Merging nucleophilic and hydrogen bonding catalysis: An anion binding approach to the kinetic resolution of propargylic amines

Article abstract of DOI:10.1021/ja105337h

An efficient kinetic resolution of primary propargylic amines with s-factors of up to 56 is reported. The strategy is based on a dual catalytic approach, namely the use of a newly developed and easy-to-make thiourea-amide anion binding catalyst in combination with 4-(dimethylamino)pyridine (DMAP), both employed at a 5 mol % catalyst loading. Benzylic amines are also resolved with s-factors of up to 38.

Full text of DOI:10.1021/ja105337h

Published on Web 09/15/2010
Merging Nucleophilic and Hydrogen Bonding Catalysis: An Anion Binding
Approach to the Kinetic Resolution of Propargylic Amines
Eric G. Klauber, Chandra Kanta De, Tejas K. Shah, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received June 17, 2010; E-mail: seidel@rutchem.rutgers.edu
Table 1. Evaluation of Reaction Parametersa
Abstract: An efficient kinetic resolution of primary propargylic
amines with s-factors of up to 56 is reported. The strategy is
based on a dual catalytic approach, namely the use of a newly
developed and easy-to-make thiourea-amide anion binding cata-
lyst in combination with 4-(dimethylamino)pyridine (DMAP), both
employed at a 5 mol % catalyst loading. Benzylic amines are also
resolved with s-factors of up to 38.
Propargylic amines constitute versatile synthetic intermediates
and are found as substructures in natural products and medicinal
drugs.1 Consequently, significant efforts have been devoted to
synthesize propargylic amines in enantioenriched form.2 The
majority of catalytic enantioselective approaches have focused on
the addition of alkynes to imines.3 In most cases, the resulting
secondary propargylic amines cannot be readily transformed into
the often synthetically more useful primary amines. A practical
approach to enantioenriched primary propargylic amines would be
the kinetic resolution of the corresponding and readily available
racemic amines. Although small-molecule catalyzed kinetic resolu-
tions of propargylic alcohols have been reported,4 the equivalent
reaction with propargylic amines has remained elusive. Here we
report the first example of such a process.
entry
catalyst (mol %)
DMAP (mol %)
conversion (%)
s-factor
1
2
3
4
5
6
7
8
1a (20)
1b (20)
2 (20)
3a (20)
3b (20)
3c (20)
4a (20)
5 (20)
6 (20)
4a (10)
4a (5)
4a (2)
4a (2)
4a (1)
none
20
20
20
20
20
20
20
20
20
10
5
2
2
1
5
none
none
5
5
5
49
42
30
48
50
51
50
27
38
47
46
41
46
24
<5
<2
26
43
42
42
41
39
11
9
1
8.6
14
9.2
33
1
1.5
33
38
35
35
18
N/A
N/A
1.6
18
28
14
13
3.0
9
10
11
12
13b
14b
15
16
17
18
19
20
21
22
The inherent nucleophilicity of primary amines presents a
significant challenge for their kinetic resolution by small-molecule
based chiral nucleophilic catalysts.5 In fact, the nucleophilicity of
the amine substrate is often comparable to that of potential catalysts.
Although a few elegant approaches to the kinetic resolution of
amines and some of their less nucleophilic derivatives have been
reported,6,7 there is still no general solution that is applicable to a
broad range of unmodified and highly reactive amines.
none
4a (5)
4b (5)
4c (5)
4d (5)
4e (5)
4f (5)
5
5
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 4 h.
We have recently reported a new concept for asymmetric
catalysis that provides an alternative to the use of chiral nucleophilic
catalysts (eq 1).8-11 A simple achiral acyl pyridinium salt (e.g.,
ion pair I), formed in situ from DMAP and an acylating reagent, is
rendered chiral upon binding of the associated anion to a chiral
thiourea compound. The latter functions as an anion receptor to
form chiral ion pair II. Conditions were identified under which
primary benzylic amines react predominantly with ion pair II over
ion pair I or a free acylating reagent. This approach enabled the
kinetic resolution of benzylic amines.8
resolution of propargylic amine 7a with an s-factor13 of 11 (Table
1, entry 1). In order to determine what structural parameters affect
catalyst performance and to ultimately identify a more efficient
catalyst, we performed a systematic modification of the basic
catalyst framework. Exchanging both of the thiourea moieties for
3,5-bis(CF3)benzamide groups resulted in the ineffective catalyst
2 (entry 3). Replacement of only one of the thiourea functions with
a simple acetyl group led to the improved catalyst 3b (entry 5). A
significantly more efficient catalyst (4a) resulted from the replace-
ment of one thiourea subunit for 3,5-bis(CF3)benzamide (entry 7).
This catalyst performed equally well at a 10 mol % loading (entry
10) and, remarkably, even better if used in only 5 mol % (entry
Gratifyingly, our previously optimized conditions with catalyst
1a12 (20 mol %) and DMAP (20 mol %) allowed for the kinetic
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13624 J. AM. CHEM. SOC. 2010, 132, 13624–13626
10.1021/ja105337h  2010 American Chemical Society

C O M M U N I C A T I O N S
Chart 2. Kinetic Resolution of Benzylic Aminesa
Chart 1. Scope of the Propargylic Amine Resolutiona
a See footnote in Chart 1. Numbers in parentheses correspond to results
obtained with 20 mol % of each, catalyst 1a, and DMAP.
In summary, we have introduced a new and easy-to-make
thiourea-amide anion binding catalyst that, in combination with
catalytic amounts of simple DMAP, enables the efficient kinetic
resolution of propargylic and benzylic amines with s-factors of up
to 56. The use of catalyst 4a is currently being explored in other
reactions that could proceed through chiral anionic intermediates.
Acknowledgment. Financial support from Rutgers, The State
University of New Jersey is gratefully acknowledged. We thank
Dr. Tom Emge for crystallographic analysis. T.K.S. acknowledges
support from the Aresty Research Center for Undergraduates.
Supporting Information Available: Experimental procedures and
characterization data, including X-ray crystal structures of catalyst 4a
and product 8e (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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). b The reaction was run for 8 h.
11). Under these conditions, 7a was resolved with an s-factor of
38. The efficiency was still high at a 2 mol % catalyst loading but
diminished markedly when only 1 mol % of each, DMAP and 4a,
were used. Very little conversion occurred in the absence of 4a or
both, DMAP and 4a (entries 15 and 16). Catalyst 4a in the absence
of DMAP catalyzed the reaction but led to much lower conversion
and essentially no resolution (s-factor ) 1.6, entry 17). Benzyl-
thiourea 5 and sulfonamide-thiourea 6 proved to be inefficient
catalysts (entries 8 and 9). Other benzamide-thiourea catalysts were
also evaluated but gave inferior results with regard to selectivity
(entries 18-22).14
The scope of the reaction was explored under the optimized
conditions (Chart 1). A number of propargylic amines were resolved
with good to excellent selectivities. Arylpropargylic amines bearing
substituents on different ring positions were readily accommodated.
Substitution in the 3-position of the aromatic ring gave rise to the
highest s-factors, regardless of the electronic nature of the sub-
stituent. Substrates 7j and 7k, with alkyl groups other than methyl,
were resolved with even better selectivities as compared to the
parent substrate 7a.
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