Kinetic resolution of amines via dual catalysis: Remarkable dependence of selectivity on the achiral cocatalyst

Article abstract of DOI:10.1021/ol301155b

A dual-catalysis/anion-binding approach with a chiral hydrogen bonding (HB) catalyst and an achiral nucleophilic cocatalyst was applied to the kinetic resolution of amines. Out of a structurally diverse collection of 22 nucleophilic species, 4-di-n-propylaminopyridine emerged as the most efficient cocatalyst, allowing for the kinetic resolution of benzylic amines with s-factors of up to 67.

Full text of DOI:10.1021/ol301155b

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3084–3087
Kinetic Resolution of Amines via Dual
Catalysis: Remarkable Dependence of
Selectivity on the Achiral Cocatalyst
Nisha Mittal, Diana X. Sun, 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 April 28, 2012
ABSTRACT
A dual-catalysis/anion-binding approach with a chiral hydrogen bonding (HB) catalyst and an achiral nucleophilic cocatalyst was applied to the
kinetic resolution of amines. Out of a structurally diverse collection of 22 nucleophilic species, 4-di-n-propylaminopyridine emerged as the most
efficient cocatalyst, allowing for the kinetic resolution of benzylic amines with s-factors of up to 67.
The discovery of 4-dimethylaminopyridine (DMAP) by
€
has enabled the development of many synthetically valuable
acyl-transfer processes.3 Pioneering contributions by Vedejs,4
Fu,5 Kawabata/Fuji,6 and others7 have resulted in the
identification of powerful chiral DMAP analogues and
related nucleophilic catalysts. Among the various asym-
metric reactions that have been studied with chiral nucleo-
philic catalysts, the kinetic resolution of alcohols has
received much attention.8 In contrast, the corresponding
kinetic resolution of amines with small-molecule catalysts
has remained in its infancy.9 This fact is readily explained
by the difficulties associated with this substrate class,
as the high reactivity of unmodified amines results in
high background reaction rates with many acylating re-
agents. The first small-molecule catalysis approach to the
kinetic resolution of unmodified primary amines, specifi-
cally benzylic amines, was reported by Fu et al. in 2001.10
In this landmark study, an azlactone derived acylating
reagent was utilized with a planar chiral 4-pyrrolidinopyr-
idine catalyst (PPY*). Other important contributions were
1
Litvinenko/Kirichenko and independently Steglich/Hofle
2
(1) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk SSSR
1967, 176, 97.
(2) Steglich, W.; Hoefle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981.
(3) Selected reviews on DMAP catalysis: (a) Hoefle, G.; Steglich, W.;
Vorbrueggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (b) Spivey,
A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436. (c) De
Rycke, N.; Couty, F.; David, O. R. P. Chem.;Eur. J. 2011, 17, 12852.
(4) Vedejs, E.; Chen, X. H. J. Am. Chem. Soc. 1996, 118, 1809.
(5) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230.
(6) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem.
Soc. 1997, 119, 3169.
(7) Selected key contributions by others: (a) Vedejs, E.; Daugulis, O.;
Diver, S. T. J. Org. Chem. 1996, 61, 430. (b) Oriyama, T.; Hori, Y.; Imai,
K.; Sasaki, R. Tetrahedron Lett. 1996, 37, 8543. (c) Miller, S. J.; Copeland,
G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc.
1998, 120, 1629. (d) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem.
2000, 65, 3154. (e) Birman, V. B.; Uffman, E. W.; Hui, J.; Li, X. M.;
Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226.
(8) Selected reviews on nucleophilic catalysis and asymmetric acyl
transfer: (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412. (b) France, S.;
Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985. (c) Fu,
G. C. Acc. Chem. Res. 2004, 37, 542. (d) Miller, S. J. Acc. Chem. Res.
2004, 37, 601. (e) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44,
3974. (f) Wurz, R. P. Chem. Rev. 2007, 107, 5570. (g) Denmark, S. E.;
Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560. (h) Spivey, A. C.;
Arseniyadis, S. Top. Curr. Chem. 2010, 291, 233. (i) Mueller, C. E.;
Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50, 6012. (j) Krasnov,
V. P.; Gruzdev, D. A.; Levit, G. L. Eur. J. Org. Chem. 2012, 1471.
(k) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41,
2109.
€
(9) Selected reviews on enzymatic resolutions of amines: (a) Hohne, M.;
Bornscheuer, U. T. ChemCatChem 2009, 1, 42. (b) Gotor-Fernandez, V.;
Gotor, V. Curr. Opin. Drug Discovery Dev. 2009, 12, 784. (c) Turner, N. J.
Nat. Chem. Biol. 2009, 5, 567. (d) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J.
Eur. J. Org. Chem. 2010, 999.
(10) (a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem.,
Int. Ed. 2001, 40, 234. See also: (b) Arp, F. O.; Fu, G. C. J. Am. Chem.
Soc. 2006, 128, 14264. (c) Anstiss, M.; Nelson, A. Org. Biomol. Chem.
2006, 4, 4135.
(11) (a) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W.
J. Am. Chem. Soc. 2006, 128, 6536. (b) Yang, X.; Bumbu, V. D.; Birman,
V. B. Org. Lett. 2011, 13, 4755.
r
10.1021/ol301155b
Published on Web 05/31/2012
2012 American Chemical Society

reported by Birman11 and Miller,12 who successfully de-
vised methods to resolve amine derivatives with attenuated
reactivities. Very recently, a unique dual-catalysis redox
approachtothe kineticresolution of secondaryamines was
reported by Bode et al.13À15 Our group has advanced a
dual-catalysis approach in which a chiral acylating reagent
is generated in situ via the interplay of a chiral anion
receptor/H-bonding (HB) catalyst,16 DMAP as an achiral
nucleophilic cocatalyst, and a stoichiometric amount of
benzoic anhydride as the acylating reagent.17À19 Here we
report the results of a systematic study aimed at identifying
the ideal nucleophilic cocatalyst for this process.
(12) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem. Soc.
2010, 132, 2870.
(13) Binanzer, M.; Hsieh, S. Y.; Bode, J. W. J. Am. Chem. Soc. 2011,
133, 19698.
(14) Other approaches to amine resolution: (a) Arnold, K.; Davies,
B.; Herault, D.; Whiting, A. Angew. Chem., Int. Ed. 2008, 47, 2673.
(b) Reznichenko, A. L.; Hampel, F.; Hultzsch, K. C. Chem.;Eur. J.
2009, 15, 12819.
(15) Selected reviews on dual catalysis: (a) Paull, D. H.; Abraham,
C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res.
2008, 41, 655. (b) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745.
(c) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2999. (d) Rueping, M.;
Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J. 2010, 16, 9350.
(e) Piovesana, S.; Scarpino Schietroma, D. M.; Bella, M. Angew. Chem.,
Int. Ed. 2011, 50, 6216. (f) Briere, J. F.; Oudeyer, S.; Dalla, V.; Levacher,
V. Chem. Soc. Rev. 2012, 41, 1696. (g) Allen, A. E.; MacMillan, D. W. C.
Chem. Sci. 2012, 3, 633.
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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) Connon, S. J. Chem.;Eur. J. 2006, 12, 5418. (e) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (f) Akiyama, T. Chem. Rev.
2007, 107, 5744. (g) Yu, X.; Wang, W. Chem.;Asian J. 2008, 3, 516.
(h) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187. (i) Schenker,
S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B. Eur. J. Org. Chem. 2011,
2209.
(17) (a) De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 17060. (b) Klauber, E. G.; De, C. K.; Shah, T. K.; Seidel, D. J. Am.
Chem. Soc. 2010, 132, 13624. (c) Klauber, E. G.; Mittal, N.; Shah, T. K.;
Seidel, D. Org. Lett. 2011, 13, 2464. (d) De, C. K.; Seidel, D. J. Am.
Chem. Soc. 2011, 133, 14538. (e) De, C. K.; Mittal, N.; Seidel, D. J. Am.
Chem. Soc. 2011, 133, 16802.
Figure 1. Dual-catalysis/anion-binding approach to amine
resolution.
Previous results for the kinetic resolution of benzylic
amines are summarized in Figure 1. Our initial study with
known urea and thioureacatalysts revealedthat the readily
available Nagasawa catalyst (3)20 provides good selectiv-
ities in the kinetic resolution of benzylic amine 1a.17a
A
subsequent evaluation of a range of previously unknown
catalysts led to the development of thiourea-amide catalyst
4, which enabled improved selectivities at lower catalyst
loadings.17b Although either chiral catalyst 3 or 4 can cata-
lyze the amine acylation in the absence of a nucleophilic
cocatalyst, this leads to almost no resolution. Addition of
the achiral nucleophilic cocatalyst DMAP is required in
order to obtain high levels of selectivity. The reaction is
thought toinvolve anin situformedchiralion pairinwhich
the benzoate anion of the acylpyridinium salt is bound to the
HB catalyst (Figure 1). The crucial role of DMAP led us to
consider that its replacement by other nucleophilic cocata-
lysts might present an avenue for further selectivity im-
provement. In addition to the changes in selectivity that
could be brought about by simple structural modifications,
we hypothesized that an increase in nucleophilicity may lead
to more efficient catalysis. Furthermore, as 4 displays
relatively poor solubility in toluene, a nucleophilic cocata-
lyst more soluble than DMAP was thought to potentially
(18) Examples of anion binding approaches to catalysis: (a) Kotke,
M.; Schreiner, P. R. Tetrahedron 2006, 62, 434. (b) Kotke, M.; Schreiner,
P. R. Synthesis 2007, 779. (c) Raheem, I. T.; Thiara, P. S.; Peterson,
E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (d) Reisman,
S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198.
(e) Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887. (f) Zuend,
S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358. (g) Xu, H.;
Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327,
986. (h) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010,
132, 5030. (i) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2010, 132, 9286. (j) Singh, R. P.; Foxman, B. M.; Deng, L. J. Am.
Chem. Soc. 2010, 132, 9558. (k) Veitch, G. E.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2010, 49, 7332. (l) Knowles, R. R.; Jacobsen, E. N. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 20678. (m) Kim, H. Y.; Oh, K. Org.
Lett. 2011, 13, 1306. (n) Opalka, S. M.; Steinbacher, J. L.; Lambiris,
B. A.; McQuade, D. T. J. Org. Chem. 2011, 76, 6503. (o) Birrell, J. A.;
Desrosiers, J.-N.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 13872.
(p) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011,
133, 14578.
(19) Other examples of chiral anion catalysis: (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) Mayer, S.; List, B. Angew.
Chem., Int. Ed. 2006, 45, 4193. (f) Rueping, M.; Antonchick, A. P.;
Brinkmann, C. Angew. Chem., Int. Ed. 2007, 46, 6903. (g) Hamilton,
G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
(h) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (i) Wang,
X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119. (j) Hamilton, G. L.;
Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984. (k) Garcia-
Garcia, P.; Lay, F.; Garcia-Garcia, P.; Rabalakos, C.; List, B. Angew.
Chem., Int. Ed. 2009, 48, 4363. (l) Lacour, J.; Moraleda, D. Chem.
Commun. 2009, 7073. (m) Liao, S. H.; List, B. Angew. Chem., Int. Ed.
2010, 49, 628. (n) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2010, 49, 9685. (o) Yazaki, R.; Kumagai, N.; Shibasaki, M.
J. Am. Chem. Soc. 2010, 132, 10275. (p) Rueping, M.; Uria, U.; Lin,
M. Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732. (q) Jiang, G.;
Halder, R.; Fang, Y.; List, B. Angew. Chem., Int. Ed. 2011, 50, 9752.
(r) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science
2011, 334, 1681. (s) Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.;
Krische, M. J. Science 2012, 336, 324.
(20) (a) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589. (b) Sohtome, Y.; Takemura, N.;
Takagi, R.; Hashimoto, Y.; Nagasawa, K. Tetrahedron 2008, 64, 9423.
(21) Selected reports on the reactivity of DMAP and derivatives:
(a) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H. Angew.
Chem., Int. Ed. 2003, 42, 4826. (b) Xu, S.; Held, I.; Kempf, B.; Mayr, H.;
Steglich, W.; Zipse, H. Chem.;Eur. J. 2005, 11, 4751. (c) Held, I.;
Villinger, A.; Zipse, H. Synthesis 2005, 1425. (d) Fischer, C. B.; Xu,
S. J.; Zipse, H. Chem.;Eur. J. 2006, 12, 5779. (e) Brotzel, F.; Kempf, B.;
Singer, T.; Zipse, H.; Mayr, H. Chem.;Eur. J. 2007, 13, 336. (f) Lutz, V.;
€
Glatthaar, J.; Wurtele, C.; Serafin, M.; Hausmann, H.; Schreiner, P. R.
Chem.;Eur. J. 2009, 15, 8548.
Org. Lett., Vol. 14, No. 12, 2012
3085

improve the overall efficiency of the process by enabling the
formation of a more soluble chiral ion pair.
(s-factor = 1.9, entry 1).22 On the other hand, the combina-
tion of DMAP and 4 gave an s-factor of 13 at 41% con-
version (entry 2). Remarkably, the simple switch from
DMAP to 4-diethylaminopyridine (6b) led to a dramatic in-
crease in selectivity (s-factor = 24, entry 3). Another incre-
mental increase in selectivity was observed upon switching
to 4-di-n-propylaminopyridine (6c) (s-factor = 27, entry 4).23
Further extension of the alkyl chain led to a drop-off in
s-factors (entries 5À9). Interestingly, for alkyl groups beyond
n-pentyl, the s-factor remained nearly constant at 18.
Table 1. Evaluation of Nucleophilic Cocatalystsa
Two isomers of 4-di-n-propylaminopyridine (6c) were
tested: 4-(N-methyl-N-pentylamino)pyridine (6i) and
4-diisopropylaminopyridine (6j). While the latter cocata-
lyst reached almost the same level of selectivity as 6c, the
former showed a selectivity similar to those of the longer
chain analogues.24 Just as we had observed in the kinetic
resolution of allylic amines,17c PPY (7) offered a slight but
measurable improvement over DMAP (entry 13). In con-
trast, 4-piperidinopyridine (8) gave inferior results. Ana-
logues of DMAP with enhanced nucleophilicities25 (9 and
10aÀd) provided unsatisfactory results (entries 15À19).
Amidine-type catalysts such as N-methylimidazole (11),
DBN (12), and DBU (13) as well as isothiourea 14 were
completely ineffective (entries 20À23).26 When the best
nucleophilic catalyst of this survey, 6c, was paired with
bisthiourea catalyst3, an s-factor of 11 was obtained (entry
24). This represents an improvement over DMAP (s-factor
= 8.5, Figure 1) but one that is not nearly as pronounced
as in the case of catalyst 4. Thiourea 5, developed by the
Jacobsen group and previously shown to be an excellent
anion-binding catalyst for a number of reactions, was
inefficient in the amine resolution (entry 25).
As outlined in Figure 2, a number of benzylic amines
were resolved efficiently via benzoylation with benzoic
anhydride in the presence of 5 mol % of each catalyst 4
and cocatalyst 6c. Dramatic improvements in selectivity
were achieved over the previous catalytic system.17a,b
While a range of alkyl groups were well tolerated, substrate
1cbearing anisopropyl group was resolvedmostefficiently
(s-factor = 67), providing the highest level of selectivity
achieved with our approach thus far. Differentiation be-
tween phenyl and benzyl was readily achieved as shown by
substrate 1e, for which an s-factor of 24 was obtained.
Substitution of the phenyl ring in different positions was
also readily accommodated. An excellent result was achi-
eved for substrate 1i (s-factor = 64). Here, the presence of
HB-catalyst
(5 mol %)
Nu-catalyst
(5 mol %)
conversion
(%)
entry
s-factor
1
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3
5
À
34
41
50
49
49
50
46
50
49
44
48
46
50
38
50
<5
50
45
46
30
17
21
26
49
36
1.9
13
2
6a
6b
6c
6d
6e
6f
3
24
4
27
5
22
6
22
7
18
8
6g
6h
6i
19
9
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
17
6j
25
6k
7
8.9
15
8
12
9
6.6
ND
7.7
6.0
4.1
1.3
1.0
1.0
1.1
11
10a
10b
10c
10d
11
12
13
14
6c
6c
(22) 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.
(23) In this specific example, product 2a was isolated in 50% yield
(82% ee). Starting material 1a was recovered in 47% yield (85% ee).
(24) Spivey et al. have previously observed varying selectivities upon
modification of alkyl groups on an axially chiral DMAP analogue:
Spivey, A. C.; Leese, D. P.; Zhu, F. J.; Davey, S. G.; Jarvest, R. L.
Tetrahedron 2004, 60, 4513.
(25) (a) Singh, S.; Das, G.; Singh, O. V.; Han, H. Org. Lett. 2007, 9,
401. (b) De Rycke, N.; Berionni, G.; Couty, F.; Mayr, H.; Goumont, R.;
David, O. R. P. Org. Lett. 2011, 13, 530.
(26) (a) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006, 47,
4347. (b) Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9, 37. (c) Maji,
B.; Joannesse, C.; Nigst, T. A.; Smith, A. D.; Mayr, H. J. Org. Chem.
2011, 76, 5104.
1.3
a Reactions were performed on a 0.2 mmol scale. The s-factors were
determined by HPLC analysis; see the Supporting Information (SI) for
details.
A structurally diverse collection of 22 nucleophilic co-
catalysts encompassingabroadrange of nucleophilicities21
was evaluated in combination with amide-thiourea catalyst
4 (Table 1). All experiments were conducted with 5 mol %
catalyst loadings. As alluded to earlier, 4 was active in the
absence of any cocatalysts but led to very poor resolution
3086
Org. Lett., Vol. 14, No. 12, 2012

nucleophilic catalysis in the presence of anion-binding
additives.
Table 2. Evaluation of PPY* as a Chiral Nucleophilic
Cocatalysta
HB-catalyst
(5 mol %)
Nu-catalyst
(5 mol %)
conversion
(%)
entry
s-factor
Figure 2. Scope of the kinetic resolution of benzylic amines.
1
2
3
4
4
15
36
33
20
34
1.8
1.9
1.0
1.0
4
ent-15
ent-15
ent-15
an extended π-system might lead to additional stabilizing
interactions of one substrate enantiomer with the inter-
mediate ion pair.
À
16
a Reactions were performed on a 0.2 mmol scale. The s-factors were
determined by HPLC analysis, see the SI for details.
Intrigued by the possibility of observing matched/mis-
matched scenarios, we decided to perform the kinetic
resolution of amine 1a by catalyst 4 in the presence of a
chiral nucleophilic cocatalyst. For this purpose, we se-
lected the commercially available Fu catalyst PPY* 15.
The results of this brief survey are summarized in Table 2.
The combination of catalysts 4 and 15 provided an un-
favorable result (s-factor = 1.8, Table 2, entry 1). Un-
fortunately, performing the sameexperimentwithent-15in
place of 15 led to virtually identical results (s-factor = 1.9,
Table 2, entry 2). In fact, bothexperimentsmatch the result
obtained when 4 was used as the sole catalyst (see entry 1 in
Table 1), indicating that 15 or ent-15 do not engage in
cooperative catalysis with 4 under the reaction conditions.
Catalyst ent-15 by itself led to low conversion and no
resolution (s-factor = 1.0, Table 2, entry 3).
In summary, we have identified 4-di-n-propylaminopyr-
idine (6c) as a highly efficient nucleophilic cocatalyst for
the kinetic resolution of benzylic amines with s-factors of
up to 67. Further applications of the dual catalysis ap-
proach are currently being explored in our laboratory.
Acknowledgment. Financial support received from the
Charles and Johanna Busch Memorial Fund at Rutgers,
The State University of New Jersey, is gratefully acknowl-
edged. We thank Drs. Eric G. Klauber and Chandra
Kanta De (both of Rutgers University) for conducting
preliminary experiments. D.S. is a fellow of the Alfred P.
Sloan Foundation and the recipient of an Amgen Young
Investigator Award.
The combined use of ent-15 and the achiral Schreiner
catalyst (16)27 resulted in higher conversion but again no
resolution (s-factor = 1.0, Table 2, entry 4). Other catalyst
combinations may prove to be more efficient, and there
are tremendous opportunities for future investigations of
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(27) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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