Novel highly modular C2-symmetric oxazoline ligands - Application in titanium-catalyzed diethylzinc additions to aldehydes

Article abstract of DOI:10.1016/S0040-4039(02)00087-4

Novel C₂-symmetric tetradentate bis-oxazoline ligands were efficiently prepared from α-amino acids, 1,2-amino alcohols and 1,2- or 1,3-diacids. The ligands were employed in the titanium-catalyzed addition of diethylzinc to benzaldehyde, and depending on conditions used, moderate to high enantioselectivities of the formed 1-phenylpropanol were obtained.

Full text of DOI:10.1016/S0040-4039(02)00087-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1743–1746
Novel highly modular C2-symmetric oxazoline
ligands—application in titanium-catalyzed diethylzinc
additions to aldehydes
Isidro M. Pastor and Hans Adolfsson*
Department of Organic Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden
Received 19 October 2001; revised 18 December 2001; accepted 11 January 2002
Abstract—Novel C2-symmetric tetradentate bis-oxazoline ligands were efficiently prepared from a-amino acids, 1,2-amino alcohols
and 1,2- or 1,3-diacids. The ligands were employed in the titanium-catalyzed addition of diethylzinc to benzaldehyde, and
depending on conditions used, moderate to high enantioselectivities of the formed 1-phenylpropanol were obtained. © 2002
Elsevier Science Ltd. All rights reserved.
Herein we report on a novel class of highly modular
O
O
O
O
C2-symmetric oxazoline based ligands. The chiral pool
serves as an outstanding and inexpensive source of
asymmetric material for the preparation of ligands
intended for metal-catalyzed reactions.1 The hetero-
cyclic compounds 2-substituted 4,5-dihydrooxazoles, or
2-oxazolines, originally introduced to the synthetic
community as base-stable protecting groups for car-
boxylic acids,2,3 are presently extensively used as ligand
motifs in asymmetric catalysis.4 The relative ease with
which oxazolines are prepared (formally a fusion reac-
tion between a carboxylic acid and an amino alcohol),
combined with their metal coordinating ability, make
these compounds highly attractive for catalytic applica-
tions. With a huge number of commercial non-racemic
amino alcohols available, the oxazoline structure is
easily modified for optimum catalytic activity and stere-
ocontrol. We have designed a new class of tetradentate
C2-symmetric bis-oxazoline ligands based on the combi-
nation of a 1,2- or 1,3-diacid, an a-aminoacid and a
1,2-amino alcohol according to Scheme 1.5
R1
R1
NH HN
R1
O
R1
NH HN
O
O
N
N
O
N
N
R2
R2
R2
R2
1
2
Scheme 1.
from the N-Boc protected a-amino acids
L
-valine or
(R)-phenylglycine. The acids were coupled with the
appropriate 1,2-amino alcohols to form amides 3, using
isobutyl chloroformate (3a; R1=R2=isopropyl, 89%,
3b; R1=isopropyl, R2=(R)-phenyl, 91% and 3c; R1=
(R)-phenyl, R2=isopropyl, 82%). Boc-deprotection fol-
lowed by chloride displacement of the alcohol
functionality yielded the chloro-amides 4 (4a; 52%, 4b;
43% and 4c; 39%) which subsequently were coupled
with either oxalyl chloride or dimethylmalonyl dichlo-
ride to form tetraamides 5 and 6. The final step to the
tetradentate ligands involved treatment of tetraamides 5
and 6 with a methanolic sodium hydroxide solution in
THF to facilitate the ring closure to the oxazoline
heterocycles (1; 57% from 4a, 2a; 83% from 4a, 2b; 71%
from 4b and 4c; 75% from 2c).
The ligand structure can easily be modified by the
proper choice of either the amino acid or the amino
alcohol, hence this concept opens up a very modular
approach towards finding efficient ligands providing the
necessary prerequisites for asymmetric induction.
The ligands were efficiently prepared according to the
general synthetic route outlined in Scheme 2, starting
Initially, a different strategy was employed. We antici-
pated that 2-aminomethyloxazolines would serve as
efficient building blocks for the tetradentate ligands.
* Corresponding author. Tel.: +46-8-162479; fax: +46-8-154908;
e-mail: hansa@organ.su.se
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00087-4

1744
I. M. Pastor, H. Adolfsson / Tetrahedron Letters 43 (2002) 1743–1746
O
O
O
O
R2
O
O
i, ii, iii
OH
H2N
BocHN
NH HN
OH
N
H
NH HN
R1
R1
O
O
N
N
3
O
N
N
O
O
R2
iv, v
H2N
Cl
N
H
1
2a
R1
4
O
O
O
O
O
O
R2
O
O
R2
NH HN
Ph
NH HN
Ph
O
vi
vii
vii
4
4
Cl
Cl
NH HN
Cl
Cl
1
2
N
N
H
H
R1
O
O
N
N
O
O
N
N
R1
5
Ph Ph
O
R2
2b
2c
O
O
R2
viii
NH HN
N
H
N
H
Scheme 3.
R1
R1
6
O
OH
Et2Zn (2 eq)
Scheme 2. Reagents and conditions: (i) Boc2O, NaOH, THF/
H2O, rt; (ii) BuiOCOCl, THF, −15°C; (iii) 1,2-amino alcohol,
rt; (iv) HCl (3 M, aq): MeOH (1:1), 0°C; (v) SOCl2, 1,2-
dichloroethane, rt; (vi) oxalyl chloride, Et3N, CH2Cl2, 0°C to
rt; (vii) NaOH (0.5 M in MeOH), THF, reflux; (viii) dimethyl-
malonyl dichloride, Et3N, CH2Cl2, 0°C to rt.
Ligand (10 mol%)
Ti(OPri)4 (8 mol%)
Toluene, -15 oC
Ph
H
Ph
7
Scheme 4.
diethylzinc to aldehydes has previously been performed
using tetradentate ligands.10
The ring closure forming the oxazoline ring was, how-
ever, quite unselective and substantial amounts of by-
products were observed. We therefore decided to
perform the coupling with the 1,2- or 1,3-diacid prior to
the formation of the oxazoline rings. The direct ring
forming method reported by Vorbru¨ggen,6 starting
from either the hydroxy amide or from a N-Boc pro-
tected a-amino acid and a 1,2-amino alcohol using
triphenyl phosphine and carbon tetrachloride, did not
result in formation of 2-aminomethyloxazolines.
Thus, employing ligand 1 as the chiral mediator
together with a catalytic amount of titanium isopropox-
ide for the diethylzinc addition to benzaldehyde,
resulted in a high yield of 1-phenylpropanol (7), how-
ever, the enantioselectivity was very poor (Table 1,
entry 1).11 Replacing 1 with the malonic acid derived
ligand 2a resulted in good conversion to 7 and a
significantly increased enantiomeric excess (entry 4).
Interestingly, performing the reaction with a stoichio-
metric amount of titanium, resulted in lower conversion
to the alcohol product (entry 3). A substantial decrease
in enantioselectivity was also observed. This is highly
contradictive to previous reports using the titanium
system, where high yields and enantioselectivities were
only achieved using an excess of the Lewis acidic metal
source.
Thus, the tetradentate ligands prepared according to
the above procedure are shown in Scheme 3. Ligand 1
was prepared from
L-valine, (S)-valinol and oxalyl
chloride. Ligands 2a–c are based on dimethylmalonic
acid and prepared from; -valine and (S)-valinol (2a),
-valine and (R)-phenylglycinol (2b), and (R)-phenyl-
glycine and (S)-valinol (2c).
L
L
Excluding titanium isopropoxide from the reaction mix-
ture resulted in low conversion to, and modest enan-
tioselectivity of 7 (entry 2). Changing the temperature
to −78°C completely inhibited product formation (entry
5), whereas performing the reaction at room tempera-
ture proved to be detrimental to the enantioselectivity
(entry 6). The ratio of titanium versus ligand turned out
to be crucial. As shown above, a full equivalent of the
titanium alkoxide resulted in decreased conversion and
selectivity. Performing the reaction with 5 mol% of the
ligand and 10 mol% of the titanium source gave similar
results (entry 7). Employing equimolar amounts (5
mol%) of titanium isopropoxide and ligand 2a gave the
secondary alcohol 7 in slightly lower yield but the
With the tetradentate ligands in hand we decided to
investigate their efficiency in a typical catalytic asym-
metric benchmark reaction; the addition of diethylzinc
to aldehydes.7 This particular carbonꢀcarbon bond
forming reaction is a frequently studied system, and it
serves well as a model for evaluating how ligand struc-
ture affects the enantioselectivity of the product. The
experimental conditions chosen for the study are out-
lined in Scheme 4. The typical reaction setup employs
zinc catalysts coordinated to amino alcohols, but the
use of titanium based catalysts tends to be more
efficient and selective.8,9 Furthermore, the titanium-
mediated protocol for the enantioselective addition of

I. M. Pastor, H. Adolfsson / Tetrahedron Letters 43 (2002) 1743–1746
Table 1. Enantioselective addition of diethylzinc to benzaldehydea
1745
Entry
Ligand
M(OR)4
T (°C)
Yieldb (%)
eec (%)
1
1
Ti(OPri)4
−
−15
−15
−15
−15
−78
20
−15
−15
−15
−15
−15
−15
−15
−15
90
19
56
87
–
95
61
67
65
85
90
93
83
18
4 (S)
2
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
37 (S)
54 (S)
78 (S)
–
47 (S)
64 (S)
78 (S)
75 (S)
70 (S)
79 (S)
73 (R)
89 (S)
25 (S)
3d
4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
Zr(OBut)4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
Ti(OPri)4
5
6
7e
8f
9
10
11
12
13
14
a Reaction conditions: benzaldehyde (1 equiv.), Et2Zn (2 equiv.), ligand (10 mol%) and M(OR)4 (8 mol%) in toluene. Reaction time 6 h.
b Determined by GLC using internal standard.
c Determined by chiral GLC (CP-Chirasil-Dex CB Chrompack 7503).
d Ti(OPri)4 (1 equiv.). The catalyst was preformed prior to aldehyde addition.
e Ligand 2a (5 mol%), Ti(OPri)4 (10 mol%).
f Ligand 2a (5 mol%), Ti(OPri)4 (5 mol%).
enantioselectivity was however unchanged (entry 8).12
When performing the catalytic reaction with ligand 2b,
prepared from L-valine and (R)-2-phenylglycinol, high
7 in high yield and with a similar ee (73%) to that
previously obtained using 2a (entry 12). In this case,
however, the (R)-product was observed. Next, we used
ligands 2e and 2f, respectively, in the catalytic reaction.
Ligand 2e, prepared from the achiral amino alcohol
conversion and good enantioselectivity of
7 was
achieved (entry 10). Surprisingly, the (S)-isomer of the
product was formed in excess, although the absolute
configuration of the chiral centers in the oxazoline parts
of the ligand were interconverted.
2-amino-2-methylpropanol and
L-valine (prepared in
85% yield from 4e), when used in the diethylzinc addi-
tion, resulted in high yield and good enantioselectivity
of the adduct (entry 13). When instead the regioisomer
2f (obtained in 77% yield from 4f) was employed, a
huge drop in conversion and enantioselectivity was
observed (entry 14). The results obtained above in the
diethylzinc additions to benzaldehyde show one clear
difference in comparison to previous studies, the
amount of titanium alkoxide necessary for efficient
catalysis. The use of a stoichiometric amount, or even
an excess, of the titanium source was in earlier work
considered to be an important requirement for efficient
catalysis. The increase in the reaction rate observed
under those conditions was suggested to be a result of
efficient removal of the product alkoxide, thereby
reconstituting the active catalyst.13 On the contrary, we
observed a decrease in reaction rate and enantioselec-
tivity when performing the reaction using 1 equiv. of
titanium isopropoxide.
Replacing ligand 2b for its regioisomer 2c, resulted in
high yield and good enantioselectivity, again in favor of
the (S)-isomer of the product (entry 11).
The somewhat puzzling results obtained using ligands
2a–c in the diethylzinc additions encouraged us to
further study the effects of having different configura-
tions of the stereocenters in the ligands. We therefore
prepared ligand 2d (Scheme 5), from
D-valine and
(S)-valinol (prepared in 76% yield from 4d), where the
configuration on the stereocenters next to the amide
functionalities are reversed in comparison to its
diastereomer 2a. The stereocenters in the oxazolines
remain, however, the same. Performing the titanium-
catalyzed diethylzinc addition to benzaldehyde in the
presence of this ligand (2d), gave the secondary alcohol
O
O
O
O
O
O
NH HN
NH HN
NH HN
O
N
N
O
O
N
N
O
O
N
N
O
2e
2f
2d
Scheme 5.

1746
I. M. Pastor, H. Adolfsson / Tetrahedron Letters 43 (2002) 1743–1746
We believe this effect originates from either a different
mechanism of the reaction and/or that the structure of
the active catalyst is distinctively different. The latter
seems more likely considering the nature of this novel
class of ligands. The poly-denticity of the ligands pro-
vides plenty of room for the formation of bi- or even
oligomeric homo- or heterometallic complexes. The
important site of coordination, as suggested by the
results presented in Table 1, is probably the bis-amide
part of the ligand. In preliminary studies, we observed
no complex formation upon mixing the ligand and
titanium isopropoxide. However, upon addition of
diethylzinc to this mixture, the amide-protons are
Asymmetry 1998, 9, 1; (d) Nishiyama, H. Adv. Catal.
Processes 1997, 2, 153.
5. For other tetradentate oxazoline ligands, see; (a) Glorius,
F.; Pfaltz, A. Org. Lett. 1999, 1, 141; (b) End, N.; Macko,
L.; Zehnder, M.; Pfaltz, A. Chem. Eur. J. 1998, 4, 818; (c)
End, N.; Pfaltz, A. J. Chem. Soc. Chem. Commun. 1998,
589; (d) Go´mez, M.; Jansat, S.; Muller, G.; Panyella, D.;
van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Goubitz, K.;
Fraanje, J. Organometallics 1999, 18, 4970; (e)
Nishiyama, H.; Park, S. B.; Haga, M.; Aoki, K.; Itoh, K.
Chem. Lett. 1994, 1111.
6. (a) Vorbru¨ggen, H.; Krolikiewicz, K. Tetrahedron 1993,
49, 9353; (b) Vorbru¨ggen, H.; Krolikiewicz, K. Tetra-
hedron Lett. 1981, 22, 4471.
1
abstracted as observed by H NMR spectroscopy. This
observation further supports a bimetallic complex to be
responsible for (1) the activation of the substrate by
Lewis acid–base interaction and (2) transfer of the ethyl
group. The structure of the catalyst is, however, cur-
rently unknown and further studies within this field are
being performed.
7. (a) Pu, L.; Yu, H. Chem. Rev. 2001, 101, 757; (b) Soai,
K.; Niwa, S. Chem. Rev. 1992, 92, 833.
8. Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807.
9. For selected recent examples, see; (a) Lake, F.; Moberg,
C. Tetrahedron: Asymmetry 2001, 12, 755; (b) Xu, Q.;
Wang, H.; Pan, X.; Chan, A. S. C.; Yang, T. Tetrahedron
Lett. 2001, 42, 6171; (c) Yang, X.; Shen, J.; Da, C.;
Wang, H.; Su, W.; Liu, D.; Wang, R.; Choi, M. C. K.;
Chan, A. S. C. Tetrahedron Lett. 2001, 42, 6573.
10. (a) Zhang, X.; Guo, C. Tetrahedron Lett. 1995, 36, 4947;
(b) Qiu, J.; Guo, C.; Zhang, X. J. Org. Chem. 1997, 62,
2665; (c) Guo, C.; Qiu, J.; Zhang, X.; Verdugo, D.;
Larter, M. L.; Christie, R.; Kenney, P.; Walsh, P. J.
Tetrahedron 1997, 53, 4145; (d) Gennari, C.; Ceccarelli,
S.; Piarulli, U.; Montalbetti, C. A. G. N.; Jackson, R. F.
W. J. Org. Chem. 1998, 63, 5312.
11. General procedure for the addition of diethylzinc to
benzaldehyde. Et2Zn (2 equiv., 1.0 M solution in hex-
anes) was added to a cooled solution (−15°C) of the
ligand (10 mol%; 0.1 mmol) and Ti(OPri)4 (8 mol%; 0.08
mmol; 15 mg) in dry toluene (3 mL) under inert atmo-
sphere. A solution of benzaldehyde (1 mmol; 1 mL of 1
M solution in dry toluene containing dodecane (20 mL/
mmol of aldehyde as internal standard)) was added drop-
wise. Samples were taken at different time intervals
(aliquots: 100 mL), quenched with HCl (1 M) and
extracted with Et2O. The yield and the enantioselectivity
was determinated by chiral GLC (CP-Chirasil-Dex CB
Chrompack 7530; 25 m×0.32 mm) using dodecane as
internal standard. GLC conditions: injector: 200°C;
detector: 200°C; T (initial): 110°C; T (final): 200°C; rate:
80°C/min; t (initial): 10 min. Retention times for ben-
zaldehyde and the enantiomers of 1-phenylpropanol: ben-
zaldehyde: 3.35 min; (R)-1-phenylpropanol: 10.98 min;
(S)-1-phenylpropanol: 11.03 min.
To conclude, we have designed and prepared a novel
class of C2-symmetric oxazoline-based ligands. The lig-
ands were readily synthesized in a straightforward fash-
ion from commercially available enantiomerically pure
starting materials. We have further demonstrated the
use of these ligands in the titanium-catalyzed addition
of diethylzinc to benzaldehyde. Depending on the reac-
tion conditions employed, moderate to high enantiose-
lectivities of the formed 1-phenylpropanol were
obtained.
Acknowledgements
The Swedish Natural Science Research Council, the
Carl Trygger Foundation and the Royal Swedish
Academy of Sciences are gratefully acknowledged for
financial support.
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