Ultrasound-mediated synthesis of camphoric acid-based chiral salens for the enantioselective trimethylsilylcyanation of aldehydes

Article abstract of DOI:10.1002/chir.20758

New chiral salen ligands were prepared by the ultrasound-irradiated condensation of optically active (1R, 3S)-1,2,2-trimethyl-1,3- diaminocyclopentane with aromatic 1-hydroxyaldehydes. The ultrasound-mediated process is more convenient due to shorter reac

Full text of DOI:10.1002/chir.20758

CHIRALITY 22:425–431 (2010)
Ultrasound-Mediated Synthesis of Camphoric Acid-Based
Chiral Salens for the Enantioselective
Trimethylsilylcyanation of Aldehydes
MARIA E. SILVA SERRA,* DINA MURTINHO, ALBERTINO GOTH, ANTONIO M. D’A. ROCHA GONSALVES,
PAULO E. ABREU, AND ALBERTO A. C. C. PAIS
´
Departamento de Qu ı´ mica, Faculdade de Ci eˆ ncias e Tecnologia, Universidade de Coimbra, P-3004-535 Coimbra, Portugal
ABSTRACT
New chiral salen ligands were prepared by the ultrasound-irradiated
condensation of optically active (1R, 3S)-1,2,2-trimethyl-1,3-diaminocyclopentane with
aromatic 1-hydroxyaldehydes. The ultrasound-mediated process is more convenient due
to shorter reaction times, energy economy, and easier isolation of the products. The
in situ formed Ti(IV)(salen) complexes, evaluated as catalysts in the enantioselective
trimethylsilylcyanation of benzaldehyde, were found to be efficient for this process, orig-
inating the corresponding product in high yields (72–99%) and selectivities of up to 79%.
The lowest energy transition states were determined by computational studies. These
results were in qualitative agreement with the experimentally observed ones. Chirality
2
2:425–431, 2010. VV C 2009 Wiley-Liss, Inc.
KEY WORDS: salens; camphoric acid; ultrasound; enantioselective; trimethylsilylcyanation;
benzaldehyde
INTRODUCTION
may go from 2 to 24 h or more, depending on the specific
reagents and are therefore time and energy consuming. It
is well known that ultrasound irradiation is a form of
speeding up many synthetic transformations, having
advantages such as shorter reaction times, energy conser-
vation, and simpler workup, which make it an attractive
alternative to classical synthetic procedures. Accordingly,
we chose to study the application of ultrasound irradiation
to the synthesis of several chiral salen ligands (Scheme 1),
to be subsequently tested in the enantioselective tri-
methylsilylcyanation of benzaldehyde.
The enantioselective trimethylsilylcyanation of alde-
hydes to give optically active cyanohydrins is a versatile
and useful synthetic method. The products of this reaction
are of great interest because of their use as precursors of
molecules with other important functional groups, namely,
a-hydroxyacids, a-hydroxyketones, primary and secondary
b-hydroxyamines, a-aminonitriles, and a-hydroxyesters,
among others. Chiral ligand–metal complexes have been
used as Lewis acid catalysts in the enantioselective tri-
methylsilylcyanation of aldehydes. The metals used in-
clude titanium, vanadium, and aluminum and the nature of
chiral ligands which have proven efficient in this process
1
–6
7–9
are diverse.
Since Oguni’s initial studies,
many tri-
EXPERIMENTAL
General
dentate and tetradentate Schiff bases have been used and
found very efficient in the enantioselective trimethylsilyl-
1
0–16
All solvents were dried before use following standard
7–19 procedures. Titanium tetraisopropoxide was obtained from
Aldrich, and trimethylsilylcyanide from Fluka. Benzalde-
cyanation of aldehydes.
Extending our studies on enantioselective catalysis,
1
we undertook the synthesis of optically active salen
ligands derived from (1R, 3S)-1,2,2-trimethyl-1,3-diamino-
cyclopentane, (1R, 3S)-1, a diamine which is readily
obtained from natural camphoric acid, (1R, 3S)-1,2,2-tri-
methyl-1,3-cyclopentanedicarboxylic acid, (1R, 3S)-2. The
structural characteristics of these salens seemed appropri-
ate for their application in the enantioselective trimethyl-
silylcyanation of aromatic aldehydes. The usual synthetic
˚
hyde was distilled before use and stored over 4 A molecu-
lar sieves. All other reagents were used as commercially
acquired.
Melting points were determined using a Leitz-Wetzler
7
99 microscope with a heated plate (values are uncor-
Contract grant sponsor: FCT; Contract grant number: POCI/QUI/55931/
004.
2
procedure for obtaining this type of ligands is the reaction Contract grant sponsor: Chymiotechnon.
*
Correspondence to: M. Elisa Silva Serra, Departamento de Qu ´ı mica, Fac-
of a diamine with 2 equiv of a 1-hydroxyaldehyde in etha-
uldade de Ci eˆ ncias e Tecnologia, Universidade de Coimbra, P-3004-535
nol or toluene reflux, usually in the presence of a water Coimbra, Portugal. E-mail: melisa@ci.uc.pt
Received for publication 29 January 2009; Accepted 9 June 2009
DOI: 10.1002/chir.20758
Published online 14 July 2009 in Wiley InterScience
sponge such as silica, sodium sulfate, alumina, and trieth-
ylorthoformate, among others, to favor the formation of
the diimine. This procedure requires reaction times which (www.interscience.wiley.com).
VV C 2009 Wiley-Liss, Inc.

4
26
SERRA ET AL.
(9.3 g, 143 mmol) was added in small portions at intervals.
The reaction mixture was stirred at the same temperature
until gas evolution ceased, usually overnight. Subse-
quently, the mixture was poured into a water/ice mixture,
and solid NaOH was added to pH 14. The product was
extracted several times with chloroform, and the com-
bined organic extracts were washed with water and dried
over anhydrous Na SO . After filtering and evaporating
2
4
the solvent, the diamine was vacuum dried to give a pale
2
5
yellow oil (62%), which is used directly. [a] 5 130 (c1,
D
2
3
ethanol) [135.3 (c1, ethanol)].
An analytical sample of the dihydrochloride was
obtained by treating the diamine with HCl. The resulting
Scheme 1. Ultrasound-mediated synthesis of chiral salens.
product was recrystallized from methanol/ether and fully
1
characterized. m.p.: 2408C (dec.). H NMR (CD OD): 1.11
rected). Optical rotations were measured with an optical
activity AA-5 polarimeter. NMR spectra were recorded on
a Bruker AMX 300. TMS was used as the internal stand-
ard, chemical shifts are referred in d, and coupling con-
stants, J, in Hz. Infrared spectra were recorded on a Per-
kin-Elmer 1720X FTIR or Thermo Scientific Nicolet 6700
FTIR (liquids and oils were processed as films and solids
as KBr pellets). Elemental analyses were carried out on a
Fisons Instruments EA 1108 CHNS-O elemental analyzer.
GC analyses were recorded on a HP 5890A instrument
coupled to an HP 3396A integrator using a capillary col-
umn (Supelcowax 10, 30 m, 0.25 i.d., 0.25 lm). Mass spec-
tra were recorded on a HP 5973 MSD chromatograph with
3
(
2
s, 3H); 1.20 (s, 3H); 1.38 (s, 3H); 1.76–2.01 (m, 2H); 2.13–
.34 (m, 2H); 3.55 (t, 1H, J 5 8.8). C NMR (CD OD):
7.92, 21.34, 22.77, 25.73, 34.47, 46.11, 59.22, 64.28. IR
cm ): 3427, 3404, 3322, 3049, 3028, 2988, 2970, 2933,
1
3
3
1
(
21
2
903, 2885, 2866, 2842, 2812, 1600, 1522. m/z (ES1): 143
1
[(M11) ], 126.
General Procedure for the Synthesis of Chiral Salens
In a 25-mL Erlenmeyer flask, diamine (1R, 3S)-1 (1.5
mmol, 0.139 g) was dissolved in 5 mL of dry dichloro-
methane, and then the aldehyde (3 mmol) and silica
(
0.900 g) were added. The mixture was placed in an ultra-
sound bath until the reaction was complete, as monitored
by TLC, approximately 30 min. The silica was filtered off,
the solvent was evaporated, and the product was isolated
by crystallization as described later.
7
0 eV (EI), Agilent 6890 series, equipped with an HP-5MS
column (30 m 3 0.25 mm 3 0.25 lm) or on a Fisons
Instruments-Platform with an APCI probe coupled to a
Thermo Separation Spectra Series P200 chromatograph.
Sonication was performed in a Bandelin Sonorex RK100H
cleaning bath with a frequency of 35 Hz and a nominal
power of 80/160 W.
Trimethylsilylcyanation reactions were carried out in an
inert atmosphere using standard Schlenk-type techniques.
Reaction products were identified by GC/MS analysis and
NMR. Catalytic experiments were repeated to confirm the
results. Enantiomeric excesses were determined using a
chiral g-cyclodextrin capillary column (FS-Lipodex-E,
0
(
1R, 3S)-N ,N@-Bis[salicylidene]-1,3-diamino-1,2,
2
-trimethylcyclopentane (4a)
The product was crystallized in ethyl acetate to yield
2
5
8
5% of the title compound. m.p.: 156–1578C. [a] 5 135
D
23,24 1
(
(
c2, CHCl ) [134 (c2, CHCl )].
H NMR (CDCl ): 0.96
3
3
3
s, 3H); 0.98 (s, 3H); 1.32 (s, 3H); 1.82–1.88 (m, 1H); 1.98–
.08 (m, 1H); 2.14–2.24 (m, 1H); 2.29–2.36 (m, 1H); 3.60
approx. t, 1H, J 5 8.62); 6.89 (t, 2H, J 5 7.40); 6.96 (d,
2
(
2
1
3
H, J 5 8.20); 7.28–7.34 (m, 4H); 8.35 (s, 2H). C NMR
2
5 m, 0.25 i.d.) from Machery-Nagel on an HP 5890A
(
CDCl ): 18.89, 20.70, 24.50, 28.14, 33.90, 48.33, 70.73,
instrument coupled to an HP 3396A integrator. The
absolute configuration of the major enantiomer was
determined by comparison of the optical rotation with
literature values.
For the computational studies, calculations were carried
out with MOPAC2007. The geometry of the transition
state was optimized with MOPAC2007, and a subsequent
Hessian calculation was performed to assess the rank of
the critical point obtained. All the calculations in
MOPAC2007 used the PM6 Hamiltonian, and the local-
ization of the transition state geometry was performed
3
7
1
1
1
6.31, 117.01, 117.12, 118.40, 118.56, 118.74, 119.01,
31.22, 131.36, 132.14, 132.26, 161.22, 161.34, 161.44,
21
1
4,20
63.82. IR (cm ): 1629, 1496, 1413, 1282, 1167, 1120,
030, 988, 757. Elemental Analysis for (C H N O ꢀ0.5
22 22
2
2
2
1
CH CH OH): calculated, N: 7.8; C: 75.39; H: 7.48; found,
3
2
N: 8.08; C: 75.67; H: 7.61. GC-MS: m/z (EI): 350 (M1,
7
9%), 162 (40), 148 (100), 122 (42), 107 (21).
0
(
1R, 3S)-N ,N@-Bis[3-methoxysalicylidene]-1,
2
2
3
-diamino-1,2,2-trimethylcyclopentane (4b)
˚
The product was crystallized in ethyl acetate/hexane to
until the gradient was less than 0.01 kcal/A.
2
5
yield 65% of the title compound. m.p.: 173–1758C. [a]
5
D
1
1
95 (c1, CHCl ). H NMR (CDCl ): 0.97 (s, 3H); 0.99 (s,
3
3
(1R, 3S)-1,3-Diamino-1,2,2-trimethylcyclopentane (1)
3
H); 1.32 (s, 3H); 1.83–1.89 (m, 1H); 1.99–2.03 (m, 1H);
To a two-necked round-bottomed flask, 10.15 g (50 2.16–2.23 (m, 1H); 2.28–2.36 (m, 1H); 3.62 (approx. t, 1H,
mmol) of (1R, 3S)-camphoric acid, 30 mL concentrated sul- J 5 8.67); 3.90 (s, 3H); 3.91 (s, 3H); 6.77–6.84 (m, 3H);
furic acid, and 100 mL chloroform were added, and the 6.88–6.94 (m, 6H); 8.33 (s, 1H); 8.34 (s, 1H); 14.26 (s, 1H);
1
3
reaction was placed at 55–608C with stirring. Sodium azide 14.85 (s, 1H). C NMR (CDCl ): 18.78, 20.31, 24.59,
3
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE TRIMETHYLSILYLCYANATION OF ALDEHYDES
427
2
1
1
1
8.00, 33.74, 48.33, 55.95, 56.01, 70.41, 75.54, 113.43,
13.74, 117.45, 117.82, 118.38, 118.41, 122.70, 122.84,
48.56, 148.73, 152.17, 152.92, 161.36, 163.86. IR (cm ):
626, 1461, 1420, 1255, 1092, 1080, 1000, 973, 745. Elemen-
2
1
tal Analysis for (C H N O ): calculated, N: 6.82; C: 70.22;
2
4
30
2
4
H: 7.37; found, N: 6.70; C: 70.21; H: 7.04. LC-MS: m/z 411
1
[
(M11) ], 394, 260, 152.
Scheme 2. Synthesis of (1R, 3S)-1,3-diamino-1,2,2-trimethylcyclopen-
0
tane from camphoric acid.
(
1R, 3S)-N ,N@-Bis[6-bromo-3-methoxysalicylidene]-1,
3-diamino-1,2,2-trimethylcyclopentane (4c)
To the resulting oil, hexane was added and the product H: 9.19; found, N: 5.96; C: 76.21; H: 8.78. LC-MS: m/z 463
1
crystallized to yield 65% of the title compound. m.p.: 213– [(M11) ], 286, 178.
2
5
1
3 3
2
(
2
6
148C. [a] 5 150 (c1, CHCl ). H NMR (CDCl ): 1.02
D
0
(
1R, 3S)-N ,N@-Bis[3,5-di-t-butylsalicylidene]-1,
-diamino-1,2,2-trimethylcyclopentane (4e)
s, 3H); 1.05 (s, 3H); 1.41 (s, 3H); 1.92–2.07 (m, 2H); 2.26–
.39 (m, 2H); 3.74 (approx. t, 1H, J 5 8.55); 3.87 (s, 6H);
.67 (d, 1H, J 5 8.46); 6.71 (d, 1H, J 5 8.52); 6.87 (d, 1H,
3
The product was crystallized by concentrating the solu-
J 5 8.46); 6.92 (d, 1H, J 5 8.52); 8.69 (s, 2H); 15.48 tion and adding several drops of water, yielding 70% of the
1
3
25
D
(
s, 1H); 16.10 (s, 1H). C NMR (CDCl ): 18.71, 20.16, title compound. m.p.: 181–1838C. [a]
5 125 (c1,
3
2
5 1
2
1
1
1
4.21, 27.85, 34.19, 48.38, 55.90, 56.01, 69.94, 74.27, 113.51, CH Cl ).
13.97, 114.66, 114.92, 115.07, 115.23, 119.62, 120.50, 1.30 (s, 3H); 1.31 (s, 9H); 1.32 (s, 9H); 1.43 (s, 9H); 1.44
49.35, 149.88, 157.73, 159.85, 161.96, 164.50. IR (cm ): (s, 9H); 1.79–1.88 (m, 1H); 2.02–2.23 (m, 2H); 2.28–2.38
618, 1460, 1249, 1085, 971, 892, 813, 758. Elemental Anal- (m, 1H); 3.56 (approx. t, 1H, J 5 8.5) 7.11–7.13 (m, 2H);
H NMR (CDCl ): 0.97 (s, 3H); 0.99 (s, 3H);
2
2
3
2
1
ysis for (C H N O Br ): calculated, N: 4.91; C: 50.88; H: 7.38–7.39 (m, 2H); 8.35 (s, 1H); 8.36 (s, 1H); 13.86 (bs,
2
4
28
2
4
2
1
3
4
[
.99; found, N: 4.81; C: 50.86; H: 4.89. LC-MS: m/z 569 1H); 14.22 (bs, 1H). C NMR (CDCl ): 19.02, 20.79, 24.71,
3
1
(M11) ], 338, 232.
28.23, 29.41, 31.51, 31.53, 34.02, 34.13, 35.04, 35.05, 48.31,
7
1
1
0.65, 117.82, 118.09, 125.80, 125.94, 126.63, 126.83,
36.70, 136.76, 139.74, 139.92, 158.20, 158.31, 162.28,
64.74. IR (cm ): 2961, 1628, 1465, 1391, 1170, 1069, 873.
0
(
3
1R, 3S)-N ,N@-Bis[3-t-butylsalicylidene]-1,
-diamino-1,2,2-trimethylcyclopentane (4d)
21
The product was crystallized from ether/water, yielding Elemental Analysis for (C38
H
N
O
ꢀ0.5 CH
CH OH):
3 2
58
2
2
25
7
1% of the title compound. m.p.: 69–708C. [a] 5 170 (c1, calculated, N: 4.87; C: 79.39; H: 10.17; found, N: 4.69; C:
D
1
1
CH Cl ). H NMR (CDCl ): 0.99 (bs, 6H); 1.32 (s, 3H); 78.34; H: 10.28. LC-MS: m/z 575 [M ], 519, 342, 234.
2
2
3
1
3
7
.43 (s, 9H), 1.45 (s, 9H); 1.84–1.89 (m, 1H); 2.08–2.37 (m,
H); 3.58 (approx. t, 1H, J 5 8.13); 6.82 (t, 2H, J 5 7.65);
.11–7.16 (m, 2H); 7.32 (d, 2H, J 5 7.74); 8.34 (s, 1H); 8.36
0
(
1R, 3S)-N ,N@-Bis[naphthylidene]-1,3-diamino-1,2,
-trimethylcyclopentane (4f)
2
1
3
(s, 1H); 14.04 (s, 1H); 14.44 (s, 1H). C NMR (CDCl3):
The product was crystallized in ethyl acetate/hexane to
2
5
1
7
1
1
1
9.05, 20.83, 24.53, 28.22, 29.32, 34.07, 34.83, 48.37, 70.65, yield 50% of the title compound. m.p.: 250–2518C. [a]
6.56, 117.53, 117.71, 118.64, 118.93, 129.09, 129.29, 275 (c1, CH Cl ). H NMR (CDCl ): 1.08 (s, 3H); 1.14 (s,
29.60, 129.74, 137.38, 137.43, 160.54, 160.69, 161.95, 3H); 1.53 (s, 3H); 2.02–2.14 (m, 2H); 2.37–2.47 (m, 2H);
64.43. IR (cm ): 2959, 2872, 1628, 1436, 1384, 1269, 3.79 (m, 1H); 6.97 (approx. t, 2H, J 5 9.5); 7.23–7.30 (m,
200, 1144, 1088, 750. Elemental Analysis for 2H); 7.44–7.49 (m, 2H); 7.65 (approx. t, 2H, J 5 6.8); 7.72
5
D
1
2
2
3
2
1
(
C H N O ꢀ0.5 H O): calculated, N: 5.94; C: 76.39; (dd, 2H, J 5 5.5; 9.2); 7.92 (dd, 2H, J 5 8.4; 13.7); 8.84 (s,
3
0
42
2
2
2
Scheme 3. Synthesis of chiral salens derived from (1R, 3S)-1,3-diamino-1,2,2-trimethylcyclopentane.
Chirality DOI 10.1002/chir

4
28
SERRA ET AL.
TABLE 1. Classical versus ultrasound method in the
synthesis of Salens (1R, 3S)-4(a–g)
and trimethylsilylcyanide (4 mmol, 0.54 mL) were added
and the reaction stirred for 24 h at 2308C.
At the end of the reaction, hexane was added and the
precipitated solids were filtered off. Conversions were
determined by GC, and the ee of the resulting cyanosily-
lethers were determined by chiral GC analysis.
Classical method Ultrasound method
Salen
Yield (%)
62
Time (h)
Yield (%)
Time (h)
(
(
(
(
(
(
(
1R, 3S)-4a
1R, 3S)-4b
1R, 3S)-4c
1R, 3S)-4d
1R, 3S)-4e
1R, 3S)-4f
1R, 3S)-4g
4
74
63
59
71
69
51
80
0.5
0.5
0.5
0.5
0.5
0.5
0.5
65
68
–
5
3
–
RESULTS AND DISCUSSION
Synthesis of Chiral Salen Ligands
81
59
68
24
48
14
Diamine (1R, 3S)-1 was obtained directly from (1R, 3S)-
2
by refluxing with sodium azide and sulfuric acid in chlo-
roform, according to a slightly modified literature proce-
2
3
dure (Scheme 2).
1
3
To prepare the salen derivatives of (1R, 3S)-1 (Scheme
), we started off by using the classical method, refluxing
the diamine with the appropriate aldehydes in ethanol and
controlling the reaction by TLC. Using salicylaldehyde
3a), 3-methoxysalicylaldehyde (3b), 6-bromo-3-methoxy-
salicylaldehyde (3c), 3-t-butylsalicylaldehyde (3d), 3,5-di-t-
butylsalicylaldehyde (3e), and 1-hydroxynaphthaldehyde
3f), the corresponding salens (1R, 3S)-4(a–f) were
obtained in moderate to good yields (Table 1). The reac-
tion of (1R, 3S)-2 with 1-hydroxyacetophenone 3g gave
1
(
7
1
1
H); 8.87 (s, 1H); 14.93 (s, 1H); 15.39 (s, 1H). C NMR
3
CDCl ): 18.53, 20.27, 23.80, 27.76, 34.68, 48.21, 67.96,
3
2.43 106.74, 107.08, 117.68, 118.07, 122.76, 122.95, 123.63,
24.65, 126.29, 126.57, 127.92, 129.30, 129.35, 133.34,
33.71, 136.73, 137.13, 154.23, 157.78, 173.42, 175.60. IR
(
2
1
(
cm ): 1625, 1523, 1492, 1427, 1314, 834. Elemental Anal-
ysis for (C H N O ꢀ0.5 CH CH OH): calculated, N: 6.22;
3
0
30
2
2
3
2
(
C: 79.97; H: 6.71; found, N: 5.91; C: 78.62; H: 7.02. LC-MS:
1
m/z 451[M ], 307, 280.
(
1R, 3S)-4g in moderate yield. The synthesis of salens 4a
0
(
1R, 3S)-N ,N@-Bis[2-hydroxyphenoylidene]-1,
3
and 4e by the aforementioned method has been previ-
ously described.
-diamino-1,2,2-trimethylcyclopentane (4g)
23–26
The reaction times varied for the dif-
The product crystallized by the addition of ether to yield ferent aldehydes used, and consequently, reactions were
2
5
5
(
1
3
6
7
9% of the title compound. m.p.: 225–2278C. [a] 5 1215 stopped after complete conversion or when no further evo-
D
1
c1, CHCl ). H NMR (CDCl ): 1.13 (s, 3H); 1.21 (s, 3H); lution was observed.
3
3
2
7
.41 (s, 3H); 1.87–1.94 (m, 1H); 2.12–2.28 (m, 3H); 2.41 (s,
Stefani and coworkers achieved the efficient condensa-
H); 2.47 (s, 3H); 4.03–4.10 (m, 1H); 6.72–6.81 (m, 2H); tion of simple amines with aromatic aldehydes in dichloro-
.91 (dd, 1H, J 5 1.2, 5.0); 6.94 (dd, 1H, J 5 1.2, 5.0); methane under ultrasound irradiation and in the presence
.26–7.33 (m, 2H); 7.52 (approx. t, 1H, J 5 1.53); 7.55 of silica as a promoter. We decided to try these conditions
1
3
(
approx. t, 1H, J 5 1.53); 16.72 (s, 1H); 17.14 (s, 1H).
C
for the synthesis of our salen ligands. The condensation of
NMR (CDCl ): 14.56, 18.45, 18.93, 20.57, 24.10, 28.44, diamine (1R, 3S)-1 with 2 equiv of salicylaldehyde (3a)
3
3
1
1
1
5.92, 49.84, 63.67, 68.96, 116.61, 116.93, 118.85, 118.93, under ultrasound irradiation for 15 min at room tempera-
19.25, 119.63, 127.80, 128.12, 132.61, 132.74, 164.33, ture gave (1R, 3S)-4a in low yield, about 30%. We
21
64.64, 169.76, 171.21. IR (cm ): 1610, 1502, 1447, increased the amount of promoter and irradiation times as
303, 1252, 839, 760, 753, 635. Elemental Analysis for well, resulting in the formation of (1R, 3S)-4a in 74% yield
(
C H N O ): calculated, N: 7.40; C: 76.16; H: 7.99; after 30 min.
2
4
30
2
2
found, N: 7.62; C: 76.57; H: 7.59. LC-MS: m/z 397
The condensation of (1R, 3S)-1 with other aromatic
aldehydes originated the corresponding salens (1R, 3S)-
1
[
(M11) ], 244, 227.
General Procedure for the
Trimethylsilylcyanation Reactions
TABLE 2. Enantioselective trimethylsilylcyanation
a
of benzaldehyde
To a solution of the chiral salen ligand (0.44 mmol) in dry
b
c
Entry
Salen
Conversion (%)
ee (%)
dichloromethane (5 mL), Ti(O-i-Pr) (0.40 mmol, 0.12 mL)
4
was added under an inert atmosphere at room temperature.
The resulting mixture was stirred overnight and subse-
quently cooled to 2308C. Benzaldehyde (2 mmol, 0.2 mL)
1
2
3
4
5
6
7
(1R, 3S)-4a
(1R, 3S)-4b
(1R, 3S)-4c
(1R, 3S)-4d
(1R, 3S)-4e
(1R, 3S)-4f
(1R, 3S)-4g
97
72
89
98
93
95
92
43 (R)
8 (S)
22 (S)
56 (S)
79 (S)
59 (S)
6 (S)
a
Reaction was carried out on a 2 mmol scale in 5 ml of dry CH
2 2
Cl at
2
308C, using a molar ratio of Ti:ligand:aldehyde:TMSCN of 1:1.1:5:10.
b
Determined by GC.
c
Scheme 4. Trimethylsilylcyanation of benzaldehyde.
Chirality DOI 10.1002/chir
Of the silylether, determined by chiral GC.

ENANTIOSELECTIVE TRIMETHYLSILYLCYANATION OF ALDEHYDES
429
Fig. 1. The two transition states (not all hydrogen atoms are displayed so as not to hinder visibility): (a) TS1 and (b) TS2 (images produced using
38
VMD ). The light blue corresponds to carbon atoms, brown to titanium, red to oxygen, dark blue to nitrogen, and white corresponds to hydrogen.
Note that the ‘‘white’’ bond, corresponds to the cyano attack to the carbon. (c) and (d) schematic representations of TS1 and TS2, respectively. [Color
figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
4
(b–g) (Table 1). In all cases, even when yields are com- in agreement with previous studies which have shown that
0
parable with the classic method, the procedure is more bulky groups in C3 and C3 of the aldehyde moieties are
convenient due to much shorter reaction times, energy essential for high selectivity.
economy, and a much simpler isolation of the product.
7
–12,28
Also, bulky groups in
0
C5 and C5 have been described as important. The order
of selectivity (1R, 3S)-4e > (1R, 3S)-4f > (1R, 3S)-4d of
the most selective ligands can thus be explained. The low
Enantioselective Trimethylsilylcyanation
The titanium(IV) complexes of chiral salens (1R, 3S)- ee of the products obtained when (1R, 3S)-4(a–c) were
(a–g) were evaluated as catalysts in the enantioselective used may be a consequence of both the presence of sub-
4
trimethylsilylcyanation of aldehydes, using benzaldehyde stituents with reduced steric bulk on the aldehyde moiety
as model substrate (Scheme 4). All reactions were carried and of their electronic characteristics.
out in an inert atmosphere at 2308C for 24 h, using
All cyanosilylethers obtained presented (S) absolute
dichloromethane as solvent. The Ti:ligand:aldehyde: configuration except when ligand (1R, 3S)-4a was used,
TMSCN ratio used was 1:1.1:5:10. The results of these cat- resulting in the product with (R) absolute configuration.
alytic experiments are summarized in Table 2.
All catalysts were found to be very active in promoting be attributed to the presence of bulky substituents on the
As previously referred, this inversion of configuration may
1
3,29
the trimethylsilylcyanation of benzaldehyde under the aldehyde moieties.
reaction conditions used. The ee of the products varied
according to the ligand used. The most selective ligand
was found to be (1R, 3S)-4e, which gave the correspond-
Computational Studies
ing cyanosilylether with an ee of 79%, followed by (1R, 3S)-
Theoretical studies were carried out to illustrate the
4
f, which gave the product with 59% ee. These results are stereochemistry and enantiomeric excess of the product.
Chirality DOI 10.1002/chir

4
30
SERRA ET AL.
For these studies, we used our most selective system, the
Ti-(1R, 3S)-4e system.
TABLE 4. Charges and bond orders for the atoms involved
in the transition state
The details of the structure of the catalysts in trimethyl-
silylcyanations are not yet completely known. While some
studies point to a dimeric titanium species, others point to q(N)
a monomeric one. The studies of Belokon and North sup- q(C)
TS1
TS2
20.45 (0.56)
20.25 (20.15)
0.54 (0.53)
0.88 (1.35)
0.363
20.53 (0.52)
20.36 (20.25)
0.54 (0.52)
0.90 (1.37)
0.123
0
port the existence of a dimeric titanium species, with the q (C)
q(Ti)
two titanium atoms connected through two oxygen
5
,15,30–32
B.O. (C ꢁꢁ C)
bridges.
species is suggested by others
favored when there are large substituents, such as t-butyl,
The involvement of a monomeric titanium
1
0,33–36
B.O (C ꢁꢁ N)
2.896
2.881
and is said to be
The values in parenthesis are the Mulliken charges and the others are
on the aldehyde moiety. It has been referred that the cata- MOPAC charges.
lyst structure (monomeric, dimeric, or a mixture of both)
is probably related to some reaction conditions such as are presented in Figure 1. Some relevant parameters con-
3
3
molar ratios, solvents, and ligand structures.
Concerning the reaction mechanism, another question and 4.
cerning the two transition states are found in Tables 3
arises with respect to the reactive nucleophile and whether
From the proposed transition states, the cyanide can
it is TMSCN or HCN. Results of several studies indicate attack both from the diamine side of the molecule, TS1,
HCN as the actual reactive nucleophile, possibly gener- and from the salicylaldehyde moiety of the molecule, TS2.
i
12,36,37
ated from the reaction of TMSCN and PrOH.
The calculated heats of formation (Table 3) indicate that
In our calculations, we considered the existence of a the attack from the diamine side constitutes the predomi-
monomeric titanium species and of the cyanide ion as the nant pathway for these reactions. The process therefore
attacking agent, assumptions which have previously been involves the intermolecular attack of the cyanide ion to the
used by others. Also, in our calculations, solvent effects Si-face of the aldehyde giving rise to O-trimethylsilyl-(S)-
were not considered. The computational studies were car- mandelonitrile as the major reaction product. It can there-
ried out to predict the lower energy transition states and fore be concluded that there is qualitative agreement
the mode of attack of cyanide to benzaldehyde. To estab- between the theoretical predictions and the observed ex-
lish the transition state, a search for the minimum of the perimental results.
charged species was first carried out. Subsequently, cya-
To clarify the inversion of configuration observed when
nide ion was added to the minimized structure in the ligand (1R, 3S)-4a was used, similar computational studies
appropriate position. These structures were then allowed were carried out for this ligand. These studies confirm
to relax to their minimum energy configurations.
that preferential attack of the cyanide occurs to the Re-face
A transition state search was then performed and some of the aldehyde, originating O-trimethylsilyl-(R)-mandelo-
care was taken in following the path from the minimum to nitrile as the major product in this case, confirming the ex-
the transition state: the Hessian (matrix of the second perimental results.
derivatives of the energy to the nuclear coordinates) was
calculated at every point so as to provide a suitable guide
CONCLUSIONS
for finding the transition state. Small enough trust radii
˚
(
0.05 A or 0.05 radian) were imposed in order to not over-
In conclusion, we have prepared chiral salen ligands
shoot the saddle point.
(1R, 3S)-4(a–f) by ultrasound mediated condensation in
After the localization of the putative saddle point, the good yields with short reaction times and easy isolation of
respective character was confirmed by inspecting the cor- the products.
responding Hessian matrix, in which only one imaginary
Our studies demonstrated that the Ti(IV)(salen) com-
frequency should be present. We noted that the normal plexes of these ligands are very active in the trimethylsilyl-
mode associated with the imaginary frequency corre- cyanation of benzaldehyde, where conversions of up to
sponds to the attack of the cyanide ion to the carbon atom 97% were observed. A selectivity of 79% was obtained in
in both transition states.
the presence of (1R, 3S)-4f with two sterically demanding
D representations of the lowest energy transition t-butyl substituents on each aldehyde moiety of the salen
3
8
3
states, as well as the corresponding schematic drawings, ligand. The computational studies carried out for this
ligand are in qualitative agreement with the observed
results.
TABLE 3. Energetics and structural parameters for the two
transition states depicted in Figure 1
LITERATURE CITED
1
. Brunel J-M, Holmes IP. Chemically catalyzed asymmetric cyanohy-
drin synthesis. Angew Chem Int Ed 2004;43:2752–2778.
TS1
TS2
Heat of formation (kcal/mol)
2230.92
2.266
1.150
178.98
2318.6
2209.78
2.674
1.155
179.68
2161.70
2. Mori A, Inoue S. Cyanation of carbonyl and imino groups. In: Jacob-
son EN, Pfaltz A, Yamamoto H, editors. Comprehensive asymmetric
catalysis, Vol. 2. New York: Springer; 1999. Chapter 28.
˚
r(CC) (A)
˚
r(CN) (A)
3
. Gregory RJH. Cyanohydrins in nature and the laboratory:
biology, preparations, and synthetic applications. Chem Rev 1999;99:
Angle (C ꢁꢁ C ꢁꢁ N)
2
1
Imaginary frequency (cm
)
3
649–3682.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE TRIMETHYLSILYLCYANATION OF ALDEHYDES
431
4
5
6
. Brunel JM, Holmes IP. Chemically catalyzed asymmetric cyanohydrin
syntheses. Angew Chem Int Ed 2004;43:2752–2778.
22. Stewart JJP. Optimization of parameters for semi empirical methods
V: modification of NDDO approximations and application to 70
elements. J Mol Modell 2007;13:1173–1213.
. North M, Usanov DL, Young C. Lewis acid catalyzed asymmetric cya-
nohydrin synthesis. Chem Rev 2008;108:5146–5226.
23. Yang Z-H, Wang L-X, Zhou Z-H, Zhou Q-L, Tang C-C. Synthesis of
new chiral Schiff bases and their application in the asymmetric trime-
thylsilylcyanation of aromatic aldehydes. Tetrahedron: Asymmetry
2001;12:1579–1582.
. Gawronski J, Wascinska N, Gajewy J. Recent progress in Lewis base
activation and control of stereoselectivity in the additions of trimethyl-
silyl nucleophiles. Chem Rev 2008;108:5227–5252.
7
8
9
. Hayashi M, Miyamoto Y, Inoue T, Oguni NJ. Enantioselective tri-
methylsilylcyanation of some aldehydes by chiral titanium Schiff’s
base complexes. J Chem Soc Chem Commun 1991;1752–1753.
24. Yang Z, Zhou ZG, Tang C. Asymmetric trimethylsilylcyanation of alde-
i
hydes catalyzed by chiral Schiff bases-Ti(O Pr) complex. Synth Com-
4
mun 2001;3:3031–3036.
. Hayashi M, Miyamoto Y, Inoue T, Oguni N. Enantioselective trime-
thylsilylcyanation of some aldehydes catalyzed by chiral Schiff base-
titanium alkoxide complexes. J Org Chem 1993;58:1515–1522.
2
5. Vogt A, Wołowiec S, Prasad RL, Gupta A, Skarzewski J. Synthesis and
characterization of nickel (II), copper(II), manganese(III) and iron(II)
0
complexes with new chiral salen-type ligand {N,N -bis(3,5-di-tert-butyl-
. Hayashi M, Inoue T, Miyamoto Y, Oguni N. Asymmetric carbon–
carbon bond forming reactions catalyzed by chiral Schiff base-titanium
alkoxide complexes. Tetrahedron 1994;50:4385–4398.
salicylidene)-(1R, 3S)-1,3-diamine-1,2,2-trimethylcyclopentane}. Poly-
hedron 1998;17:1231–1240.
2
6. Zhou Z, Li Z, Li K, Yang Z, Zhao G, Wang L, Zhou Q, Tang C. Asym-
metric ring-opening of cyclohexane oxide with mercaptan (thiophe-
1
1
1
1
0. Flores-Lop e´ z LZ, Parra-Hake M, Somanathan R, Walsh PJ. Structure/
enantioselectivity study of the asymmetric addition of trimethylsilyl-
cyanide to benzaldehyde catalyzed by Ti(IV)-Schiff base complexes.
Organometallics 2000;19:2153–2160.
nols) catalyzed by chiral Schiff base/Ti(OPr-i) or (2)-(S)-binaphthol/
4
Ti(OPr-i) . Phosphorus Sulfur Silicon 2003;178:1771–1779.
4
´
2
2
2
7. Guzen KP, Guarezemini AS, Orf ˜a o ATG, Cella R, Pereira CMP, Stefani
1. Gama A, Flores-Lop e´ z LZ, Aguirre G, Parra-Hake M, Somanathan R,
Walsh PJ. Steric effects in the design of chiral Schiff base-titanium
complexes: new catalysts for asymmetric trimethylsilylcyanation of
aldehydes. Tetrahedron: Asymmetry 2002;13:149–154.
HA. Eco-friendly synthesis of imines by ultrasound irradiation. Tetra-
hedron Lett 2007;48:1845–1848.
8. Jiang Y, Gong L, Feng X, Hu W, Pan W, Li Z, Mi A. Salen-Ti(OR)
complex catalyzed trimethysilylcyanation of aldehydes. Tetrahedron
997;53:14327–14338.
4
2. Gama A, Flores-Lop e´ z LZ, Aguirre G, Parra-Hake M, Somanathan R,
Cole T. A study of substituent effects on the enantioselective tri-
methylsilylcyanation of benzaldehyde catalyzed by chiral Schiff base-
titanium(IV) complexes. Tetrahedron: Asymmetry 2005;16:1167–1174.
1
9. Belokon Y, Moscalenko M, Ikonnikov N, Yashkina L, Antonov D,
Vorontsov E, Rozenberg V. Asymmetric trimethylsilylcyanation of
benzaldehyde catalyzed by (salen)Ti(IV) complexes derived from (R)-
and/or (S)-4-hydroxy-5-formyl[2.2] paracyclophane and diamines.
Tetrahedron: Asymmetry 1997;19:3245–3250.
3. Belokon YN, Chusov D, Borkin DA, Yashkina LV, Dimitriev AV,
Katayev D, North M. Chiral Ti(IV) complexes of hexadentate Schiff
bases as precatalysts for the asymmetric addition of TMSCN to alde-
hydes and the ring opening of cyclohexene oxide. Tetrahedron: Asym-
metry 2006;17:2328–2333.
30. Khan NH, Kureshy RI, Abdi R, Agrawal S, Jasra RV. Metal catalyzed
asymmetric cyanation reactions. Coord Chem Rev 2008;252:593–623.
1
1
1
4. Rodr ´ı gues B, Pasto M, Jimeno C, Peric a` s MA. Parallel synthesis of
modular chiral Schiff base ligands and evolution in the titanium (IV)
catalyzed asymmetric trimethylsilylcyanation of aldehydes. Tetrahe-
dron: Asymmetry 2006;17:151–160.
31. Belokon YN, Green B, Ikonnikov NS, Larichev VS, Lokshin BV,
Moskalenko MA, North M, Orizu C, Peregudov AS, Timofeeva GI.
Mechanistic investigation of the asymmetric addition of trimethylsilyl-
cyanide to aldehydes catalysed by diniclear chiral (salen)titanium
complexes. Eur J Org Chem 2000;2655–2661.
5. Belokon YN, Clegg W, Harrington RW, Young C, North M. Asymmet-
ric cyanohydrin synthesis using heterobimetallic catalysts obtained
from titanium and vanadium complexes of chiral and achiral salen
ligands. Tetrahedron 2007;63:5287–5299.
3
3
3
2. Belokon YN, Green B, Ikonnikov NS, North M, Parsons T, Tararov
VI. Optimized catalysts for the asymmetric addition of timethylsilyl
cyanide to aldehydes and ketones. Tetrahedron 2001;57:771–779.
6. Zeng Z, Zhao G, Gao P, Tang H, Chen B, Zhou Z, Tang C. Synthesis
of a novel chiral Schiff base of (R,R)-11,12-diamino-9,10-dihydro-9,10-
ethanonanthracene and its application as ligand in Ti(IV) complex cat-
alyzed asymmetric silylcyanation of aldehydes. Catal Commun 2007;
3. Qin S, Hu C, Yang H, Su Z, Tang D. Computational investigation on
stereochemistry in titanium-salicylaldehydes-catalyzed cyanation of
benzaldehyde. J Org Chem 2008;73:4840–4847.
4. Ilyashenko G, Motevalli M, Watkinson M. An alternative model for
the asymmetric addition of cyanide to aldehydes catalysed by tita-
8
:1443–1446.
1
7. Rocha Gonsalves AM, Serra MES, Murtinho D, Silva VF, Matos Beja
A, Paix ˜a o JA, Ramos Silva M, Alte da Veiga L. Pyrrolidine-based
amino alcohols: novel ligands for the enantioselective alkylation of
benzaldeyde. J Mol Catal A 2003;195:1–9.
nium-salen complexes based on
a structurally related iron-salen
complex. Tetrahedron: Asymmetry 2006;17:1625–1628.
3
5. Yang F, Wei S, Chen C-A, Xi P, Yang L, Lan J, Gau H-M, You J. A new
2
strategy for designing non-c -symmetric monometallic bifunctional
catalysts and their application in enantioselective cyanation of
aldehydes. Chem Eur J 2008;14:2223–2231.
1
1
2
8. Rocha Gonsalves AM, Serra MES, Murtinho D. Approach to a better
understanding and modelling of b-pyrrolidinoalcohol ligands for enan-
tioselective alkylation. J Mol Catal A 2006;250:104–113.
3
6. Moreno RM, Rosal M, Moyano A. Salicylaldehyde Schiff bases
derived from 2-ferrocenyl-2-amino alcohols. Part 1: New chiral ligands
for the titanium-catalyzed enantioselective cyanation of aldehydes.
Tetrahedron: Asymmetry 2006;17:1089–1103.
9. Serra MES, Murtinho D, Goth A, Rocha Gonsalves AM. Chiral pyrroli-
dine-based salen ligands for the enantioselective alkylation of aromatic
aldehydes. Lett Org Chem 2007;4:80–85.
0. Belokon YN, Yashkina LV, Moscalenko MA, Chesnokov AA, Kublit-
sky VS, Ikonnikov NS, Orlova SA, Tararov VI, North M. Asymmetric
37. Li Y, He B, Qin B, Feng X, Zhang G. Highly enantioselective cyanosi-
lylation of aldehydes catalyzed by novel b-amino alcohol-titanium com-
plexes. J Org Chem 2004;69:7910–7913.
IV
trimethylsilylcyanation of aldehydes catalyzed by chiral salen Ti
1
complexes with C symmetry. Russ Chem Bull 1997;46:1936–1938.
2
1. Stewart JJP. MOPAC2007, Stewart computational chemistry. Colorado
Springs, CO; 2007. Available at http://openmopac.net.
38. Humphrey W, Dalke A, Schulten K. VMD-Visual molecular dynamics.
J Mol Graphics 1996;14:33–38.
Chirality DOI 10.1002/chir