Synthesis of new chiral Schiff bases and their application in the asymmetric trimethylsilylcyanation of aromatic aldehydes

Article abstract of DOI:10.1016/S0957-4166(01)00252-X

The new chiral Schiff base ligands 1a-1c were synthesized from (1R)-(+)-camphor and found to be efficient catalysts for the enantioselective silylcyanation of aromatic aldehydes. The corresponding aromatic cyanohydrins were obtained in good yields and with enantiomeric excesses (e.e.s) of up to 73%.

Full text of DOI:10.1016/S0957-4166(01)00252-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1579–1582
Synthesis of new chiral Schiff bases and their application in the
asymmetric trimethylsilylcyanation of aromatic aldehydes
Zhuo-Hong Yang, Li-Xin Wang, Zheng-Hong Zhou, Qi-Lin Zhou and Chu-Chi Tang*
The State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
Received 23 April 2001; accepted 28 May 2001
Abstract—The new chiral Schiff base ligands 1a–1c were synthesized from (1R)-(+)-camphor and found to be efficient catalysts
for the enantioselective silylcyanation of aromatic aldehydes. The corresponding aromatic cyanohydrins were obtained in good
yields and with enantiomeric excesses (e.e.s) of up to 73%. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
have been utilized in conjunction with titanium include
Schiff bases, phosphorus ligands, binol and diammine.
Herein, we report the synthesis of a new series chiral
Schiff bases 1a–1c from (1R)-(+)-camphor and their use
in the asymmetric silylcyanation of aldehyde.
Cyanohydrins are highly versatile synthetic intermedi-
ates, which can be easily converted into a wide variety
of important products including a-hydroxy acids, a-
amino acids and b-amino alcohols. They are also
important components of many biologically active
compounds. In view of their importance, the synthesis
of optically active cyanohydrins has been a topic of
major interest in recent years.1–3 A number of catalysts
for the asymmetric addition of cyanide to aldehydes
have been reported, the most useful of which are
enzymes,1 synthetic peptides2,3 and chiral transition
metal complexes.4–6 Although the structural modifica-
tion of enzymes to increase their substrate compatibility
is a long and difficult undertaking, the structural mod-
ification of chiral transition metal complexes is more
viable. Previous work on the transition metal-induced
asymmetric cyanohydrin synthesis has largely concen-
trated on titanium complexes. The chiral ligands which
2. Results and discussion
2.1. Preparation of chiral Schiff base ligands
The chiral Schiff bases 1a–1c were prepared from (1R)-
(+)-camphor as shown in Scheme 1. Firstly (1R)-(+)-
camphor was oxidized to (+)-cis-1,2,2-trimethyl-1,
3-cyclopentanedicarboxylic acid, which was treated
with sodium azide to give (+)-cis-1,2,2-trimethyl-1,3-
diamino-cyclopentane. Because this diamine is difficult
to purify, it was used directly in the reaction with
salicylaldehyde or its derivatives to produce ligands
1a–1c.
Scheme 1.
* Corresponding author. Fax: +86 22 23503438; e-mail: c.c.tang@eyou.com
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00252-X

1580
Z.-H. Yang et al. / Tetrahedron: Asymmetry 12 (2001) 1579–1582
The reaction temperature was also found to be an
essential factor to the enantioselectivity of the reac-
tion. For example, when the reaction was carried out
at 0°C, the enantiomeric excess of the product was
only 46% (entry 4), whereas reaction at −30°C
increased the e.e. of the product to 66% (entry 8);
furthermore, 70% e.e. was obtained in the reaction at
−40°C (entry 9).
2.2. Asymmetric trimethylsilylcyanation of arylalde-
hydes catalyzed by chiral Schiff base 1a–1c
The Schiff bases 1a–1c were found to be efficient in
the enantioselective silylcyanation of aldehydes. The
reactions were carried out in methylene chloride using
Ti(O-Pri)4 as pre-catalyst. To optimize the reaction,
the effects of amounts of catalyst, molar ratio of lig-
and and Ti(O-Pri)4, the use of iso-propyl alcohol as an
additive, the reaction temperature and substrates on
the enantioselectivity of the process were examined.
All the results were summarized in Table 1.
Having optimized reaction conditions, the asymmetric
additions of trimethylsilylcyanide to a range of aro-
matic aldehydes catalyzed by 20 mol% of Ti(O-Pri)4
and 22 mol% of 1a were investigated. The results
showed that better selectivities were obtained with
electron-rich aromatic aldehydes, while electron-
deficient aromatic aldehydes gave lower product e.e.s.
As shown in Table 1, the enantioselectivity was
markedly influenced by the nature of the Schiff base
employed. The best ligand was found to be compound
1a, which was derived from salicylaldehyde (entries
1–3).
In conclusion, this work has resulted in the discovery
of a new class of ligands for the titanium-catalyzed
asymmetric addition of trimethylsilyl cyanide to aro-
matic aldehyde. Moderate to fair e.e.s were obtained
using ligand 1a.
The amount of catalyst had a dramatic influence on
the enantioselectivity of the reaction. Thus, the use of
20 mol% of catalyst led to the expected cyanohydrin
in high yield with e.e. of 70% (entry 9), while the use
of 50 mol% catalyst only gave moderate enantioselec-
tivity (entry 10, 48% e.e.). Moreover, it was found that
the optimal molar ratio of ligand 1 to Ti(O-Pri)4 is
1.1:1. We found that the use of iso-propyl alcohol as
an additive led to a dramatic decrease the enantio-
selectivity (entry 5), which was different from Oguni’s
results.6c
3. Experimental
1H NMR spectra were recorded in CDCl3 as solvent
on AC-P200 instruments using TMS as internal stan-
dard. Elemental analyses were conducted on MF-3
automatic analyzer. Optical rotations were measured
Table 1. Asymmetric silylcyanation of aromatic aldehyde catalyzed by 1a–1c
Entry
R
Schiff base
(mol%)
Ti(O-Pri)4
(mol%)
Temp. (°C)
Yield (%)a
[h]2D5
(c 1, CHCl3)
E.e.b (%)
E.e.c (%)
47.8
Config.
1
2
3
H
H
H
H
H
H
H
H
1a (10)
1b (22)
1c (22)
1a (20)
1a (22)
1a (5.5)
1a (11)
1a (22)
1a (22)
1a (55)
1a (20)
1a (22)
1a (22)
1a (22)
1a (22)
10
20
20
20
20
5
10
20
20
50
10
20
20
20
20
−20
−20
−20
0
94.0
94.0
75.2
97.7
97.7
94.0
100
97.7
97.7
94.0
94.0
92.5
92.0
92.0
89.0
+19.5
+6.2
+12.4
+20.5
+8.6
+13.7
+24.9
+29.7
+31.4
+19.5
+25.9
+13.5
+33.3
+19.4
+36.0
43
9
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
28
46
19
30
61
66
70
48
58
33
65
72
73
4
5d
6
0
−30
−30
−30
−40
−30
−30
−40 to 50
−40 to 50
−40 to 50
−40 to 50
7
8
9
10
11
12
13
14
15
H
H
H
66.1
30.0
p-Cl
p-CH3
o-CH3O
p-CH3O
a Isolated yield.
b Determined by the comparison of specific rotation values: R=H, [h]D20=+45 (c 1, CHCl3) in Ref. 1; R=Cl, [h]D25=+27.2 (c 1.487, CHCl3) with
66% e.e. in Ref. 11; R=CH3, [h]2D5=+47.4 (c 1.822, CHCl3) with 92% e.e. in Ref. 11; R=o-OCH3, [h]D20=−21.0 (c 1.25, CHCl3) with 77% e.e.
in Ref. 1; R=p-OCH3, [h]2D5=+49 (c 1, CHCl3) with >99% e.e. in Ref. 10.
c Determined by chiral GC on Supelco b-DEX120 after acetylation with acetic acid anhydride.
d 20 mol% iso-propanol was used.

Z.-H. Yang et al. / Tetrahedron: Asymmetry 12 (2001) 1579–1582
1581
1
on a Perkin–Elmer 241MC polarimeter. Ti(O-Pri)4 was
purchased from Fluka. CH2Cl2 was distilled from cal-
cium hydroxide. Me3SiCN was prepared according to
the literature.7
1.5, CHCl3); H NMR (l, ppm): 0.96 (s, 6H, 2CH3),
1.32 (s, 3H, CH3), 1.40 (d, 18H, Bu-H), 2.28 (m, 7H,
CH3+2CH2), 3.54 (t, 1H, CH), 7.20 (m, 4H, Ar-H), 8.34
(s, 1H, OH), 13.24 (s, 1H, OH). Anal. calcd for
C32H46N2O2: C, 78.32; H, 9.45; N, 5.71. Found: C,
78.14; H, 9.36; N, 5.45%.
3.1. Preparation of (+)-cis-1,2,2-trimethyl-1,3-cyclopen-
tanedicarboxylic acid8
3.6. Typical procedure for the trimethylsilylcyanation of
aldehydes
A mixture of (1R)-(+)-camphor (19.0 g, 0.125 mol),
FeSO4·7H2O (1.0 g, 0.0036 mol), H2O (85 mL) and
HNO3 (65–68% 180 mL) was refluxed at 100–105°C for
30 h, then the resulting solution was cooled to room
temperature. The white solid precipitate was collected
by filtration and washing with H2O (2×10 mL) afforded
the desired product (+)-cis-1,2,2-trimethyl-1,3-cyclopen-
tanedicarboxylic acid (12.2 g, 49%). Mp 202–205°C,
[h]2D5=+44.5 (c 10, EtOH). (lit.: yield: 53.5%, mp: 204–
205°C).
To a solution of Schiff base 1a (154 mg, 0.44 mmol) in
CH2Cl2 (5 mL) was added Ti(O-Pri)4 (114 mg, 0.4
mmol) and the mixture was stirred for 1 h at room
temperature. The reaction mixture was cooled to
between −40 and −50°C, then freshly distilled benzalde-
hyde (212 mg, 2 mmol) and trimethylsilylcyanide (400
mg, 4 mmol) were added. After stirring for 24 h at this
temperature, the mixture was poured into a mixture of
HCl (1N, 30 mL) and ethyl acetate (60 mL) and stirred
for 4 h at room temperature, washing the organic layer
with distilled water and saturated NaHCO3 (each 20
mL), drying with anhydrous sodium sulfate and concen-
trating the reaction mixture followed by column chro-
matography (eluent: petroleum ether/ethyl acetate 5:1)
yielded the expected (S)-cyanohydrin (260 mg, 98%).
After measuring the optical rotation, the pure cyanohy-
drin was converted directly into the corresponding
acetates by reaction with two equivalents of acetic acid
anhydride and pyridine in CH2Cl2 (20 mL) at room
temperature for 12 h, washing the organic layer with 5%
H2SO4, distilled water and saturated NaHCO3 (each 20
mL), drying with anhydrous sodium sulfate and concen-
trating followed by column chromatography (eluent:
petroleum ether/ethyl acetate 5:1) yielded the acetylated
cyanohydrin, which was used for further analysis.
3.2. Preparation of (+)-cis-1,2,2-trimethyl-1,3-diamino-
cyclopentane9
A mixture of (+)-cis-1,2,2-trimethyl-1,3-cyclopentanedi-
carboxylic acid (20.3 g, 0.1 mol), CHCl3 (200 mL) and
H2SO4 (60 mL) was stirred at 55–60°C with NaN3 (18.6
g, 0.286 mol) added at intervals, and reacted until gas
evolution ceased. The resulting solution was cooled to
room temperature and adjusted to pH >14 with satu-
rated NaOH. The solution was deposited overnight and
filtered, and washed with CHCl3 (2×30 mL). The
organic layer was separated and the aqueous layer was
extracted with CHCl3 (2×30 mL). The combined organic
layer was dried over anhydrous sodium sulfate, then the
solvent was removed in vacuo to give crude (+)-cis-
1,2,2-trimethyl-1,3-diaminocyclopentane (12.2 g, 86%).
3.3. Preparation of ligand 1a (typical procedure)
Acknowledgements
A mixture of toluene (40 mL), salicylaldehyde (2.44 g,
20 mmol), (+)-cis-1,2,2-trimethyl-1,3-diaminocyclopen-
tane (1.42 g, 10 mmol), and p-toluenesulfonic acid (0.01
g) was stirred under reflux for 2 h. After evaporation of
the solvent, the crude product was recrystallized from
ethyl acetate to give a yellow solid (2.80 g, 80%). Mp
159–161°C; [h]D25=+34.0 (c 2, CHCl3); 1H NMR (l,
ppm): 0.95 (s, 3H, CH3), 0.97 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 2.15 (m, 4H, 2CH2), 3.71 (t, 1H, CH), 7.11 (m,
8H, Ar-H), 8.45 (s, 2H, OH). Anal. calcd for
C22H26N2O2: C, 75.36; H, 7.49; N, 7.99. Found: C,
75.15; H, 7.50; N, 7.88%.
We are grateful to the National Natural Science Foun-
dation of China (Nos. 29872016 and 29725204) for
generous financial support.
References
1. Schmidt, M.; Herve, S.; Klempier, N.; Griengl, H. Tetra-
hedron 1996, 52, 7833–7840.
2. Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33,
1555–1564.
3.4. Preparation of ligand 1b
3. Mori, A.; Nitta, H.; Kudo, M.; Inoue, S. Tetrahedron
Lett. 1991, 32, 4333–4336.
Yellow solid, 77% yield, mp 237–240°C. [h]2D5=+37.7 (c
4. (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J.
Org. Chem. 1993, 58, 1515–1522; (b) Belokon, Y. N.;
Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.;
Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.;
North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo, M.;
Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc.
1999, 121, 3968–3973; (c) Belokon, T.; Flego, M.; Ikon-
nikov, N.; Moscalenko, M.; North, M.; Orizu, C.;
Tararov, V.; Tasinazzo, M. J. Chem. Soc., Perkin. Trans.
1 1997, 1293–1295; (d) Feng, X. M.; Gong, L. Z.; Hu, W.
1
1, CHCl3); H NMR (l, ppm): 0.95 (s, 3H, CH3), 0.97
(s, 3H, CH3), 1.36 (s, 3H, CH3), 2.04 (m, 4H, 2CH2),
3.68 (t, 1H, CH), 7.29 (m, 4H, Ar-H), 8.24 (s, 2H, OH).
Calcd for C22H22Cl4N2O2: C, 54.12; H, 4.54; N, 5.74.
Found: C, 54.08; H, 3.96; N, 5.63%.
3.5. Preparation of ligand 1c
Yellow solid, 80% yield, mp 137–139°C. [h]2D5=+41.9 (c

1582
Z.-H. Yang et al. / Tetrahedron: Asymmetry 12 (2001) 1579–1582
H.; Li, Z.; Pan, W. D.; Mi, A. Q.; Jiang, Y. Z. Chem. J.
Chinese Universities (in Chinese) 1998, 19, 1416–1421.
Chem. Commun. 1990, 1364–1365.
7. Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org.
Chem. 1974, 39 (7), 914–917.
8. Manufacture, J. R. B. Fr. 1 511 610 (1968).
9. Suszko, J.; Trzebniak, F. Roczniki Chem. 1937, 17, 105–
110.
10. Brussee, J.; Loos, W. T.; Kruse, C. G. Tetrahedron 1990,
46, 979–986.
11. Matthews, B. R.; Jackson, W. R.; Jayatilake, G. S.;
Wilshire, C.; Jacobs, H. A. Aust. J. Chem. 1988, 41,
1697–1709.
5. (a) Brunel, J. M.; Constantieux, T.; Buono, G. Tetra-
hedron: Asymmetry 1999, 10, 1979–1984; (b) Hamashima,
Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 1999, 121, 2641–2642; (c) Kanai, M.; Hamashima,
Y.; Shibasaki, M. Tetrahedron Lett. 2000, 41, 2405–2409.
6. (a) Mori, M.; Imma, H.; Nakai, T. Tetrahedron Lett.
1997, 38, 6229–6232; (b) Qian, C.; Zhu, C.; Huang, T. J.
Chem. Soc., Perkin. Trans.
1 1998, 2131–2132; (c)
Hayashi, M.; Matsuda, T.; Oguni, N. J. Chem. Soc.,
.