Asymmetric cyanosilylation of aldehydes catalyzed by novel chiral tetraaza-titanium complexes

Article abstract of DOI:10.1055/s-2006-939724

The asymmetric addition of trimethylsilyl cyanide (TMSCN) to a range of aldehydes was efficiently catalyzed by a novel, easily prepared C ₂-symmetric chiral tetraaza-Ti(IV) complex in high yields with up to 92% ee under mild conditions. A negative nonlinear effect between the ee of the ligand and the ee of the product was observed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939724

LETTER
1085
Asymmetric Cyanosilylation of Aldehydes Catalyzed by Novel Chiral
Tetraaza-Titanium Complexes
A
symmetric Cyano
a
silylation o
n
f
Aldehydesling Liu,a Xiaohua Liu,a Junguo Xin,a Xiaoming Feng*a,b
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
b
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Received 11 January 2006
stituted at the 4¢ and 5¢ position of the pyrrolidine ring had
a negative effect on the reaction enantioselectivity
(Table 1, entry 7). Ligands 2c and 2e, which contained a
piperidine ring and a primary amine, respectively, also
Abstract: The asymmetric addition of trimethylsilyl cyanide
(TMSCN) to a range of aldehydes was efficiently catalyzed by a
novel, easily prepared C2-symmetric chiral tetraaza-Ti(IV) complex
in high yields with up to 92% ee under mild conditions. A negative
nonlinear effect between the ee of the ligand and the ee of the gave poor enantioselectivities (Table 1, entries 8 and 10).
product was observed.
On the other hand, ligand 2a containing a thiazolidine ring
could promote the reaction with a slightly better product
enantioselectivity (Table 1, entry 6). When the two L-pro-
linamide units of 1a were replaced by two (S)-1,2,3,4-
tetrahydroisoquinolinamide groups (2d),13,14 the best
enantioselectivity was obtained (Table 1, entry 9).
Key words: C2-symmetric chiral tetraaza ligand, cyanosilylation,
aldehydes, enantioselectivity, organotitanium
Enantiomerically pure cyanohydrins are important inter-
mediates in the synthesis of a variety of natural and non-
natural biologically active compounds, such as b-amino
alcohols, a-hydroxy acids and their derivatives.1 Because
of their importance in organic synthesis and life science, a
large number of studies have been devoted to the develop-
ment of cyanohydrin synthesis including enzymes2 and
peptides.3 The addition of TMSCN to carbonyl com-
pounds is one of the most popular methods to prepare cy-
anohydrins, which can be catalyzed by many different
reagents.4–11 Recently, C2-symmetric chiral tetraaza
ligands have attracted considerable attention.12 They can
be used in asymmetric catalysis such as reduction of C=C
and C=O bonds, allylic alkylation, cyclopropanation and
hydrosilylation. In this article, a new, easily prepared C2-
symmetric ligand 2d (Figure 1) was reported for the
asymmetric addition of trimethylsilyl cyanide (TMSCN)
to aldehydes.
We then further optimized the reaction conditions by
changing the molar ratio of 2d to Ti(Oi-Pr)4. When the
molar ratio between Ti(Oi-Pr)4 and 2d was 2:1, a better
yield and a slightly higher enantioselectivity were ob-
tained (Table 1, entry 11 vs. entry 9).
O
O
X
N
N
H
H
HN
NH
Y
S
NH HN
O
Y
1a: X =
1b: X =
2a: Y =
2b: Y =
(1R,2R)
NH
O
(1R,2R)
(1S,2S)
NH
O
In our initial studies, several C2-symmetric tetraaza
ligands 1a–e (Figure 1) which were derived from readily
available L-proline, were mixed with Ti(Oi-Pr)4, and the
catalytic properties of the cyanosilylation of aldehydes
were investigated. As illustrated in Table 1, amongst the
five ligands, ligand 1a, prepared from (1R,2R)-1,2-di-
phenylethylenediamine, afforded silylated cyanohydrin
with the best ee value (Table 1, entry 1). Based on the
successful (1R,2R)-1,2-diphenylethylenediamine skele-
ton, we then modified the prolinamide parts and prepared
a series of carboxylic acid derivatives 2a–e (Figure 1,
Table 1, entries 6–10). It was found that the carboxamide
parts also played an important role in determining the
enantioselectivity of the reaction. The ligand 2b sub-
1c: X =
1d: X =
2c: Y =
NH
O
(R)
2d: Y =
2e: Y =
NH
O
1e: X =
(S)
NH2
SYNLETT 2006, No. 7, pp 1085–1089
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939724; Art ID: W01006ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
5.
2
0
0
6
Figure 1 Ligands evaluated for asymmetric cyanosilylation of
benzaldehyde

1086
Y. Liu et al.
LETTER
Table 1 Asymmetric Cyanosilylation of Benzaldehyde Catalyzed
by Different C2-Symmetric Chiral Tetraaza Ligand–Titanium
Complexesa
screening showed that the optimized catalytic system was
15 mol% 2d–Ti(Oi-Pr)4 (1:2), 0.25 M benzaldehyde, 2.1
equivalents TMSCN in 1.0 mL of CH2Cl2 in the presence
of p-nitrobenzoic acid (0.0186 mmol, 7.5 mol%) at 0 °C
(Table 2, entry 11).
OTMS
O
10 mol% L*-Ti(OiPr)4
2.1 equiv TMSCN
CH2Cl2, 14 h, 0 °C
*
CN
H
Encouraged by the result obtained for the benzaldehyde, a
range of aldehydes were investigated under the optimized
conditions.15 The asymmetric cyanosilylation of aromatic,
conjugated and heteroaromatic aldehydes proceeded
smoothly to provide the corresponding cyanohydrin O-
TMS ethers in high yields with moderate to good enantio-
selectivities (Table 3). Aldehydes with substituents on the
aromatic ring gave cyanohydrins similar ee to benzalde-
hyde (entries 2–5, 7 and 9), while 3-phenoxybenzalde-
hyde and 3-chlorobenzaldehyde only gave products with
moderate enantioselectivities (entries 6 and 8). The reac-
tion of a heteroaromatic aldehyde took place in high yield
with 84% ee (entry 11). 2-Naphthaldehyde and a,b-unsat-
urated aldehyde also gave good yields and enantioselec-
tivities (entries 10, 12 and 13).
Entry
Le
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2d
Yield (%)b
ee (%)c
55
1
2
86
51
61
49
61
94
63
76
93
95
98
35
3
36
4
18
5
21
6
64
7
25
8
16
Finally, in order to obtain the information on possible
structure of the C2-symmetric chiral tetraaza–Ti(IV)
complex in solution, a series of experiments about the
relation between the enantiopurity of the ligand 1a16
(Figure 1) and the ee value of the product were studied. A
clear negative nonlinear effect was observed in this
reaction (Figure 2). The result indicated that polymeric
1a–Ti(Oi-Pr)4 (1:2) complexes were involved in the
stereodiscriminating step of the reaction.17,18 This
negative nonlinear effect can also act as a probe to gain
information on the subtle mechanisms.
9
76
10
11d
27
84
a Reactions were carried out on a 0.25-mmol scale of benzaldehyde in
1.0 mL of CH2Cl2; 2d:Ti(Oi-Pr)4 (10 mol%) = 1:1; TMSCN (2.1
equiv).
b Isolated yield of the TMS ether.
c Determined by HPLC on a Chiralcel OD column after conversion to
the corresponding acetate.
d Ratio of 2d:Ti(Oi-Pr)4 (20 mol%) = 1:2.
e Structural identity of all ligands were determined by 1H NMR,
13C NMR and HRMS.
In conclusion, a novel and efficient C2-symmetric chiral
tetraaza–Ti(IV) complex for asymmetric cyanosilylation
of aldehydes with high yields and enantioselectivities un-
der mild conditions had been developed. The catalyst sys-
tem was simple and practical. In addition, the ligands
were easily prepared from commercially available materi-
als. Future efforts are devoted to finding more effective
C2-symmetric tetraaza ligands for improving reactivity,
enantioselectivity and substrate generality.19 Further
mechanistic study is underway in our laboratory.
Accordingly, other conditions of the asymmetric cyano-
silylation of benzaldehyde were evaluated in the presence
of the complex 2d–Ti(Oi-Pr)4 (1:2). First, a series of
solvents including THF, toluene, Et2O, CH2Cl2 were
screened (Table 2, entries 1–4). The best solvent was
found to be CH2Cl2 (Table 2, entry 4). Further studies
indicated that the concentration of benzaldehyde had a
slight influence upon the enantioselectivity (Table 2, en-
tries 4–6). The optimum concentration of benzaldehyde
was 0.25 M (Table 2, entry 4). Both the yield and enan-
tioselectivity were found to vary with temperature. The
satisfying temperature was 0 °C (Table 2, entry 4). De-
creasing or increasing the temperature caused a drop in
yield and enantioselectivity (Table 2, entries 7 and 8). The
most favorable catalyst loading was found to be 15 mol%
(Table 2, entry 10).
To further improve the product enantioselectivity, many
additives such as benzoic acid and some substituted ben-
zoic acids were used. Surprisingly, the enantioselectivity
was increased in the presence of p-nitrobenzoic acid
(Table 2, entry 11 vs. entry 10), whereas both yield and
enantioselectivity were decreased in the presence of ben-
zoic acid (Table 2, entry 12 vs. entry 10). Extensive
Figure 2 (–)-NLE in asymmetric cyanosilylation of benzaldehyde
catalyzed by 1a (Figure 1)
Synlett 2006, No. 7, 1085–1089 © Thieme Stuttgart · New York

LETTER
Asymmetric Cyanosilylation of Aldehydes
1087
Table 2 Optimization of the Cyanosilylation of Benzaldehyde in the Presence of 2d–Ti(IV) Complexa
Entry
1
2d (mol%)
Solvent
THF
Temp (°C)
Time (h)
14
Yield (%)b
ee (%)c
68
20
20
20
20
20
20
20
20
10
15
15
15
0
80
64
70
98
84
88
80
88
68
93
92
58
2
Toluene
Et2O
0
14
71
3
0
14
73
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
14
84
5d
6e
7
0
16
81
0
16
80
–20
26
0
75
75
8
21
72
9
17
80
10
11f
12g
0
17
84
0
17
88
0
17
80
a Unless otherwise specified, reactions were carried out on a 0.25-mmol scale of benzaldehyde in 1.0 mL of solvent; TMSCN (2.1 equiv);
2d:Ti(Oi-Pr)4 (20 mol%) = 1:2.
b Isolated yield of the TMS ether.
c Determined by HPLC on a Chiralcel OD column, after conversion to the corresponding acetate.
d Concentration of benzaldehyde = 0.5 M.
e Concentration of benzaldehyde = 0.125 M.
f In the presence of p-nitrobenzoic acid (0.0186 mmol, 7.5 mol%).
g In the presence of benzoic acid (0.0186 mmol, 7.5 mol%).
Table 3 Asymmetric Cyanosilylation of Aldehydes Catalyzed by
2d–Ti(IV) Complexa
Table 3 Asymmetric Cyanosilylation of Aldehydes Catalyzed by
2d–Ti(IV) Complexa (continued)
O
CN
O
15 mol% 2d-Ti(OiPr)4
CN
*
15 mol% 2d-Ti(OiPr)4
R
H
R
*
OTMS
2.1 equiv TMSCN, CH2Cl2, 0 °C
R
H
R
OTMS
2.1 equiv TMSCN, CH2Cl2, 0 °C
7.5 mol% p-nitrobenzoic acid
7.5 mol% p-nitrobenzoic acid
Yield (%)b ee (%)c
(Config)e
Entry Aldehydes
Yield (%)b ee (%)c
(Config)e
Entry Aldehydes
1
2
3
4
5
6
7d
8
9
Benzaldehyde(3a)
98
94
90
96
91
73
90
91
88
82
86
88 (S)
80 (S)
82 (S)
85 (S)
81 (S)
76 (S)
92 (S)
76 (S)
81 (S)
84 (S)
84 (S)
12
13
(E)-Cinnamaldehyde (3l)
(E)-Crotonaldehyde(3m)
93
49
85 (S)
74 (S)
4-Methylbenzaldehyde (3b)
3-Methylbenzaldehyde (3c)
4-Methoxybenzaldehyde (3d)
3-Methoxybenzaldehyde (3e)
3-Phenoxybenzaldehyde (3f)
4-Fluorobenzaldehyde (3g)
3-Chlorobenzaldehyde (3h)
4-Chlorobenzaldehyde (3i)
2-Naphthaldehyde (3j)
a See ref. 15 for a general procedure of the reaction; TMSCN (2.1
equiv); ratio of 2d:Ti(Oi-Pr)4 (15 mol%) = 1:2.
b Isolated yield of the TMS ether.
c Determined by chiral HPLC analysis (Chiralcel OD and OD-H col-
umn) or GC on a Chirasil DEX CB after conversion to the corre-
sponding acetates.
d The amount of 20 mol% 2d was used.
e Absolute configurations were determined by comparison of optical
rotations and the retention times in analyses with those reported in the
literature.5b,f,i,k,l,p,7d,e,8i,10f
Acknowledgment
10
11
The authors thank the National Natural Science Foundation of
China (Nos. 20225206, 20390055, 20502019 and 20472056) and
the Ministry of Education, China (Nos. 104209, 20030610021 and
others) for financial support.
2-Furaldehyde (3k)
Synlett 2006, No. 7, 1085–1089 © Thieme Stuttgart · New York

1088
Y. Liu et al.
LETTER
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(13) General Procedure for the Preparation of C2-Symmetric
Tetraaza Ligands.
Step 1: To a solution of S-2-tert-butoxycarbonyl-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid (3.467 g, 12.5
mmol) in CH2Cl2 was added Et3N (2.1 mL, 15 mmol) and
isobutyl isobutyl chlorocarbonate (1.8 mL, 13.75 mmol) at
0 °C under stirring. After 20 min, (1R,2R)-1,2-diphenyl-
ethane-1,2-diamine (1.061 g, 5 mmol) was added. It was
warmed to r.t. and stirred for 10 h. The mixture was washed
with 1 M KHSO4, sat. NaHCO3 and brine, dried over anhyd
MgSO4 and concentrated. The residue was used for the next
step directly.
Synlett 2006, No. 7, 1085–1089 © Thieme Stuttgart · New York

LETTER
Step 2: To a solution of the residue in CH2Cl2 (20 mL) was
Asymmetric Cyanosilylation of Aldehydes
1089
CH2Cl2 (0.5 mL) at r.t., then the mixture was stirred at 35 °C
for 1 h under N2 atmosphere. To this solution, aldehyde (0.25
mmol), TMSCN (70 mL, 0.525 mmol) and CH2Cl2 (0.1 mL)
were added, in that order, at 0 °C under an N2 atmosphere.
After the aldehyde was completely converted (monitored by
TLC, 14–36 h), the crude product was purified by column
chromatography to give the corresponding cyanohydrin
trimethylsilyl ether as colorless oil. After conversion into the
acetate, the ee value was determined.
added TFA (12.5 mL) and stirred for 5 h. Then the solution
was concentrated in vacuo, and H2O (25 mL) was added.
The pH of the mixture was brought into the range of 11–12
by the addition of 2 M NaOH. The aqueous phase was
extracted with CH2Cl2. The CH2Cl2 extracts were pooled,
washed with brine, dried over anhyd MgSO4 and evaporated
in vacuo. The crude product was purified by recrystallization
to afford C2-symmetric tetraaza ligands 2d as a white solid
(2.388 g, 90% yield).
(16) Physical, NMR and HRMS data of 1a: mp 140.5–141.3 °C;
[a]D25 –73.3° (c 1.86, CH2Cl2). 1H NMR (600 MHz, CDCl3):
d = 8.37 (s, 2 H), 7.06–7.12 (m, 6 H), 7.00–7.02 (m, 4 H),
5.14 (m, 2 H), 3.63 (m, 2 H), 2.93 (m, 2 H), 2.86 (m, 2 H),
2.23 (s, 2 H), 2.07 (m, 2 H), 1.76 (m, 2 H), 1.63 (m, 4 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 26.0, 30.6, 47.2,
58.1, 60.5, 127.4, 127.5, 128.2, 139.0, 174.5 ppm. HRMS
(ESI): m/z calcd for C24H30N4O2: 407.2442 [M + H]+; found:
407.2456 [M + H]+.
(17) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios,
J. C. Tetrahedron: Asymmetry 1997, 8, 2997.
(18) Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37,
2922.
(14) The following are the physical, NMR and HRMS data of 2d:
mp 200.0–201.1 °C; [a]D25 –86.3 (c 1.62, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 8.09 (2 H, s), 6.95–7.26 (18 H, m),
5.31 (2 H, m), 3.88 (2 H, m), 3.48 (4 H, m), 2.74–3.07 (4 H,
m), 2.3 (2 H, m) ppm. 13C NMR (100 MHz, CDCl3): d =
30.5, 47.1, 56.3, 58.8, 125.6, 126.2, 126.4, 127.6, 127.7,
128.5, 129.2, 133.7, 135.4, 138.7, 173.2 ppm. HRMS (ESI):
m/z calcd for C34H34N4O2 531.2755 [M + H]+; found:
531.2760 [M + H]+.
(15) General Procedure for Asymmetric Cyanosilylation of
Aldehydes.
To a solution of 2d (19.9 mg, 0.0375 mmol) and p-nitro-
benzoic acid (3.1 mg, 0.0186 mmol) in CH2Cl2 (0.4 mL) was
added Ti(Oi-Pr)4 (1 M in toluene, 75 mL, 0.075 mmol) and
(19) Only 16–24% ee was obtained for aliphatic aldehydes.
Synlett 2006, No. 7, 1085–1089 © Thieme Stuttgart · New York