New applications of bis(oxazoline) ligands in catalysis: Asymmetric 1,2-and 1,4-addition of ZnR2 to carbonyl compounds

Article abstract of DOI:10.1021/ol016925g

(Matrix Presented) The enantioselective addition of ZnR₂ to aldehydes (1,2) and cyclic enones (1,4) was accomplished using bis(oxazolines) as chiral ligands. The requirement for hydroxymethylene side chains in the ligands strongly suggests that bimetallic catalysts are decisive for high enantiocontrol in these additions.

Full text of DOI:10.1021/ol016925g

ORGANIC
LETTERS
2
001
Vol. 3, No. 26
259-4262
New Applications of Bis(oxazoline)
Ligands in Catalysis: Asymmetric
4
1
,2- and 1,4-Addition of ZnR to
2
Carbonyl Compounds
Marina Schinnerl, Michael Seitz, Anja Kaiser, and Oliver Reiser*
Institut f u¨ r Organische Chemie, UniVersit a¨ t Regensburg, UniVersit a¨ tsstr. 31,
93053 Regensburg, Germany
oliVer.reiser@chemie.uni-regensburg.de
Received October 17, 2001
ABSTRACT
2
The enantioselective addition of ZnR to aldehydes (1,2) and cyclic enones (1,4) was accomplished using bis(oxazolines) as chiral ligands. The
requirement for hydroxymethylene side chains in the ligands strongly suggests that bimetallic catalysts are decisive for high enantiocontrol
in these additions.
7
Conjugate additions of carbon nucleophiles to R,â-unsatur-
phosphite ligands in combination with copper(I) or copper-
(II) salts have been found to be highly efficient chiral ligands,
promoting especially the asymmetric 1,4-addition of orga-
ated carbonyl compounds are among the most useful
1
transformations in organic synthesis. Most prominently, this
8
,9
chemistry has been developed with organocuprates; never-
theless, the design of asymmetric variants for such processes
has proved to be very difficult.2
nozinc reagents to cyclic enones.
The common mechanism of the reaction calls for the
transfer of an alkyl group from zinc to a chiral copper
complex, which is subsequently capable of delivering the
alkyl group to the enone enantioselectively. However, if this
is the mode of action, it is surprising that many chiral copper
catalysts fail to give useful asymmetric inductions in 1,4-
addition processes. For example, bis(oxazolines) such as 1
form a superior chiral environment, for both copper(I) and
copper(II), which has been applied to asymmetric cycload-
The conjugate 1,4-addition of alkylzinc compounds to
enones has found considerable attention because of the mild
reaction conditions and high functional group tolerance zinc
3
reagents offer. This process could be rendered asymmetric
by employing chiral nickel catalysts with amino, pyridinyl,
4
or mercapto alcohols as chiral ligands. Recently, phosphora-
5
6
midites, peptide-based phosphine ligands and oxazoline-
(
1) Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis,
(6) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755-756.
(7) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879-2888.
(8) Reviews: (a) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92,
711-806. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061.
(c) Krause, N.; Hoffmann-R o¨ der, A. Synthesis 2001, 2, 171-196 and
references therein.
(9) Recent examples: (a) Dieguez, M.; Deerenberg, S.; Pamies, O.;
Claver, C.; van Leeuwen, P.; Kamer, P. Tetrahedron: Asymmetry 2000,
11, 3161-3166. (b) Pamies, O.; Dieguez, M.; Net, G.; Ruit, A.; Claver, C.
Tetrahedron: Asymmetry 2000, 11, 4377-4383. (c) Mandoli, A.; Arnold,
L. A.; de Vries, A. H. M.; Salvadori, P.; Feringa, B. L. Tetrahedron:
Asymmetry 2001, 12, 1929-1937.
Tetrahedron Organic Chemistry Series; Pergamon Press: Oxford, 1992.
(
2) Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Heidelberg, 1999; Vol. III, pp 1105-1120.
(3) Review: Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4414-4435.
(
Asymmetry 2000, 11, 3329-3333 and references therein. (b) Soai, K.;
Yokoyama, S.; Hayasaka, T.; Ebihara, K. J. Org. Chem. 1988, 53, 4149.
4) (a) Yin, Y. W.; Li, X. S.; Lee, D. S.; Yang, T. K. Tetrahedron:
(
5) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Imbos,
R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1,
23-625.
6
1
0.1021/ol016925g CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/05/2001

a chiral environment to achieve 1,4-additions enantioselec-
tively. Amino alcohols are the ligands of choice in diethylzinc
Scheme 1. Mechanism for the Copper-Catalyzed 1,4-Addition
1
3
of Diorganozinc to 2-Cyclohexenone
1,2-additions to aldehydes, and also oxazolines having
hydroxymethylene side chains have been employed for this
14
reaction, albeit enantioselectivities have been moderate. We
1
5
reasoned that bis(oxazolines) 2, 3, and 4 are also suitable
ligands for this process by coordinating zinc via one
oxazoline and its adjacent alcohol functionality. Moreover,
the bis(oxazoline) moiety should be able to coordinate
copper, therefore 2 could be able to proVide two spatially
separated coordination sites for zinc and copper.
To test this hypothesis we first carried out diethylzinc
additions to benzaldehyde in the presence of catalytic
amounts of various ligands 1-4 (Table 1). Again, 1a
Table 1. Addition of ZnEt
Ligands 1-4
2
to Benzaldehyde in the Presence of
ditions, Mukaiyama aldol reactions, cyclopropanations,
Michael reactions, carbonyl ene reactions or allylic oxidations
with excellent results.10
time
(h)
yield
(%)
entry
ligand
% ee
20
1
2
3
4
5
6
7
8
9
1a
2a
2b
40
48
45
96
48
48
52
96
96
96
60
0
96
56
0
0
5
53
19
31
93
83
2c
(ent)-2d
(ent)-2e
(ent)-2f
3a
3b
4
0
50
0
1
0
49
promoted the reaction quite well, giving rise to 6 in 60%
yield (entry 1), but the selectivity was low. With bis-
(oxazoline) ligands 2-4 bearing hydroxymethylene side
chains, more promising results were obtained, which, how-
ever, varied greatly with the ligand structures. Compound
In contrast, the addition of diethylzinc to cyclohexenone
in the presence of Cu(OTf)
2
‚1a or Cu(OTf) ‚1b proceeded
2
2
a, being the only anionic ligand in this series as a result of
well (>65% yield); however, we obtained only racemic
product. Similar unsuccessful results were also reported by
Pfaltz et al. using semicorrine ligands.7,11 Very recently, the
asymmetric 1,4-addition of Grignard reagents to enamidoma-
lonates was achieved by Sibi et al. using an anionic bis-
its methyleno bridge that is easily deprotonated, failed to
catalyze the diethyl zinc addition at all (entry 2). In contrast,
the gem-dimethyl-substituted ligands 2b and 2c are highly
active promoters (entries 3 and 4). We attribute the lower
yield and selectivity of 2c to the decreased solubility in
toluene/hexane compared to that of 2b. Interestingly, the
mono(oxazoline) 4 as well as the bis(oxazoline) 3a, having
the two oxazoline units spatially separated, promoted the
(
oxazoline). However, stoichiometric amounts of ligand were
12
required.
We were intrigued by the question whether both metals,
zinc and copper, involved in this process need to reside in
(
13) Reviews: (a) Soai, K.; Shibata, T. In ComprehensiVe Asymmetric
(
10) Representative examples: (a) Johnson, J. S.; Evans, D. A. Acc.
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin
Heidelberg, 1999; Vol. II, pp 911-922. (b) Pu, L.; Yu, H.-B. Chem. ReV.
2001, 101, 757-824.
(14) Allen, J. V.; Frost, C. G.; Williams, J. M. J. Tetrahedron: Asymmetry
1993, 4, 649-650.
(15) The syntheses of the following ligands have been reported before.
2a: Hall, J.; Lehn, J.-M.; DeCian, A.; Fischer, J. HelV. Chim. Acta 1991,
74, 1-6. 2b: Aggarwal, V. K.; Bell, L.; Coogan, M. P.; Jubault, P. J. Chem.
Soc., Perkin Trans. 1 1998, 2037-2042. 4: Schumacher, D. P.; Clark, J.
E.; Murphy, B. L.; Fischer, P. A. J. Org. Chem. 1990, 55, 5291-5294.
Chem. Res. 2000, 33, 325-335. (b) Evans, D. A.; Faul, M. M.; Bilodeau,
M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328-
329. (c) Johannnsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757-
762. (d) Gokhale, A. S.; Minidis, A. B. E.; Pfaltz, A. Tetrahedron Lett.
995, 36, 1831-1834. (e) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045-
048.
5
5
1
2
(
11) (a) Knobel, A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997, 1429-
431.
12) Sibi, M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708-9709.
1
(
4260
Org. Lett., Vol. 3, No. 26, 2001

formation of 6 with moderate but considerably decreased
enantioselectivty (entries 8 and 10) compared to that of 2b.
Obviously, a second oxazoline unit plays a key role to
achieve high selectivity, which might suggest that 2b
coordinates two zinc metals acting in a cooperative way.
Increasing the steric bulk in the chiral pocket might therefore
not be tolerated (entries 5 and 6), but also the introduction
of a more flexible linker was detrimental for the catalysis of
the reaction (entry 7).
Table 3. 1,4-Addition of Et
2
Zn (2 equiv) to Enones in the
Presence of Cu(OTf) (2.5 mol %) and 1-3 (3 mol %)
2
Having identified 2b as the best ligand, other aldehydes
for diethylzinc addition were tested. Indeed, these reactions
proceeded well, and high enantioselectivites could be ob-
tained especially with aromatic aldehydes (Table 2, entries
temp
(°C)
time
(h)
yield
(%)
entry
ligand
enone
% ee
1
2
3
4
5
6
7
8
9a
1a
1b
2a
2b
2b
2b
2b
2b
2b
2b
2c
(ent)-2d
(ent)-2e
(ent)-2f
3a
3b
2b
2b
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
0
0
0
20
10
5
0
-18
0
40
22
43
15
17
19
20
40
14
50
48
30
28
40
48
48
21
140
65
70
72
82
83
81
93
80
79
81
81
43
52
57
55
64
71
42
0
0
1-6).
6 (S)
77 (S)
89 (S)
92 (S)
94 (S)
67 (S)
0
32 (S)
90 (S)
21 (R)
8 (R)
42 (R)
0
Table 2. Addition of ZnEt
2
to Aldehydes in the Presence of 2b
(2 mol %)
1
1
1
1
1
1
1
1
1
0b
1
2
3
4
5
6
7
8
0
0
0
0
0
0
0
0
n-BuLi
time
(h)
yield
(%)
entry
R
(mol %)
% ee
1
2
3
4
5
6
7
8
9
Ph
p-OMe-Ph
p-Cl-Ph
p-Cl-Ph
p-F-Ph
p-F-Ph
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
0
0
0
4
0
4
0
2
4
6
7
45
50
45
90
89
90
90
100
25
25
25
96
99
76
92
74
84
31
60
78
68
61
93
95
83
87
88
87
36
66
75
47
38
0
41c
8c
0
a
Additive: 2.0 equiv of TMSCl. b Additive: 0.5 equiv of water.
c
Configuration not determined.
addition in the presence of the anionic ligand 2asalbeit
requiring longer reaction times compared to the neutral
analogue 2bsproceeded smoothly (72% yield, entry 3), but
virtually no enantioselectivity was induced. Again, 2b and
1
1
0
1
2
c proved to be superior ligands, yielding (S)-8a in up to
In the case of aliphatic aldehydes (entries 7-11) both yield
94% ee (entries 4-11). In difference to the phosphoramidite
ligands, which work best at -30 °C, for our ligand system
5
and enantioselectivity could be considerably increased by
the addition of catalytic amounts of butyllithium. This
additive most likely causes the deprotonation of the alcohol
functionality in 2b, as was also observed when amino
alcohols are used as chiral ligands.16 A systematic variation
of the added amount of butyllithium revealed that optimal
results are obtained if the ratio of 2b and the base is 1:2,
thus indicating that deprotonation of both hydroxyl groups
in the ligand is important. Likewise, the addition of butyl-
lithium had a beneficial effect on the yield for aromatic
aldehydes bearing electron withdrawing substituents (entries
we determined the optimal reaction temperature between 0
and +10 °C, allowing this transformation to be carried out
conveniently in an ice bath.
The importance of the interplay of zinc and copper in the
coordination sphere of the ligand became apparent, in
addition to the failure of 1a and 1b to induce selectivity
(entries 1 and 2), with the sharp decrease of enantioselectivity
17
18
in the presence of TMSCl or water (entries 9 and 10),
being generally useful additives in 1,4-additions of dieth-
ylzinc. While TMSCl could serve to coordinate the carbonyl
group of the enone instead of zinc or silylate the hydroxy
groups of the ligand, water might compete as an external
ligand with the hydroxy group in 2b for a zinc atom. In both
cases the communication of the ligand side chain with the
3
-6).
Encouraged by these results, we next attempted to apply
and 3 toward copper(II)-catalyzed conjugate additions of
diethylzinc to enones (Table 3). In contrast to the 1,2-
additions, all ligands promoted the addition of diethylzinc
to cyclohexenone reasonably well (43-93% yield), although
the enantioselectivities greatly varied (0-94% ee). The 1,4-
2
(17) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368-
3370.
(18) (a) Keller, E.; Maurer, J.; Naasz, R.; Schader, T.; Meetsma, A.;
Feringa, B. L. Tetrahedron: Asymmetry 1998, 9, 2409-2413. (b) Delapierre,
G.; Constantieux, T.; Brunel, J. M.; Buono, G. Eur. J. Org. Chem. 2000,
2507-2511.
(
16) Compare Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28,
5
233.
Org. Lett., Vol. 3, No. 26, 2001
4261

phenylated products 8a and 9 (entry 2). However, with a
mixture of diphenyl- and dimethylzinc, being optimal at a
ratio of 1:3, an exclusive phenyl transfer was reached, giving
Table 4. 1,4-Phenylation of 2-Cyclohexenone (7a)
9
in 74% ee.
We reason that a bimetallic complex21 such as 10 is
decisive for 1,4-additions, in which the substrate is locked
in a two-point binding mode via a zinc and a copper atom.
Such restricted coordination would explain the high enan-
tiocontrol in the alkyl transfer along with the limited substrate
tolerance of the catalyst. Further studies to change the size
of the chiral pocket by varying the ligand backbone and the
geometry of the side chains are therefore under investigation
in our laboratories.
ZnPh2
additive
(equiv)
Cu(OTf)2/2b time yield
entry (equiv)
(mol %)
(h)
(%)
% ee
1
2
3
4
1.5
1.0
1.0
1.06
3.0/4.1
3.0/4.1
11.0/14.9
10.6/14.9
90
20
18
21
0
53a
53
73
Et2Zn (1.0)
Me2Zn (1.0)
Me2Zn (3.2)
69 (S)
59 (S)
74 (S)
a
In addition 41% (79% ee) 8a was isolated.
enone would be disrupted. Also, separating the bis(oxazoline)
units by a larger spacer (entries 15 and 16) results in a
complete loss of selectivity.
The stringent requirement of two metals coordinating in
the ligand sphere might be the cause for the high substrate
specifity of the catalyst. Cycloheptenone (7b) already yielded
the 1,4-adduct with diethylzinc with considerably diminished
enantioselectivity (41% ee, entry 17), while substitution in
the 4-position of the enone as seen with 7c (entry 18) was
not tolerated at all.
We were also able to achieve a 1,4-phenylation, marking
to the best of our knowledge the first example of an
asymmetric phenyl transfer to enones with diphenylzinc as
a reagent.19 Diphenylzinc alone proved to be not reactive
Figure 1. Postulated binding mode between bifunctional catalyst
and substrate.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (RE 948-5/1), the Fonds
der Chemischen Industrie and Degussa AG.
Supporting Information Available: Experimental pro-
1
cedures and analytical data of all new ligands, as well as H
enough (entry 1), whereas a mixture of diphenyl- and
diethylzinc2 resulted in a 1:1 mixture of ethylated and
0
NMR and HPLC data of all 1,2- and 1,4-addition products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
19) Reviews: ref 8 and Bolm, C.; Hildebrand, J. P.; Muniz, K.;
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284-3308.
20) (a) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muniz, K. Angew.
Chem., Int. Ed. 2000, 39, 3465. (b) Huang, W.-S.; Pu, L. J. Org. Chem.
(
OL016925G
1
999, 64, 4222-4223. (c) Bolm, C.; Muniz, K. Chem. Commun. 1999,
(21) Leading review on bifunctional catalysts: Rowlands, G. J. Tetra-
hedron 2001, 57, 1865.
1
295-1296.
4262
Org. Lett., Vol. 3, No. 26, 2001