Oxazoline-based organocatalyst for enantioselective strecker reactions: A protocol for the synthesis of levamisole

Article abstract of DOI:10.1002/chem.201302007

A chiral oxazoline-based or-ganocatalyst has been found to efficiently catalyze asymmetric Strecker reactions of various aromatic and aliphatic N-benzhydrylimines with trime-thylsilyl cyanide (TMSCN) as a cyanide source at -20°C to give α-aminoni-triles in high yield (96%) with excellent chiral induction (up to 98% ee). DFT calculations have been performed to rationalize the enantioselective formation of the product with the organo-catalyst in these reactions. The organo-catalyst has been characterized by single-crystal X-ray diffraction analysis, as well as by other analytical methods. This protocol has been extended to the synthesis of the pharmaceutically important drug molecule levamisole in high yield and with high enantioselectivity.

Full text of DOI:10.1002/chem.201302007

DOI: 10.1002/chem.201302007
Oxazoline-Based Organocatalyst for Enantioselective Strecker Reactions: A
Protocol for the Synthesis of Levamisole
Arghya Sadhukhan,[a] Debashis Sahu,[b, c] Bishwajit Ganguly,*[b, c] Noor-ul H. Khan,*[a, c]
Rukhsana I. Kureshy,[a, c] Sayed H. R. Abdi,[a, c] E. Suresh,[b, c] and Hari C. Bajaj[a, c]
Abstract: A chiral oxazoline-based or-
ganocatalyst has been found to effi-
ciently catalyze asymmetric Strecker
reactions of various aromatic and ali-
phatic N-benzhydrylimines with trime-
thylsilyl cyanide (TMSCN) as a cyanide
source at À208C to give a-aminoni-
triles in high yield (96%) with excel-
lent chiral induction (up to 98% ee).
DFT calculations have been performed
to rationalize the enantioselective for-
mation of the product with the organo-
catalyst in these reactions. The organo-
catalyst has been characterized by
single-crystal X-ray diffraction analysis,
as well as by other analytical methods.
This protocol has been extended to the
synthesis of the pharmaceutically
important drug molecule levamisole in
Keywords: aminonitriles · enantio-
selectivity · organocatalysis · oxazo-
line · Strecker reaction
high
yield
and
with
high
enantioselectivity.
Introduction
transfer catalysts.[18,19] Close inspection of previous reports
reveals that the activity of an organocatalyst mainly depends
on weakly acidic sites capable of forming hydrogen bonds
with the substrate, and at the same time weakly basic sites
are also required in order to activate the cyanide source.[19]
With this understanding, we designed an organocatalyst in
which an oxazoline ring is appended to a sulfonamide group
(Figure 1). Such a design should not only fulfill the require-
Chiral a-aminonitriles constitute a valuable class of com-
pounds[1–4] and can be synthesized by an elegant asymmetric
Strecker reaction.[5] Although in the last ten years both
metal-containing[6] and metal-free[7] asymmetric Strecker re-
actions have been accomplished, metal-free protocols are
desirable in the pharmaceutical industry in order to avoid
metal contamination in the final drug formulations. Lipton
et al.[8] in 1996 were the first to apply organocatalysis (a
chiral cyclic dipeptide) to the asymmetric Strecker reaction,
which was followed by various other organocatalysts, such
as bicyclic guanidine,[9] ureas and thioureas,[10] carbohy-
drates,[11] N-oxides,[12] bisformamides,[13] ammonium salts,[14]
Brønsted acids,[15] amino acids,[16] alkaloids,[17] and phase-
[a] A. Sadhukhan, Dr. N.-u. H. Khan, Dr. R. I. Kureshy,
Dr. S. H. R. Abdi, Dr. H. C. Bajaj
Figure 1. Structural features of the organocatalyst.
Discipline of Inorganic Materials and Catalysis
Central Salt & Marine Chemicals Research Institute
(CSIR-CSMCRI)
ment of acidic and basic sites, but also facilitate the con-
struction of analogues with varying steric features, which is
critical for practical application. Although oxazoline deriva-
tives have been used as ligands with metals for various
asymmetric transformations, they have been rarely used as
organocatalysts.[20] The design of the present catalyst also
allows flexibility in terms of creating chiral centers with
matched or mismatched stereogenicity, which may have a
bearing on the product enantioselectivity. As anticipated, all
of the catalysts with the present design were found to be
fairly active (product yield up to 93%) at a moderate reac-
tion temperature (À208C). However, the catalyst (S,S)-1j
gave a-aminonitriles with excellent enantioselectivity (up to
98% ee in some cases) with trimethylsilyl cyanide (TMSCN)
as the cyanide source. We also extended the present
G.B. Marg, Bhavnagar, 364002 (India)
E-mail: khan2512@yahoo.co.in
[b] D. Sahu, Dr. B. Ganguly, Dr. E. Suresh
Computation and Simulation Unit
(Analytical Discipline and Centralized Instrument Facility)
Central Salt & Marine Chemicals Research Institute
(CSIR-CSMCRI)
G.B. Marg, Bhavnagar, 364002 (India)
E-mail: ganguly@csmcri.org
[c] D. Sahu, Dr. B. Ganguly, Dr. N.-u. H. Khan, Dr. R. I. Kureshy,
Dr. S. H. R. Abdi, Dr. E. Suresh, Dr. H. C. Bajaj
Academy of Scientific and Innovative Research
Central Salt & Marine Chemicals Research Institute
(CSIR-CSMCRI)
Bhavnagar, 364002 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302007.
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FULL PAPER
protocol to the synthesis of the chiral drug molecule
levamisole.[21]
additive and a source of protons, and the results are given in
Scheme 2. It is evident from the results that all of the cata-
lysts, 1a–j, were highly efficient in catalyzing the Strecker
reaction with the model substrate; however, not all of the
catalysts showed good enantioselectivity. It can be seen
from the results that catalysts with matching chiral centres
gave products with higher ee values than their counterparts
with mismatched chiral centres (e.g., entries 1 and 3). How-
ever, steric factors seem to be more pronounced; for exam-
ple, catalyst 1 f bearing an isopropyl group (entry 6;
17% ee) was far less enantioselective than catalyst 1g
(entry 7; 29% ee) bearing a tert-butyl group at the same po-
sition on its amino acid motif. Among the catalysts synthe-
sized for the present study, organocatalyst (S,S)-1j bearing
two sterically demanding tert-butyl groups derived from
both the amino acid and amino alcohol precursors was
found to induce moderate enantioselectivity (72% ee) under
the catalyst screening reaction conditions.
With these initial results with organocatalyst (S,S)-1j, we
next worked on optimization of the reaction parameters in
order to improve the results, particularly the enantioselectiv-
ity, using N-benzhydrylimine as a model substrate and
TMSCN as the cyanide source at room temperature. The
role of additives in the asymmetric Strecker reaction is well
documented.[6] Therefore, we first explored the effect of dif-
ferent protic additives (mainly alcohols), specifically MeOH,
EtOH, and isopropyl alcohol (IPA; 2.0 equiv; Table 1, en-
Results and Discussion
The organocatalysts 1a–j were assembled by using chiral
amino acids (I) and amino alcohols as basic building blocks
according to Scheme 1. At first, various chiral amino acids
having variable steric features were allowed to react with
tosyl chloride. The resultant tosylated acids (II) were react-
ed with SOCl2 to obtain the respective acid chlorides, which
were directly reacted with various chiral amino alcohols to
obtain the substituted chiral alkanolamides (III) in quantita-
tive yields. Finally, oxazoline catalysts 1a–j were prepared
by cyclization of the corresponding amides III in the pres-
ence of a catalytic amount of 4-dimethylaminopyridine
(DMAP).[22] A single crystal of organocatalyst (S,S)-1j ob-
tained from dichloromethane/hexanes (1:2) was subjected to
X-ray structure analysis[23] (Scheme 1). Characterization
data are given in the Supporting Information, which proved
useful for understanding the structures of intermediates in-
volved in the Strecker reaction.
The catalysts 1a–j were screened for their efficacy in the
asymmetric Strecker reaction of N-benzhydrylimine (as a
test substrate) by using TMSCN as a cyanide source in THF
at room temperature (RT) in the presence of water as an
Scheme 1. Synthesis of catalysts and ORTEP diagram of oxazoline-based organocatalyst (S,S)-1j with atom numbering scheme (50% probability factor
for the thermal ellipsoids).
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B. Ganguly, N. H. Khan et al.
Scheme 2. Screening of catalysts.
tries 1–3) on this reaction. Evidently, the use of IPA signifi-
cantly improved the enantioselectivity (77% ee) of the prod-
uct a-aminonitrile without affecting its yield. We next opti-
mized the amount of IPA by keeping the other parameters
constant (Table 1, entries 3–5).
It was found that by lowering the IPA loading (1.0 equiv)
there was a decrease in the product ee and yield, whereas
with an increase in the amount of IPA (3.0 equiv) the reac-
tivity increased, but the enantioselectivity decreased. There-
fore, an additive loading of 2.0 equivalents was taken to be
optimal (Table 1, entry 3).
Further, it was found that lowering the temperature to
À208C had a beneficial effect on the product ee (92% com-
pared with 77% at RT) although a longer reaction time was
required (24 h compared with 12 h at RT). A further reduc-
tion in the temperature (À408C) did not have any positive
impact on the product ee and, moreover, the reaction
became very sluggish (36 h). Therefore, À208C was taken as
optimal for further studies.
Additionally, the catalyst loading of 5 mol%, as used in
the preceding experiments, was found to be optimal as it
was observed that upon decreasing the catalyst loading
(2.5 mol%) the product yield (75%) and ee (81%) dropped
significantly. On the other hand, with an increase in catalyst
loading (10 mol%), although the reaction was faster, there
was a marginal drop in ee (87%), while the product yield re-
mained the same (Table 2, entry 3).
To vary the solvent, CH2Cl2, CHCl3, and THF were used
to carry out the Strecker reaction under the above opti-
mized conditions (Table 2, entries 4–6). However, THF re-
mained the solvent of choice (Table 2, entry 1). Having es-
tablished the reaction parameters for the use of catalyst
(S,S)-1j in the asymmetric Strecker reaction with the reac-
tants N-benzhydrylimine and TMSCN at À208C, we next
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Organocatalyst for Strecker Reaction
FULL PAPER
Table 1. Effect of additives and temperature on asymmetric Strecker
reaction.[a]
Table 3. Scope of substrates catalyzed by catalyst (S,S)-1j.[a]
Entry
Additive
[equiv]
T
[8C]
t
Yield
[%][b]
ee
Entry
R
t
Yield
[%][b]
ee
[%][c]
[h]
[%][c]
G
[h]
1
2
3
4
5
6
7
8
MeOH (2.0)
EtOH (2.0)
IPA (2.0)
IPA (1.0)
IPA (3.0)
IPA (2.0)
IPA (2.0)
IPA (2.0)
RT
RT
RT
RT
RT
0
12
12
12
15
10
24
24
36
87
82
93
82
94
90
90
80
58
47
77
73
71
85
90
89
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph (2a)
24
24
24
24
24
20
20
24
24
24
24
27
24
24
24
24
24
24
24
90
90
93
89
78
90
93
90
96
94
85
90
90
91
94
90
93
88
91
90 (R)[d]
94
96
90
91
82
80
82
98
82
60
91
87
93
90
71
90
2-MeC6H4 (2b)
2-MeOC6H4 (2c)
4-MeC6H4 (2d)
2-FC6H4 (2e)
2-ClC6H4 (2 f)
2-BrC6H4 (2g)
2-O2NC6H4 (2h)
2-naphthyl (2i)
2-thioenyl (2j)
3-pyridinyl (2k)
PhCH2 (2l)
PhCH2CH (2m)
tert-butyl (2n)
isobutyl (2o)
hexyl (2p)
PhCH=CH (2q)
CH3CH=CH (2r)
Ph (2a)
À20
À40
[a] Enantioselective Strecker reaction of N-benzhydrylimine (0.25 mmol)
was carried out with catalyst (S,S)-1j in toluene by using TMSCN
(0.3 mmol) as a source of cyanide. [b] Yield of the isolated product.
[c] The ee values were determined by chiral HPLC by using an AD-H
column.
Table 2. Optimization of the appropriate catalyst loading (mol%) and
effect of solvent for the asymmetric Strecker reaction.[a]
92
90 (S)[e]
[a] Enantioselective Strecker reaction of the imine (0.25 mmol) was car-
ried out with catalyst (S,S)-1j by using TMSCN (0.3 mmol) as a source of
cyanide in the presence of IPA (2 equiv). [b] Yield of the isolated prod-
uct. [c] The ee values were determined by chiral HPLC by using AD-H
and OD-H columns. [d] Absolute configurations were assigned by com-
parison with literature reports[5] and on the basis of optical rotation.
[e] Reaction was carried out with the catalyst (R,R)-1j.
Entry
Catalyst loading
[mol%]
Solvent
t
Yield
[%][b]
ee
G
[h]
[%][c]
1
2
3
4
5
6
5
2.5
10
10
10
10
THF
THF
THF
CH2Cl2
CHCl3
toluene
24
24
24
12
12
36
90
75
88
93
90
40
90
81
87
67
68
61
(60%, Table 3, entry 11), possibly due to the additional
basic center that would also be involved in the activation of
HCN (generated in situ) and would trigger a parallel Streck-
er loop. Aliphatic substrates, including phenyl-substituted
alkyl substrates (Table 3, entries 12–16), also gave very good
product yields (90–94%) and ee values (71–93%). We also
checked the generality of the catalyst with enolizable imines
(Table 3, entries 17 and 18) and we achieved very good
product yields of up to 93% and ee values of up to 92%. Fi-
nally, we used the opposite configuration of the catalyst with
substrate 2a under similar reaction conditions and obtained
exactly the same results with opposite configuration of the
product. This gave us very good flexibility in terms of select-
ing the appropriate chirality of the catalyst for the required
product, which we demonstrated by the synthesis of the
powerful anthelmintic drug levamisole by using the present
protocol.
[a] Enantioselective Strecker reaction of N-benzhydrylimine (0.25 mmol)
was carried out with catalyst (S,S)-1j by using TMSCN as a source of cy-
anide in the presence of IPA (2 equiv). [b] Yield of the isolated product.
[c] The ee values were determined by chiral HPLC by using an AD-H
column.
extended this protocol to imine substrates bearing various
substituents on the phenyl group derived from the aldehyde
precursor (Table 3, entries 2–8).
In general, electron-donating substituents resulted in
better ee values in the product (90–96%; Table 3, entries 2–
4) than electron-withdrawing groups (80–82% ee; Table 3,
entries 6–8), with the exception of the fluoro-substituted
imine, with which 91% ee was obtained, albeit with lower
product yield (78%). The best ee value (98%) and yield
(96%) were obtained with the bulkier naphthyl-derived
imine (Table 3, entry 9). The presence of heteroatoms (S
and N, Table 3, entries 10 and 11), particularly of nitrogen in
the aromatic ring, significantly reduced the product ee value
Application of the catalyst to the synthesis of levamisole:
The present asymmetric catalytic Strecker protocol with the
chiral-oxazoline based organocatalyst (R,R)-1j was success-
fully extended to the synthesis of the pharmaceutically im-
portant drug molecule levamisole (Scheme 3). Compound 7
was obtained in fewer steps than previously, in high yield
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B. Ganguly, N. H. Khan et al.
Scheme 3. Transformation of a chiral a-aminonitrile into levamisole.
and with high enantioselectivity (experimental procedures
and characterization data are provided in the Supporting
Information).
Kinetic study: To understand the mechanism of the hydro-
cyanation of imines, kinetic experiments as a function of the
concentration of catalyst (S,S)-1j were performed with
imine 2a as a model substrate and TMSCN as a source of
cyanide. For all of the kinetic runs, plots of the formation of
a-aminonitrile versus time were found to be initially linear,
but were indicative of saturation near completion (Figure 2).
Figure 3. Plot of catalyst (S,S)-1j concentration versus kobs at À208C,
[imine]=0.48mm, [TMSCN]=1.92mm.
tration of substrate (dlogkobs/dlog[substrate]ꢀ1) showed
first-order dependence of the process on the substrate con-
centration (Figure 4). Finally, the effect of the concentration
of TMSCN over the range 0.48–3.84 mm on the rate of the
Strecker reaction of imine 2a was studied, keeping the cata-
lyst (0.012 mm) and imine (0.48 mm) concentrations con-
stant. First-order dependence (dlogkobs/dlog[TMSCN]ꢀ1)
was observed (Figure 5). Overall, the kinetic data revealed
first-order dependences on TMSCN, substrate 2a, and cata-
lyst (S,S)-1j.
Figure 2. Temporal evolution of the formation of a-aminonitrile at
À208C.
DFT calculations: A density functional theory (DFT) study
was performed to examine the formation of an enantiomeric
excess of (R)-a-aminonitriles in the Strecker reaction with
imines, specifically the hydrocyanation of N-benzhydryl-
Based on this observation, the initial rate constants kobs
were determined by directly estimating the amount of a-
aminonitrile formed up to completion of the reaction. Ini-
tially, we carried out kinetic experiments at different con-
centrations of catalyst (S,S)-1j (0.003–0.024 mm) and con-
stant concentrations of imine (0.48 mm) and TMSCN
(1.92 mm). From the kinetic data, a linear plot of kobs of a-
aminonitrile formation versus log[catalyst] with unit slope
(dlogkobs/dlog[catalyst]ꢀ1) that passes through the origin
was obtained, indicating that the Strecker reaction follows
first-order kinetics with respect to the concentration of the
catalyst (Figure 3).
Next, we performed kinetic experiments at different ini-
tial concentrations of imine 2a in the range 0.12–0.96 mm,
keeping the concentration of the catalyst (0.012 mm) and
TMSCN (1.92 mm) and the physical conditions unchanged.
The rate was calculated and a plot of kobs versus the concen-
AHCTUNGTREGiNNUN mine, by the chiral oxazoline-based organocatalyst. B3LYP-
D/6-31G(d)//B3LYP/6-31G(d) calculations were performed
with the imine substrate (2a) and organocatalyst (S,S)-1j as
a representative case to explore the mechanism of this
Strecker reaction. Recently, for computational studies on or-
ganocatalytic reactions, B3LYP methods have been used[12e]
and the results have been in excellent agreement with exper-
imental observations.[24–27] We have also considered disper-
sion corrections in the calculations at the B3LYP/6-31G(d)
level.[28] The crystal structure of the chiral oxazoline-based
organocatalyst (S,S)-1j was used to model the reactions.
In the asymmetric Strecker reaction, HCN is generated in
situ by the addition of controlled amounts of an alcohol to a
solution of TMSCN in an appropriate solvent.[10f,j] General-
ly, the accepted mechanism for the Strecker reaction in-
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Organocatalyst for Strecker Reaction
FULL PAPER
a previously reported value.[30]
However, the generated HNC
is more reactive than HCN in
the reaction medium[31] because
it is energetically less stable
than the latter by 72.29 kJmolÀ1
(Figure 6).[32–34]
It has been reported that an
organocatalyst can reduce the
activation barrier for the iso-
merization of HCN to HNC in
Strecker reactions.[30] The crys-
tal structure of the chiral oxazo-
line-based organocatalyst (S,S)-
1j was employed to examine
the isomerization process of
HCN to HNC at the B3LYP-D/
6-31G(d)//B3LYP/6-31G(d)
Figure 4. Plot of substrate imine 2a concentration versus kobs at À208C, [catalyst]=0.012 mm, [TMSCN]=
1.92 mm.
level of theory. The calculated
results showed the transition
state for the isomerization of
HCN
to
HNC
to
be
7.72 kJmolÀ1 higher in energy
than the separated reactants
(Figure 7). HNC complexed
with the organocatalyst (S,S)-1j
(complex 2) is energetically less
stable than complex 1 and
hence a reactive species for fur-
ther reaction.
Experimental study of the
hydrocyanation reaction of N-
benzhydrylimine (2a) in the
presence
of
organocatalyst
(S,S)-1j showed that the (R)-a-
aminonitrile is favored over the
corresponding (S)-a-aminoni-
trile. To examine the preferen-
tial formation of (R)-a-amino-
Figure 5. Plot of substrate TMSCN concentration versus kobs at À208C, [catalyst]=0.012 mm, [imine]=
0.48 mm.
volves the isomerization and activation of HCN in the pres-
ence of the catalyst.[29] The isomerization of the nascent
HCN is a highly energetic process. The activation barrier
calculated for the isomerization of HCN to HNC at the
B3LYP-D/6-31G(d)//B3LYP/6-31G(d) level of theory is
217.38 kJmolÀ1 (Figure 6), which is in good agreement with
nitriles, by using the chiral oxazoline-based organocatalyst
(S,S)-1j complex (complex 2) for this Strecker reaction with
N-benzhydrylimine, transition states were located for both
the R and S configurations (Figure 8).
The B3LYP-D/6-31G(d)-calculated relative energies show
that the transition state (TS) of the R configuration is
20.58 kJmolÀ1 more stable than that of the corresponding S
configuration in the THF medium. From the transition-state
À
geometries, it is evident that strong N H···N hydrogen
bonding (2.132 ꢁ) is present between the imine substrate
and the oxazoline-based chiral catalyst in the (R)-TS
(Figure 8).[35,36] The N H···N hydrogen-bond length in the
À
(S)-TS is much longer (3.898 ꢁ). These calculated results
À
show that the strong N H···N hydrogen bonding is primarily
responsible for stabilizing the (R)-TS compared to the (S)-
TS, thus rationalizing the experimental result of higher ee
for (R)-a-aminonitriles over (S)-a-aminonitriles for this
Strecker reaction.
Figure 6. Relative energy profile [kJmolÀ1] for the isomerization of HCN
to HNC in THF medium computed at the B3LYP-D/6-31G(d)//B3LYP/6-
31G(d) level of theory. All the distances are in ꢁ.
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B. Ganguly, N. H. Khan et al.
Conclusion
The chiral organocatalyst (S,S)-
1j is highly efficient in catalyz-
ing the asymmetric Strecker re-
action of aromatic and aliphatic
aldimines with TMSCN as a
source of cyanide. High yields
and ee values have been ach-
ieved with a wide range of sub-
strates. The catalyst (S,S)-1j has
also been successfully employed
in the synthesis of the pharma-
ceutically important drug leva-
misole in good yield and with
high enantioselectivity in a few
steps. DFT calculations have
been performed to rationalize
the formation of (R)-a-amino-
nitriles in higher ee than (S)-a-
À
Figure 7. Relative energy profile [kJmolÀ1] for the isomerization of HCN to HNC mediated by organocatalyst
(S,S)-1j in THF medium computed at the B3LYP-D/6-31G(d)//B3LYP/6-31G(d) level of theory. All the distan-
ces are in ꢁ.
aminonitriles in this Strecker reaction. Strong N H···N hy-
drogen bonding between the catalyst and the substrate is
primarily responsible for stabilizing the (R)-TS compared to
the (S)-TS, which provides a rationale for the experimental
results.
Experimental Section
General: All solvents were dried by using standard procedures, distilled,
and stored under nitrogen. NMR spectra were obtained on a Bruker
F113V spectrometer (200 and 500 MHz) and referenced internally to tet-
ramethylsilane (TMS). Enantiomeric excess (ee) values were determined
by HPLC (Shimadzu SCL-10AVP) using Daicel Chiralpak AD, AD-H,
OD-H, and OD chiral columns with 2-propanol/hexane as eluent. Prod-
ucts were purified by flash column chromatography on silica gel of 230–
400 mesh.
Typical experimental procedure for the enantioselective Strecker reaction
of N-benzhydrylimines by using catalyst (S,S)-1j: In a reaction vial, cata-
lyst (S,S)-1j (5 mol%) and the imine (0.25 mmol) were dissolved in THF
(1 mL) and the solution was stirred for 1 h at RT. It was then cooled to
À208C and TMSCN (0.3 mmol) was slowly added over a period of 2 h,
which was followed by the very slow addition of IPA (0.6 mmol). The re-
action was monitored by TLC, eluting with hexane/ethyl acetate (90:10).
On completion of the reaction, the solvent was removed on a rotavapor
and the product was purified by flash column chromatography on silica
gel (eluting with hexane/ethyl acetate, 90:10). The purified products were
characterized by 1H NMR spectroscopy and the spectra were in agree-
ment with those reported previously.[5]
Computational methods: Full geometrical optimizations were carried out
in the gas phase employing the Becke three-parameter hybrid density
functional combined with the Lee–Yang–Parr correlation functional
(B3LYP)[37–40] with the standard 6-31G(d) basis set.[41] Frequency calcula-
tions were performed at the same level of theory to confirm that each
stationary point was a local minimum (with zero imaginary frequency) or
a transition state (with one imaginary frequency). Single-point calcula-
tions were executed at the same level of theory, considering the disper-
sion correction (dft-D)[42] with a polarizable continuum model (PCM)[43]
in THF medium (e=7.4257) employing the B3LYP/6-31G(d)-optimized
geometries. All DFT calculations were performed with the Gaussian 09
suite of programs.[44]
Figure 8. B3LYP-D/6-31G(d)//B3LYP/6-31G(d)-calculated transition-state
geometries of the (R)- and (S)-enantiomeric forms with their relative
energy values in THF medium. All the distances are in ꢁ. [Pale blue=
carbon; white=hydrogen; red=oxygen; blue=nitrogen; green=sulfur].
14230
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Chem. Eur. J. 2013, 19, 14224 – 14232

Organocatalyst for Strecker Reaction
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Acknowledgements
A.S. is grateful to the CSIR for a fellowship and N.H.K. is grateful to the
DST and the CSIR Network project on Catalysis for financial assistance.
D.S. is grateful to the UGC, New Delhi, India, for a Junior Research Fel-
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Received: May 24, 2013
Revised: June 27, 2013
Published online: September 5, 2013
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Chem. Eur. J. 2013, 19, 14224 – 14232