Enantioselective Strecker reaction of aldimines using potassium cyanide catalyzed by a recyclable macrocyclic V(v) salen complex

Article abstract of DOI:10.1039/c5ra18914d

A chiral dimeric macrocyclic V(v) salen complex based on a chiral macrocyclic salen ligand derived from 1R, 2R-(-) diaminocyclohexane with trigol bisaldehyde was synthesized and evaluated as an efficient catalyst (5 mol%) for asymmetric addition of potass

Full text of DOI:10.1039/c5ra18914d

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Enantioselective Strecker reaction of aldimines using potassium
cyanide catalyzed by recyclable macrocyclic V(V) salen complex
S. Saravanan,a, b Noor-ul H. Khan,* a, b Ajay Jakhar,a,b Amamudin Ansari,a,b Rukhsana I. Kureshy,a, b
Sayed H. R. Abdi, a, b Gaurav Kumara, b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Chiral dimeric macrocyclic V(V) salen complex based on chiral macrocyclic salen ligand derived from 1R, 2R-(-)
diaminocyclohexane with trigol bisaldehyde was synthesized and evaluated as efficient catalyst (5 mol%) for asymmetric
addition of potassium cyanide and trimethylsilyl cyanide to various N-benzylimines at -20 oC. The dimeric chiral
macrocyclic salen complex was found to be an effecient recyclable catalyst to give high yield (91%) of α-aminonitrile with
and high chiral induction (ee up to 99%) in case of 2-methoxy substituted N-benzylimines in 16 h. The catalytic system
worked well with both organic and inorganic cyanide sources and the catalyst was recycled up to five cycles with retention
of enantioselectivity. Based on the NMR investigation and kinetics a probable mechanism was proposed for the catalytic
www.rsc.org/
enantioselective
Strecker
reaction.
substrate generality over a broad spectrum of reactions. Due
to the high cost of chiral ligands we have also taken care of
issue of catalyst recovery and reuse while designing the chiral
ligands for asymmetric Strecker reaction. In the present work
we wish to report the use of chiral macrocyclic V(V) salen
complex as efficient recyclable catalyst for the asymmetric
addition of cyanide to various aldimines which delivers
excellent enantioselectivity (ee up to 99%) of α-aminonitrile in
16h with over all good yield and added advantage of catalyst
recyclability. These catalysts however, required an additive like
Introduction
The catalytic asymmetric Strecker reaction represents one of
the most direct and viable methods for efficient asymmetric
synthesis of naturally occurring and non-proteinogenic α-
amino acid,1 nucleic acids, various nitrogen and sulphur
containing heterocycles,2 chiral building blocks for organic
synthesis and pharmaceuticals.3 The classical Strecker reaction
reported in 1850 comprises of three component reaction for
the synthesis of α-amino nitrile,1a which after hydrolysis yield
α-amino acids4 in racemic form. Enormous efforts have been
devoted to the development of non-recyclable chiral catalysts
to effect the enantioselective Strecker reaction, which includes
Schiff base complexes,5 organocatalysts,6 bi-functional
catalysts7 and various metal based catalysts.8 Notable amongst
these catalysts was Jacobsen’s metal based salen complexes
under homogeneous catalytic system in terms of enantio-
induction and yield.5 Recently we have developed efficient
recyclable catalytic systems for different enantioselective
transformations9 including asymmetric Strecker reaction.
Nevertheless, there are only very few systems which work
efficiently with different cyanide sources.8b, 8v This prompted
us to develop a recyclable catalytic system which can handle
both the organic, easy to handle and safe cyanide source like
TMSCN and also the cost effective inorganic cyanide source
like potassium cyanide; that display high enantioselectivity and
water as
a promoter in order to show high catalytic
performance.
Results and Discussion
The synthesis of macrocyclic complexes was implemented in
three step sequence, as illustrated in Scheme 1. The reaction
of 3-t-Bu -5-chloromethyl-2-hydroxy benzaldehyde with trigol
was carried out in dry THF containing sodium hydride to give
trigol bis aldehyde 1 10
1:1 and 1: 2 molar ratio in dry MeOH and THF respectively
gave macrocyclic chiral Schiff base ligands 2'-5' The
.
The interaction of 1 with diamines in
.
complexation of chiral macrocyclic ligands with vanadyl
sulphate hydrate was done followed by auto-oxidation to get
10
V(V) macrocyclic complex 2-5
.
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Journal Name
Ph
N
Ph
O
V
N
O
O
V
EtSO4
O
N
O
N
O
EtSO4
O
O
OH2
O
OH2
t-Bu t-Bu
O
t-Bu t-Bu
O
VOSO4.5H2O
EtOH
O
O
O
VOSO4.5H2O
EtOH
3
2
Ph
N
Ph
N
N
N
OHHO
OHHO
O
O
O
O
t-Bu t-Bu
t-Bu t-Bu
Ph
Ph
NH2
NH2
NH2
O
O
O
O
2'
NH2
3'
Dry MeOH
Dry MeOH
O
O
O
O
O
OH
t-Bu
t-Bu
1
O
HO
Ph
Ph
NH2
NH2
NH2
THF
NH2
O
THF
O
O
O
O
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
Ph
Ph
Ph
N
N
OH
OH
HO
N
N
N
N
OH
HO
N
OH
HO
HO
N
t-Bu
t-Bu
O
O
O
O
O
O
O
O
5'
4'
VOSO4.5H2O
EtOH
VOSO4.5H2O
EtOH
O
O
O
O
O
O
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
OH2
t-Bu
t-Bu
Ph
Ph
N
O
Ph
Ph
N
O
N
O
N
O
N
O
V
O
O V OH2
H2O V O
H2O V O
N
O
N
O
N
O
t-Bu
2EtSO4
O
2EtSO4
O
O
O
O
O
O
O
5
4
Scheme
1:
Synthesis
of
V(V)
macrocyclic
complex
2-5
2 | J. Name., 2012, 00, 1-3
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2.5 to 5 mol% there was an improvement in the yield (76%)
and 79% ee of the corresponding product. However a further
increase in the catalyst loading (10 mo%) does not enhance
the results in term of yield and enantioselectivity (Figure 1).
Hence 5 mol% catalyst was sufficient enough to progress the
reaction smoothly.
Table1: Screening of V(V) macrocyclic salen complex for asymmetric
Strecker reactiona
CN
Catalyst
N
N
H
KCN
Toluene
Entry Catalyst
Yield
ee
TONd
TOF (min-1)e
(%)b
(%)c
1
2
3
4
2
3
4
5
66
56
13.2
12.4
15.2
14.6
9.16x10-3
8.61x10-3
10.56x10-3
10.14x10-3
62
50
76
79
73
69
a
Reaction condition: catalyst (5 mol%), substrate (0.2 mmol), in
toluene (1 mL) with 1.5 equiv. KCN at -20 oC for 24 h.
b Isolated yield
Figure
1: Asymmetric addition of KCN to 4-methyl-N-
c ee were determined using chiral OD column
d TON is calculated by the expression [product]/[catalyst]
e TOF is calculated by the expression TON/reaction time (min-1)
benzylimine using chiral macrocyclic V(V) salen complex 4 for
optimizing the reaction condition by screening the loading of
catalyst and solvent.
The reactivity and enatioselectivity of the asymmetric Strecker
reaction is strongly dependent on the nature of solvent used.
Thus asymmetric addition of KCN to 4-methyl imines was
conducted in various solvents viz. toluene, chloroform,
dichloromethane and THF, whereas toluene was found to be
the solvent of choice (Figure 1). As temperature plays a crucial
Our initial study commenced with the screening of catalyst 2-5
for the enantioselective Strecker reaction using 4-methyl imine
as representative substrate and toluene as solvent at -20 oC.
For purposes of comparison, initially the chiral macrocyclic
mononuclear complexes
2 and 3 with varied chiral collars were
screened for its catalytic activity and found that the complex role in achieving high chiral induction of the desired product α-
aminonitrile in asymmetric Strecker reaction, therefore, we
have varied the reaction temperature from 0 to -30 oC. On
increasing the reaction temperature from -20 to -10 and 0 C,
with 1R, 2R-(-) diaminocyclohexane as a collar results in better
yield and enantioselectivity (Table 1, entries 1&2). Then among
o
the dinculear variants
this counterpart
enantioselectivity (79%). The enhanced activity of the chiral
dinuclear macrocyclic V(V) salen complex may be attributed
4
and
5, the catalyst 4 fared better than
there is increase in yield with considerable loss in
enantioselectivity (Figure 2). Whereas on further decreasing
the temperature from -20 to -30 oC there is no significant
change in the yield and enantioselectivity of the desired
product. So, the best results in term of yield of α-aminonitrile
with high chiral induction (ee, 84%) was achieved at -20 oC and
was considered as the optimum reaction temperature (Figure
2).
5
in terms of yield (76%) and
4
to the increase in the active reaction sites that are functioning
in synergy.
With these initial results it was found that the catalyst
4 was
distinctly better in terms of reactivity, then in order to find
optimal reaction conditions such as catalyst loading, solvent
variation, temperature, use of additives the Strecker reaction
of 4-methyl N-benzylimine was carried out. The catalyst
loading was screened ranging from 2.5 mol% -10 mol% for the
asymmetric Strecker reaction using toluene as solvent at -20
oC. On conducting the Strecker reaction using 2.5 mol%
catalyst loading gave 65% yield of α-aminonitrile with 69% ee
within 16 h (Figure 1). On increasing the catalyst loading from
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methoxybenzylidene)-1,1-diphenylmethanamine,
N-(4-
bromobenzylidene)-1,1-diphenylmethanamine for asymmetric
Strecker reaction with KCN excellent enantio-induction (ee,
>99%) in α-aminonitrile was achieved in case of N-(2-
methoxybenzylidene)-1,1-diphenylmethanamine
with
excellent yield. This protocol also worked well with trimethyl
acetaldehyde in term of yield (71%) and enantioselectivity
(91%) in their respective α-aminonitrile. To the best of our
knowledge, the chiral macrocyclic V(V) salen complex 4 is the
efficient recyclable catalyst for the asymmetric Strecker
reaction of various N-benzylimines with KCN as cyanide source
in presence of water as additive giving good yields of chiral α-
aminonitrile with excellent enantioselectivity. Further to
Figure
2: Asymmetric addition of KCN to 4-methyl-N-
benzylimine using chiral macrocyclic V(V) salen complex 4 for
optimization of reaction temperature
compare the activity of the V(V) dinuclear complex
4 with an
Use of additive play a crucial role in asymmetric Strecker
reaction [7]. Therefore, different additives viz., H2O, MeOH,
EtOH, iPrOH, t-BuOH were screened in asymmetric addition of
KCN to 4-methyl N-benzylimine as representative substrate in
toluene at -20 oC. Although all the additive used (Figure 3)
helped in improving the reactivity (time 16 h) and
enantioselectivity (ee, 88%) of α-aminonitrile however, water
was proved to be the best additive to give 82% yield of α-
aminonitrile.
organic cyanide source like TMSCN, the obtained results (Table
2, in parenthesis) showed that the catalyst is efficient to work
with both inorganic and organic cyanide sources. In all
catalytic runs the 1R,2R chiral macrocyclic dimeric V(V) salen
complex gave the S-form of corresponding α-aminonitriles.
Table 2
:
Substrate scope of catalytic asymmetric Strecker
reaction of N-benzylimines using catalyst 4a
S. No.
1
Imine
Yield (%)b,d
89 (92)
91 (93)
84 (86)
88 (85)
90 (91)
86 (82)
90 (84)
87 (89)
83 (80)
92 (94)
90 (95)
89 (91)
86 (90)
84 (89)
71 (83)
ee (%)c,d
84 (80)
93 (83)
79 (73)
90 (76)
91 (89)
80 (75)
89 (85)
92 (80)
91 (76)
96 (92)
93 (90)
99 (83)
87 (80)
90 (85)
91 (88)
C6H5CH=NCH2Ph
2
4-MeC6H4CH=NCH2Ph
3-MeC6H4CH=NCH2Ph
2-MeC6H4CH=NCH2Ph
4-MeOC6H4CH=NCH2Ph
3-MeOC6H4CH=NCH2Ph
2-MeOC6H4CH=NCH2Ph
4-FC6H4CH=NCH2Ph
4-ClC6H4CH=NCH2Ph
C6H5CH=NCH(Ph)2
3
4
5
6
7
Figure 3: Asymmetric addition of KCN to 4-Me-N-Benzylimine
using chiral macrocyclic V(V) salen complex
additive.
4 for the choice of
8
9
Thus, with the promising results under optimized reaction
conditions, the catalytic protocol was explored for various N-
benzylimines in order to see the generality of the catalytic
system and the results are summarized in Table 2. Both the
electron donating and electron withdrawing substituent
present on imine demonstrated the effectiveness of this
protocol on the asymmetric Strecker reaction. The electron
donating (-Me, -OMe) groups at 4- positions of N-benzylimines
gave higher yields as well as ee (Table 2, entries 1 and 4) than
in the cases where these substituents were on 2- and 3-
position (Table 2, entries 2, 3, 5, 6). The presence of electron
withdrawing group on the aromatic ring of imines gave
moderate yield and ee (Table 2, entries 7, 8).
10
11
12
13
14
15
4-MeC6H4CH=NCH(Ph)2
2-MeOC6H4CH=NCH(Ph)2
4-BrC6H4CH=NCH(Ph)2
C10H8CH=NCH(Ph)2
(CH3)3CCH=NCH(Ph)2
a
Reaction conditions: catalyst
4 (5mol%), N-benzylimines as
substrates using KCN (1.5 equiv.), H2O as an additive using
toluene (1mL) at -20 oC.
Furthermore, on increasing the bulkiness on N-benzylimines
b Isolated yield
viz.,
N-benzylidene-1,1-diphenylmethanamine,
N-(4-
N-(2-
c ee were determined using Chiral OD, ADH and ODH column
methylbenzylidene)-1,1-diphenylmethanamine,
4 | J. Name., 2012, 00, 1-3
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d
Results in parenthesis were obtained using TMSCN (1.5 Strecker reaction is of first order with respect to the
equiv) as a source of cyanide.
concentration of the catalyst (Figure 5).
Next we extended the study for its applicability in one pot
three component reaction using catalyst
4 with 4-methyl
80
70
60
50
40
30
20
10
0
benzaldehyde, benzyl amine as model substrates and KCN as a
source of cyanide to examine its effect under this optimized
condition, it results in good yield (90%) with loss of
enantioselectivity (55%). This is possibly due to the rapid
release of HCN, thereby increasing the rate of the non-
enantioselective background reaction. We also tried with
ketimine substrate derived from acetophenone and benzyl
amine using catalyst
4 under the optimized condition, we
found that the reaction is relatively sluggish and gave low yield
because of the low reactivity of ketone derived substrates.4b
0
10
20
30
40
50
60
[Catalyst] x 104
M
Kinetic Studies
In order to understand the mechanism of hydrocyanation of
Figure 5: Plot of catalyst 4
concentration versus kobs at -20 oC, [4-
methyl N- benzylimine] = 0.06M, [KCN] = 0.09M.
imine, kinetic experiments were done using catalyst
4 with 4-
methyl N-benzyl benzylimine as a model substrate and KCN as
source of cyanide. During the kinetic run, the plot for the
product formation with time was found to be increasing
linearly in the initial period and saturation point was obtained
during the later stage of the reaction9a (Figure 4). Based on
this observation, the initial rate constants kobs were
determined by the amount of product formed with respect to
time.
Effect of substrate concentration on rate of the reaction
To study the influence of substrate concentration on reaction
rate, kinetic experiments were carried out at different initial
concentration of benzylimine ranging from (0.03 M–0.08M) by
keeping all parameter constant from which the rate was
calculated and the plot of rate constant (kobs) versus the
concentration of substrate (d log kobs/d log[substrate] ~1)
showed the first order dependence of the reaction on the
substrate concentration (Figure 6).
100
80
60
80
70
60
50
40
30
20
10
0
Yield
ee
40
20
0
0
200
400
600
800
Time (min)
Figure 4: Time dependent plot of the formation of α-
aminonitrile at -20 oC, [catalyst] = 0.003M, [benzylimine] =
0.06M, [KCN] = 0.09M.
0
10
20
30
40
50
60
70
80
[Substrate] x 103 M
Effect of catalyst concentration on rate of the reaction
o
Figure 6: Plot of substrate concentration versus kobs at -20 C,
[catalyst] = 0.003M, [KCN] = 0.09M.
To find out the dependence of catalyst concentration on the
reaction rate, we have carried out Strecker reaction of 4-
methyl N-benzylimine with different concentration of the
Effect of cyanide concentration on rate of the reaction
To evaluate the effect of concentration of the KCN (0.01M -
0.15M) on the rate of Strecker reaction of the 4-methyl N-
benzyl benzylimine were studied, under similar condition
(catalyst [0.003M] and benzylimine [0.06M]) which also
indicates the first order dependence (d log kobs/d log[KCN] ~1)
in terms of the concentration of KCN (Figure 7). Overall the
catalyst
4 [0.001 M-0.0057 M] at constant concentration of
benzylimine [0.06M] and KCN [0.09M]. From the kinetic data a
linear plot of formation of product, α-aminonitrile (kobs) versus
log[catalyst] with unit slopes (d log kobs/d log[catalyst] ~1) was
obtained which passes through the origin, indicating that the
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kinetic data revealed a first order dependence of rate on KCN,
substrate and catalyst 4.
Journal Name
O
KCN
+
H2O
V
R
N
R
N
HCN
90
80
70
60
50
40
30
20
10
0
Catalytic
Cycle
O
O
V
V
NC
R
N
0
20
40
60
80
100
120
140
160
[KCN] x 103
M
CN
R
N
Figure 7: Plot of KCN versus Kobs at -20 oC, [catalyst 4] =
0.003M, [4-methyl N-benzylimine] = 0.06M.
H
Scheme 2: Probable catalytic cycle for asymmetric Strecker reaction
To understand the mechanism a series of experiments were
carried out. We have already disclosed the role of trigol (ether
linkage) which helps in attracting alkali metals and hence
activate the cyanide source, KCN for the cyanation reaction.10
In order to assess the reuse of chiral macrocyclic dinuclear V(V)
salen complex 4, 2-MeO substituted imine (Table 2, entry 11)
With this backdrop,
a probable catalytic cycle for the
was used for the catalytic runs. Consequently, after the first
catalytic run, the catalyst was retrieved quantitatively by
precipitating the catalyst by the addition of hexane. The
recovered catalyst was then washed repeatedly with hexane,
dried and reused for further catalytic runs. The recovered
catalyst was reused five times with no loss in their
performance (Figure 9) which indicates that there is no
structural changes during the catalytic run as well as during
post-catalytic work-up unit operation.
enantioselective Strecker reaction is shown in Scheme 2. In the
catalytic cycle, the imine was polarized by the weak interaction
through its lone pair of electrons with metal centre of the
catalyst
4
and it was also observed in the 51V NMR by the
downfield shift (Figure 8). To this intermediate A, upon
addition of the cyanide source, KCN there was a significant
downfield shift which in terms confirm the interaction with the
catalyst and the generated cyanide ion attacks the polarized
carbon of imines (intermediate B), resulting in formation of the
product and the catalyst was resumed back almost to its
original ppm which indicates the catalyst is free to takes part in
another catalytic cycle. Based on the kinetics data and from
the NMR studies, a probable mechanism is proposed here
(Scheme 2).
Figure 9: Recycling data for enantioselective Strecker reaction
using
N-(2-methoxybenzylidene)-1,1-diphenylmethanamine
and KCN at -20 oC.
Conclusions
Figure 8:
51V NMR in CDCl3 for (a) Catalyst (b) Catalyst and imine (c)
reaction mixture containing catalyst, imine and KCN (d) after the
completion of reaction.
In conclusion chiral macrocyclic V(V) dimeric salen complex
demonstrated the effectiveness in asymmetric Strecker
protocol for various aldimines with KCN in presence of water
6 | J. Name., 2012, 00, 1-3
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as additive at -20 oC in toluene with good yield and
enantioselectivity of α-aminonitriles. The catalyst worked well
with both organic and inorganic cyanide sources. The chiral
macrocyclic V(V) dimeric salen complex used in the present
study can be easily separated from the reaction system and re-
used effectively. Based on the kinetic and NMR studies a
probable catalytic cycle was proposed for the asymmetric
Strecker reaction.
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Synthesis of complex 2-5
The chiral macrocyclic dimeric and monomeric V(V) salen
complexes 2-5 were synthesized by our reported procedure.10
Typical experimental procedure for addition of cyanide to N-
benzylimines
1999, 1, 157; (p) S. Saravanan, A. Sadhukhan, N. H. Khan, R. I.
The chiral V(V) dinuclear salen complex (5 mol%) was dissolved in
toluene11 (1 ml) and the solution was cooled to -20 oC under N2
atmosphere. To the cooled solution N-benzylimine (0.2 mmol) was
Kureshy, S. H. R. Abdi, H. C. Bajaj, J. Org. Chem. 2012, 77, 4375;
(q) A. Sadhukhan, S. Saravanan, N. H. Khan, R. I. Kureshy, S. H.
R. Abdi, H. C. Bajaj, J. Org. Chem. 2012, 77, 7076; (r) J. Martens,
added which was followed by the addition of KCN (1.5 equiv) slowly
over 30 min with stirring. To this stirred solution, H2O (20 µl) was
added and an over a period of 10 min. The reaction was monitored
on TLC using hexane/ethyl acetate (90/10) as eluent. Then
saturated NH4Cl aqueous solution was added and the mixture was
extracted with dichloromethane. The extracts were combined,
dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure. The product was purified by flash column
chromatography on silica gel (eluted with hexane/ethyl acetate =
90:10). The purified products were characterized by 1H NMR and
were in agreement with the reported values.4, 8u
ChemCatChem 2010,
Kureshy, S. H. R. Abdi, H. C. Bajaj, ACS Catal., 2013,
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2
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(12),
3
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Graphical Abstract
Enantioselective Strecker reaction of aldimines using potassium cyanide catalyzed by
recyclable macrocyclic V(V) salen complex
S. Saravanan,a, b Noor-ul H. Khan,* a, b Ajay Jakhar,a,b Immamudin Ansari,a,b Rukhsana I.
Kureshy,a, b Sayed H. R. Abdi, a, b Gaurav Kumara, b