Small molecule as a chiral organocatalyst for asymmetric strecker reaction

Article abstract of DOI:10.1021/cs400742d

A simple and novel chiral amide-based organocatalyst 6 was synthesized from readily available starting materials for the asymmetric Strecker reaction. A variety of N-benzhydryl- and N-tosyl-substituted imines were found to be suitable substrates with i-Pr

Full text of DOI:10.1021/cs400742d

Research Article
pubs.acs.org/acscatalysis
Small Molecule as a Chiral Organocatalyst for Asymmetric Strecker
Reaction
S. Saravanan,†,‡ Noor-ul H. Khan,*,†,‡ Rukhsana I. Kureshy,†,‡ Sayed H. R. Abdi,†,‡ and Hari C. Bajaj†,‡
‡
†Discipline of Inorganic Materials and Catalysis and Academy of Scientific and Industrial Research, Central Salt and Marine
Chemicals Research Institute (CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar-364 021,
Gujarat, India
S
* Supporting Information
ABSTRACT: A simple and novel chiral amide-based organocatalyst 6 was
synthesized from readily available starting materials for the asymmetric Strecker
reaction. A variety of N-benzhydryl- and N-tosyl-substituted imines were found to be
suitable substrates with i-PrOH as an additive in the presence of chiral organocatalyst
6 at 0 °C with ethylcyanoformate as a source of cyanide for the synthesis of chiral α-
amino nitriles. High yield (up to 91%) with excellent enantioselectivity (ee up to 99%
of product) were achieved in 24−30 h in the case of both N-benzhydryl- and N-tosyl-
substituted imines. To understand the mechanism of the catalytic Strecker reaction,
NMR studies and kinetic investigations were carried out with different concentrations
of the catalyst 6, ethylcyanoformate, and substrate. It was found that the asymmetric
Strecker reaction was first-order with respect to the concentration of the catalyst,
EtOCOCN, and saturation kinetics in substrate. An appropriate stereochemical model for the enantioselective Strecker reaction
is proposed. We further extend our study, using chiral α-amino nitriles [2-(benzhydrylamino)-2-(pyridin-3-yl)acetonitrile] for the
synthesis of chiral amino amide and hydantoin in high yield with high enantioselectivity.
KEYWORDS: Strecker reaction, organocatalyst, aldimines, enantioselective, amino amides
organocatalysts with the requisite stereogenic centers and
ability to act as a hydrogen bond donor are efficient for the
catalysis of hydrocyanation of imines in an enantioselective
pathway. Thus, the designing of a simple (in terms of
preparation) and highly effective chiral organocatalyst would
be a major undertaking.
Recently, the chiral sulfinyl motif (R−S(O)−) has been
shown to hold great promise as an important functional group
for asymmetric synthesis because of its capability to transfer the
chirality to a wide range of centers.7 Despite the focused
interest in the sulfinyl motif, the development of chiral
sulfinamide as a chiral organocatalyst is still in its infancy,
and furthermore, its application in the asymmetric Strecker
reaction is scarce. Being intrigued by this motif, we
conceptualized a design of an organocatalyst in which two
different chiral moieties are appended with a spacer (Figure 1).
Hypothetically, this design should provide reliable weak acidic
sites with steric features and thereby be capable of interacting
with the substrates in a stereogenic pathway. To our delight,
INTRODUCTION
■
A standing area of interest in modern organic synthesis is to
prepare optically active compounds which are often observed as
fundamental building blocks for numerous applications. Chiral
α-amino acids and their derivatives are a class of compounds
that find use in a broad spectrum of applications, including
synthesis,1 catalysis,2 and enzymology.3 Among the diverse
approaches, the asymmetric Strecker reaction is one of the most
prominent, direct, and effective method for the synthesis of α-
amino acids via hydrolysis of α-amino nitriles (Strecker
product).4 The state-of-the-art in the synthesis of chiral α-
amino nitriles largely relies on both metal5 and organo
catalysts.6 Various recent and past disclosures indicate that
the organocatalyst-based protocols are preferred to avoid metal
contamination; consequently, they have received a great deal of
attention. Impressive organocatalytic systems such as Lipton’s
cyclic dipeptide, Corey’s bicylic guanidine, Jacobsen’s ureas and
thioureas, Feng’s N-oxides and bisformamides, and various
Brønsted acids, carbohydrates, ammonium salts, amino acids,
alkaloids, and phase transfer catalysts have been developed for
this reaction.6 Although the ground-breaking advances in the
organocatalytic Strecker reaction are gratifying , there is still
limited use of existing methodologies exemplifying drawbacks,
such as the complex nature and multistep synthesis of the
catalyst, the need for a very low temperature, and the requisite
use of hazardous cyanide sources such as HCN, TMSCN,
Bu3SnCN, NaCN, and KCN. Mechanistically, a close
examination of the preceding works has revealed that
Figure 1. Design of the small molecule as a chiral organocatalyst.
Received: August 29, 2013
Revised: October 19, 2013
Published: October 22, 2013
© 2013 American Chemical Society
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Scheme 1. Synthesis of Catalyst 1
a
Table 1. Asymmetric Cyanation of Aldimine Catalyzed by Various Chiral Organocatalysts
a
Enantioselective Strecker reaction of substrate (0.10 mmol) was carried out with catalysts 1−12 (5 mol %) using TMSCN (0.15 mmol) as the
b
c
source of cyanide. Isolated yield. ee’s were determined by chiral HPLC using an AD-H column.
this new chiral organocatalyst is small and simple, easy to
synthesize in two steps, and robust. The notable features of this
system include a small molecule that can induce high
enantioselectivities (up to 99%) in both N-benzhydryl- and
N-tosyl-substituted imines under affordable reaction conditions
such as catalyst loading (5 mol %) and temperature (0 °C to
RT). Moreover, it is compatible to work efficiently with safer
cyanide sources such as ethylcyanoformate.
First, the commercial (S)-1-phenylethanamine was converted
into the 2-chloro-N-(1-phenylethyl)acetamide 1′, which on
further treatment with potassium carbonate and (S)-1-phenyl-
ethanamine was refluxed in dry ethanol, resulting in bifunc-
tional catalyst 1.8 Incidentally, other bases, such as NaH and
TEA, do not give the desirable products in quantitative yields.
Notably, catalyst 1 could easily be synthesized and fully
characterized. With the successful synthesis of the catalyst, we
started investigating the catalytic activity of 1 for the
hydrocyanation of heterocylic derived N-benzhydryl imine as
the benchmark reaction. It was found that a good yield of 62%
with low enantioselectivity (12% ee) was obtained by
employing 5 mol % of catalyst 1 (Table 1, entry 1). Although
the result was inferior, it encouraged us to study further the
structural modification of the catalyst, which incorporated the
alteration of the spacer and requisite modification of the chiral
scaffolds. In this regard, we attempted to change the spacer,
which led to catalyst 2 (Table 1, entry 2) and which clearly
discloses the necessity of a spacer containing the carbonyl
moiety to form an amide scaffold. On the other hand, to check
RESULTS AND DISCUSSION
■
When designing the chiral organocatalyst, at the outset, we
selected a starting material that is inexpensive and readily
available, (S)-1-phenylethanamine, which, by introduction of a
spacer (−COCH2−) allows the formation of an amide−amine
containing bifunctional catalyst 1. This spacer offers several
possible structural modifications to be explored for the
development and fine-tuning of a chiral organocatalyst. This
type of bifunctional catalyst was synthesized according to the
following strategy (Scheme 1).
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the steric influences of a chiral amine, catalyst 3 was
synthesized. It resulted in enhanced enantioselectivity, but it
showed a deleterious effect on the yield (Table 1, entry 3).
Moreover, it is understood from the body of literature available
that the acidity and steric features of the organocatalyst
influence the outcome of the reaction, in terms of both rate and
enantioselectivity.9
Table 2. Optimization Studies Using Chiral Organocatalyst 6
for the Asymmetric Strecker Reaction
a
On the basis of the precedents, we decided to assay the
organocatalyst with two different amide moieties; thereby,
catalyst 4 with a chiral amine and achiral amide appended with
the spacer was synthesized. To our delight, the yield was
improved (Table 1, entry 4). The enantioselectivity observed
was moderate, revealing the necessity of two chiral centers
bearing the amide groups to ensure this chiral sulfinamide motif
was introduced to address the enantioinduction issue. In
addition, it is well-known that the chiral sulfinamide motif
bearing a −SO− group interacts with the silicon; thereby, it
facilitates liberation of HCN after the weak interaction with
trimethylsilylcyanide.10
The organocatalyst 6 surrogate, the putative chiral urea type
catalyst, was used for the Strecker reaction.6e A promising result
(71% yield) with increased enantioselectivity (68%) was
obtained using the chiral organocatalyst 6 (5 mol %) in the
presence of toluene as the solvent. Switching over the chiral
centers initiated the mismatching chirality in the catalysts 5 and
7 and gave products with lower ee’s, 54% and 53%, respectively
(Table 1, entries 5 and 7). The organocatalyst 8 with matching
chiral centers (R, R) gave similar results with an inversion of the
configuration in the product (Table 1, entry 8). Replacement of
chiral 1-phenylethanamine with nonchiral 1-phenylethanamine
led to a deteriorated enantiomeric excess, 21% with 70% yield.
This unambigously indicates the need for chiral 1-phenylethan-
amine to catalyze the asymmetric Strecker reaction.
b
c
entry catalyst (mol %)
solvent
time (h) yield (%)
ee (%)
1
2
3
4
5
5
toluene
toluene
toluene
THF
8
8
8
8
8
8
8
71
88
59
70
81
79
82
68
55
61
63
54
51
59
10
2.5
5
5
5
5
CH2Cl2
CHCl3
toluene
6
d
7
a
Enantioselective Strecker reaction of substrate (0.10 mmol) was
carried out with catalyst 6 using TMSCN (0.15 mmol) as the source of
cyanide. Isolated yield. ee’s were determined by chiral HPLC using
b
c
d
an AD-H column. Using 1.5 equiv of IPA as an additive.
sequence of addition and the cyanide sources (Figure 2).
Although changing the sequence of addition, that is, instead of
To evaluate further the activity of the catalyst, we decided to
increase the steric factors of the catalyst by replacing the (S)-1-
phenylethanamine of catalyst 6 with the bulkier (S)-1-
(napthalen-2-yl)ethanamine 9 (68% yield, 51% ee), (S)-1-
phenylpropanamine 10 (71% yield, 62% ee), and (S)-N-benzyl-
1-phenylpropanamine 11 (59% yield, 21% ee) and the aliphatic
(S)-3,3-dimethylbutan-2-amine 12 (62% yield, 42% ee). These
fortuitous results clearly indicate that the chiral organocatalyst 6
with a flexible nature and conformationally appropriate
functional groups with the requisite placement in space are
key elements responsible for the potential activity of the
catalyst in the asymmetric Strecker reaction.
Having identified 6 as the catalyst of choice, accordingly,
optimization of the reaction conditions was investigated (Table
2) by varying the catalyst loading. The catalyst loading of 5 mol
% used in the preceding experiments was found to be optimum
because upon increasing the catalyst loading from 5 mol % to
10 mol %, the yield of the desired product was increased to
88% witha drop in ee of 55% (Table 2, entry 2). On the other
hand, decreasing the catalyst loading (2.5 mol %) affects both
the yield (59%) and ee (61%). Solvent screening showed that
toluene was the best solvent (Table 2, entry 1). Other solvents,
such as THF, CH2Cl2, and CHCl3, gave lower enantioselectiv-
ities (Table 2, entries 4−6). Moreover, an attempt was made by
using IPA as an additive to check its effect in the asymmetric
Strecker reaction using TMSCN as a source of cyanide, and
there was no significant enhancement in the reactivity, but the
enantioselectivity was reduced (Table 2, entry 7).
Figure 2. Screening of cyanide sources for the asymmetric Strecker
reaction catalyzed by chiral organocatalyst 6a.
adding the imine to catalyst 6 followed by cyanide source
(catalyst 6 ← imine ← cyanide source), we first added the
cyanide source to the catalyst 6, and then the imine was added
(catalyst 6 ← cyanide source ← imine) which resulted in a
drastic change in the enantioselectivity with all three cyanide
sources (Figure 2e). This demonstrated that there is some
interaction of the cyanide sources with catalyst 6. The imine
remains uninteracted with the catalyst, which leads to the
achiral background reaction. To confirm this, 1H NMR spectra
were recorded, which showed that the cyanide source was
interacting with the −S(O)−NH− and affected the substrate−
These optimization studies did not result in the expected
change in the enantioselectivity, so we attempted to modify the
catalyst vis-a-vis interactions (for details please see the
̀
Mechanism section, Figure 8). While using acetone cyanohy-
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drin as the source of cyanide, no significant change in the yield
and ee was observed in 8 h, but gratifyingly, while using
ethylcyanoformate (EtOCOCN), the inexpensive and safer
cyanide source, we could observe a vivid change in
enantioselectivity (87%) in 12 h. Furthermore, for the sake of
clarity, optimization of the enantioselective Strecker reaction
using ethylcyanoformate was also carried out (see the
Supporting Information)
Table 4. Scope of N-Benzhydryl-Substituted Imine
Substrates for the Asymmetric Cyanation of Aldimines
a
Catalyzed by Chiral Organocatalyst 6
The role of additives in the activity and enantioselectivity of
the asymmetric Strecker reaction is well documented; therefore,
we chose different protic solvents such as MeOH, EtOH, and i-
PrOH (Table 3, entries 1−3) as a proton source. Evidently, the
b
c
entry
R
time (h)
yield (%)
ee (%)
d
1
2
C6H5 (2a)
24
24
24
24
28
28
24
30
30
30
24
24
30
30
30
88
90
88
88
86
85
87
84
82
82
82
95 (R)
84
4-Me-C6H4 (2b)
2-Me-C6H4 (2c)
3-Me-C6H4 (2d)
4-Br-C6H4 (2e)
2-Br-C6H4 (2f)
3
99
Table 3. Asymmetric Strecker Reaction Catalyzed by Chiral
a
4
92
Organocatalyst 6
5
99
6
97
7
4-MeO-C6H4 (2g)
4-NO2-C6H4 (2h)
2-NO2-C6H4 (2i)
3-NO2-C6H4 (2j)
2-F-C6H4 (2k)
99
8
93
9
99
10
11
12
13
14
15
94
82
b
c
entry
additive
temp (°C)
time (h)
yield (%)
ee (%)
e
e
3-pyridinyl (2l)
87 (89)
97 (96)
94
1
2
3
4
5
MeOH
EtOH
RT
RT
RT
0
12
12
12
24
24
87
84
89
87
84
81
82
88
97
95
tert-butyl (2m)
81
84
79
(CH3CH2)2CH (2n)
(CH3)2CCH (2o)
81
i-PrOH
i-PrOH
i-PrOH
82
a
Enantioselective Strecker reaction of substrate (0.10 mmol) was
carried out with catalyst 6 using EtOCOCN (0.15 mmol) as the
source of cyanide. Isolated yield. ee’s were determined by chiral
−10
a
b
c
The enantioselective Strecker reaction of the substrate (0.10 mmol)
was carried out with catalyst 6 using TMSCN (0.15 mmol) as the
d
HPLC using an AD-H and OD-H column. Absolute configurations
b
c
were assigned in comparison with a literature report6p and optical
source of cyanide. Isolated yield. ee’s were determined by chiral
e
HPLC using an AD-H column.
rotation. Reaction conducted at 1 g scale under optimized condition.
Table 5. Scope of N-Tosyl-Substituted Imine Substrates for
the Asymmetric Cyanation of Aldimines Catalyzed by Chiral
Organocatalyst 6
use of i-PrOH significantly improves the yield (89%) without
affecting the enantioselectivity of the desired product (Table 3,
entry 3). Because the enantioselective reactions are highly
dependent on the temperature, we next investigated the
Strecker reaction under different temperatures (RT, 0 °C and
−10 °C). The best result was found at 0 °C (Table 3, entry 4).
Further lowering the temperature is not beneficial in terms of
yield and ee (Table 3, entry 5).
a
b
c
entry
R
time (h)
yield (%)
ee (%)
d
1
2
C6H5 (4a)
30
30
30
30
30
30
30
30
30
30
88
85
83
81
85
87
82
86
83
80
91 (R)
99
With the optimal conditions, the scope of the organocatalyst
6 was explored; the results are summarized in Tables 4 and 5.
Interestingly, in the case of N-benzhydryl-substituted imine,
which includes electron-donating and -withdrawing groups at
ortho, meta, and para positions gave good to excellent
enantioselectivity (ee, 81−99%, Table 4). Notably, aliphatic
substrates were also found to be suitable for the asymmetric
Strecker reaction using catalyst 6 (Table 4, entries 13−15).
Moreover, when attempts were made to conduct the
asymmetric Strecker reaction with the bulkier N-tosyl-
substituted imine having electron-donating and -withdrawing
substituents at the ortho, meta, and para positions, excellent
reactivity and enantioselectivity (Table 5) resulted. It indicates
that the simple chiral organocatalyst 6 is capable of catalyzing a
wide range of substrates to give an enantioselective Strecker
product. The reaction was carried out at the 1 g scale using
optimized reaction conditions, and it was found that the
product formed in excellent yield with high enantioinduction
(Table 4, entry 12). Conclusively, the orgnaocatalyst 6 was able
to catalyze an asymmetric Strecker reaction using a wide range
of substrates, including N-benzhydryl- and N-tosyl-substituted
4-MeO-C6H4 (4b)
2-MeO-C6H4 (4c)
2-Me-C6H4 (4d)
2-F-C6H4 (4e)
2-naphthyl (4f)
4-Br-C6H4 (4g)
4-Me-C6H4 (4h)
3-Me-C6H4 (4i)
3-NO2-C6H4 (4j)
3
99
4
99
5
98
6
91
7
90
8
99
9
91
10
99
a
Enantioselective Strecker reaction of substrate (0.10 mmol) was
carried out with catalyst 6 using EtOCOCN (0.15 mmol) as the
b
c
source of cyanide. Isolated yield. ee’s were determined by chiral
d
HPLC using an AD-H and OD-H column. Absolute configurations
were assigned in comparison with a literature report5y and optical
rotation.
aldimines with excellent enantioselectivity for the desired
product.
Applications. The present catalytic protocol using chiral
organocatalyst 6 was successfully extended to the synthesis of
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Scheme 2. Application of α-Amino Nitrile for the Synthesis of Chiral Amino Amides and Hydantoin
bioactive products, such as chiral amino amides and hydantoins.
This compound was obtained in fewer steps with high yield and
enantioselectivity (Scheme 2). Amino amides and hydantoins
have been of considerable interest because they frequently
contain a significant structural moiety found in various natural
products, biologically active, and therapeutically useful
compounds. Moreover, hydantoins substituted with hetero-
cycles have played a key role in medicinal chemistry because
their derivatives are associated with biological properties such
as anticovascular, antidepressant, and antiviral activities.11
Kinetic Studies. To understand the mechanism of the
hydrocyanation of an imine, kinetic experiments were
performed with 1,1-diphenyl-N-(pyridin-3-ylmethylene)-
methanamine, 2j, as a model substrate and as a function of
the concentration of catalyst 6 and substrate and using
EtOCOCN as the source of cyanide. In all the kinetic runs,
the plots of formation of the aminonitrile with time was found
to be linear in the beginning of the reaction and attained
saturation near its completion (Figure 3). On the basis of this
observation, the initial rate constants, kobs, were determined by
directly estimating the amount of α-aminonitrile formed up to
the completion of the reaction.
Dependence of the Rate on the Catalyst Concen-
tration. The Strecker reaction of imine 2j was studied by
conducting the kinetic experiments at different concentrations
of catalyst 6 (0.001−0.006 M) at a constant concentration of
pyrdine-derived N-benzhydrylimine (0.06 M) and EtOCOCN
(0.09 M). From the kinetic data, a linear plot of kobs of the α-
aminonitrile formation versus log[catalyst] with unit slopes (d
log kobs/d log[catalyst] ∼ 1) was obtained, which passes
through the origin, indicating that the Strecker reaction is of
first-order with respect to the concentration of the catalyst
(Figure 4).
Figure 4. Plot of catalyst 6 concentration versus kobs at 0 °C, [imine] =
0.06 M, [EtOCOCN] = 0.09 M.
Dependence of the Rate on Substrate Concentration.
Kinetic experiments were carried out at different initial
concentrations of imine 2j ranging from 0.03 to 0.08 M by
keeping the concentration of the other reactants and physical
conditions constant, from which the rate was calculated and the
plot of the rate constant (kobs) versus the concentration of
Figure 3. Time-dependent plot of the formation of α-aminonitrile.
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substrate (d log kobs/d log[substrate] ∼ 1) was created, which
showed the saturation kinetics with respect to the substrate
concentration (Figure 5).
out kinetic studies of the hydrocyanation of imine and found
that the transformation obeys Michaelis−Menten kinetics, with
a first-order dependence on catalyst and cyanide source,
EtOCOCN, and saturation kinetics with respect to imine.
This result is similar to Jacobsen’s thiourea system6e and clearly
indicates that the imine catalyst binds through a bridge
structure through hydrogen bonding. Moreover, a series of
experiments and studies were carried out to understand the
mechanism of the asymmetric Strecker reaction with the
present simple chiral catalyst. At the outset, we tried to explore
by conducting a series of NMR experiments in which we
looked for the interaction of the catalyst with the substrate.
From this, we understood that the N-H’s of both the carbonyl
and sulfonyl moieties were shifted upfield, clearly indicating
that the imine was hooked up with catalyst 6 in a stereoselective
manner (Figure 7 a,b). This unusual shift is mechanistically
Figure 5. Plot of substrate concentration versus kobs at 0 °C, [catalyst]
= 0.003 M, [EtOCOCN] = 0.09 M.
Dependence of the Rate on EtOCOCN Concentration.
The effect of the concentration of the EtOCOCN over the
range of 0.01−0.15 M on the rate of the Strecker reaction of the
imine 2j were studied, keeping the catalyst (0.003 M) and
imine (0.06 M) concentrations as constant, which also indicates
the first-order dependence (d log kobs/d log[EtOCOCN] ∼ 1)
in terms of the concentration of EtOCOCN (Figure 6).
1
Figure 7. H NMR spectra recorded in CDCl3: (a) spectra represent
sulfonyl N-H (3.733 ppm) and carbonyl N-H (6.829 ppm) of catalyst
6; (b) catalyst 6 after interaction with imine; (c) catalyst 6 after
interaction with imine and EtOCOCN.
akin to Jacobsen’s6e model, in which an imine shifts back and
forth between amide and sulfonamide protons. This was further
confirmed by the observation of a downfield shift of the imine
proton after interaction with the catalyst (Figure 8). In
addition, after the addition of EtOCOCN to the catalyst−
imine equilibrating structure, the N-H of both the carbonyl and
sulfonyl moieties shifted downfield (Figure 7c). Moreover,
when catalyst 6 was mixed with the cyanide source EtOCOCN,
the N-H of the sulfinamide was shifted toward the downfield
Figure 6. Plot of EtOCOCN versus kobs at 0 °C, [catalyst 6] = 0.003
M, [imine] = 0.06 M.
Overall, the kinetic data revealed a first-order dependence of
the rate on EtOCOCN, catalyst 6, and saturation kinetics with
respect to the imine. On the basis of these data and conclusions
drawn from the previous reports,6e a probable stereochemical
model is proposed here (Figure 10).
Mechanism. To develop a useful understanding to ascertain
the precise role of catalyst 6 in the Strecker reaction, we carried
1
Figure 8. H NMR spectra recorded in CDCl3:imine (−CHN−)
after interaction with the catalyst.
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region (Figure 9). That verifies that the EtOCOCN finds its
suitable place during the catalytic process and releases the
Figure 11. Recyclability of catalyst 6.
CONCLUSION
■
This work has uncovered a new small and simple class of chiral
amide-based organocatalyst that is highly efficient for the
catalysis of the asymmetric Strecker reaction of N-benzhydryl-
and N-tosyl-substituted imines using a safer cyanide source,
EtOCOCN. Excellent enantioselectivities and good yields were
achieved with a wide range of substrates. The kinetic
investigations show first-order dependence on the concen-
trations of catalyst 6, ethylcyanoformate, and saturation kinetics
with respect to substrate. An appropriate stereoselection model
for the asymmetric Strecker reaction is proposed. We further
extend our study to the synthesis of bioactive compounds such
as chiral amino amide and hydantoin in good yield and
enantioselectivity.
Figure 9. 1H NMR spectra recorded in CDCl3:catalyst 6 after
interaction with the cyanide source, EtOCOCN.
cyanide in a stereochemical pathway. With these observations
we have proposed a stereochemical model for the enantiose-
lective Strecker reaction (Figure 10), where EtOCOCN is
placed on the Si face of the substrate to give preferentially the R
form of the product, which is line with the experimental results.
EXPERIMENTAL SECTION
■
General. All the solvents were dried using standard
procedures, distilled, and stored under nitrogen. NMR spectra
were obtained with a Bruker F113 V spectrometer (200 and
500 MHz) and are referenced internally to trimethylsilane
(TMS). Enantiomeric excess (ee) values were determined by
HPLC (Shimadzu SCL-10AVP) using Daicel Chiralpak AD-H
and OD-H chiral columns with 2-propanol/hexanes eluent. For
the product purification, flash chromatography was performed
using 230−400 mesh silica gel.
Typical Experimental Procedure for the Enantiose-
lective Strecker Reaction of N-Substituted Imines Using
Catalyst 6. In an oven dried reaction vial, catalyst 6 (5 mol %)
and imine (0.2 mmol) were dissolved in dry toluene12 (1 mL),
and the resulting solution was stirred for 2 h at RT. Then the
solution was cooled to 0 °C, and EtOCOCN (0.3 mmol) was
added slowly over a period of 30 min, followed by the very slow
addition of i-PrOH (20 μL). The reaction was monitored by
TLC using hexane/ethyl acetate (90/10) as the eluent. After
the reaction was complete, the solvent was removed on a
rotavapor, and the product was purified by flash column
chromatography on silica gel (eluted with hexane/ethyl acetate
Figure 10. The proposed stereoselection model for the hydro-
cyanation of imines.
Recyclability of Catalyst 6. In general, homogeneous
catalysts are not recycled because of their inherent problem of
separation in the postcatalysis workup. However, it is prudent
to attempt catalyst recyclability to know its stability under the
reaction conditions.12 In addition, the increased turnover
number of the catalyst as a result of its successful reuse
would offset the overall catalyst cost and make the protocol
suitable for practical application. Therefore, reuse experiments
were conducted using N-benzhydrylimine 2j as a representative
substrate with catalyst 6 (5 mol %) and ethyl cyanoformate as
the source of cyanide at 0 °C using toluene as the solvent in the
presence of i-PrOH. After the catalytic run, the amount of the
solvent was reduced, and the organocatalyst 6 was precipitated
by addition of an excess amount of n-hexane. The precipitate
was then passed through a silica gel column to get the pure
catalyst, which was then dried in vacuum, and used for the
subsequent catalytic run. The recovered catalyst worked very
well for the asymmetric Strecker reaction without any loss of its
activity and enantioselectivity (Figure 11).
1
= 90:10). The purified products were characterized by H
NMR, which was in agreement with the reported values.6p
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, H NMR, 13C NMR spectra, and
HPLC chromatograms. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: +91-0278-2566970. E-mail: khan251293@yahoo.in.
■
2879
dx.doi.org/10.1021/cs400742d | ACS Catal. 2013, 3, 2873−2880

ACS Catalysis
Research Article
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S. Saravanan and N. H. Khan are thankful to CSIR-SRF
fellowship, DST, and CSIR Network Project on Catalysis for
financial assistance. S.S. is thankful to AcSIR and also thankful
to the Analytical Discipline and Centralized Instrument Facility
of CSMCRI for providing instrumentation facilities.
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