Aza-bis(oxazolines): New chiral ligands for asymmetric catalysis

Article abstract of DOI:10.1021/ol005947k

diagram presented Aza-bis(oxazolines) are introduced as chiral ligands for asymmetric catalysis combining the advantages of easy availability of bis(oxazolines) and backbone variability of aza-semicorrins. Especially, the title ligands could be attached t

Full text of DOI:10.1021/ol005947k

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2045-2048
Aza-bis(oxazolines): New Chiral Ligands
for Asymmetric Catalysis†
Martin Glos and Oliver Reiser*
Institut fu¨r Organische Chemie der UniVersita¨t Regensburg, UniVersita¨tsstrasse 31,
D-93040 Regensburg, Germany
oliVer.reiser@chemie.uni-regensburg.de
Received April 13, 2000
ABSTRACT
Aza-bis(oxazolines) are introduced as chiral ligands for asymmetric catalysis combining the advantages of easy availability of bis(oxazolines)
and backbone variability of aza-semicorrins. Especially, the title ligands could be attached to a polymeric support, which allowed the development
of easily recoverable copper(I)-catalysts for asymmetric cyclopropanation reactions.
Among the most successful developments in the area of
chiral ligands for asymmetric catalysis is the introduction
of C2-symmetrical semicorrins 1,1,2 aza-semicorrins 2,1,2 and
bis(oxazolines) 3.1,3 These ligands form superior catalysts
panations,2b,c,3a-f,p aziridinations,3c,g Diels-Alder3h-m or aldol
reactions,3n-o ruthenium-catalyzed oxidations,3p-q palladium-
(3) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005-6008. (b) Lowenthal, R. E.; Masamune, S. Tetrahedron
Lett. 1991, 32, 7373-7376. (c) Evans, D. A.; Woerpel, K. A.; Hinman, M.
M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726-728. (d) Bedekar, A.
V.; Andersson, P. G. Tetrahedron Lett. 1996, 37, 4073-4076. (e) Bedekar,
A. V.; Koroleva, E. B.; Andersson, P. G. J. Org. Chem. 1997, 62, 2518-
2526. (f) Boulch, R.; Scheurer, A.; Mosset, P.; Saalfrank, R. W. Tetrahedron
Lett. 2000, 41, 1023-1026. (g) Evans, D. A.; Faul, M. M.; Bilodeau, M.
T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-
5329. (h) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-
6810. (i) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
Soc. 1999, 121, 7559-7573. (j) Evans, D. A.; Barnes, D. M.; Johnson, J.
S.; Lectka, T.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E.
A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7482-7594. (k) Evans,
D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem. 1998, 110,
3554-3557. (l) Johannsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60,
5757-5762. (m) Johannsen, M.; Jørgensen, K. A. Tetrahedron 1996, 52,
7321-7328. (n) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C.
S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999,
121, 669-685. (o) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay,
S. W. J. Am. Chem. Soc. 1999, 121, 686-699. (p) End, N.; Pfaltz, A. Chem.
Commun. 1998, 589-590. (q) End, N.; Macko, L.; Zehnder, M.; Pfaltz, A.
Chem. Eur. J. 1998, 4, 818-824. (r) Mu¨ller, K.; Umbricht, G.; Weber, B.;
Pfaltz, A. HelV. Chim. Acta 1991, 74, 232-240. (s) Nishiyama, H.;
Yamaguchi, S.; Park, S.-B.; Itoh, K, Tetrahedron: Asymmetry 1993, 4, 143-
150. (t) Hishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo,
M.; Itoh, K. Organometallics 1989, 8, 846-848. (u) Imai, Y.; Zhang, W.;
Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron: Asymmetry 1996, 7, 2453-
2462. (v) Lee, S.; Lim, C. W.; Song, C. E.; Kim, I. O.; Jun, C.
Tetrahedron: Asymmetry 1997, 8, 2927-2932. (w) Gokhale, A. S.; Minidis,
A. B. E.; Pfaltz, A. Tetrahedron Lett. 1995, 36, 1831-1834. (x) Andrus,
M. B.; Argade, A. B.; Chen, X.; Pamment, M. G. Tetrahedron Lett. 1995,
36, 2945-2948.
with a broad variety of metals to promote a number of
transformations, including copper-catalyzed cyclopro-
† Presented in part at the 219th National Meeting of the American
Chemical Society, San Francisco, CA.
(1) Reviews: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetra-
hedron: Asymmetry 1998, 9, 1-45. (b) Pfaltz A. Synlett 1999, 835-842.
(c) Pfaltz A. Heterocycl. Chem. 1999, 36, 1437-1451. (d) Pfaltz, A. Acc.
Chem. Res. 1993, 26, 339-345. (e) Doyle, M. P.; Protopova, M. N.
Tetrahedron 1998, 54, 7919-1946. (f) Meyers, A. I. J. Heterocycl. Chem.
1998, 991-1002. (g) Meyers, A. I.; Price, A. J. Org. Chem. 1998, 63, 412-
413. (h) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360. (i)
Reiser, O. Nachr. Chem. Technol. Lab. 1996, 44, 744-750. (j) Bolm, C.
Angew. Chem. 1991, 103, 556-558.
(2) (a) Fritschi, H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A.; Keller,
W.; Kratky, C. HelV. Chim. Acta 1988, 71, 1541-1552. (b) Fritschi, H.;
Leutenegger, U.; Pfaltz, A. HelV. Chim. Acta 1988, 71, 1553-1565. (c)
Leutenegger, U.: Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A.
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28, 60-61.
10.1021/ol005947k CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

catalyzed allylations,2c,3r cobalt-catalyzed reductions,2d rhodium-
catalyzed hydrosilylations,3s-v and copper-catalyzed allylic
oxidations.3w,x
benzaldehyde, 6 underwent condensation with formal loss
of ammonia to give 7 in good yields. In the absence of
benzaldehyde, the yield of 7 decreased significantly and, as
already noted by Kampe,6 complex mixtures of products were
obtained.
In contrast to the aza-semicorrins 2,2c 7 could not be
alkylated directly by simply stirring with alkyl iodides.
Deprotonation of 7 with n-butyllithium readily occurred,
however, and the resulting anion could be cleanly trapped
with alkyl halides to give rise to 9.
The development of polymer-bound ligands and catalysts
is an important new goal for increasing the efficiency of
organic reactions. Apart7,8 from semicorrins 1 and 2 and bis-
(oxazolines) 3, several other classes of chiral ligands
including binaphthyls,9 salens,10 TADDOLs,11 or the ligands12
for the Sharpless dihydroxylation and aminohydroxylation
have been attached to different polymers to arrive at easily
manageable and reusable catalysts.13
Of the three types of ligands, the bis(oxazolines) 3 are in
general the easiest to prepare using readily available amino
alcohols 5 as the source of chirality. Aza-semicorrins 2,
however, offer a greater structural flexibility than bis-
(oxazolines), because the central nitrogen atom can be
functionalized by alkylating reagents. Moreover, they display
a more rigid conformation due to the planar bridging nitrogen
functionality.
We would like to report aza-bis(oxazolines)4 4 as a new
class of chiral ligands which combine the advantages of easy
accessibility of 3 and the structural flexibility of 2.
We therefore investigated the possibility of immobilizing
aza-bis(oxazolines) 4 on supports. An attractive polymeric
support for catalysts is methoxypolyethylene glycole
(MeOPEG), because it is soluble in many organic solvents
but can be precipitated with diethyl ether.14 Various attempts
to attach MeOPEG directly to 7b failed, but 8 which contains
a benzylidene spacer linked to MeOPEG could be success-
fully coupled with the conjugate base of 7b to yield 10 in
A distinct advantage of these ligands is that they can be
attached to methoxypoly(ethylene glycol)e (MeOPEG 5000)
as a soluble support, giving rise to the immobilized aza-bis-
(oxazoline) 10, which could be successfully applied in
asymmetric catalysis.
1
Aminooxazolines 6 (Scheme 1) serve as the key building
blocks for the assembly of aza-bis(oxazolines). The ami-
55% yield as determined by H NMR spectroscopy.
To benchmark our new ligands in their ability to promote
asymmetric reactions, we carried out palladium-catalyzed
allylic alkylations (Table 1) and copper-catalyzed cyclopro-
Scheme 1a
Table 1. Enantioselective Allylic Substitution of
1,3-Diphenylallyl Acetatea
entry
ligand
% yield
% ee of 12b
1
2
3
4
7
0
66
38
99
9a
9b
2d
97
97
95
a All reactions were carried out under nitrogen. b Determined by HPLC
using a Chiralpak AD column. c Entry taken from ref 2c. d R ) CH2OSiMe2t-
Bu, R1 ) Me.
a (a) BrCN, CH3OH, 0 °C; (b) pTsOH‚H2O (5%), PhCHO, Tol,
4; (c) nBuLi, MeI, THF (6a-b); nBuLi, BnBr, THF (6c); (d)
n-BuLi, THF, -78 to 0 °C, 44 h (6b).
panations of alkenes (Tables 2 and 3). Using the nonalkylated
ligand 7 in the palladium-catalyzed reaction between dim-
nooxazoline attached were readily synthesized from amino
alcohols 5 following literature procedures.5 Upon heating in
toluene in the presence of p-toluenesulfonic acid and
(6) Kampe, K.-D. Liebigs Ann. Chem. 1974, 593-607.
(7) Polymer-supported pyridineoxazolines have been reported: (a) Hall-
mann, K.; Macedo, E.; Nordstro¨m, K.; Moberg, C. Tetrahedron: Asymmetry
1999, 10, 4037-4046. (b) Brunner, H.; Brandl, P. Z. Naturforsch. 1992,
47b, 609-613.
(8) Achiral dendritic bis(oxazoline)copper(II) catalysts have been re-
ported: Chow, H.-F.; Mak, C. C. J. Org. Chem. 1997, 62, 5116-5127.
(4) Rational name: bis[4,5-dihydro-1,3-oxazole-2-yl)amines.
(5) (a) Wittekind, R. R.; Rosenau, J. D.; Poos, G. I. J. Org. Chem. 1961,
26, 444-446. (b) Poos, G.; Carson, J.; Rosenau, J.; Roszkowski, A.; Kelley,
N.; McGowin, J. J. Med. Chem. 1963, 6, 266-272.
2046
Org. Lett., Vol. 2, No. 14, 2000

described by Masamune et al.3a in which the active copper-
(I) complex was generated in situ using copper(II) triflate,
ligand, and phenylhydrazine for reduction. Both procedures
gave almost identical results, so that for reasons of conven-
ience we used the latter one in general.
Table 2. Enantioselective Cyclopropanation of Styrenea
Consistent with the reported results for the copper-
catalyzed cyclopropanation of styrene (13) (Table 2) using
2 or 3, the most effective aza-bis(oxazoline) turned out to
be 9b bearing the sterically demanding tert-butyl groups. This
ligand compared well in terms of selectivity and yield (entry
5) to the best reported results of 2 (entry 7) and 3 (entry 8),
although somewhat lower enantioselectivities were obtained.
Furthermore, it is interesting to note that catalysis also
proceeded well with the nonalkylated ligand 7b (entry 4),
since only alkylated aza-semicorrins 2 have been reported
as ligands for asymmetric catalysis to date. Most importantly,
the polymer-bound ligand 10 gave similar yields and
selectivities compared to 9b (entry 6), indicating that the
immobilization of aza-bis(oxazolines) has no detrimental
effects on their ability to serve as catalysts.
Similar results were obtained in the cyclopropanation of
1,1-diphenylethylene 17 (Table 3); this time, however, the
nonalkylated aza-bis(oxazoline) 7b (entry 3) was superior
to the alkylated derivative 9b both in terms of yield and
selectivity (entry 4). In accord with our expectations that
polymer-bound catalysts would improve the efficiency of
these reactions, the polymeric catalyst derived from 10 gave
the best results of all aza-bis(oxazolines) (entry 5).
entry ligand
% yield
85
78
44
75
82
69
45 (ent-)
77
15:16b % ee of 15c % ee of 16c
1
2
3
4
7a
9a
9c
7b
9b
62:38
66:34
64:36
67:33
73:27
71:29
75:25
73:27
56
66
62
87
92
91
95
99
42
44
47
80
84
87
90
97
5
6
7d
8f
10
2e
3g
a All reactions were carried out under nitrogen. b Determined by GC using
DB 1301 column. c Determined by GC using a CP-Chiralsil DEX CB
column. d Entry taken from ref 2c. e R ) CMe2OSiMe2t-Bu, R1 ) Me.
f Entry taken from ref 3c. g R ) t-Bu, R1 ) Me.
ethylmalonate and 1,3-diphenylallyl acetate (11), no product
was obtained (entry 1). With 9a (entry 2) and 9b (entry 3),
high enantioselectivity was achieved, although the reaction
was considerably slower than the reaction with aza-semi-
corrin 22c (entry 4) as catalyst. These results indicate that
aza-bis(oxazolines) 4 form more electron-rich palladium allyl
complexes compared to the aza-semicorrins 2 and therefore
display a lower reactivity toward nucleophiles.
To examine the possibility of reusing 10, we repeated the
cyclopropanation of styrene (13) several times. A total of
13 cycles were conducted (Figure 1). During the first 10
Cyclopropanation reactions using aza-bis(oxazolines) 4
were initially conducted following either the procedure of
Evans et al.3c using copper(I) triflate directly or the procedure
Table 3. Enantioselective Cyclopropanation of
1,1-Diphenylethenea
Figure 1. Copper-catalyzed cyclopropanation of styrene (13) with
14 using Cu(I)‚10 (cf. Table 2).
entry
ligand
% yield
% ee of 18b
1
2
3
4
5
6c
7a
9a
7b
9b
10
3d
70
49
63
41
78
70
47
56
86
83
90
99
cycles, no copper salts were added nor was activation of the
catalyst with phenylhydrazine necessary. When the yield
dropped to 39% in the 10th cycle phenylhydrazine was added
in the following cycles and the yield increased. Throughout
all 13 cycles the enantiomeric excess was 87-90% for the
trans-product 15 and 81-85% for the cis-product 16.15
In conclusion, aza-bis(oxazolines) are efficient ligands for
enantioselective catalysis. In particular, these ligands open
a All reactions were carried out under nitrogen. b Determined by HPLC
using a Chiralpak AD column. c Entry taken from ref 3c. d R ) t-Bu, R1 )
Me.
Org. Lett., Vol. 2, No. 14, 2000
2047

up the possibility to readily attach bis(oxazolines)sbeing
among the most versatile ligands for asymmetric catalysiss
to a polymer support, as was demonstrated by the preparation
of polyethylene glycole bound aza-bis(oxazoline) 10. Copper-
(I) complexes of 10 turned out to be highly effective and
easily recyclable catalysts in cyclopropanation reactions.
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Acknowledgment. This work was supported by the
Degussa-Hu¨ls AG and the Fonds der Chemischen Industrie
Strukturhilfe Bioinformation.
1
Supporting Information Available: H NMR spectra and
experimental procedures of all new ligands. This material is
available free of charge via the Internet at http://pubs.acs.org.
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OL005947K
were added. Methyl diazoacetate (14) (1 mmol, 8 mL of a 1% solution in
dichloromethane) was added over 8 h using a syringe pump. Stirring was
continued for 3 h, and the reaction mixture was transferred via cannula to
a 250 mL septum capped flask. The reaction vessel was rinsed with 3 mL
of dry dichloromethane. The volume of the solvent was reduced to
approximately 5 mL by applying vacuum, and 100 mL of dry diethyl ether
was added to precipitate the polymer-supported catalyst. After cooling with
ice for 15 min, the catalyst was separated from the products by filtration
through a sintered glass funnel under a nitrogen atmosphere. The filtrate
was evaporated in vacuo to give a slightly yellow oil, which was purified
by chomatography on silica gel (3 × 25 cm silica, 9:1 hexanes/EtOAc).
The products were obtained as a clear oil showing spectroscopical properties
identical to those described in the literature.3c For the following reaction
cycle the catalyst was dissolved in 10 mL of dry dichloromethane and
transferred into a new reaction vessel. Styrene (13) and methyl diazoacetate
(14) were added as described above.
(13) (a) Smith, K. Solid Supports and Catalysts in Organic Chemistry;
Ellis Horwood Limited: 1993. (b) Shuttleworth. S. J.; Allin, S. M.; Sharma,
P. K. Synthesis 1997, 1217-1239.
(14) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-509.
(15) Cyclopropanation of styrene using 10: Under a nitrogen atmo-
sphere Cu(OTf)2 (3.6 mg, 0.01 mmol) and 10 (200 mg, 0.02 mmol) were
dissolved in dichloromethane (5 mL). Phenylhydrazine (22 µL of a 5%
solution in dichloromethane) and styrene (13) (312 mg, 3 mmol, 345 µL)
2048
Org. Lett., Vol. 2, No. 14, 2000