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

Article abstract of DOI:10.1021/ja9079435

(Chemical Equation Presented) A new concept for asymmetric nucleophilic catalysis is presented. Acyl pyridinium salts derived from 4-(dimethylamino) pyridine (DMAP) and benzoic anhydride are rendered chiral via interaction with a chiral thiourea anion rec

Full text of DOI:10.1021/ja9079435

Published on Web 11/06/2009
Merging Nucleophilic and Hydrogen Bonding Catalysis: An Anion Binding
Approach to the Kinetic Resolution of Amines
Chandra Kanta De, Eric G. Klauber, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received September 17, 2009; E-mail: seidel@rutchem.rutgers.edu
Table 1. Evaluation of Reaction Parametersa
Nucleophilic catalysis is a powerful concept for instilling asymmetry
into a variety of different reactions.1,2 Chiral derivatives of 4-(dim-
ethylamino)pyridine (DMAP) feature prominently among the catalysts
used for kinetic resolution and desymmetrization processes.1 The
intermediate chiral ion pairs (e.g., I) are more reactive than the acylating
reagents used to generate them, thus enabling enantioselective acyl
transfer pathways. Here we present a new concept for asymmetric
nucleophilic catalysis and its application to the kinetic resolution of
primary amines.
catalyst
(mol %)
DMAP
(mol %)
concn
[M]
conversion
(%)
entry
s-factor
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (15)
1a (10)
1a (5)
50
50
50
50
50
40
30
20
10
5
0.06
0.03
0.02
0.01
0.005
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
47
47
47
45
44
47
47
45
43
44
46
46
44
<1
<2
40
40
43
21
44
42
30
38
5.5
7.0
8.6
9.5
9.4
9.4
10
We envisioned a simple achiral acyl pyridinium salt to be rendered
chiral upon binding of the corresponding anion to a chiral anion
receptor (e.g., a thiourea compound), resulting in the formation of chiral
ion pair III. This strategy provides an alternative to the use of chiral
DMAP analogues and might offer potential advantages. First, III could
be a better acylating agent than II, as binding of a chiral receptor to
the anion should serve to lower interactions of the latter with the acyl
pyridinium species, making it more electrophilic. In addition, the proper
choice of X- and the reaction medium could cause II to be significantly
less soluble than III, further favoring reaction of the substrate to occur
with III over II. Furthermore, the achiral nucleophilic promoter or
the acyl pyridinium salt itself (e.g., II) could be used in stoichiometric
amounts. Inspiration for this concept was drawn from the field of anion
binding receptors3 as well as the recent elegant contributions by
Jacobsen,4 Schreiner,5 and others.6,7
10
8.5
7.7
9.0
9.0
8.5
N/A
N/A
1.4
8.6
4.5
4.1
7.2
3.7
1.2
1.5
15
10
5
none
none
none
20
none
20
20
20
20
20
20
20
1a (20)
1b (20)
1c (20)
1d (20)
2 (20)
3 (20)
4 (20)
The kinetic resolution of amines was considered a worthy challenge,
suited ideally to demonstrate the potential of this new concept. The
inherent nucleophilicity of primary amines, being comparable to the
reactivity of many potential nucleophilic promoters, has hampered the
development of small molecule catalysts that can efficiently resolve
this important class of substrates. We are aware of only one example,
an insightful contribution by Fu and co-workers, in which simple
amines such as 6a were resolved successfully using a combination of
a chiral PPY catalyst and an azlactone based acylating reagent.8,9
In the realm of small molecule catalysis,10 there are no examples
that employ catalytic amounts of a chiral promoter in combination
with a simple acylating reagent.11 Table 1 summarizes our efforts in
identifying a viable hydrogen bonding (HB) catalyst12,13 for the process
outlined in eq 1. Toluene solutions of benzoic anhydride and DMAP
were prepared at room temperature in the presence of molecular sieves,
followed by cooling to -78 °C and addition of catalyst and amine.
Enantioenriched products were obtained at various substrate concentra-
tions, with a 0.01 M concentration providing the best s-factor (entry
4).14 We next studied the efficiency of this process with regards to
5 (20)
a Reactions were performed on a 0.2 mmol scale. The s-factors were
determined by HPLC analysis; see the Supporting Information for details.
the amount of DMAP used. Remarkably, the use of only 20 mol % of
DMAP gave rise to an improved s-factor of 10 (entry 8). Lower
amounts of DMAP resulted in reduced s-factors. While loadings for
both catalysts could be lowered further (entries 11-13), the s-factors
were slightly reduced in these instances. Interestingly, virtually no
conversion occurred in the absence of both DMAP and catalyst 1a
(entry 14). Addition of DMAP (20 mol %) as the only catalyst had no
discernible effect on the reaction rate (entry 15). Use of the thiourea
catalyst 1a (20 mol %) in the absence of DMAP gave rise to significant
amounts of enantioenriched product (entry 16). However, the efficiency
of this process is considerably lower in comparison to the optimized
process in which the DMAP cocatalyst is present. Other HB catalysts
were also evaluated but gave inferior results (entries 17-23).15 We
9
17060 J. AM. CHEM. SOC. 2009, 131, 17060–17061
10.1021/ja9079435  2009 American Chemical Society

C O M M U N I C A T I O N S
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propose that catalysis in the absence of DMAP involves HB activation
of the anhydride via an intermediate such as A.16 In the presence of
DMAP, intermediates related to B appear to dominate the outcome of
this reaction, as the direct interaction of an acyl pyridinium species
with a thiourea is unlikely.4a Binding of benzoate to thiourea 1a may
have an effect on the equilibrium concentrations of DMAP and its
corresponding acyl pyridinium salt, a factor that is likely playing an
important role in the overall process.17-19
(2) Nucleophilic catalysis is also classified as a type of Lewis base catalysis:
Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
(3) For selected reviews, see: (a) Kang, S. O.; Begum, R. A.; Bowman-James,
K. Angew. Chem., Int. Ed. 2006, 45, 7882. (b) Sessler, J. L.; Gale, P. A.;
Cho, W.-S. Anion Receptor Chemistry; Royal Society of Chemistry:
Cambridge, UK, 2006; p 413. (c) Caltagirone, C.; Gale, P. A. Chem. Soc.
ReV. 2009, 38, 520.
(4) (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 13404. (b) Raheem, I. T.; Thiara, P. S.; Jacobsen,
E. N. Org. Lett. 2008, 10, 1577. (c) Reisman, S. E.; Doyle, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2008, 130, 7198. (d) Klausen, R. S.; Jacobsen,
E. N. Org. Lett. 2009, 11, 887. (e) Peterson, E. A.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2009, 48, 6328.
(5) (a) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434. (b) Kotke, M.;
Schreiner, P. R. Synthesis 2007, 779.
(6) For examples of asymmetric catalysis involving chiral anions, see: (a) Alper,
H.; Hamel, N. J. Am. Chem. Soc. 1990, 112, 2803. (b) Llewellyn, D. B.;
Adamson, D.; Arndtsen, B. A. Org. Lett. 2000, 2, 4165. (c) Lacour, J.;
Hebbe-Viton, V. Chem. Soc. ReV. 2003, 32, 373. (d) Carter, C.; Fletcher,
S.; Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995. (e) Llewellyn,
D. B.; Arndtsen, B. A. Tetrahedron: Asymmetry 2005, 16, 1789. (f) Mayer,
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Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. (h) Rueping,
M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed. 2007, 46,
6903. (i) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (j)
Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am.
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Lacour, J. Chem. Commun. 2008, 829. (l) Wang, X.; List, B. Angew. Chem.,
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The scope of the reaction was explored under the previously
optimized conditions (Chart 1). A number of benzylic amines were
resolved with good selectivities. Notably, electron-poor substrates gave
higher s-factors, regardless of the position of the electron-withdrawing
group. Catalysis via the competing and s-factor lowering pathway A
is likely reduced in these cases. Remarkably, the seemingly more
challenging substrates 6l and 6n were resolved with better selectivities
as compared to the parent substrate 6a. Using only 5 mol % of each
DMAP and 1a, amine 6g could be resolved with an only slightly
reduced s-factor of 19 (47% conversion, 2 h). This trend appears to
be general, and other substrates performed well at this lower catalyst
loading.20
(7) Asymmetric Brønsted acid catalysis frequently involves chiral ion pairs.
For a review, see: Akiyama, T. Chem. ReV. 2007, 107, 5744.
(8) (a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234. For the kinetic resolution of indolines, see: (b) Arp, F. O.; Fu,
G. C. J. Am. Chem. Soc. 2006, 128, 14264.
Chart 1. Scope of the Reactiona
(9) For the kinetic resolution of oxazolidinones, see: Birman, V. B.; Jiang, H.;
Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc. 2006, 128, 6536.
(10) Remarkable advances have been made in enzymatic amine resolutions. For
examples, see: (a) Alexeeva, M.; Carr, R.; Turner, N. J. Org. Biomol. Chem.
2003, 1, 4133. (b) Paetzold, J.; Ba¨ckvall, J. E. J. Am. Chem. Soc. 2005,
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M.; Bornscheuer, U. T. ChemCatChem 2009, 1, 42.
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reagents have been reported. For examples, see: (a) Ie, Y.; Fu, G. C. Chem.
Commun. 2000, 119. (b) Arseniyadis, S.; Valleix, A.; Wagner, A.;
Mioskowski, C. Angew. Chem., Int. Ed. 2004, 43, 3314.
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ReV. 2003, 32, 289. (b) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(d) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int.
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107, 5713. (f) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. (g) Zhang,
Z.; Schreiner, P. R. Chem. Soc. ReV. 2009, 38, 1187.
(13) For selected uses of the catalysts employed in this study, see: (a) Sohtome,
Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004,
45, 5589. (b) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 6576. (c) Fleming, E. M.; McCabe, T.; Connon,
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T.-R.; Hu, Z.-K.; Chen, Y.-C. J. Am. Chem. Soc. 2008, 130, 2456. (e)
Rampalakos, C.; Wulff, W. D. AdV. Synth. Catal. 2008, 350, 1785. (f)
Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.; Nagasawa, K.
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a Reactions were performed on a 0.25 mmol scale. The s-factors were
determined by HPLC analysis; see the Supporting Information for details
(14) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(15) Cocatalysts such as pyridine, NMI, PPY, DBU, and DABCO are less
efficient than DMAP. The use of Et3N in place of DMAP gave results
almost identical to those using 1a as the only catalyst (Table 1, entry 16).
(16) HB activation of anhydrides by (thio)urea catalysts is a well precedented
concept. For examples, see: (a) Peschiulli, A.; Gun’ko, Y.; Connon, S. J.
J. Org. Chem. 2008, 73, 2454. (b) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee,
J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed. 2008, 47,
7872. (c) Wang, S.-X.; Chen, F.-E. AdV. Synth. Catal. 2009, 351, 547.
(17) The acyl pyridinium salt derived from DMAP and benzoic anhydride is
not formed quantitatively but is likely present in equilibrium concentrations
only. For an excellent study on such equilibria, see: (a) Lutz, V.; Glatthaar,
J.; Wu¨rtele, C.; Serafin, M.; Hausmann, H.; Schreiner, P. R. Chem.sEur.
J. 2009, 15, 8548. See also: (b) Xu, S.; Held, I.; Kempf, B.; Mayr, H.;
Steglich, W.; Zipse, H. Chem.sEur. J. 2005, 11, 4751.
(18) The nature of the anion is crucial with benzoate giving the best results.
Acylating reagents such as PhCOF, PhCOCl, PhCOBr, Ac2O, and trifluo-
roacetic anhydride were inferior to benzoic anhydride.
In summary, we have introduced a new concept for asymmetric
nucleophilic catalysis that involves the use of chiral anion receptors to
generate chiral ion pairs in situ from simple acyl pyridinium salts. This
strategy was successfully applied to the kinetic resolution of amines.
Current efforts are aimed at developing a more complete mechanistic
understanding of this reaction and at exploring related processes.
Acknowledgment. Financial support from Rutgers, The State
University of New Jersey is gratefully acknowledged.
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) The role of the second thiourea subunit is not clear at present.
(20) Additional results using 1a (5 mol%) and DMAP (5 mol%): 6d (s ) 15,
References
46% conv.), 6f (s ) 19, 44% conv.), 6l (s ) 12, 41% conv.).
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JA9079435
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