The synthesis and application of novel C2-symmetric chiral N,N,O,O bisoxazoline ligands with a ferrocene backbone

Article abstract of DOI:10.1016/j.tetlet.2006.11.088

Novel C₂-symmetric bisoxazoline ligands 5 with a ferrocene backbone and a hydroxyl group at the substituent of the oxazoline ring were designed and prepared. With these ligands, up to 94% ee was obtained for the alkylation of arylaldehyde with diethylzinc.

Full text of DOI:10.1016/j.tetlet.2006.11.088

Tetrahedron Letters 48 (2007) 385–388
The synthesis and application of novel C2-symmetric chiral
N,N,O,O bisoxazoline ligands with a ferrocene backbone
Genghong Hua, Delong Liu, Fang Xie and Wanbin Zhang*
School of Chemistry and Chemical Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
Received 1 September 2006; revised 12 November 2006; accepted 14 November 2006
Available online 4 December 2006
Abstract—Novel C2-symmetric bisoxazoline ligands 5 with a ferrocene backbone and a hydroxyl group at the substituent of the
oxazoline ring were designed and prepared. With these ligands, up to 94% ee was obtained for the alkylation of arylaldehyde with
diethylzinc.
Ó 2006 Elsevier Ltd. All rights reserved.
Chiral oxazoline ligands derived from readily available
amino acids have found widespread use in metal-cata-
lyzed asymmetric reactions.1 The synthesis and applica-
tion of novel bisoxazoline ligands with a chiral
backbone such as 1,3-dioxolane,2 ferrocene1j,3 and bi-
aryl4 had received much attention in the past decades.
C2-symmetric bisoxazoline ligands 1 and 2 with an
axis-fixed and -unfixed biaryl backbone, respectively,
were developed previously and it was found that these
kind of ligands afforded excellent enantioselectivity in
the asymmetric alkylation of benzaldhyde with diethyl-
zinc.5 On the other hand, the other types of ligands 3
and 4 possessing both planar chirality and central chiral-
ity were prepared by selective lithiation of bisoxazoline
ferrocene followed by the reaction with electrophilic
attack.6 Both ligands 3 and 4 showed that the ferrocene
backbone had great effect on the enantioselectivity and
catalytic activity. So it is expected that some interesting
and effective asymmetric inductions may be found by
the combination of ferrocene backbone and the easily
introduced hydroxyl group in the substituent of the
oxazoline ring. Here, we wish to report the preparation
of the novel C2-symmetric bisoxazoline ligands 5 with a
ferrocene backbone bearing a hydroxyl group in the
substituent of the oxazoline ring, and their application
in the asymmetric alkylation of arylaldehyde with
diethylzinc.
HO
O
R
R
HO
O
Me
Me
O
R
R
Me
Me
N
N
N
N
R
OH
N
O
OH
Fe
O
R
OH
OH
R
N
R
1
2
O
5 (a: R=H, b: R=Me, c: R=Et, d: R=Ph)
O
O
R
R
R
N
N
Ligand 5 was synthesized easily from 1,10-ferrocenedi-
carboxylic acid dichloride and L-serine methyl ester
hydrochloride through the intermediates 6 and 7 as
shown in Scheme 1. Thus, in the presence of triethyl-
amine, 1,10-ferrocenedicarboxylic acid dichloride reacted
with L-serine methyl ester hydrochloride to give amide
compound 6 with a yield of 92%. Then, the hydroxyl
group of 6 was activated by Burgess Reagent [(methoxy-
carbonylsulamoyl)-triethylammonium hydroxide inner
CPh2OH
N
CPh2OH
CPh2OH
Fe
Fe
N
R
O
CPh2OH
O
3 (a: R=
i
-Pr, b: R=
t
-Bu)
4 (a: R=i-Pr, b: R=t-Bu)
*
Corresponding author. Tel./fax: +86 21 5474 3265; e-mail:
wanbin@sjtu.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.088

386
G. Hua et al. / Tetrahedron Letters 48 (2007) 385–388
HO
COOMe
O
H
CH2OH
NH3Cl
COOMe
COOMe
COCl
COCl
Burgess Reagent
70%
NH
H
N
Fe
Fe
92%
O
HO
6
O
LiAlH4, THF
61%
CH2OH
CH2OH
N
Fe
N
O
O
COOMe
COOMe
N
Fe
5a
N
R
O
O
R
N
N
OH
RMgBr, THF
65-75%
Fe
OH
7
R
R
O
5b,c,d
Scheme 1.
COOMe
CH2OH
HO
O
H
COCl
Burgess Reagent
74%
NH3Cl
N
COOMe
Fe
Fe
H
94%
O
N
O
CH3MgI, THF
66%
OH
COOMe
N
Fe
Fe
8
Scheme 2.
OH
*
With the present new kinds of bisoxazoline ligands in
hand, we investigated their performance in zinc(II)—
catalyzed asymmetric alkylation of arylaldehyde with
diethylzinc (Scheme 3, Tables 1–3). The alkylation of
benzaldehyde with diethylzinc using ligand 5b was first
examined.5
ZnEt2, Ligand
ArCHO
Ar
Et
Ar=Ph, p-MeO-C6H4, p-Br-C6H4, o-Br-C6H4
Scheme 3.
The effect of solvent on the catalytic reaction with 5b as
a ligand (Table 1, entries 1–3) was examined at first. It
was shown that when the solvent was toluene, it gave
the best result of 87% ee. When using THF and dichloro-
methane instead of toluene, the value of enantiomeric
excess decreased to 81% and 79%, respectively. The
effect of the temperature to the reaction was also
investigated (entries 4–5). It was observed that lower
temperatures gave higher enantioselectivity. At room
temperature, the ee value was only 74%. While the tem-
perature was reduced to ꢀ25 °C, the enantioselectivity
salt] and the formation of oxazoline ring was carried out
to afford bisoxazoline compound 7 in 70%.5,7 Finally,
reduction of 7 with LiAlH4 at room temperature for
6 h afforded the desired ligand 5a bearing a hydroxyl
group in the yield of 61%.8 While treating 7 with
Grignard reagent in THF at 0 °C afforded other analogous
ligands 5b–d in the yields of 65–75%.9
The C1-symmetric monooxazoline ligand 810 was also
synthesized in the same way with the overall yield of
46% in three steps (Scheme 2).

G. Hua et al. / Tetrahedron Letters 48 (2007) 385–388
387
Table 1. Zn(II)-catalyzed asymmetric alkylation of benzaldehyde with
O
O
diethylzinca
O
O
Zn Zn
Yieldb
(%)
% eec
(config)d
ZnEt2
Entry
Ligand
Solvent
Conditions
(°C/h)
N
N
Et
Et
N
N
OH
OH
Fe
O
O
1
2
3
4
5
5b
5b
5b
5b
5b
Toluene
THF
DCM
Toluene
Toluene
0/48
0/48
0/48
rt/24
ꢀ25/144
93
77
86
92
40
87 (R)
81 (R)
79 (R)
74 (R)
94 (R)
Fe
9
Ph
H
Et
Zn
a The reactions were carried out with 2.2 equiv of ZnEt2 and 10 mol %
Et
O
of ligand.
b Isolated yield.
O
O
Zn Zn
c Determined by HPLC using chiral OD–H column.
d Determined by comparing the sign of its optical rotation with the
literature data.
PhCHO
ZnEt2
Et
Et
N
N
O
O
Fe
Table 2. Zn(II)-catalyzed asymmetric alkylation of benzaldehyde with
diethylzinc using different ligandsa
10
Scheme 4.
Entry Ligand Conditions (°C/h) Yieldb (%) % eec (config)d
1
2
3
4
5a
5b
5c
5d
8
0/48
0/48
0/48
0/48
0/48
0/24
0/24
0/24
0/8
92
93
86
86
89
25
68
63
97
79 (R)
87 (R)
45 (R)
41 (R)
20 (R)
70 (R)
83 (R)
91 (R)
93 (R)
be concluded that the bulkiness of ligand has great effect
on catalytic enantioselectivity. In sharp contrast, how-
ever, the reaction with the C1-symmetric monooxazoline
ligand 8 resulted in a low enantiomeric excess [20% ee
(R)] (entry 5) under the identical conditions. Further-
more, we compared the enantioselectivity of ligands 3
and 4 possessing both planar chirality and central chiral-
ity with ligands 5, which are easier to be prepared, and
have much simple structures than 3 and 4.6 Ligand 5b
showed higher enantioselectivity than ligands 3a and
4a having iso-propyl groups and similar enantioselectiv-
ity with ligands 3b and 4b having tert-butyl groups in the
oxazoline ring (entries 6–9).
5
6e
7e
8e
9e
3a
4a
3b
4b
a The reaction was carried out with 2.2 equiv of ZnEt2 and 10 mol % of
ligand in toluene.
b Isolated yield.
c Determined by HPLC using OD–H column.
d Determined by comparing the sign of its optical rotation with the
literature data.
e See Ref. 6.
The ligand 5b was then used as the catalyst for the addi-
tion of diethylzinc to the other aromatic aldehydes
(Scheme 3, Table 3). The reactions were performed using
10 mol % of the catalyst in toluene at 0 °C. With regard
to the additions to the aldehydes, electronic effects of the
aromatic ring substituents did not seem to have great
influence in this case. Bearing a strong electron donating
substituted group such as methoxyl in the para-position
of the benzene ring, it afforded a better enantioselectivity
(92% ee, entry 2), although the reaction rate was a little
lower. When the substituent group on the benzene ring
was changed to electron withdrawing group such as bro-
mo, the value of enantiomeric excess was decreased to
83%. On the other hand, it was shown that the steric
hindrance played an important role in determining the
degree of the enantioselectivity of the reaction: ortho-
was enhanced to 94% although the reaction proceeded
very slowly and only 40% isolated yield of chiral alcohol
was obtained even after 6 days.
Then the effect of the bulkiness of ligand was investi-
gated. As shown in Table 2, the ligand 5b with the
methyl as substituted group showed high catalytic activ-
ity and enantioselectivity for asymmetric reaction (entry
2). When the bulkiness became much larger by changing
methyl to ethyl and phenyl, the enantioselectivities were
dramatically decreased to 45% and 41%, respectively
(entries 3–4). Ligand 5a with no substituted groups also
showed good catalytic activity, although the enantiose-
lectivity was a little lower than the ligand 5b. It could
Table 3. Zn(II)-catalyzed asymmetric alkylation of several kinds of arylaldehydes with diethylzinca
Entry
Ligand
Aldehyde
Conditions (°C/h)
Yieldb (%)
% ee (config)c
1
2
3
4
5b
5b
5b
5b
C6H5CHO
0/48
0/96
0/48
0/48
93
92
95
93
87 (R)
p-MeO–C6H4CHO
p-Br–C6H4CHO
o-Br–C6H4CHO
92d (R)
83e (R)
66d (R)
a The reaction was carried out with 2.2 equiv of ZnEt2 and 10 mol % of ligand in toluene.
b Isolated yield.
c Determined by comparing the sign of its optical rotation with literature data.
d Determined by HPLC using chiral AD–H column.
e Determined by HPLC using chiral OJ–H column.

388
G. Hua et al. / Tetrahedron Letters 48 (2007) 385–388
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Synlett 2000, 2, 239–241.
substituted benzaldehyde gave lower enantiomeric
excess than their para-substituted analogues (entries 3–4).
By comparing the results from C2-symmetric bisoxazo-
line ligand 5b and the C1-symmetric one 8, we could sug-
gest that the reaction catalyzed by N,N,O,O ligand 5b
may proceed in a catalytic mechanism totally different
from that of the N,O ligand 8. Similar to the binuclear
aluminum catalytic mechanism11 and binuclear zinc cat-
alytic mechanism5,12 reported before, a plausible mecha-
nism was presented as shown in Scheme 4. A binuclear
zinc intermediate 9 might be formed, followed by the
coordination with arylaldehyde and additional diethyl-
zinc to form complex 10. Then, the coordinated diethyl-
zinc attacked the carbonyl group stereoselectively to
afford the corresponding chiral alcohol from the back
of benzaldehyde for less steric hindrance. It was interest-
ing to observe that the C2-symmetric bisoxazoline
ligands 5c,d with bulkier substituent groups gained
much lower enantiomeric excess than ligands 5a,b with
smaller substituent groups, which might be caused by
the unmatching of the catalyst and substrate.
6. Zhang, W.; Yoshinaga, H.; Imai, Y.; Kida, T.; Nakatsuji,
Y.; Ikeda, I. Synlett 2000, 10, 1512–1514.
In summary, a series of novel bioxazoline ligands with a
ferrocene backbone were synthesized, and their ability
to catalyze the asymmetric alkylation of arylaldehyde
with diethylzinc was also studied. The N,N,O,O ligand
5b with the methyl as substituent groups showed the best
catalytic activity and enantioselectivity. A possible bi-
nuclear zinc catalytic mechanism was proposed finally.
7. Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907–910.
25
8. Data for 5a: mp 188 °C (decomposed). ½aꢁD +161.8 (c 0.5
MeOH). 1H NMR (400 MHz, CDCl3) d 3.53 (d, 2H,
J = 12.4 Hz), 4.14 (d, 2H, J = 12.4 Hz), 4.20–4.25 (m,
2H), 4.26 (br s, 2H), 4.41 (dd, 2H, J = 8.0, 11.2 Hz), 4.54
(t, 2H, J = 8.0 Hz), 4.59 (br s, 2H), 4.69 (br s, 2H), 4.82 (br
s, 2H). HRMS: (MALDI) Calcd for C18H20FeN2O4
[M+H]+: 385.0845. Found: 385.0864.
25
9. Data for 5b: mp 83–85 °C. ½aꢁD +15.8 (c 0.075 MeOH). 1H
Acknowledgements
NMR (400 MHz, CDCl3) d 1.17 (s, 6H), 1.38 (s, 6H), 4.10
(t, 2H, J = 9.6 Hz), 4.28 (t, 2H, J = 8.0 Hz), 4.37 (br s,
2H), 4.39 (br s, 2H), 4.44 (br s, 2H), 4.70 (br s, 4H).
HRMS: (MALDI) Calcd for C22H28FeN2O4 [M+H]+:
441.1471. Found: 441.1486. Data for 5c: mp 104–105 °C.
This work was partly supported by the Excellent Young
Teachers Program of MOE, PR China and the National
Natural Science Foundation of China (No. 20572070).
25
½aꢁD ꢀ101.5 (c 0.36 CHCl3). 1H NMR (400 MHz, CDCl3)
d 0.90 (t, 6H, J = 7.6 Hz), 0.97 (t, 6H, J = 7.6 Hz), 1.35 (q,
4H, J = 7.2 Hz), 1.54 (q, 4H, J = 7.2 Hz), 4.22 (dd, 2H,
J = 8.4, 10.8 Hz), 4.32 (d, 2H, J = 0.8 Hz), 4.34 (d, 2H,
J = 0.8 Hz), 4.35 (br s, 2H), 4.44 (br s, 2H), 4.65 (br s, 2H),
4.70 (br s, 2H). HRMS: (MALDI) Calcd for
C26H36FeN2O4 [M+H]+: 497.2097. Found: 497.2098.
References and notes
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Data for 5d: mp 198–199 °C. ½aꢁD ꢀ395.3 (c 0.36 CHCl3)
1H NMR (400 MHz, CDCl3) d 3.49 (t, 2H, J = 8.4 Hz),
3.87 (t, 2H, J = 8.4 Hz), 4.29 (br s, 2H), 4.54 (br s, 2H),
4.60 (br s, 2H), 4.71 (br s, 2H), 5.21 (t, 2H, J = 8.4 Hz),
7.04 (t, 2H, J = 7.2 Hz), 7.18 (t, 4H, J = 7.6 Hz), 7.22 (t,
2H, J = 7.2 Hz), 7.30 (t, 4H, J = 7.6 Hz), 7.37 (d, 4H, J =
7.2 Hz), 7.59 (d, 4H, J = 7.2 Hz). HRMS: (MALDI) Calcd
for C42H36FeN2O4 [M+Na]+: 711.1917. Found: 711.1916.
25
1
10. Data for 8: mp 85–87 °C. ½aꢁD +96.5 (c 1.05 CHCl3). H
NMR (400 MHz, CDCl3) d 1.20 (s, 3H), 1.34 (s, 3H), 4.10
(dd, 1H, J = 8.0, 10.0 Hz), 4.21 (s, 5H), 4.27 (t, 1H,
J = 8.0 Hz), 4.34 (br s, 1H), 4.37 (br s, 2H), 4.33–4.39 (m,
1H), 4.77 (br s, 1H), 4.80 (br s, 1H). HRMS: (MALDI)
Calcd for C16H19FeNO2 [M+H]+: 314.0838. Found:
314.0857.
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