The synthesis of novel tetradentate ligands derived from salen and their application in enantioselective silylcyanation of aldehydes

Article abstract of DOI:10.1016/j.tetasy.2010.05.050

Two new tetradentate ligands derived from salen have been prepared and their titanium complexes are used as chiral catalysts in the enantioselective silylcyanation of aldehydes, which give the silyl ethers of cyanohydrins in moderate to good enantiomeric

Full text of DOI:10.1016/j.tetasy.2010.05.050

Tetrahedron: Asymmetry 21 (2010) 1869–1873
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The synthesis of novel tetradentate ligands derived from salen and their
application in enantioselective silylcyanation of aldehydes
Chengwei Lv a,b, Mei Wu a,b, Shoufeng Wang a, Chungu Xia a, Wei Sun a,
*
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
b Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new tetradentate ligands derived from salen have been prepared and their titanium complexes are
used as chiral catalysts in the enantioselective silylcyanation of aldehydes, which give the silyl ethers of
cyanohydrins in moderate to good enantiomeric excesses.
Received 18 April 2010
Accepted 24 May 2010
Available online 2 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
chiral catalysts have been introduced. Among them, salen–Ti com-
plexes are highly promising catalysts for this reaction.7
During the last few decades, chemists witnessed a remarkable
advancement of catalytic asymmetric synthesis. Important efforts
have been devoted to the development of more efficient catalysts
and various types of chiral metal- and organocatalysts have been
developed.1 Among these, chiral metal–salen complexes have been
demonstrated as one of the most versatile catalysts owing to their
high asymmetry-inducing ability, ready availability, and structural
diversity, which endow them with various catalytic performances.2
To date the easy to prepare chiral metal–salen complexes have
been used as excellent catalysts for a wide range of organic trans-
formations including epoxidation, aziridination, sulfoxidation and
Michael reaction, epoxide opening, and Henry reaction, amongst
others.1,3 In order to construct some more efficient catalysts that
have the ability to efficiently enhance reactivity and to regulate
orientation in an asymmetric atmosphere, considerable efforts
have been made and a series of tetradentate ligands derived from
salen ligands have been synthesized, such as a semi-reduced salen-
type ligand (so-called salalen) or a fully reduced salen (salan). The
recent work by Katsuki et al. based on salalen and salan complexes
has successfully achieved high enantioselectivity in a number of
asymmetric reactions.3d,e,4–6
However, the asymmetric silylcyanation of a broad range of
substrates including aliphatic aldehydes and ketones with low cat-
alyst loadings under mild reaction conditions is still a challenge.9
We have previously reported the use of salen derivatives as cata-
lysts in the oxidative carbonylation of b-amino alcohols,10 oxida-
tive kinetic resolution of secondary alcohols,11 and asymmetric
epoxidation of olefins.12 In this manuscript, in order to expand
the catalyst library and enhance the catalytic efficiency, we de-
scribe a simple and practical method for the synthesis of two novel
ligands prepared from salen and Grignard reagents and focus on
their application in enantioselective cyanohydrin synthesis.
2. Results and discussion
Recently, we have successfully synthesized a series of new chiral
tetradentate nitrogen ligands together with their manganese com-
plexes, which exhibit rapid, highly enantioselective epoxidation of
various a
,b-enones.13 Encouraged by this conceptual strategy to im-
prove the stereoselectivity and reactivity of catalysts, we design and
prepare some new ligands by the same method of reacting the Grig-
nard reagents with the C@N of salen ligands to construct the C–N
bond. The experimental procedure is shown in Scheme 1. Different
Grignard reagents such as Ph-MgBr, p-MeOC6H4-MgBr, p-(t-Bu)-
C6H4-MgBr, t-Bu-MgCl, and CH3-MgI were used toward the synthe-
sis of the desired ligands containing the C–N bond, but only Ph-MgBr
could react with the salen ligand successfully. The t-Bu-MgCl
reagent could not react with the salen ligand. Other Grignard
reagents led to very complicated products that were difficult to
isolate by chromatography. The corresponding Ti complexes were
obtained by the reaction of equimolar amounts of ligand and
Ti(Oi-Pr)4 in CH2Cl2 under an argon atmosphere at reflux for 12 h.
Based on our previous study, the configurations of the ligands 3
and 4 are shown in Scheme 1.13,14
The asymmetric addition of cyanide to carbonyl compounds is
one of the most useful carbon–carbon bond-forming reactions in or-
ganic synthesis for producing optically active cyanohydrin deriva-
tives. This is because the resultant compounds can be easily
converted to a variety of chiral building blocks such as optically ac-
tive
a-hydroxy carboxylic acids and a
-amino alcohols.7 After the
pioneering work by Oguni and Hayashi on the enantioselective sily-
lcyanation of aldehydes using an optically active Schiff base ligand,8
many efforts have been devoted to this reaction and many effective
* Corresponding author. Tel.: +86 931 496 8278; fax: +86 931 827 7088.
E-mail addresses: wsun@licp.cas.cn, weisun76@gmail.com (W. Sun).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.050

1870
C. Lv et al. / Tetrahedron: Asymmetry 21 (2010) 1869–1873
R3
R3
N
N
NH HN
OH HO
R1
OH HO
R1
R3 MgX
R1
R1
+
R2
R2
R2
R2
1
2
3. R1 = t-Bu, R2 = t-Bu, R3 = Ph
4. R1 = H, R2 = Ph, R3 = Ph
Scheme 1. Synthesis of the ligands derived from salen.
With ligands 3 and 4 in hand, their catalytic properties in sily-
lcyanation were evaluated. Initially, benzaldehyde was chosen as a
model substrate with an excess (2 equiv) of TMSCN in the presence
of ligand 3 or 4 in combination with an equimolar amount of Ti(Oi-
Pr)4, and the reaction was performed at 0 °C for 24 h. The catalytic
system was first prepared in situ by stirring ligand 3 or 4 with
Ti(Oi-Pr)4 at room temperature for 1 h in the appropriate solvent.
As the results show in Table 1 (entries 1 and 2), the ligand 3 to-
gether with Ti(Oi-Pr)4 resulted in a better asymmetric induction
in the addition of TMSCN to benzaldehyde. Having determined that
ligand 3 was the preferred ligand, the amount of the catalyst and
reaction solvent was then investigated. Among the solvents tested,
acetonitrile was proved to be favorable to the reaction, a 66% ee was
observed using catalyst prepared in situ at 0 °C for 24 h (Table 1, en-
try 10). When the corresponding Ti-complex of ligand 3 (Ti-3) was
directly employed as a catalyst, a comparable result was achieved
only in the presence of 3 mol % of complex Ti-3 (Table 1, entry 12).
Further reducing the amount of the catalyst led to a low yield (Ta-
ble 1, entry 13). In general, the enantioselectivity of the asymmetric
reaction could be improved by lowering the reaction temperature.
To our delight, the silyl ether was obtained quantitatively in 70%
ee, when the temperature was lowered to ꢀ20 °C. While the temper-
ature was lowered to ꢀ40 °C, the product was formed in a nearly
quantitative yield with an 81% ee (Table 1, entry 15).
series of additives as mentioned above.7 The results are summa-
rized in Table 2. It should be noted that only i-PrOH or Ph3PO gave
similar ee values to those without an additive (Table 2, entries 1
and 2). With DMAP or DABCO as an additive, an excellent yield
but racemic product was obtained (Table 2, entries 3 and 4). With
CF3COOH as an additive, only 5% yield of product was obtained (Ta-
ble 2, entry 5). Moreover, C6H5COOH also showed a negative effect
on the outcome of the reaction (Table 2, entry 6). All attempts to
convert Ti-3 into the corresponding bis-oxo-bridged bimetallic
complex analogous according to the literature had no significant
influence on the reaction outcome (Table 2, entry 7).15 Based on
the discussion above, we concluded that the optimized conditions
involved an aldehyde that reacted with an excess (2 equiv) of
TMSCN in the presence of (3 mol %) Ti-3 complex as catalyst in ace-
tonitrile at ꢀ40 °C for 48 h.
Table 2
Effect of varying the additives on the enantiomeric excessa
OTMS
CHO
Ti-3 (3 mol%)
CN
2eq. TMSCN
*
+
º
CH3CN/-40 C
Entry
Additive
Yieldb (%)
eec (%)
Many papers have reported that using an additive could im-
prove the enantiomeric excess and conversion, thus we tested a
1
i-PrOH
Ph3PO
DMAP
DABCO
CF3COOH
C6H5COOH
H2O
98
98
100
100
5
79 (S)
82 (S)
0
5 (S)
43 (S)
65 (S)
83 (S)
2d
3
4
5
6
7
Table 1
The screening of reaction conditions for the addition of TMSCN to benzaldehydea
76
80
OTMS
CHO
a
b
c
All reactions were carried out with 3 mol % additive in CH3CN at ꢀ40 °C for 48 h.
GC yield.
Enantiomeric excess of silyl ether determined by chiral GC with a CP-Chirasil-
Catalyst
CN
2eq. TMSCN
*
+
Dex CB column.
d
6 mol % of Ph3PO.
Entry
Catalyst (mol %)
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
3 + Ti(Oi-Pr)4 (15)
4 + Ti(Oi-Pr)4 (15)
3 + Ti(Oi-Pr)4 (10)
3 + Ti(Oi-Pr)4 (5)
3 + Ti(Oi-Pr)4 (1)
3 + Ti(Oi-Pr)4 (5)
3 + Ti(Oi-Pr)4 (5)
3 + Ti(Oi-Pr)4 (5)
3 + Ti(Oi-Pr)4 (5)
3 + Ti(Oi-Pr)4 (5)
Ti-3 (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
>99
32
>99
>99
46
59
35
51
93
92
99
99
50
60 (S)
10 (S)
57 (S)
59 (S)
44 (S)
24 (S)
13 (S)
6 (S)
54 (S)
66 (S)
64 (S)
66 (S)
64 (S)
70 (S)
81 (S)
With the optimized reaction conditions in hand, the asymmetric
addition of trimethylsilyl cyanide to a range of aldehydes catalyzed
by Ti-3 complex was investigated. The results shown in Table 3 indi-
cate that excellent enantiomeric excesses are obtained with elec-
tron-rich aromatic aldehydes, while electron-deficient aromatic
aldehydes give lower enantiomeric excesses (Table 3, entries 2, 3,
6). It is evident that the steric properties of the aromatic aldehyde
have a great effect on the ee of the product in this reaction. The
ortho-substituted aromatic aldehydes gave lower ee values than
the para-substituted aromatic aldehydes (Table 3, entries 3, 4, 6,
7). No reaction occurred with two aliphatic aldehydes as substrates
under the same conditions (Table 3, entries 10 and 11).
Et2O
CHCl3
9
10
11
12
13
14d
15e
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Ti-3 (3)
Ti-3 (1)
Ti-3 (3)
Ti-3 (3)
99
99
a
b
c
All reactions were carried out at 0 °C for 24 h.
GC yield.
Enantiomeric excess of the silyl ether determined by chiral GC with a CP-
3. Conclusion
Chirasil-Dex CB column.
d
In summary, we have successfully designed and synthesized
two novel chiral tetradentate ligands derived from salen ligands
The reaction was performed in CH3CN at ꢀ20 °C for 24 h.
e
The reaction was performed in CH3CN at ꢀ40 °C for 48 h.

C. Lv et al. / Tetrahedron: Asymmetry 21 (2010) 1869–1873
1871
Table 3
All reactions were carried out under argon in dried glassware.
CH2Cl2, acetonitrile, and CHCl3 were distilled from CaH2 and stored
under argon prior to use. Toluene was distilled from Na and stored
under argon prior to use. THF and diethyl ether were freshly dis-
tilled from Na/benzophenone under argon. Ti(OiPr)4 (from Alfa)
was distilled and diluted to 0.1 M in CH2Cl2 and stored under
argon.
Cyanation of aldehydes or ketones with TMSCN catalyzed by Ti-3a
OTMS
CN
Ti-3
48 h, -40 C
+ 2 eq. TMSCN
RCHO
º
CH3CN
Yieldb (%)
99 (95)d
R
Entry
Aldehyde
CHO
eec (%)
1
2
3
81 (S)
92 (S)
66 (S)
4.2. Synthesis of the desired ligands derived from chiral salen
and the corresponding Ti-3 complex
99 (94)d
50
H3CO
CHO
CHO
4.2.1. Preparation of chiral ligands 3 and 4
Cl
A solution of 1 (5 mmol) in Et2O was added dropwise to a vig-
orously stirred Grignard reagent (50 mmol) in Et2O (20 mL) at
room temperature and the reaction mixture was stirred at same
temperature for 24 h. Saturated NH4Cl was added to quench the
reaction. The organic phase was dried over anhydrous Na2SO4
and purified by column chromatography on silica gel (petroleum
ether/EtOAc = 20:1) to afford the corresponding ligand 3 and 4.
Cl
Cl
4
5
93
97
30 (R)
CHO
CHO
34
4.2.1.1. N,N0-bis[(R)-Phenyl(2-hydroxy-3,5-di-tert-butylbenzyl)]
Cl
cyclohexane-(1R,2R)-diamine 3. Yield, 76%;
½
a 2D0
ꢂ
¼ ꢀ65:5 (c
0.01, CH2Cl2); 1H NMR (400 MHz, CDCl3): d = 11.26 (s, 1H, OH),
7.61–7.18 (m, 7H, ArH), 6.60 (s, 1H, NH), 5.08 (s, 1H, CH), 2.41 (s,
1H, CH), 2.17 (s, 1H, CH2), 1.64 (s, 1H, CH2), 1.45 (s, 9H, CH3),
1.19 (s, 9H, CH3), 1.13–1.11 (m, 2H, CH2); 13C NMR (100 MHz,
CDCl3): d = 153.96, 140.74, 140.30, 136.34, 128.98, 128.73,
128.42, 127.71, 127.16, 125.56, 123.63, 123.08, 64.46, 57.58,
35.06, 34.12, 31.68, 29.66, 29.47, 23.66. HRMS (ESI-MS) calcd for
6
7
84 (80)d
50
90 (S)
37 (R)
H3C
CHO
CH3
CHO
Br
8
9
98
96
29
33
48H67N2O2 [M+H]+: 703.5197, found: 703.5201.
CHO
OCH3
C
CHO
CHO
CHO
NH HN
10
11
—
—
—
—
t-Bu
OH HO
t-Bu t-Bu
t-Bu
a
b
c
All reactions were carried out in CH3CN for 48 h at ꢀ40 °C.
GC yield.
Enantiomeric excess of silyl ether determined by chiral GC with a CP-Chirasil-
Dex CB column. The absolute configurations were determined by comparison of the
sign of the specific rotations with the literature data.
4.2.1.2. N,N0-bis[(R)-Phenyl (2-hydroxy-3-phenylbenzyl)] cyclo-
hexane-(1R,2R)-diamine 4. Yield, 70%; ½a D20
¼ ꢀ212:7 (c 0.01,
ꢂ
d
The isolated yield is indicated in parentheses.
CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 7.60–6.72 (m, 13H, ArH),
5.08 (s, 1H, CH), 2.48 (s, 1H, CH), 2.11 (s, 1H, CH2), 1.61 (s, 1H,
CH2), 1.26–1.17 (m, 2H, CH2); 13C NMR (75 MHz, CDCl3):
d = 154.06, 140.81, 138.42, 129.83, 129.22, 129.50, 129.39,
129.04, 128.10, 127.92, 127.66, 126.85, 119.18, 115.22, 63.71,
57.66, 29.61, 23.43. HRMS (ESI-MS) calcd for C44H43N2O2 [M+H]+:
631.3319, found: 631.3314.
and their titanium complexes are applied in the enantioselective
cyanation of aldehydes that show moderate to good asymmetric
induction. Further studies will focus on expanding the scope of
these ligands in asymmetric reactions.
4. Experimental
4.1. General
NH HN
OH HO
The 1H and 13C NMR spectra were recorded on a Bruker Avance
III 400 MHz or a Varian Mercury Plus-300 spectrometer. The chem-
ical shifts (d) are reported in parts per million (ppm) and coupling
constants (J) in Hertz. High resolution mass spectra (HRMS) were
obtained on a Bruker Daltonics APEX II 47e FT-ICR mass spectrom-
eter or on a Bruker Daltonics micrOTOF-QII mass spectrometer.
Enantiomeric excesses (ee) were determined with an Agilent-
6820 GC (column, CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm).
Optical rotations were measured on the Perkin–Elmer instruments,
Model 341 LC polarimeter. Column chromatography was generally
performed on silica gel (200–300 mesh).
Ph
Ph
4.2.2. Preparation of Ti-3 complex
The corresponding Ti-3 complex was synthesized by the reac-
tion of equimolar amounts of ligand 3 and Ti(OiPr)4 (0.1 M in
CH2Cl2) in dry CH2Cl2 under an argon atmosphere at reflux for
12 h. Then the solvent was evaporated under vacuum to give the

1872
C. Lv et al. / Tetrahedron: Asymmetry 21 (2010) 1869–1873
product as a yellow solid. HRMS (ESI-MS; CH2Cl2/MeOH) calcd for
49H67N2O3Ti: [M-2OiPr+OMe]+, 779.4637, found: 779.4631.
detector temperature = 280 °C): tR (minor) = 38.4 min, tR (major) =
38.9 min.
C
4.4.7. 2-Trimethylsilyloxy-2-(2-methylphenyl)acetonitrile
(Table 3, entry 7)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 115 °C (isothermal), inject temperature = 250 °C,
detector temperature = 280 °C): tR (minor) = 29.1 min, tR (major) =
30.1 min.
HN
O
NH
Ti
t-Bu
O
Oi-Pr
t-Bu
i-PrO
t-Bu
t-Bu
4.4.8. 2-Trimethylsilyloxy-2-(2-bromophenyl)acetonitrile
(Table 3, entry 8)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 125 °C (isothermal), inject temperature = 230 °C,
detector temperature = 250 °C): tR (minor) = 35.5 min, tR (major) =
36.5 min.
4.3. General procedure for the asymmetric addition of
trimethylsilylcyanide to aldehyde
The chiral Ti-3 complex 0.0052 g (0.006 mmol) 3%, substrate
(0.2 mmol), and nonane were added to the solvent of CH3CN
(1 mL) under an Ar atmosphere in the test tube and the solution
was stirred for 70 min at ꢀ40 °C. Then 2 equiv of TMSCN
(0.4 mmol) was added to the solution and the reaction was kept
at ꢀ40 °C for 48 h. After that time, the ee and yields were analyzed
by GC (CP-Chirasil-Dex CB column). Absolute configuration was as-
signed by comparison of the sign of the specific rotation with the
literature.9,16
4.4.9. 2-Trimethylsilyloxy-2-(2-methoxyphenyl)acetonitrile
(Table 3, entry 9)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 125 °C (isothermal), inject temperature = 230 °C,
detector temperature = 250 °C): tR (major) = 36.3 min, tR (minor) =
38.2 min.
Acknowledgments
4.4. GC analysis for determination of the enantiomeric excesses
We are grateful for financial support from the Chinese Academy
of Sciences and National Natural Science Foundation of China
(20873166, 20625308).
4.4.1. 2-Trimethylsilyloxy-2-phenylacetonitrile (Table 3, entry 1)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 110 °C (isothermal), inject temperature = 230 °C,
detector temperature = 250 °C): tR (major) = 27.7 min, tR(minor) =
28.5 min.
References
1. (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.. In Comprehensive Asymmetric
Catalysis; Springer: Berlin, 1999; Vol. II; (b) Ojima, I. Catalytic Asymmetric
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4.4.2. 2-Trimethylsilyloxy-2-(4-methoxyphenyl)acetonitrile
(Table 3, entry 2)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 125 °C (isothermal), inject temperature = 230 °C,
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60.3 min.
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53.6 min.
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4.4.4. 2-Trimethylsiloxy-2-(2-chlorophenyl)acetonitrile
(Table 3, entry 4)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 120 °C (isothermal), inject temperature = 230 °C,
detector temperature = 250 °C): tR (minor) = 29.5 min, tR (major) =
30.2 min.
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(Table 3, entry 5)
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35.1 min.
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4.4.6. 2-Trimethylsilyloxy-2-(4-methylphenyl)acetonitrile
(Table 3, entry 6)
GC (CP-Chirasil-Dex CB coulmn 25 m ꢁ 0.32 mm, column
temperature = 115 °C (isothermal), inject temperature = 250 °C,

C. Lv et al. / Tetrahedron: Asymmetry 21 (2010) 1869–1873
1873
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file of Cu-4 complex is available as Supplementary data. The stereochemistry of
ligand 3 was assigned by analogy of ligand 4.
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