.; Vorbruggen, H. Angew. Chem., Int. Ed. 1978, 17, 569.
(b) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129. (c) Heinrich, M. R.;
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2004, 43, 5436. (e) Held, I.; Villinger, A.; Zipse, H. Synthesis 2005, 1425
and references cited therein.
(20) The requisite racemic allylic amines were conveniently obtained
in one step from the corresponding R,β-unsaturated ketones by follow-
ing a modified literature procedure: Miriyala, B.; Bhattacharyya, S.;
Williamson, J. S. Tetrahedron 2004, 60, 1463. See the Supporting
Information for details.
2466
Org. Lett., Vol. 13, No. 9, 2011

A broader range of allylic amines20 were resolved by
utilizing the optimized reaction conditions with benzoic
anhydride (4a) as the acylating reagent (Scheme 3).
Whereas an exchange of methyl for ethyl in the parent
substrate led to a slight drop in s factor, substrates bearing
the bulkier substituents isopropyl and tert-butyl were
resolved with higher s factors. Introduction of a methyl
substituent in either the para, meta, ororthoposition of the
phenyl ring of the parent substrate led to lower s factors. In
contrast, a chloro substituent in the para position had a
positive effect on the efficiency of the resolution, while the
same substituent in the meta or ortho position led to a drop
in selectivity.
Furthermore, the corresponding product 7 was obtained
with the same absolute configuration as other products,
establishing control of propargyl over phenyl.
Scheme 4. Comparison of Allylic and Propargylic Aminesa
Scheme 3. Scope of the Allylic Amine Resolutiona
a See footnote in Scheme 2.
In the present study, the analogous allylic amine 3o was
found to be significantly more reactive than 6. Although
the overallselectivity was lower for substrate3o(s factor =
5.5), our catalytic system again was found to be capable of
distinguishing between two different π-systems, with ap-
parent control of allyl over phenyl. The absolute config-
urations of 5o and recovered, enantioenriched 3o were
independently determined on the basis of literature
precedents.1a,21
In summary, we have reported the first small-molecule
catalyzed kinetic resolution of racemic allylic amines.
These substrates were resolved with s factors of up to 20
by using a dual catalyst approach that utilizes an achiral
nucleophilic catalyst in combination with a chiral HB
catalyst. Further applications of this strategy are currently
being developed in our laboratory.
Acknowledgment. Financial support from Rutgers, The
State University of New Jersey, is gratefully acknowl-
edged. We thank Dr. Tom Emge (Rutgers University)
for crystallographic analysis. E.G.K. thanks the US De-
partment of Education for a GAANN fellowship. T.K.S.
acknowledges support from the Aresty Research Center
for Undergraduates. D.S. is a fellow of the A. P. Sloan
Foundation.
a See footnote in Scheme 2.
Substrates with further extended π-systems, such as 3k
and 3l, were resolved with s factors approaching 10. The
trisubstituted allylic amine 3m gave a modest level of
selectivity (s factor = 5.8). Amine 3n gave a poor result
(s factor = 3.5), suggesting the importance of conjugation
of the allylic amine to another π- system.
We had previously observed that propargylic amines
that are also benzylic are significantly less reactive than pro-
pargylic amines with aliphatic side chains (Scheme 4, eq 5).13b
Nevertheless, compound 6 was resolved with an s factor
of 12, indicating that the catalytic system is capable
of distinguishing between two different π-systems.
Supporting Information Available. Experimental proce-
dures and characterization data, including an X-ray crystal
structure of product 5h (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(21) Bishop, J. A.; Lou, S.; Schaus, S. E. Angew. Chem., Int. Ed. 2009,
48, 4337.
Org. Lett., Vol. 13, No. 9, 2011
2467