Unsymmetric salen ligands bearing a Lewis base: Intramolecularly cooperative catalysis for cyanosilylation of aldehydes

Article abstract of DOI:10.1039/c1ob05695f

A series of unsymmetric salen ligands derived from 1,2-diaminocyclohexane bearing an appended Lewis base on the three-position of one aromatic ring were synthesized by the reaction of various functional salicyaldehydes with the condensation product of 1,2-diaminocyclohexane mono(hydrogen chloride) and 3,5-di-tert-butylsalicylaldehyde. These ligands in conjunction with Ti(O ⁱPr)₄ exhibited excellent activity in catalyzing the cyanosilylation of aldehydes with trimethylsilyl cyanide (TMSCN) at mild conditions. The highest activity was observed in the catalyst system with regard to the salen ligand bearing a diethylamino group, which proved to be active even at a high [aldehyde]/[catalyst] ratio up to 50000. In a low catalyst loading of 0.05 mol%, the quantitative conversion of benzaldehyde to the corresponding cyanosilylation product was found within 10 min. at ambient temperature. An intramolecularly cooperative catalysis was proposed wherein the central metal Ti(iv) is suggested to play a role of Lewis acid to activate aldehydes while the appended Lewis base to activate TMSCN.

Full text of DOI:10.1039/c1ob05695f

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PAPER
Unsymmetric salen ligands bearing a Lewis base: intramolecularly
cooperative catalysis for cyanosilylation of aldehydes†
Ye-Qian Wen, Wei-Min Ren and Xiao-Bing Lu*
Received 2nd May 2011, Accepted 15th June 2011
DOI: 10.1039/c1ob05695f
A series of unsymmetric salen ligands derived from 1,2-diaminocyclohexane bearing an appended
Lewis base on the three-position of one aromatic ring were synthesized by the reaction of various
functional salicyaldehydes with the condensation product of 1,2-diaminocyclohexane mono(hydrogen
chloride) and 3,5-di-tert-butylsalicylaldehyde. These ligands in conjunction with Ti(OiPr)4 exhibited
excellent activity in catalyzing the cyanosilylation of aldehydes with trimethylsilyl cyanide (TMSCN) at
mild conditions. The highest activity was observed in the catalyst system with regard to the salen ligand
bearing a diethylamino group, which proved to be active even at a high [aldehyde]/[catalyst] ratio up to
50000. In a low catalyst loading of 0.05 mol%, the quantitative conversion of benzaldehyde to the
corresponding cyanosilylation product was found within 10 min. at ambient temperature. An
intramolecularly cooperative catalysis was proposed wherein the central metal Ti(IV) is suggested to
play a role of Lewis acid to activate aldehydes while the appended Lewis base to activate TMSCN.
to be more effective catalyst for the cyanosilylation involving
Introduction
aliphatic aldehyde.10 Kim11 and Trost12 independently developed
Proline-derived catalysts for this reaction. Feng and coworkers
synthesized N,N¢-dioxide-Ti(OiPr)4 bifunctional catalyst for the
asymmetric cyanosilylation of aldehydes.13 Tang et al.14 chose
cyclic o-hydroxylarylphosphonodiamides as ligands for asymmet-
ric trimethylsilylcyanation of aromatic aldehydes. You and co-
workers15 reported non-C2-symmetric BINOL-based bifunctional
catalyst, which showed active in the absence of any additive. Salen-
Ti complexes have been proved to be effective catalysts in the
asymmetric cyanosilylation of aldehydes.5a,16 In the continuation
of our work on intramolecularly cooperative catalysis,17 we have
designed a series of unsymmetric salen ligands (Fig. 1) bearing an
appended Lewis base on the three-position of one aromatic ring
and applied them to the cyanosilylation of aldehydes and TMSCN
by the combination with Ti(OiPr)4, in which the central metal ion
is expected to play a role of Lewis acid to activate aldehydes while
the appended Lewis base to activate TMSCN.
Cyanationreactionof carbonylcompounds is oneof the important
methods for forming new C–C bonds. The resulting cyanohydrins
are versatile synthetic intermediates in organic chemistry. Owing
to the hydroxyl and nitrile groups, they can be transformed into
a variety of valuable functional compounds, such as a-hydroxy
acids, a-hydroxy aldehydes, b-hydroxy amines, and a-amino acid
derivatives.1 The cyanosilylation of aldehydes with trimethylsilyl
cyanide (TMSCN) is the much-studied reaction for synthesizing
cyanohydrins. Numerous catalyst systems, including Lewis acids,2
Lewis bases,3 N-heterocyclic carbenes,4 metal complexes,5 inor-
ganic salts,1e,6 and bifunctional catalysts,7 have been developed for
this transformation. Among them, Lewis acid–base bifunctional
catalyst systems are more efficient for this reaction. The first
example reported by Shibasaki et al.8 in 1999 is a BINOL-based
bifunctional catalyst. In this system, dual activation mechanism
where the two substrates were activated simultaneously at defined
position was proposed. Although the products were obtained
generally with excellent enantiomeric excess, high catalyst loading
up to 9 mol% and the addition of phosphine oxide up to 36 mol%
are prerequisite for efficient transformation. Following this work,
Na´jera et al.9 designed a monometallic bifunctional catalyst
BINOLAM-AlCl for this reaction. Notably, the ligand could
be recovered by a simple method, and reused without loss of
activity. Slight modification of this catalyst by replacing diethyl
amine group with morpholine, the resulting complex proved
Results and discussion
The unsymmetric salen ligands L1, L2 and L4–L9 derived
from 1,2-diaminocyclohexane in Fig. 1 were synthesized by the
reaction of the corresponding functional salicyaldehydes with the
condensation product of 1,2-diaminocyclohexane mono(hydrogen
chloride) and 3,5-di-tert-butylsalicylaldehyde.18 And symmetrical
ligand L3 was obtained through the condensation of aldehyde and
1,2-diaminocyclohexane. The key is the preparation of various
functional salicyaldehydes. All ligands were obtained in moderate
yields and characterised by NMR and HRMS.†
State key laboratory of fine chemicals, Dalian University of Technology,
Dalian, 116024, China. E-mail: lxb-1999@163.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05695f
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ligand L2 containing a long spacer was synthesized using 5-tert-
butyl-2-hydroxybenzaldehyde 11 as starting material. In the proce-
dure of synthesizing this ligand, the preparation of 5-tert-butyl-3-
(3-(diphenyl-phosphoryl)propyl)-2-hydroxybenzaldehyde 20 is a
key step. It can be synthesized via an eight-step sequence from
compound 11. The bromo-compound 18 was converted to the
phosphine oxide 19 via a coupling reaction with the lithiation
product of diphenylphosphinic chloride, followed by oxidation
with H2O2. Through deprotection and formylation in turn, we
finally achieved compound 21. Ligand L2 came to hand after two-
step sequential condensations (Scheme 2).17a,20
Fig. 1 Various salen ligands.
Ligand L1 bearing a phosphane oxide on the three-position
of one aromatic ring was synthesized with 5-tert-butyl-2-
hydroxybenzaldehyde 11 as starting material according to the
following procedure (Scheme 1). 3-(bromomethyl)-5-tert-butyl-2-
hydroxybenzaldehyde 12 was first prepared by the bromomethy-
lation of compound 11. Then Arbusov reaction was carried out
between compound 12 and Ph2POC2H5, affording the correspond-
ing phosphane oxide 13.19 Finally, the reaction of compound
13 and the condensation product of 1,2-diaminocyclohexane
mono(hydrogen chloride) with 3,5-di-tert-butylsalicylaldehyde
provided the unsymmetrical salen ligand L1.
Scheme 2 Synthesis of ligand L2.
For a comparison purpose, symmetrical ligand L3 that pos-
sessed two phosphane oxide groups on both 3- and 3¢-position
was synthesized by reaction of 13 and 1,2-diaminocyclohexene.
Ligand L4 in which the phosphane oxide group was appended
on the 5-position of one aromatic ring was also synthesized
through a similar procedure of L1 starting with 3-tert-butyl-4-
hydroxybenzaldehyde (Scheme 3).
To investigate the influence of basicity of the functional group
appended on the salen ligand framework, ligand L5 in which di-
ethylamino group instead of diphenylphosphane oxide is attached
on the ligand framework was synthesized. As shown in Scheme 4,
direct addition of diethylamine to 3-(bromomethyl)-5-tert-butyl-
2-hydroxybenzaldehyde 12 afforded compound 25,21 then ligand
L5 came to hand through the reaction with condensation product
of 1,2-diaminocyclohexane mono(hydrogen chloride) and 3,5-di-
tert-butylsalicyladehyde.
Additionally, a series of functionalized salen ligands L6–L9 were
synthesized in a similar procedure of L1 for further studying the
effect of stereo-hindrance of the appended Lewis base (Scheme 5).
Furthermore, ligand L10 bearing a quaternary ammonium salt
Scheme 1 Synthesis of ligand L1.
In order to examine the influence of the linker between salen
ligand framework and phosphane oxide on the catalytic activity,
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Table 1 Addition of TMSCN to benzaldehyde using bifunctional
catalystsa
Substrate:
Catalyst
Entry
Ligand
Time
Yield (%)b
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L5
L5
L5
L5
L5
100: 1
100: 1
100: 1
100: 1
100: 1
100: 1
100: 1
100: 1
100: 1
100: 1
200: 1
1000: 1
2000: 1
5000: 1
50000: 1
4 h
4 h
3 h
24 h
10 min.
1 h
3 h
3 h
40 min.
24 h
10 min.
10 min.
10 min.
90 min.
24 h
99
96
99
70
99
97
< 5
98
99
98
99
97
97
99
58
Scheme 3 Synthesis of ligand L4.
9
10
11
12
13
14
15
a All reactions were carried out in 2.5 mL CH2Cl2 at room temperature.
b Isolated yield.
phosphane oxide on the salen ligand 1 or 2 is more beneficial to
cooperatively catalyzing this reaction than free Ph3PO.
As expected, the catalyst system with regard to the symmetrical
ligand L3 exhibited higher activity (Table 1, entry 3) than that
concerning ligand 1 or 2 case. Interestingly, ligand L4 with a
diphenylphosphane oxide appended on 5-position of one aromatic
ring in conjunction with Ti(OiPr)4 showed a very low activity
(Table 1, entry 4), comparable to the catalyst system consisted
of ligand 11, Ph3PO and Ti(OiPr)4. It is tentatively ascribed
to the far distance between the Lewis acid and Lewis base
in the system concerning L4, which is unfavourable to bring
the activated TMSCN into appropriate position for attacking
aldehyde coordinated to titanium.
Surprisingly, the catalyst system based on L5–L9 exhibited more
active for the cyanosilylation of TMSCN with benzaldehyde (Ta-
ble 1, entries 5–9). The highest activity was observed in the catalyst
system with regard to ligand L5 bearing a diethylamino group
(Table 1, entries 5, 11–15). In a low catalyst loading of 0.05 mol%,
the quantitative conversion of benzaldehyde to the corresponding
cyanosilylation product was found within 10 min. at ambient
temperature, with a TOF (turnover frequency) up to 12000 h-1
(Table 1, entry 13). Notably, even at a high [aldehyde]/[catalyst]
ratio up to 50000, the catalyst system consisted of ligand L5 and
Ti(OiPr)4 also exhibited excellent activity (Table 1, entry 15).
However, the catalyst system concerning ligand L10 with an
appended quaternary ammonium salt showed very low activity
for this reaction under the same conditions. No or little product
was found when the reaction was performed 1 h. Only with a
prolonged time of 24 h and 1 mol% catalyst loading, quantitative
conversion of benzaldehyde to 2-hydroxy-2-phenylacetonitrile was
found (Table 1, entry 10). The results demonstrated the important
role of the Lewis basicity of the appended functional group.
Although much effort was paid to isolate the metal complex
from the mixtures of salen ligands and Ti(OiPr)4, we failed to
obtain the single crystal for structure determination. It is obvious
Scheme 4 Synthesis of ligands L5 and L10.
on the three-position of one aromatic ring was also synthesized. It
is relatively easy to prepare via simple quaterisation of ligand L5
with CH3I (Scheme 4).
We started our investigation with cyanosilylation of benzalde-
hyde at room temperature, with the use of ligand L1. Initially,
the catalytic system was prepared by ligand L1 combined with
Ti(OiPr)4 in CH2Cl2 in a glove box at room temperature for
2 h, then benzaldehyde and TMSCN was added. We delightedly
found that in the presence of 1 mol% of L1/Ti(OiPr)4 the reaction
proceeded smoothly at room temperature to give an excellent yield
up to 99% after 4 h (Table 1, entry 1). The similar result was
obtained in the catalyst system regarding ligand L2 (Table 1, entry
2), indicating that the linker length between salen framework and
phosphane oxide has no obvious influence on the catalytic activity.
For a comparison purpose, we also performed Jacobsen salen
ligand L11 together with Ti(OiPr)4 as catalyst (1 mol% loading)
for this reaction, in the presence of 1 equimolar Ph3PO. Only 70%
yield was found in the resulting catalyst system with a prolonged
reaction time of 24 h. This result indicates that the appended
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Scheme 5 Synthesis of ligands L6–L9.
that both the central metal ion and the appended functional group
on the ligand framework play important roles in synergistically
catalyzing this reaction. We tentatively propose a synergistic
mechanism wherein the central metal Ti(IV) is suggested to play a
role of Lewis acid to activate aldehydes while the appended Lewis
base to activate TMSCN.
For further confirming the intramolecular cooperation catalysis,
some control experiments were performed. Plots of conversion
versus reaction time are showed in Fig. 2. The rapid con-
version of benzaldehyde was observed in the catalyst system
regarding ligand L5 rather than L11/Et3N. For example, in the
cyanosilylation of benzaldehyde with TMSCN at a condition
of [benzaldehyde]/[catalyst] ratio of 10000 at room temperature,
more than 70% conversion occurred at L5/Ti(OiPr)4 system within
80 min., while only 20% conversion was observed in the catalyst
system of L11/Ti(OiPr)4 and Et3N. This result indicates that
an intramolecularly synergistic effect exists in the L5/Ti(OiPr)4
catalyst system for the cyanosilylation of aldehyde with TMSCN.
Moreover, we also explored the asymmetric cyanosilylation
of benzaldehyde with TMSCN by the use the chiral ligands.
Unfortunately, the enantioselectivity of the product was not
satisfactory, an enantiomeric excess of 81% was observed in the
catalyst system with respect to ligand L5 at ambient temperature.
The decrease of reaction temperature (even decreased to -40 ◦C)
Fig. 2 Conversion of benzaldehyde with the use of (A) L5/Ti(OiPr)4,
and (B) L11/Ti(OiPr)4 and Et3N (1 equiv. to L11) as catalyst for the
cyanosilylation with TMSCN at a condition of [benzaldehyde]/[catalyst]
ratio of 10000 at room temperature.
did not cause a distinct enhancement in enantioselectivity (see
ESI, Table S1†).
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Table 2 Synthesis of cyanohydrins using L5 as liganda
using standard Schlenk techniques. All aldehydes, Ti(OiPr)4 and
TMSCN, which were purchased from Acros company, were
vacuum distillated before use. Dichloromethane (CH2Cl2) and
acetonitrile were refluxed and distilled over CaH2 under nitrogen
atmosphere. Methanol was distilled from Mg(OCH3)2 under
nitrogen. Tetrahydrofuran (THF) and toluene were distilled from
sodium/benzophenone.
Entry
R
t (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
0.2
2
4
4
1
1
0.5
1
99
99
26
57
99
99
99
92
81
80
88
50
2
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-NO2C6H4
4-ClC6H4
PhCH CH
Synthesis of ligand L1–L10
General procedure for unsymmetric ligands (L1,L2,L4–L9).
A
68
d
dry flask charged with 1,2-diaminocyclohexane mono(hydrogen
chloride) (2.0 mmol),18 some 5 A molecular sieve, and anhydrous
˚
_
58
methanol. 3,5-Di-tert-butyl-2-hydroxybenzaldehyde (2.4 mmol)
was added in one portion and the reaction mixture was stirred
at room temperature for 1 h. Then triethylamine (0.6 mL) was
added, followed by the addition of the other aldehyde (1.6 mmol)
dissolved in ethanol. After stirring at room temperature for an-
other 4 h, some dichloromethane was added to dissolve the Schiff
base, then the mixture was filtered to remove molecular sieve. Then
the combined solvent was evaporated. The residue was purified by
column chromatography on silica gel twice using petrol ether/ethyl
acetate (10 : 1, 1% Et3N) and dichloromethane/methanol (10 : 1)
respectively as mobile phase to give the unsymmetric salen ligand
as yellow solid.
d
9
10
CH3(CH2)6
(CH3)2CH
0.5
0.5
97
99
_
_
d
a All reactions were carried out in 2.5 mL CH2Cl2 at room temperature,
with a ratio of aldehyde/catalyst of 2000 : 1. b Isolated yield. c The
enantiomeric excess was determined by Agilent HPLC after the products
were converted to the corresponding acetylesters. d Not measurable.
Furthermore, the catalytic system of ligand L5 in conjunction
with Ti(OiPr)4 was successfully applied to the cyanosilylation
of other aromatic aldehydes with TMSCN (Table 2). In the
presence of 0.05 mol% catalyst loading at ambient temperature,
substituted benzaldehydes with an electron-donating group exhib-
ited significantly low reactivity in comparison with benzaldehyde
(Table 2, entry 2–4). On the contrary, 4-nitrobenzaldehyde and
4-chlorobenzaldehyde showed excellent reactivity in the cyanosi-
lylation with TMSCN and was completely transformed into the
corresponding products within 1 h (Table 2, entries 5 and 6).
Encouraged by the results of aromatic aldehydes with
L5/Ti(OiPr)4, we also investigated some aliphatic aldehydes. To
our delight, the catalytic system was compatible with aliphatic
aldehydes, including a,b-unsaturated, functionalized, liner, and
branched substrates (Table 2, entries 7–10). Excellent yields (92–
99%) were obtained in the low catalyst loading of 0.05 mol% within
0.5 or 1 h.
L1. Yield: 55%. mp 84–86 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.67 (s, 1H), 13.49 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.66–7.77
(m, 4H), 7.30–7.45 (m, 6H), 7.25 (d, J = 2.8 Hz, 1H), 7.17 (s, 1H),
7.01 (d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 3.62–3.86 (m, 2H), 3.23–3.33
(m, 2H), 1.43–1.88 (m, 8H), 1.40 (s, 9H), 1.23 (s, 9H), 1.08 (s, 9H);
13C NMR (100 MHz, CDCl3): d 165.66, 165.16, 158.09, 156.99 (d,
J = 5.3 Hz), 140.67 (d, J = 3.1 Hz), 140.09, 136.55, 133.62, 133.26,
132.64, 132.28, 131.58 (d, J = 2.7 Hz), 131.50, 131.30 (d, J = 1.3
Hz), 131.21 (d, J = 1.4 Hz), 128.42, 128.36, 128.29, 128.23, 126.92,
126.82, 126.06, 118.71, 118.63, 117.93, 117.65, 72.55, 72.41, 35.08,
34.18, 33.82, 33.54, 33.19, 31.58, 31.28, 30.62, 29.93, 29.54, 24.39
(d, J = 4.5 Hz); 31P NMR (161 MHz, CDCl3): d 31.92; IR (KBr):
3056, 2955, 2862, 1629, 1475, 1438, 1362, 1276, 1201, 1120, 733,
721, 695 cm-1; HRMS (ESI): m/z Calcd. for C45H58N2O3P [M +
H]+: 705.4185, found: 705.4186.
Experimental
◦
L2. Yield: 52%. mp 77–79 C;1H NMR (400 MHz, CDCl3):
General information
d 13.71 (s, 1H), 13.40 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 7.66–7.71
(m, 4H), 7.40–7.49 (m, 6H), 7.30 (d, J = 2.4 Hz, 1H), 7.08 (d, J =
2.0 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 3.27–
3.34 (m, 2H), 2.65–2.79 (m, 2H), 2.28–2.35 (m, 2H), 1.44–1.96 (m,
10H), 1.40 (s, 9H), 1.22 (s, 9H), 1.19 (s, 9H); 13C NMR (100 MHz,
CDCl3): d 165.67, 165.31, 157.97, 156.82, 140.74, 139.90, 136.37,
135.21, 133.67 (d, J = 5.0 Hz), 132.72 (d, J = 5.1 Hz), 131.56, 130.88
(d, J = 2.1 Hz), 130.79 (d, J = 2.2 Hz), 129.92, 128.62, 128.51,
127.78, 126.77, 126.08, 126.02, 117.82, 117.57, 72.76, 72.20, 34.96,
34.06, 33.84, 33.44, 33.08, 31.42 (d, J = 6.9 Hz), 30.82, 30.66,
29.76, 29.43, 29.05, 24.28 (d, J = 7.1 Hz), 21.47 (d, J = 3.2 Hz);
31P NMR (161 MHz, CDCl3) d 32.70; IR (KBr): 3056, 2956, 2862,
1628, 1473, 1438, 1362, 1272, 1175, 1120, 716, 695 cm-1; HRMS
(ESI): m/z Calcd. for C47H62N2O3P [M + H]+: 733.4498, found:
733.4511.
1H, 13C and 31P NMR spectra were recorded on a Varian INOVA-
400 MHz type (1H, 400 MHz; 13C, 100 MHz; 31P, 161 MHz)
spectrometer. Their peak frequencies were referenced versus an
internal standard (TMS) shifts at 0 ppm for 1H NMR and against
the solvent, chloroform-d at 77.0 ppm for 13C NMR, phosphinic
acid (85%) as an external standard for 31P NMR respectively.
High resolution mass spectrometry (HRMS) was performed
on a Micromass Q-Tof (Micromass, Wythenshawe, UK) mass
spectrometer equipped with an orthogonal electrospray source
(Z-spray).
Infrared spectra (IR) were measured using
a Nicolet
NEXUS FT-IR spectrophotometer equipped with a temperature-
controlled high-pressure liquid cell (Harrick Scientific Corpora-
tion).
All manipulations involving air- and/or water-sensitive com-
pounds were carried out in a glove box or under dry nitrogen
L4. Yield: 40%. mp 102–104 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.90 (s, 1H), 13.66 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.66–7.71
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(m, 2H), 7.56–7.61 (m, 2H), 7.37–7.45 (m, 6H), 7.31 (d, J = 2.0 Hz,
1H), 6.98 (d, J = 2.4 Hz, 1H), 6.87 (s, 1H), 6.60 (s, 1H), 3.47–3.52
(m, 2H), 3.29–3.32 (m, 2H), 1.86–1.93 (m, 4H), 1.46–1.71 (m,
4H), 1.41 (s, 9H), 1.23 (s, 9H), 1.18 (s, 9H); 13C NMR (100 MHz,
CDCl3): d 165.77, 165.22, 159.38 (d, J = 2.5 Hz), 158.00, 139.89,
136.84 (d, J = 2.3 Hz), 136.40, 132.92, 132.49, 131.95, 131.80 (d,
J = 2.6 Hz), 131.71, 131.51, 131.42, 131.31 (d, J = 4.2 Hz), 131.20,
131.14, 131.09, 128.56, 128.44 (d, J = 2.2 Hz), 128.31, 126.79,
125.97, 119.44 (d, J = 8.0 Hz), 118.58 (J = 2.3 Hz), 117.82, 72.51,
72.05, 37.80, 37.13, 34.98, 34.51, 34.04, 33.24, 33.11, 31.44, 29.47,
29.12, 24.28; 31P NMR (161 MHz, CDCl3): d 29.53. IR (KBr):
3057, 2953, 2862, 1629, 1468, 1439, 1389, 1361, 1272, 1201, 737,
718, 695 cm-1; HRMS (ESI): m/z Calcd. for C45H58N2O3P [M +
H]+: 705.4185, found: 705.4188.
(KBr): 2967, 2868, 1630, 1509, 1477, 1442, 1363, 1275, 1091, 1050,
881 cm-1; HRMS (ESI): m/z Calcd. for C36H51N4O2 [M + H]+:
571.4012, found: 571.4009.
L9. Yield: 79%. mp 140–142 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.72 (s, 1H), 13.57 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.51 (s, 1H),
7.35 (s, 1H), 7.12 (s, 1H), 7.04 (s, 1H), 4.50–4.63 (m, 2H), 3.52–3.58
(m, 1H), 3.31–3.38 (m, 9H), 1.46–1.97 (m, 12H), 1.41 (s, 9H), 1.26
(s, 9H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3): d 166.18,
165.01, 162.68, 157.95, 151.36, 140.19, 139.69, 136.60, 133.90,
128.80, 127.05, 125.94, 123.23, 117.73, 116.46, 71.49, 70.09, 50.06,
47.98, 47.39, 45.67, 38.45, 34.97, 34.08, 33.84, 33.65, 32.11, 31.44,
31.20, 29.38, 24.19, 24.12, 21.28, 20.94; IR (KBr): 2954, 2864,
1629, 1600, 1541, 1476, 1442, 1362, 1320, 1274 cm-1; HRMS (ESI):
m/z Calcd. for C40H60N5O2 [M + H]+: 642.4747, found: 642.4753.
L5. Yield: 65%. mp 110–111 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.72 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.41 (s, 1H), 7.30 (s,
1H), 7.05 (s, 1H), 6.98 (s, 1H), 3.57–3.67 (m, 2H), 3.25–3.36 (m,
2H), 2.57–2.55 (m, 4H), 1.45–1.95 (m, 8H), 1.41 (s, 9H), 1.24 (s,
18H), 1.06 (t, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 165.71, 164.92, 158.04, 157.12, 140.50, 139.85, 136.37, 130.25,
126.72, 126.11, 117.86, 117.75, 72.82, 72.35, 51.43, 47.06, 34.97,
34.07, 33.90, 33.40, 33.17, 31.47, 31.42, 29.45, 24.36, 24.32, 11.79;
IR (KBr): 2962, 2864, 2798, 1630, 1468, 1441, 1361, 1266 cm-1;
HRMS (ESI): m/z Calcd. for C37H58N3O2 [M + H]+: 576.4529,
found: 576.4533.
Synthesis of ligand L3. A mixture of 1,2-diaminocyclohexane
(0.083 g, 72.8 mmol) and compound 13 (0.60 g, 1.5 mmol) in
ethanol (60 mL) was stirred for 2 h at room temperature before
it was allowed to remove the solvent. The crude product was
further purified by column chromatography on silica gel using
dichloromethane/methanol (10 : 1) as mobile phase to give L3 as
yellow solid (0.59 g, 95%). mp 107–110 ◦C; 1H NMR (400 MHz,
CDCl3): d 13.48 (s, 2H), 8.21 (s, 2H), 7.68–7.77 (m, 8H), 7.41–7.45
(m, 2H), 7.33–7.39 (m, 4H), 7.23–7.31 (m, 6H), 7.21 (s, 2H), 6.98
(s, 2H), 3.78–3.85 (m, 2H), 3.64–3.71 (m, 2H), 3.26–3.28 (m, 2H),
1.84–1.87 (m, 4H), 1.62–1.65 (m, 2H), 1.42–1.47 (m, 2H), 1.08
(s, 18H); 13C NMR (100 MHz, CDCl3): d 164.76, 156.88 (d, J =
5.0 Hz), 140.69 (d, J = 2.5 Hz), 133.56, 133.10, 132.58, 132.12,
131.50 (d, J = 2.2 Hz), 131.17 (d, J = 3.4 Hz), 131.08 (d, J = 3.5
Hz), 128.30 (d, J = 3.2 Hz), 128.18 (d, J = 3.2 Hz), 126.69, 118.69
(d, J = 7.4 Hz), 117.55, 72.38, 33.75, 33.32, 31.20, 30.44, 29.75,
24.17; 31P NMR (161 MHz, CDCl3): d 30.84; IR (KBr): 3055,
2952, 2860, 1629, 1475, 1437, 1395, 1279, 1195, 1120, 735, 720,
695 cm-1; HRMS (ESI): m/z Calcd. for C54H61N2O4P2 [M + H]+:
863.4107, found: 863.4100.
L6. Yield: 69%. mp 83–87 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.71 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.38 (s, 1H), 7.31 (d,
J = 2.4 Hz, 1H), 7.06 (s, 1H), 6.99 (d, J = 2.4 Hz, 1H), 3.51–3.59
(m, 2H), 3.27–3.34 (m, 2H), 2.44 (s, 4H), 1.43–1.92 (m, 14H), 1.41
(s, 9H), 1.23 (s, 18H); 13C NMR (400 MHz, CDCl3): d 165.69,
165.07, 158.00, 157.27, 140.50, 139.89, 136.39, 130.82, 126.71,
125.98, 117.85, 72.77, 72.27, 56.90, 54.43, 34.95, 34.04, 33.85,
33.36, 33.13, 31.43, 31.37, 29.43, 25.86, 24.33, 24.28; IR (KBr):
2952, 2935, 2861, 1629, 1468, 1441, 1362, 1272 cm-1; HRMS (ESI):
m/z Calcd. for C38H58N3O2 [M + H]+: 588.4529, found: 588.4520.
Synthesis of ligand L10. To a solution of L5 (0.58 g, 1.0 mmol)
in acetonitrile (20 mL) in a 50 mL flask wrapped in aluminium foil
was added iodomethane (0.10 mL, 1.5 mmol). The mixture was
stirred for 24 h at room temperature before removing the solvent.
The residue was purified by column chromatography on silica gel
using dichloromethane/methanol (10 : 1) as mobile phase to give
L7. Yield: 73%. mp 66–69 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.69 (s, 1H), 13.48 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.36 (d,
J = 1.6 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H),
7.00 (d, J = 2.0 Hz, 1H), 3.72–3.75 (m, 4H), 3.53–3.61 (m, 2H),
3.28–3.37 (m, 2H), 2.51–2.54 (m, 4H), 1.48–1.95 (m, 8H), 1.43
(s, 9H), 1.26 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 165.72, 165.18, 158.01, 157.38, 140.52, 139.92, 136.42, 130.86,
126.96, 126.76, 126.01, 125.79, 124.02, 117.87, 72.85, 72.26, 67.05,
66.82, 56.75, 53.77, 53.16, 34.98, 34.07, 33.85, 33.44, 33.14, 31.54,
31.46, 31.39, 31.34, 29.44, 24.36, 24.29; IR (KBr): 2957, 2861,
2800, 1629, 1471, 1441, 1362, 1273, 1118 cm-1; HRMS (ESI): m/z
Calcd. for C37H56N3O3 [M + H]+: 590.4322, found: 590.4319.
◦
1
L10 as yellow solid (0.50 g, 70%). mp 146–148 C; H NMR
(400 MHz, CDCl3): d 14.31 (s, 1H), 13.60 (s, 1H), 8.36 (s, 1H),
8.30 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.28
(d, J = 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 4.78 (d, J = 12 Hz,
1H), 4.66 (d, J = 12 Hz, 1H), 3.72 (m, 1H), 3.56–3.69 (m, 1H),
3.42–3.53 (m, 3H), 3.28–3.34 (m, 1H), 3.12 (s, 3H), 1.91–2.04 (m,
4H), 1.49– 1.80 (m, 4H), 1.43 (t, J = 4.0 Hz, 6H), 1.40 (s, 9H), 1.26
(d, J = 4.0 Hz, 18H); 13C NMR (100 MHz, CDCl3): d 165.75,
164.75, 160.08, 157.97, 141.59, 140.16, 136.64, 135.87, 131.13,
126.99, 125.80, 118.18, 117.78, 114.42, 72.26, 71.41, 59.54, 56.10,
47.09, 34.99, 34.15, 34.10, 33.49, 32.56, 31.46, 31.36, 29.45, 29.36,
24.28, 24.16, 8.75; IR (KBr): 2954, 2862, 1630, 1535, 1476, 1441,
1391, 1362, 1273 cm-1; HRMS (ESI): m/z Calcd. for C38H60N3O2
[M - I]+: 590.4686, found: 590.4690.
L8. Yield: 66%. mp 85–89 ◦C; 1H NMR (400 MHz, CDCl3):
d 13.65 (s, 2H), 8.32 (s, 1H), 8,28 (s, 1H), 7.59 (s, 1H), 7.32 (d,
J = 2.4 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.02 (s, 1H), 6.99–
7.01 (m, 2H), 6.96 (s, 1H), 5.14 (d, J = 16 Hz, 1H), 5.03 (d, J =
16 Hz, 1H), 3.28–3.38 (m, 2H), 1.88–1.95 (m, 4H), 1.68–1.79 (m,
2H), 1.45–1.52 (m, 2H), 1.40 (s, 9H), 1.25 (s, 9H), 1.18 (s, 9H);
13C NMR (100 MHz, CDCl3): d 165.93, 165.09, 158.11, 157.13,
141.32, 140.18, 137.84, 136.61, 129.42, 129.07, 128.33, 127.02,
126.14, 123.53, 119.54, 118.12, 117.97, 72.87, 72.29, 45.79, 35.12,
34.23, 34.02, 33.58, 33.14, 31.60, 31.41, 29.56, 24.46, 24.38; IR
General procedure of cyanosilylation of aldehydes. [Caution!
TMSCN is toxic and volatile and must be used in well ventilated
hood] To a solution of ligand L5 (1.3 mg, 2.2 ¥ 10-3 mmol)
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in 2.5 mL CH2Cl2 in a flame-dried reaction vessel, was added
Ti(OiPr)4 (0.6 mL, 2.0 ¥ 10-3 mmol) in glove box. After stirring the
mixture at ambient temperature for 2 h, aldehyde (4 mmol) and
TMSCN (8 mmol) were added. The reaction was stirred for the
time shown in Table 2 at room temperature. Then 2 N HCl (40
mL) and ethyl acetate (20 mL) was added to quench the reaction.
The resulting mixture was stirred for 5 h and then extracted with
ethyl acetate (3 ¥ 15 mL). The organic layer was washed with brine
and dried over anhydrous Na2SO4. The crude product was further
purified by column chromatography (petrol ether/ethyl acetate =
10 : 1) to give the cyanohydrins.
2-(Furan-2-yl)-2-hydroxyacetonitrile. Colourless oil, 1H NMR
(400 MHz, CDCl3): d 7.49 (d, J = 1.2 Hz, 1H), 6.60 (d, J =
3.2 Hz, 1H), 6.42–6.43 (m, 1H), 5.55 (s, 1H), 3.24 (s, 1H); 13C NMR
(100 MHz, CDCl3): 147.62, 144.34, 117.03, 110.93, 110.14, 56.94;
IR (neat): 3396, 2254; HRMS (ESI): m/z Calcd. for C8H8NO4 [M
+ CH3COO]-: 182.0453, found: 182.0455.
2-Hydroxynonanenitrile. Colourless oil, 1H NMR (400 MHz,
CDCl3): d 4.45-4.50 (m, 1H), 2.74 (s, 1H), 1.82–1.87 (m, 2H), 1.46–
1.52 (m, 2H), 1.28–1.33 (m, 8H), 0.87–0.90 (m, 3H); 13C NMR
(100 MHz, CDCl3): 120.17, 61.24, 35.10, 31.64, 28.99, 28.87, 24.55,
22.57, 14.03; IR (neat): 3442, 2248; HRMS (ESI): m/z Calcd. for
C11H20NO3 [M + CH3COO]-: 214.1443, found: 214.1441.
2-Hydroxy-2-phenylacetonitrile. Colourless oil, 1H NMR
(400 MHz, CDCl3): d 7.48–7.50 (m, 2H), 7.41–7.44 (m, 3H), 5.49
(d, J = 6.0 Hz, 1H), 3.65 (s, 1H); 13C NMR (100 MHz, CDCl3):
135.24, 129.93, 129.30, 126.80, 119.07, 63.56; IR (neat): 3416,
2249; HRMS (ESI): m/z Calcd. for C10H10NO3 [M + CH3COO]-:
192.0611, found: 192.0609.
2-Hydroxy-3-methylbutanenitrile. Colourless oil, 1H NMR
(400 MHz, CDCl3): d 4.28 (d, J = 6.0 Hz, 1H), 3.06 (s, 1H), 2.00–
2.10 (m, 1H), 1.06–1.11 (m, 6H); 13C NMR (100 MHz, CDCl3):
119.46, 67.06, 33.14, 17.81, 17.35; IR (neat): 3442, 2247; HRMS
(ESI): m/z Calcd. for C7H12NO3 [M + CH3COO]-: 158.0817,
found: 158.0819.
2-Hydroxy-2-p-tolylacetonitrile. Colourless oil, 1H NMR
(400 MHz, CDCl3): d 7.41 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.4 Hz,
1H), 5.48 (s, 1H), 2.88 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3): 139.93, 132.34, 129.83, 126.70, 119.07, 63.36, 21.24; IR
(film): 3416, 2249; HRMS (ESI): m/z Calcd. for C11H12NO3 [M +
CH3COO]-: 206.0817, found: 206.0814.
Conclusions
In summary, we have developed a series of new salen ligands
bearing an appended Lewis base on the 3-position of one aromatic
ring and succeeded in applying them to the cyanosilylation of
various aldehydes with TMSCN by combining with Ti(OiPr)4
as a bifunctional catalyst. The catalyst system with regard to
ligand L5 bearing a diethylamino group proved to be more active
even at a high [aldehyde]/[catalyst] ratio up to 50000 under mild
conditions. Although the detailed mechanism is not clear, kinetic
experiments suggest that an intramolecule cooperative catalysis
exists in the cyanosilylation using the unsymmetric salen ligands
in conjunction with Ti(OiPr)4 as catalyst. It is tentatively proposed
wherein the central metal ion Ti(IV) is suggested to play a role of
Lewis acid to activate aldehydes while the appended Lewis base to
activate TMSCN.
2-Hydroxy-2-(4-methoxyphenyl)acetonitrile. White solid, 1H
NMR (400 MHz, CDCl3): d 7.46 (d, J = 8.8 Hz, 2H), 6.96 (d,
J = 8.8 Hz, 2H), 5.48 (s, 1H), 3.85 (s, 3H), 3.21 (s, 1H); 13C
NMR (100 MHz, CDCl3): 160.67, 128.43, 127.64, 119.25, 114.61,
63.20, 55.54; IR (film): 3418, 2247; HRMS (ESI): m/z Calcd. for
C11H12NO4 [M + CH3COO]-: 222.0766, found: 222.0765.
2-Hydroxy-2-(2-methoxyphenyl)acetonitrile. Colourless oil,
1H NMR (400 MHz, CDCl3): d 7.39–7.43 (m, 2H), 6.97–7.04
(m, 2H), 5.56 (d, J = 8.8 Hz, 1H), 3.55 (d, J = 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3): 156.83, 131.27, 128.17, 123.76, 121.22,
118.81, 111.26, 60.72, 55.80; IR (film): 3417, 2248; HRMS (ESI):
m/z Calcd. for C11H12NO4 [M + CH3COO]-: 222.0766, found:
222.0762.
Acknowledgements
2-Hydroxy-2-(4-nitrophenyl)acetonitrile. Slightly yellow solid,
1H NMR (400 MHz, CDCl3): d 8.35 (d, J = 8.4 Hz, 2H), 7.89 (d,
J = 8.4 Hz, 2H), 6.45 (s, 1H), 6.05 (s, 1H); 13C NMR (100 MHz,
acetone-d6): 148.89, 144.37, 128.10, 124.44, 119.52, 62.30; IR
(film): 3406, 2250; HRMS (ESI): m/z Calcd. for C8H5N2O3 [M
- H] -: 177.0300, found: 177.0301.
This work was support by National Basic Research Program
of China (973 Program: 2009CB825300). X.-B. Lu gratefully
acknowledges the Outstanding Young Scientist Foundation of
National Natural Science Foundation of China (NSFC, Grant
20625414).
2-(4-Chlorophenyl)-2-hydroxyacetonitrile. Slightly yellow oil,
1H NMR (400 MHz, CDCl3): d 7.41–7.48 (m, 4H), 5.53 (s,
1H), 3.13 (s, 1H); 13C NMR (100 MHz, CDCl3): 135.87, 133.57,
129.39, 128.02, 118.69, 62.77; IR (KBr): 3403, 2252; HRMS (ESI):
m/z Calcd. for C10H9NO3Cl [M + CH3COO]-: 226.0271, found:
226.0274.
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