Modified Kagan's amide: Synthesis and application as a chiral solvating agent for hydrogen-bonding based chiral discrimination in NMR

Article abstract of DOI:10.1039/c5ra06959a

A modified Kagan's amide, N-((S)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-3,5-dinitrobenzamide [(S)-2] has been designed, synthesized and screened as a Chiral Solvating Agent (CSA) for discrimination of optically active substrates. The proposed mode of action for recognition of chiral isomers of analytes by CSA is based on hydrogen-bonding. The ¹H NMR signals of the two isomers of chiral amides, sulfoxides, α-substituted acids, α-hydroxy ketone, epoxy ketone and N-protected amino acids with (S)-2 were well resolved for practical applications of determination of optical purity. The CSA was also screened for detection of separation of signals in ¹⁹F NMR. This journal is

Full text of DOI:10.1039/c5ra06959a

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Modified Kagan’s Amide: Synthesis and Applications as Chiral Solvating Agent for
Hydrogen-Bonding Based Chiral Discrimination in NMR
Nilesh Jain, Ravi B. Patel and Ashutosh V. Bedekar*
O
Ph NH
(R:S = 1:2)
in NMR tube with
O
F3C
NO2
N
H
CF3 CSA
NO2
A modified Kagan’s amide, N-((S)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-3,5-
dinitrobenzamide has been designed, synthesized and screened as Chiral Solvating Agent for
discrimination of optically active substrates.

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For Paper in RSC Advances
Modified Kagan’s Amide: Synthesis and Applications as Chiral
Solvating Agent for Hydrogen-Bonding Based Chiral Discrimination
in NMR
Nilesh Jain, Ravi B. Patel and Ashutosh V. Bedekar*
Department of Chemistry
Faculty of Science
M. S. University of Baroda
Vadodara 390 002, India
Tel. No. +91 265 2795552; Email: avbedekar@yahoo.co.in
Abstract:
A
modified
Kagan’s
amide,
Nꢀ((S)ꢀ1ꢀ(3,5ꢀbis(trifluoromethyl)phenyl)ethyl)ꢀ3,5ꢀ
dinitrobenzamide [(S)ꢀ2] has been designed, synthesized and screened as Chiral Solvating
Agent (CSA) for discrimination of optically active substrates. The proposed mode of the
action of recognition of chiral isomers of analytes by CSA is based on hydrogenꢀbonding.
1
The H NMR signals of the two isomers of chiral amides, sulfoxides, αꢀsubstituted acids, αꢀ
hydroxy ketone, epoxy ketone and Nꢀprotected amino acids with (S)ꢀ2 were well resolved for
practical applications of determination of optical purity. The CSA was also screened for
1
9
detection of separation of signals in F NMR.
O
Ph
N
H
R:S = 1:2
+
O
F3C
NO2
N
H
CF3
NO2
(S)-2

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Introduction:
Advent of chemistry of chiral molecules in recent years has been triggered by discoveries of
their special properties in many fields. The specific properties of chiral molecules are often linked
with the particular optical isomer and drastically differ on its purity. In some cases different chiral
isomers have been found to posses completely divergent properties. Hence, establishing the
enantiomeric purity and absolute configuration of chiral compounds is a critical factor in the study
and applications of optically active molecules. The optical character of the chemical sample can be
1
2
analyzed by different techniques ranging from chromatography, mass spectrometry, IR, UV and
3
4
fluorescence spectroscopy, circular dichroism and electrophoresis etc. These techniques need a
certain type of structural requirement or depend on the presence of certain functional group in the
analyte or need different accessories of the analytical machine, such as special chiral columns for
the chromatographic techniques. Recently some biochemical methods are also developed to
5
determine enantiomeric excess of the chiral products.
The technique of Nuclear Magnetic Resonance (NMR) spectroscopy, with its highly
advance and sensitive mode of analysis, also offers an alternative methods of quick and accurate
6
determination of optical purity of chiral molecules. However, the standard NMR analysis of chiral
molecules in achiral environment cannot differentiate the signals of the two enantiomers. Few
7
isolated attempts to use chiral solvents in NMR analysis have met with limited success. For the
detectable NMR discrimination the enantiomers need to be converted to diastereomers, either
permanently by covalent bond formation or temporarily by nonꢀcovalent, supramolecular
interactions. One such classical technique involves in situ preparation of diastereomeric lanthanide
8
9
chelate complexes. This can also be done by the use of chiral derivatizing agents (CDA) for
formation of diastereomeric compounds, either prior to the analysis or for the in situ in NMR tube

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1
0
analysis. Similarly the diastereomer formation for NMR analysis may also be done by in situ
1
1
complex formation with chiral solvating agent (CSA) during the measurement of the spectra.
1
Although examination of H NMR is more widely investigated, the researchers have also focused
on targeting the analysis of other NMR active nuclei to determine optical purity using this
1
2ꢀ16
protocol.
These techniques involves nonꢀcovalent interactions between the test sample and the
chirally pure molecule of CSA. These are primarily hydrogenꢀbonding, πꢀπ stacking, CHꢀπ
interactions, van der Waals interactions etc. The efficiency of a given CSA to recognize two
isomers of chiral analyte depends on combination of these forces and hence they are often selective
and case sensitive in their action. The specific nature of the action of each CSA for different
substrates necessitates the need to have a library to scan for new analytes for the NMR analysis.
Chiral amide of 3,5ꢀdinitro benzoic acid 1a reported by Kagan is one of the oldest and well
1
7
studied CSA for efficiently discriminating several types of molecules by NMR analysis. This is a
simple molecule with basic functional units present to enable hydrogenꢀbonding and πꢀπ
interactions with substrates for tight complex formations in NMR conditions. These type of
compounds were first developed by Pirkle for the WhelkꢀO type materials for separation of chiral
18
compounds on HPLC colums. Over the years few more derivatives of Kagan’s amide have been
1
9
explored with good success in molecular recognition of chiral compounds (Chart 1). The range of
1
9c
17b,17d
chiral analytes successfully screened with these CSAs include amides,
sulfoxides,
19d
17c
multifunctional tertꢀalcohols, and phosphine oxides.

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O
O
NO2
NO2
N
N
H
H
1a
NO2
1b
NO2
NO2
O
N
NO2
NH
NH
HN
O
O
1
c
1d
Chart 1. Kagan’s amide 1a and its analogues
Generally accepted mode of interaction between the two molecules involve Hydrogenꢀ
bonding between the CSA and the analyte, NꢀHꢁꢁꢁꢁꢁꢁꢁꢁꢁO=X (X = C or S of analyte), and the πꢀπ
19d
interaction between the aromatic units. It is also proposed that the analyte fits between the cleft
type conformation created by perpendicularly arranged dinitro benzoyl and the naphthalene rings in
1
9c
20
case of 1b, similar type of explanations are offered for the other derivatives 1c and 1d. The
proposed interactions were also corroborated by upꢀfield and downꢀfield shifts of appropriate
1
examples in the H NMR experiments.
Result ad Discussion:
Based on these proposed models (A in Figure 1) we suggest to introduce a modification in
Kagan’s amide where the chiral amine portion will possess an aromatic ring with two strongly
electron withdrawing groups. With this modification the hydrogen attached to the nitrogen of the
amide group of CSA will be more electron deficient due to the inductive effect and may form
stronger hydrogen bonding with the carbonyl of the test sample (B in Figure 1). We propose to

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introduce two trifluoromethyl groups at the meta positions of aromatic ring at the amine portion of
the amide unit keeping the chiral centre unchanged. Our proposed model compound 2 has been
1
8c
known in the literature and has been employed as a support in chiral phase HPLC analysis. We
present the synthesis and evaluation of 2 as CSA for determining chiral purity of suitable range of
1
substrates by H NMR analysis.
EWG
EWG
EWG
O
H
H
O
R'
O
H
H
O
R'
N
N
N
N
R''
R''
*
+
*
+
δ
>δ
Kagan Type (+/-)-Analyte
Chiral CSA
Present Model (+/-)-Analyte
of Chiral CSA
A
B
O
F3C
NO2
N
H
CF3
NO2
2
Figure 1. Proposed modification in Kagan type CSA
The synthesis of chiral 2 was based on condensation of the optically pure 1ꢀ(3,5ꢀ
bis(trifluoromethyl)phenyl)ethanamine with 3,5ꢀdinitrobenzoyl chloride under suitable conditions.
Separation of isomers of optically pure alcohols using bioꢀcatalytic selective methods is a well
established protocol. Several studies have been conducted for elegant separation of alcohols based
on kinetic resolution methods, where one of the enantiomers undergoes esterification while the
2
1
other remains unaffected. As a part of our ongoing project we have separated isomers of chiral
2
2
roof shape alcohols using enzyme mediated resolution process. Some of these alcohols have been
converted to roof shape chiral amines and screened as CSAs for determination of optical purity of
2
2b
αꢀsubstituted acids.
In the present synthesis we have accessed optically pure 1ꢀ(3,5ꢀ
bis(trifluoromethyl)phenyl)ethanol 3 from its racemic sample via enzyme mediated

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transesterification process and the alcohol was converted to its amine by usual steps. The enzyme
mediated process to resolve (+/ꢀ)ꢀ3 was conducted with vinyl acetate as the acyl source in presence
of immobilized lipase (Scheme 1). The optically pure 3, which is an intermediate of aprepitant, a
potent and orally active antagonist of human neurokinin receptor, has also been accessed by similar
2
3
process. The improved and standardized parameters of the enantiomer separation study have been
summarized in Table 1.
F3C
Vinyl acetate F3C
Lipase, THF
F3C
OH
OH
OCOCH3
+
(
see Table 1)
CF3
CF3
CF3
(
+/-)-3
(S)-3
(R)-4
Scheme 1. Enzymatic resolution of (+/ꢀ)ꢀ3
Table 1: Select conditions for resolution of (+/ꢀ)ꢀ3
a
b
No
Conditions
Solvent
% ee of 4
% ee of 3
C
E
Acyl
donor
IPA
VA
EA
ꢀꢀ
BA
IPA
VA
Time
(h)
72
72
72
72
72
84
84
(% Yield) (% Yield)
1
2
3
4
5
6
7
THF
THF
THF
EA
THF
THF
THF
>99 (38)
>99 (40)
86 (37)
89 (45)
ꢀꢀ
32 (75)
ꢀꢀ
46
47
ꢀꢀ
25
ꢀꢀ
>200
>200
ꢀꢀ
44
ꢀꢀ
c
ꢀꢀ
94 (16)
d
ꢀꢀ
>99 (40)
>99 (43)
92 (35)
>99 (41)
48
>200
>200
50
a
b
All the reactions were run at r.t.; Determined by HPLC by converting to alcohol 3; Determined by HPLC;
Trace reaction, not isolated; No reaction. IPA= isoꢀpropenyl acetate, VA = vinyl acetate, EA = ethyl acetate,
c
d
BA = butyl acetate. All experiments were run with Novozymeꢀ435.
However, the kinetic resolution of chiral alcohols cannot furnish either compound in more
than 50% chemical yield in optically pure form. To overcome this difficulty a strategy of
2
4
combination of enzymatic resolution and Mitsunobu reaction has been developed by few
2
5
groups. The Mitsunobu reaction involves direct substitution of alcohols with new nucleophiles in
presence of triphenyl phosphine and diethyl azodicarboxylate (DEAD) with complete inversion of
configuration. In the above reaction (Scheme 1) the “R” isomer of the alcohol 3 was selectively

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converted to its acetate (R)ꢀ4 with excellent selectivity and moderate yield. The unaffected alcohol
S)ꢀ3 was also left in high optical purity. In the present effort the same reaction was conducted in
(
presence of acetic acid under Mitsunobu conditions, where the acetate ion acts as new nucleophile
and the unreacted alcohol (S)ꢀ3 was converted selectively to (R)ꢀ4 with complete inversion in
overall good chemical yield (Scheme 2).
F3C
Vinyl acetate F3C
Lipase, THF
F3C
OH
OH
OCOCH3
+
Enzymatic kinetic
resoluton
CF3
CF3
CF3
(
+/-)-3
(S)-3
(R)-4
AcOH, DEAD, Ph P, r.t., 6h
3
71 % Y, 98 % ee of (R)-4
Scheme 2. Combination of lipase mediated resolution and Mitsunobu reaction
Thus a practical process was developed to access optically pure (R)ꢀ4, which was converted
to chiral alcohol (R)ꢀ3 under the acidic hydrolysis conditions (Scheme 3).
HCl, MeOH F C
3
OH
o
50 C, 3 h
(R)-4
98 %
CF3
(
R)-3
Scheme 3. Synthesis of (R)ꢀ3
Optically pure alcohol (R)ꢀ3 was then converted to corresponding amine (S)ꢀ6 (Scheme 4).
This operation involved inversion of configuration by its reaction with phthalimide, Ph P and
3
DEAD in dry tetrahydrofuran, furnishing the corresponding protected amine (S)ꢀ5, which was
2
6
27
subsequently deprotected with hydrazine. The amine (S)ꢀ6 was not isolated but converted

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directly to the desired amide (S)ꢀ2 by treatment with 3,5ꢀdinitrobenzoyl chloride. Similarly (S)ꢀ6
was also converted to (S)ꢀ7 by treatment with benzoyl chloride.
The single crystal analysis of 1b indicated a cleftꢀlike arrangement caused by having the
1
9c
3
,5ꢀdinitrobenzoyl group placed orthogonal to the naphthalene plane. The selective recognition
of the two isomers of chiral amide analyte was attributed to this arrangement and was proposed to
be responsible for the supramolecular interactions. We could also grow a single crystal of (S)ꢀ2 and
2
8
its Xꢀray diffraction analysis was performed (Figure 2). We observed that the angle between the
o
planes passing through the two aromatic rings bisecting each other at an angle of 119.6 making the
arrangement of the aromatic rings quite open compared to 1b (where the same angle was noted to
o
be 99.9 ) The intramolecular hydrogen bonding NꢀHꢁꢁꢁꢁꢁꢁꢁO=C was detected with the bond distance
of 2.104 Å.
O
Phthalimide
F3C
DEAD, Ph P
N
3
(
R)-3
THF, r.t., 6 h
O
85 %
CF3
(
S)-5
NH NH
2
2
THF-EtOH,
o
6
0 C, 5 h
ArCOCl
Et N
2 2
3
F3C
(
S)-2
CH Cl
NH2
or
(
S)-7 r.t., 4 h
CF3
(S)-6
O
O
F3C
NO2 F3C
N
H
N
H
CF3
NO2
CF3
(
S)-2 [71%]
(S)-7 [73%]
Scheme 4. Synthesis of (S)ꢀ2 and (S)ꢀ7

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Figure 2. ORTEP diagram of (S)ꢀ2
Having prepared two derivatives of modified CSAs, (S)ꢀ2 and (S)ꢀ7, we next screened them
to test their ability to discriminate the signals of chiral amide analytes. We made three types of the
chiral amides Ph*CH(CH )NHCOR (8a ꢀ 8m) in the unequal ratio of its enantiomers and tested
3
them with CSAs (Table 2). The first set of amides was made with aromatic acid moieties being
phenyl, naphthyl and anthryl (8a ꢀ 8c). The second set where the phenyl was substituted with
electron donating or withdrawing groups (8d – 8i). The third set of amides was made where the
alkyl acids were condensed with αꢀmethyl benzyl amine (8j – 8m). The recognition study was
α
conducted in CDCl (400 MHz; 10 mM concentration; ratio of 1:1) targeting two protons C H of
3
Ph*CH(CH )NHCOR and methyl protons attached to the chiral center of Ph*CH(CH )NHCOR. As
3
3
can be seen there is not much difference in case of benzene and naphthalene derivatives (8a and 8b)
while the latter signals were much resolved in case of anthracene derivative (8c). When the
aromatic ring is attached with electron withdrawing group the degree of induced chemical shift (Δδ)
and nonequivalences (ΔΔδ) for both sets of protons was observed to be marginally on the lower side
(8d, 8f and 8p) while with electron donating group attached showed considerably enhance shifts in
both the parameters (8g and 8i). In case of alkyl derivatives a pattern was observed where both the
parameters were seen to increase with increase in the size of R group (8j and 8m). Higher values

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were seen in case of pivaloyl (8l) and adamantly (8m-8o) supporting this trend (Table 3). The
adamantly amide prepared from naphthyl ethyl amide (8n) showed remarkable separation of signals
with high nonequivalences of 0.502. The pattern observed for the second set of amide analytes was
consistent with the proposed hydrogen bonding model (Figure 1), where the electron donating
groups on the amide (ArCO) would make the oxygen of carbonyl more electron rich and hence
should favor the interaction by becoming better hydrogen bond acceptor. The opposite phenomena
may account for the lower values in case of electron withdrawing substituents.

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1
Table 2: H NMR induced chemical shift (Δδ) and nonequivalences (ΔΔδ) of amides 8a – 8m in
presence of CSA (S)ꢀ2 and in some cases (S)ꢀ7 [in ratio 1:1].
No
1
Amide 8
ArCHMeNHCOR
ArCHMeNHCOR
Δδ
ΔΔδ
Δδ
ΔΔδ
Me
O
ꢀ0.086
0.060
ꢀ0.018
0.025
Ph
Ph
N
H
8
a
2
3
Me
O
ꢀ0.084
0.063
ꢀ0.018
ꢀ0.049
0.022
0.045
N
H
8
b
a
a
ꢀꢀ
ꢀꢀ
Me
O
Ph
N
H
8c
4
5
6
Me
O
ꢀ0.077
ꢀ0.072
ꢀ0.046
0.043
0.044
ꢀ0.025
ꢀ0.012
ꢀ0.014
0.015
0.017
0.018
Ph
N
H
8
d
Br
Me
O
Ph
N
H
8e
Cl
a
Me
O
ꢀꢀ
NO2
Ph
N
H
8f
NO2
7
8
Me
O
ꢀ0.090
ꢀ0.091
0.059
0.059
ꢀ0.021
ꢀ0.019
0.024
0.025
Ph
N
H
8
g
Me
Me
O
Ph
N
H
8h
OMe

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9
Me
O
ꢀ0.067
0.076
0.081
ꢀ0.016
0.030
0.034
Ph
N
H
OMe
8
i
OMe
O
1
0
1
2
3
4
Me
ꢀ0.110
ꢀ0.004)
ꢀ0.028
(ꢀ0.004)
b
a,b
b
a,b
(
(ꢀꢀ )
(ꢀꢀ )
Ph
N
H
8j
1
1
1
1
Me
O
ꢀ0.154
0.108
ꢀ0.046
0.047
Ph
Ph
N
H
8k
Me
O
ꢀ0.158
ꢀ0.007)
0.156
ꢀ0.047
0.057
b
a,b
b
a,b
(
(ꢀꢀ )
(ꢀ0.004 )
(ꢀꢀ )
N
H
8
l
Me
O
ꢀ0.174
ꢀ0.39
0.163
0.502
ꢀ0.018
0.059
0.241
Ph
N
H
8
m
ꢀ0.212
Me
O
O
N
H
8n
1
5
6
Me
ꢀ0.061
ꢀ0.015
0.157
ꢀ0.036
ꢀ0.014
0.053
0.021
N
H
F
8o
c
1
Me
O
ꢀꢀ
CF3
Ph
N
H
8
p
CF3
c
a
b
Not resolved. With (S)ꢀ7. Complex pattern. All NMR recorded at 400 MHz in CDCl at 10 mM (1:1).
3
The hypothesis of designing the present modification in the Kagan’s reagent 1a hinges on
making the aromatic ring of CSA (ArNHCOꢀ) more electron deficient by attaching two strongly
electron withdrawing groups in (S)ꢀ2 (B of Figure 1). By making the ring electron deficient and the
subsequent inductive effect (ꢀI) we expect the hydrogen of NꢀH acquire more +δ character and
hence becoming a better hydrogen bond donor. This hypothesis was then tested by comparing the

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1
9c
CSA activity of Kagan’s reagent 1a, the known data for 1b, and our present study for (S)ꢀ2 for
the pivaloyl (8l) analyte derivative (Table 4). Another analogue was prepared without nitro groups
(S)ꢀ7 and also scanned for the comparison. The present modified Kagan’s reagent (S)ꢀ2 showed
marginally better values of the nonequivalences (ΔΔδ) for the amide 8l for both the targeted
1
hydrogens in the H NMR analysis supporting the concept. The other derivative (S)ꢀ7 failed to
effect the discrimination in both the protons of 8l indicating the need of strongly electron
withdrawing groups on the ArC=O of CSA to make the carbonyl oxygen sufficiently electron
deficient (+δ) for effective hydrogen bond formation. The role of hydrogen bond in the mechanism
2
9
of the action of recognition of isomers for chiral solvation has been well established.
1
Table 3. Select portion of H NMR with (S)ꢀ2 as CSA
No. Amide
ArCHMeNHCOR
ArCHMeNHCOR
1
2
3
4
8j
8k
8l
8m
All NMR recorded at 400 MHz in CDCl at 10 mM (1:1).
3
Ratio of S:R for 8j, 8l, 8m 1(R):2(S) & for 8k 1(R):3(S)

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Table 4: Comparison of CSA activity of 1a, 1b, (S)ꢀ2 and (S)ꢀ7 for amide 8l.
No
CSA
ArCHMeNHCOR ArCHMeNHCOR
ΔΔδ
ΔΔδ
1
2
3
1a
1b
(S)ꢀ2
(S)ꢀ7
0.061
0.141
0.156
0.023
0.049
0.057
a
a
4
ꢀꢀ
ꢀꢀ
a
Not resolved.
1
Further evidence of effect of polarity of solvent was studied with conducting H NMR
experiments in different solvents (Table 5). Very poor resolution was observed in polar solvents
such as acetoneꢀd and also with mixture of DMSOꢀd /CDCl which is capable of forming
6
6
3
11l
hydrogen bond, while better separation was found in less polar benzeneꢀd6. However, due to the
high cost of benzeneꢀd we have focused on the use of more commonly available chloroformꢀd for
6
further study.
Table 5: Effect of solvent on the CSA activity of (S)ꢀ2 for amide 8l.
No
Solvent
ArCHMeNHCOR ArCHMeNHCOR
ΔΔδ
ΔΔδ
1
2
3
4
CDCl3
C D
0.156
0.201
0.057
0.070
6
6
a
a
CD COCD
ꢀꢀ
ꢀꢀ
3
3
a
a
CDCl +
ꢀꢀ
ꢀꢀ
3
DMSOꢀd (9:1)
6
a
Not resolved.
1
The two sets of signals in H NMR of pivaloyl derivative 8l and (S)ꢀ2 in equimolar ratio
α
were well resolved (Figure 3). In which both the signals C H and the methyl signals of “S” isomer
experienced upꢀfield shift, more than the other isomer.

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1
Figure 3. Selected region of H NMR of 8l in CDCl (1:1 ratio, 10 mM): (a) blank 8l; (b) non
3
racemic sample of 8l ratio of S:R [2:1] in presence of (S)ꢀ2; (c) Rꢀisomer of 8l with Sꢀ2; (d) Sꢀ
isomer of 8l with (S)ꢀ2.
This separation was further studied to establish the linear relationship between the observed
and actual values of ee for establishing practical utility of the CSA (Figure 4). The observed ee
values were found to be within 0.5 % of actual values, which confirms the accuracy and
consistency of the analysis.

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1
Figure 4. Selected region of H NMR spectra of scalemic mixture of 8l in presence of (S)ꢀ2 (Left)
and its correlation between theoretical and observed % ee values (Right).
The scope of the present CSA was further explored with chiral sulfoxides to determine their
efficacy in recognition of the isomers. Since sulfoxides are also effective acceptors of hydrogen
bonding we believe the mode of action of molecular recognition of the present CSA will be on the
1
similar lines. Few derivatives of CSA are available to determine the enantiomer ratio by H NMR
1
1g,17b,17d,30
analysis.
To test the efficiency we screened a sample of unsymmetrical sulfoxides 9 with
(
S)ꢀ2 in CDCl under the established conditions (Figure 5). A distinct shift of the signals of alkyl
3
protons was observed with base line separation of the two sets of signals corresponding to the two
enantiomers, but the values were on the lower side compared to the amide analytes 8. This could be
attributed to the possibility of two point hydrogen bonding in 8 rather than one point attachment in
sulfoxides 9. For comparison, our molecules showed similar values (ΔΔδ = 0.008 ppm or 3.2 Hz)
1
7b
compared to the 1b for separation of signals for 9a.

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We further investigated application of (S)ꢀ2 to check separation of signals in case of racemic
benzoin 10a and keto epoxide10b a product of Darzen condensation, where the carbonyl is
expected to be less polarized compared to other substrates and hence may have weaker hydrogen
bonding. There are very few reports on the methods to discriminate these substrates for analytical
3
1
purpose. Since our CSA has worked well in differentiating the isomers based on hydrogen
bonding we scanned (S)ꢀ2 with racemic 10a and 10b under similar conditions and observed small
α
1
shift in the signals of the C H in H NMR (Figure 5 and 6).
δ = 0.040
δ = 0.005
δ = 0.010
δ = 0.012
δ = 0.075
δ = 0.008
δ = 0.005
δ = 0.014
O
S
O
S
S
S
O
O
9a
9b
MeOOC
9c
9d
Cl
O
O
O
HO H
H
δ = - 0.008
δ = 0.009
δ = - 0.043
δ = 0.028
10a
10b
Figure 5. Discrimination of sulfoxides 9 and benzoin 10 with (S)ꢀ2.
Figure 6. Discrimination of sulfoxides 9a (a), benzoin 10a (b) and keto epoxide 10b with (S)ꢀ2.
1
The top represents the select signal of the H NMR spectra without CSA and the bottom with CSA
(
1:1, CDCl , 10 mM).
3

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1
The use of chiral solvating agents (CSA) for determining optical purity by H NMR analysis
is emerging as a useful tool and hence we need to scan different types of analytes to prove its wider
applicability. Hence we further scanned the present CSA (S)ꢀ2 for αꢀsubstituted acids as they form
an important class of chiral compounds. Usually the CSAs used for analyzing chiral acids are basic
in nature and the mode of interactions are based on the formation of diastereometric complex or salt
3
2
with the substrates. The nature of (S)ꢀ2 is neutral and hence our initial experiment of mixing only
1
mandelic acid 11a and (S)ꢀ2 in CDCl and recording H NMR did not result in any separation of
3
signals, although a small degree of up field shift was recorded (Δδ = ꢀ 0.19 ppm). The use of
external base to help abstraction of acid proton of such analytes, making the hydrogen bonding
2
9f
possible between the carboxylate with hydrogen bond donor bisꢀthiourea type CSA is reported.
For similar phenomena in the present study we initially used DMAP along with (S)ꢀ2 to determine
α
1
α
if the C H of mandelic acid can be distinguished in H NMR. Indeed, the C H proton was observed
to shift much up field and two distinct singlets were seen for the two isomers (Table 6). Further
improved resolution was observed when the base was replaced with DABCO, with equivimolar
quantity and even better separation with excess CSA. Number of derivatives of αꢀhydroxy aryl
acetic acids, 11b to 11e, were scanned to establish generality of the analysis. An example of αꢀ
chloro phenyl acetic 11f was also scanned with good separation. All these molecules showed a clear
α
base line separation of the C H signals for practical and accurate determination of optical purity.

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Table 6. Study of CSA activity of (S)ꢀ2 for αꢀhydroxy/alkoxy acids.
No αꢀhydroxy/alkoxy acid
CSA
eq.)
Base
ArCH(OH)COOH
(
(1 eq.)
Δδ
ΔΔδ
1
OH
COOH
1a
1.0
DMAP
ꢀ0.278
0.022
1
2
3
4
11a
11a
1.0
2.0
2.0
DABCO ꢀ0.384
DABCO ꢀ0.425
DABCO ꢀ0.430
0.040
0.047
0.056
OH
COOH
Br
11b
OH
5
6
7
8
2.0
2.0
2.0
2.0
DABCO ꢀ0.402
DABCO ꢀ0.441
DABCO ꢀ0.250
DABCO ꢀ0.130
0.030
0.048
0.066
0.053
COOH
F3C
11c
OH
O
O
COOH
1
1d
OMe
COOH
1e
1
Cl
COOH
1f
1
All NMR recorded at 400 MHz in CDCl at 10 mM (2:1), with indicated amount of DMAP / DABCO.
3
Natural and unnatural amino acids in optically pure form are important intermediates in the
synthesis and study of bioactive molecules. We further extended the scope of our reagent (S)ꢀ2 to
scan for differently Nꢀprotected phenyl glycine as a test case. The effectiveness is general for some
commonly used derivatives of this amino acid (Table 7).

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Table 7. Study of CSA activity for the derivatives of Nꢀprotected phenyl glycine 12.
NHR
COOH
12a-d
No
1
R
ArCH(NHR)COOH
Δδ
ΔΔδ
0.038
[0.071]
0.030
COCH3
12a)
ꢀ0.565
ꢀ0.003]
ꢀ0.526
(
a
a
[
2
3
COPh
12a)
(
b
b
Boc
12a)
ꢀ0.284 [CαꢀH ]
0.071 [CαꢀH ]
1
1
(
b
b
ꢀ
0.409 [CαꢀH ] 0.101 [CαꢀH ]
2
2
4
Ts
ꢀ0.490
0.065
(12a)
a
b
For COCH ; For the two rotamers.
3
The importance of chiral drugs in medicinal chemistry is now a well established
phenomenon. In the present work we have scanned our CSA (S)ꢀ2 for some chiral drugs and drug
intermediates. Non steroidal antiꢀinflammatory agents such as ibuprofen 13a, ketoprofen 13b and
3
4a
flurbiprofen 13e are some of the important chiral drugs. These αꢀalkyl aryl acetic acids showed
α
1
significant baseline splitting of signal of C H in H NMR analysis (Figure 7). The separation of
1
9
signals in F NMR were also observed in case of 13e (Figure 8). There is always an advantage if
two nuclei can be analyzed in a chiral molecule to confirm its optical purity. Some of the optically
active drugs posses sulfoxide chiral center and the activity is believed to be associated with the
chirality. One of these class of drugs is used as proton pump inhibitor to treat gastroesophageal
3
4b,c
reflux disease, peptic ulcers, erosive asophagitis and ZollingerꢀEllison syndrome.
Omeprazole
13c is one such active drug commercially available. We scanned (S)ꢀ2 to detect discrimination of

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1
the signals in H NMR of 13c. However, the expected split for the αꢀprotons of SOCH ꢀ was not
2
observed but the aromatic methyl signals got separated with small chemical shift nonequivalences
(0.008 ppm). Another chiral molecule 2ꢀhydroxyꢀ3ꢀmethoxyꢀ3,3ꢀdiphenyl propionic acid 13d,
3
4d
α
which is an intermediate for few pharmaceutical entities was also tested. Although C H was not
β
1
resolved completely the signals of C OCH showed good separation in H NMR. We extend the
3
3
4e
study with the analysis of 13f, an intermediate of Nebivolol, a beta blocker agent. In this
α
1
candidate we could observe very good separation of signals of C H in H NMR along with
1
9
separation of F NMR analysis (Figure 8).
δ = 0.075
δ = 0.048
N
O
S
δ = 0.008
Me
OMe
O
H
N
H
N
H
MeO
COOH
Ph
COOH
δ = 0.008
Me
1
3a, Ibuprofen
13b, Ketoprofen
δ = 0.080
13c, Omeprazole
δ = 0.068
δ = 0.071
δ = 0.011
H
δ = 0.10
H
H CO
OH
3
F
O
COOH
COOH
Ph
Ph
COOH
Ph
F
13d
13e, Flurbiprofen
13f
Figure 7. Application of CSA (S)ꢀ2 for some drugs and drug intermediates.

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1
9
α
1
Figure 8. F NMR spectrum of 13e (a) and 13f (b); C H of 13f in H NMR, top without CSA and
bottom with (S)ꢀ2 (2.0 eq.) and DABCO (1.0 eq) in CDCl (10 mmol) (c).
3
Hence in this work we have developed a modified derivative of Kagan’s reagent capable of
1
distinguishing the protons of the enantiomers by simple H NMR experiments. We have
demonstrated the improved ability of (S)ꢀ2 to accurately detect protons of a wide variety of
compounds of amides, sulfoxides, benzoin, αꢀsubstituted aryl acetic acids, keto epoxides with good
separations. The modified CSA has been scanned for few chiral drugs and drug intermediates with
1
9
good separations. Few examples of the separation of signals in F NMR can widen the scope of
analysis for fluorine containing chiral compounds.
Experimental Section:
General procedure for the enzymatic resolution.
Synthesis of compound (S)-3 and (R)-4.
A solution of racemic alcohol (+)ꢀ3 (1.0 g, 3.87 mmol) in dry THF (10 mL) lipase (Novozymeꢀ435)
(0.3 g, 30% w/w) and vinyl acetate (0.36 mL, 3.87 mmol) were added and reaction mixture was
stirred at room temperature. The reaction was followed by TLC. The material was filtered and the
filtrate was concentrated in vacuum. Separation was carried out by column chromatography over

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silica gel using petroleum ether and ethyl acetate as the eluent. The acetate (R)ꢀ4 was isolated with
ethyl acetate in petroleum ether (2%) and the alcohol with ethyl acetate in petroleum ether (5%).
1ꢀ[3,5ꢀbis(trifluoromethyl)phenyl] ethanol: (S)ꢀ3
23c
33
m.p. = 86ꢀ87 ºC (lit. 88 ºC). [α] = ꢀ24.8(c = 1.0 CHCl ) (lit. [α] = ꢀ24.1 (c = 1.0 CHCl ))
D
3
D
3
HPLC condition for alcohol (S)ꢀ3 Chiralpak ODꢀH column: 5% IpAꢀHexane, UV= 254nm, Flow=
st
nd
0
.5 mL/min R – 9.5 min (1 Peak) ꢀ [Sꢀisomer] and R – 10.5 min (2 peak)ꢀ[Rꢀisomer].
t
t
1
H NMR (400 MHz, CDCl ) δ 1.54 (d, J = 6.4 Hz, 3H), 2.24 (s, 1H), 5.01ꢀ5.10 (q, J = 6.4 Hz, 1H),
3
7.78 (s, 1H), 7.84 (s, 2H).
1
9
F NMR (376 MHz, CDCl ): ꢀ62.88.
3
1
3
C NMR (100 MHz, CDCl ): 25.5, 69.3, 121.3 (sep, JCꢀF = 4.4Hz), 123.3 (q, JCꢀF = 271.0 Hz),
3
125.6, 131.9 (q, JCꢀF = 33.0 Hz), 148.2.
Mass (EI): 258(10), 242(100), 243(96), 240(20), 195(74), 194(87), 69(50).
ꢀ1
IR (KBr): υ 3257ꢀ3159, 2980, 1625, 1467, 1280, 1024, 924, 896, 842, 705, 683 cm.
Synthesis of 1-[3,5-bis(trifluoromethyl)phenyl]ethylacetate:(R)-4.
Procedure for Enzymatic reaction followed by Mitsunobu reaction:
After enzymatic resolution catalyst was filtered off. To the filtrate AcOH (0.11 mL, 1.93 mmol) and
triphenyl phosphine (0.51 g, 1.93 mmol) were added under nitrogen atmosphere followed by the
o
slow addtion of solution of DEAD (0.38 mL, 2.42 mmol) in dry THF (1 mL) at 0 C. The reaction
mixture was stirred (6 h). The solvent was removed under reduced pressure and the crude product
was purified by silicaꢀgel column chromatography with ethyl acetate and petroleum ether (2%).

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o
23c
White solid 0.82 g (70.7% Yield) m.p. = 59ꢀ60 C [α] = +55.2 (c = 1.0 methanol) lit. [α] = +57
D
D
(c = 1.0 methanol ) for (R)ꢀisomer.
1
H NMR (400 MHz, CDCl ): δ 1.59 (d, J = 6.8 Hz, 3H), 2.24 (s, 3H), 5.94ꢀ5.99 (q, J = 6.8 Hz, 1H),
3
7.81 (s, 1H), 7.83 (s, 2H).
1
9
F NMR (376 MHz, CDCl ): δ ꢀ62.90.
3
1
3
C NMR (100 MHz, CDCl ): δ 21.1, 22.3, 70.9, 121.9 (sep, JCꢀF = 4.4 Hz), 123.2, (q, JCꢀF = 271
3
Hz), 126.2, 131.4 (q, JCꢀF = 33 Hz), 144.3, 170.1.
Mass (EI): 299(18), 281(10), 258(100), 257(89), 239(91), 238(56), 200(47), 150(21), 71(18).
ꢀ1
IR (KBr): υ 3007, 2941.61, 1732, 1456, 1285, 1173, 1021, 898, 706, 684 cm.
General procedure for hydrolysis of (R)-4.
To a solution of (R)ꢀ4 (0.82 g, 3.18 mmol) in methanol (15 mL), HCl (0.5 mL, 4.76 mmol, 36 %)
was added. The reaction mixture was refluxed (3 h). After completion of reaction, as indicated by
TLC, MeOH was evaporated under reduce pressure. The residue was taken in ethyl acetate, and
washed with water. The organic layer was dried with sodium sulphate and concentrated to afford
(R)ꢀ3 in 0.80 g (98%).
Synthesis of 1-[3,5-bis(trifluoromethyl)phenyl]ethylphthalimide (S)-5.
o
A solution of (R)ꢀ3 alcohol (1.0 g, 3.86 mmol) in dry THF (10 mL) kept in ice bath at 0 C under
nitrogen atmosphere. To this solution PPh (1.01 g, 3.86 mmol) and pthalimide (0.57 g, 3.86 mmol)
3
were added. A solution of diethylazodicarboxylate (DEAD) (0.77 mL, 4.24 mmol) in THF (3 mL)
was added drop wise, and the reaction was stirred for 6 h. The reaction was followed by TLC. The
product was purified by column chromatography over silica gel (10% Ethyl acetateꢀ Petroleum
0
ether) affording white solid. Yield 1.2 g (80 %) m.p = 124ꢀ126 C [α] = -59.8 (c= 0.5 CHCl )
D
3

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1
H NMR (400 MHz, CDCl ) δ 1.56 (d, J = 7.2 Hz, 3H), 5.79ꢀ5.86 (q, J = 7.2Hz, 1H), 6.16 (d, J =
3
7
.2Hz, 1H), 7.28.ꢀ7.23 (m, 2H), 7.40ꢀ7.36 (m, 1H), 7.47ꢀ7.51 (m, 2H), 7.74ꢀ7.78 (m, 2H), 8.04 (s,
H).
2
1
1
9
F NMR (376 MHz, CDCl ): δ ꢀ62.76.
3
3
C NMR (100 MHz, CDCl ): δ 17.4, 48.7, 121.9 (sep, JCꢀF = 4.4 Hz), 123.2 (q, JCꢀF = 271 Hz),
3
127.9 131.6, 131.7, 132.3 (q, JCꢀF = 33 Hz), 134.3, 142.6, 167.8.
Mass (EI): 387(89), 386(53), 372(100), 371(84), 368(89), 343(42), 239(25), 159(45).
ꢀ1
IR (KBr): υ 2999, 2923, 1780, 1705, 1467, 1284, 1126, 1060, 895, 712, 528 cm.
+
HRMS (TOFꢀMS) m/z calculated for C H F NO [M+H] 388.0772, found 388.0773.
1
8
11
6
2
General Procedure for synthesis of amide ligand:
Synthesis of N-(1-(3,5-bis(triflouromethyl)phenyl)ethyl)-3,5-dinitrobenzamide (S)-2.
Phthalimide (S)ꢀ5 (0.50 g, 1.29 mmol) was dissolved in a mixture of THF (40 mL) and ethanol (10
mL) hydrazine hydrate (0.63 mL, 12.9 mmol, 99%) was added drop wise. The reaction mixture was
o
stirred at 60 C (5 h). The white suspension formed after this time was filtered washed with THF
(2X20mL) and then organic solvent was evaporated under reduced pressure. To this water was
added and extracted with dichloromethane (2X50 mL). The organic layer was concentrated in
vacuum to furnish viscous liquid. Viscous liquid was dissolved in dry chloroform (5 mL) in which
o
triethyl amine (0.18 mL, 1.28 mmol) was added. The reaction mixture was allowed to cool at 0 C.
A solution of 3,5ꢀdinitrobenzoyol chloride (0.30 g, 1.28 mmol) in chloroform was added slowly
over a period of half an hour. The reaction mixture was stirred for another 4h at room temperature.
The solvent was evaporated and residue was washed with sodium bicarbonate and extracted with
dichloromethane (2X75 mL). The organic layer were dried over sodium sulphate and concentrated
in reduce pressure. The crude product was purified by column chromatography over silica gel (30%

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o
ethyl acetateꢀ petroleum ether). white solid, Yield 0.415g (71%) m.p.=196 C. White Solid, Yield
o
m.p = 196ꢀ97 C [α] = 37.2 (c= 0.5 CHCl ).
D
3
1
H NMR (400 MHz, CDCl ): δ 1.75 (d, J = 7.2 Hz, 3H), 5.43ꢀ5.50 (m, 1H), 6.90 (d, J = 6.8 Hz,
3
1H), 7.85(s, 1H), 7.87 (s, 2H), 9.00 (d, J = 2.0 Hz, 2H), 9.20ꢀ9.211 (t, J = 2.0 Hz, 1H).
1
9
F NMR (376 MHz, CDCl ): δ ꢀ62.78.
3
1
3
C NMR (100 MHz, CDCl ): δ 21.6, 49.8, 121.5, 121.9 ((sep JCꢀF = 4.4 Hz), 127.3. 125.8 (q, JCꢀF
=
3
271 Hz), 126.6, 132.3 (q, JCꢀF = 33Hz), 136.9, 144.8, 148.7, 162.1.
Mass (EI): δ 451(29), 450(11), 240(44), 195(100).
ꢀ1
IR (KBr): υ 3343, 3088, 1647, 1544, 1348, 1278, 897, 731 cm.
ꢀ
HRMS (TOFꢀMS) m/z calculated for C H F N O [MꢀH] 450.0530, found 450.0527.
1
7
11
6
3
5
Synthesis of (S)-N-(1-(3,5-bis(triflouromethyl)phenyl)ethyl)benzamide (S)-7.
The amide was (S)ꢀ7 was prepared similarly in 73 % yield starting from (S)ꢀ5 as described above.
o
White Solid, Yield = 73 % m.p = 156 C [α] = 22.4 (c= 1, CHCl )
D
3
1
H NMR (400 MHz, CDCl ) δ 1.66 (d, J = 7.2 Hz, 3H), 5.38ꢀ5.45 (m, 1H), 6.44 (d, J = 6.8 Hz),
3
7.46ꢀ7.58 (m, 3H), 7.79ꢀ7.78 (m, 3H), 7.84 (s, 2H).
1
9
F NMR (376 MHz, CDCl ): δ ꢀ62.77.
3
1
3
C NMR (100 MHz, CDCl ): δ 21.9, 48.9, 121.4 (sep JCꢀF = 4.4 Hz), 123.3 (q, JCꢀF = 271Hz),
3
126.4, 126.9,128.7, 131.9,132.4 (q, JCꢀF = 33Hz), 133.7, 146.2, 166.9.
Mass (EI): δ 361(100), 360(58), 240(19), 105(90), 104(71).
ꢀ1
IR (KBr): υ 3340, 3087, 1639, 1530, 1382, 1124, 920, 895, 845, 703 cm.
+
HRMS (ESI+) m/z calculated for C H F NO [M+Na] 384.0799, found 384.0794.
1
7
13 6

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Acknowledgments: We thank Council of Scientific and Industrial Research (CSIR), New Delhi for
the award of Senior Research Fellowship to one of us (NJ). We are also grateful to DSTꢀPURSE for
the single crystal Xꢀray diffraction facility of the Faculty of Science. We thank Novozyme,
Bangalore (India) for the generous gift of immobilized enzyme and Navin Fluorine International
Limited, Surat (India) for the gift of 3,5ꢀbis(trifluoromethyl)acetophenone.
References and Notes:
1
. (a) W.H. Pirkle and Y. Liu, J. Chromatogr. A, 1996, 736, 31. (b) X. Gao and H.B. Kagan,
Chirality, 1998, 10, 120. (c) C. Gennary, S. Ceccarelli, U. Piarulli, C.A.G.N. Montalbetti
and R.F.W. Jackson, J. Org. Chem., 1998, 63, 5312. (d) E. Yashima, J. Chromatogr. A,
2
001, 906, 105. (e) C. Wolf and P.A. Hawes, J. Org. Chem., 2002, 67, 2727. (f) A.
Duursma, A.J. Minnaard and B.L. Feringa, Tetrahedron, 2002, 58, 5773. (g) X. Lai and S.ꢀ
C. Ng, Tetrahedron Lett., 2003, 44, 2657. (h) C. Wolf, Z. Fadul, P.A. Hawes and E.C.
Volpe, Tetrahedron: Asymmetry, 2004, 15, 1987. (i) C. Moiteiro, N. Fonseca, M.J.M. Curto,
R. Tavares, A.M. Lobo, P. RibeiroꢀClaro, V. Félix and M.G.B. Drew, Tetrahedron:
Asymmetry, 2006, 17, 3248.
2
. (a) J. Guo, J. Wu, G. Siuzdak and M.G. Finn, Angew. Chem.. Int. Ed., 1999, 38, 1755. (b)
M.T. Reetz, M.H. Becker, H.ꢀW. Klein and D. Stockigt, Angew. Chem.. Int. Ed., 1999, 38,
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758. (c) C. Markert and A. Pfaltz, Angew. Chem.. Int. Ed., 2004, 43, 2498.
3
. (a) M.T. Reetz, M.H. Becker, K.M. Kuhling and A. Holzwarth, Angew. Chem.. Int. Ed.,
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998, 37, 2647. (b) R. Eelkema, R.A. van Delden and B.L. Feringa, Angew. Chem.. Int. Ed.,
004, 43, 5013. (c) L. Zhu and E.V. Anslyn, J. Am. Chem. Soc., 2004, 126, 3676. (d) X. Mei
2

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and C. Wolf, Chem. Commun., 2004, 2078. (e) J.F. FolmerꢀAndersen, V.M. Lynch and E.V.
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2
005, 7, 4045. (g) X. Mei and C. Wolf, J. Am. Chem. Soc., 2006, 128, 13326. (h) D. Leung
and E.V. Anslyn, J. Am. Chem. Soc., 2008, 130, 12328.
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. (a) K. Ding, A. Shii and K. Mikami, Angew. Chem.. Int. Ed., 1999, 38, 497. (b) M.T. Reetz,
D. Kuhling, H. Hinrichs and D. Belder, Angew. Chem.. Int. Ed., 2000, 39, 3891. (c) S.
Nieto, J.M. Dragna and E.V. Anslyn, Chem. Eur. J., 2010, 16, 227. (d) M.W. Ghosn and C.
Wolf, J. Am. Chem. Soc., 2009, 131, 16360.
5
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