Roof shape amines: Synthesis and application as NMR chiral solvating agents for discrimination of α-functionalized acids We wish to dedicate this paper to Professor Sukh Dev on the occasion of his 90th birthday

Article abstract of DOI:10.1016/j.tet.2014.05.001

A series of new chiral roof shape amines have been prepared from anthracene involving simple chemical steps and enzymatic resolution of isomers. The amines were screened as chiral solvating agents for the discrimination of enantiomers of several α-functionalized acids by the ¹H NMR analysis. The system can also be used to accurately measure enantiomeric excess of mandelic acid by ¹H NMR analysis. The roof shape CSAs were capable of detecting the shift in the signals for the standard four nuclei of ¹H, ¹³C, ¹⁹F and ³¹P of various optically active acids.

Full text of DOI:10.1016/j.tet.2014.05.001

Tetrahedron xxx (2014) 1e12
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Roof shape amines: synthesis and application as NMR chiral
solvating agents for discrimination of
a
-functionalized acids
*
Nilesh Jain, Monali B. Mandal, Ashutosh V. Bedekar
Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara 390 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new chiral roof shape amines have been prepared from anthracene involving simple chemical
steps and enzymatic resolution of isomers. The amines were screened as chiral solvating agents for the
Received 31 March 2014
Received in revised form 25 April 2014
Accepted 1 May 2014
discrimination of enantiomers of several a
-functionalized acids by the 1H NMR analysis. The system can
also be used to accurately measure enantiomeric excess of mandelic acid by 1H NMR analysis. The roof
Available online xxx
shape CSAs were capable of detecting the shift in the signals for the standard four nuclei of 1H, 13C, 19
and 31P of various optically active acids.
F
We wish to dedicate this paper to Professor
Sukh Dev on the occasion of his 90th
birthday
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Importance of chiral molecules in different areas is now a well
established fact and the subject of asymmetric synthesis is
a universally acknowledged thrust area. Along with this growth
there is increasing demand for simultaneous development of
The nature of the functionality and the shape of chiral molecules
are important considerations for the design and applications of
optically active compounds. These aspects play significant role in
the molecular recognition and supramolecular interactions, the
essential requirements for medicinal chemistry and asymmetric
synthesis. Hence, it is a matter of interest for the contemporary
organic chemists to design and synthesize structurally diverse
novel chiral molecules. Weber introduced one such class of com-
pounds with the concept of geometrically designed roof shape
molecules.1 The basic unit of these molecules, which resembles
a roof of a house, is made up of functional groups protruding like
antenna and a bulky skeleton similar to its foundation (Fig.1). Some
other compounds, such as iptycene,2 triptycene,3 pentiptycene4 and
molecular tweezers5 have structural similarity and have found
several useful applications, mostly as devices in material chemistry.
Roof shape molecules possessing functional groups such as alcohol,
amine, acid and acid derivatives have also found applications in
medicinal chemistry,6 as ligands in catalytic transformations,7 as
mediators in organocatalytic reactions8 and in preparations of
functional materials.9 Two types of roof shape molecules are
depicted as A and B in Fig. 1, which were prepared by DielseAlder
reaction of anthracene and suitable dienophile, acrylic acid or
fumaric acid, respectively. Such molecules with acid as the func-
tional group (Fg) or their reduced alcohol form, have been obtained
as chirally pure isomers and studied for various applications.10
* Corresponding author. Tel.: þ91 265 2795552; e-mail address: avbedekar@ya-
hoo.co.in (A.V. Bedekar).
Fig. 1. Concept of roof shape molecules and proposed categories of amine derivatives.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.001
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N. Jain et al. / Tetrahedron xxx (2014) 1e12
reliable and quick methods to determine optical purity of the
chiral molecules. Usually the enantiomeric excess (ee) is con-
firmed by more than one analytical methods such as chroma-
tography (GC or HPLC with chiral stationary phase), spectroscopy
(NMR, CD), capillary electrophoresis, etc. Out of these techniques,
1H NMR spectroscopy is quite effective in detail investigation of
chiral purity of many molecules, particularly as the process of
recording spectra is quite simple; it is non-destructive and suit-
able to study dynamic interactions. With the advent of NMR
spectrometers most of the laboratories dealing with the chiral
molecules have access to high-resolution machines for the quick
analysis. The NMR spectra of the enantiomers display the same
splitting pattern and chemical shifts, when recorded in achiral
environment. However, the NMR active nuclei of diastereomeric
compounds have slightly different environment and show sig-
nificant change in the signals. Therefore, for accurate de-
termination of the ratio of enantiomers by NMR spectroscopy, it is
necessary to quantitatively convert the analyte to the di-
astereomers. This can be achieved by forming diastereomeric
derivatives of the analyte with appropriate chiral derivatizing
agents (CDAs), such as Mosher’s acid,11 involving a covalent bond.
In another approach chiral solvating agents (CSAs)12 can be mixed
during the NMR analysis where they bind with the chiral analyte,
temporarily creating in situ diastereomers and their ratio estab-
lished by detecting signals. In the case of CSA due to the forma-
tion of diastereomers the signals split into two separate sets and
can be easily measured. The latter technique has distinct advan-
tages of simplicity, accuracy and it is non-destructive due to weak
non-covalent interactions. Previously, the focus was on the use of
chiral lanthanide shift reagents for determination of enantiomeric
excess by NMR analysis. This technique involves the in situ for-
mation of diastereomers of test sample (generally behaving as
Lewis base) with externally added chiral lanthanide shift reagents
(as Lewis acid). Besides the additional cost of these reagents,
some operational difficulties such as its low solubility in NMR
solvents and broadening of signals due to paramagnetic proper-
ties, the use of alternative CSAs have emerged as an attractive
option. The intermolecular interactions including dipoleedipole,
a Lewis acid. In our ongoing work15 we have explored this reaction
to build roof shape molecules in non-racemic form and converted
them to their functionalized derivatives. We have established effi-
cient conditions for selective separation of the enantiomers of diol
1 by enzymatic transesterification, followed by their conversion to
optically pure diamines. Synthesis of structurally analogous chiral
roof shape molecules was also known in the literature.16 In some
cases the isomers of roof shape compounds have been resolved by
fractional crystallization of their covalently bonded di-
astereomers.17 In the present study we report the synthesis of chiral
roof shape alcohols, their conversion to amines and their applica-
tions as chiral solvating agents (or complexing agents) for NMR
discrimination.
Synthesis of the roof shape amines and diamines can be ach-
ieved via the alcohols or diols, which may intern be prepared by the
DielseAlder reaction of anthracene and unsaturated acid or ester.
The cycloaddition reaction of anthracene and ethyl acrylate to
furnish adduct 2, was catalyzed by anhydrous aluminium chloride
(Scheme 1). The ester was subsequently reduced with I2eNaBH4
method18 to furnish roof shape alcohol 3.
charge transfer, van der Waals,
pep stacking and formation of H-
bonding, etc. were then exploited by many researchers in de-
signing and preparing a series of molecules to act as CSA.13 At the
same time few chiral crown ethers have also been designed as
effective CSAs where the interactions could be of different
nature.14
Scheme 1. Synthesis of roof shape diol 1 and alcohol 3.
The diol 1 and the alcohol 3 were then resolved using enzymatic
transesterification and suitable acyl donor under the appropriate
conditions (Scheme 2).15 The optimization of conditions for effi-
cient separation of enantiomers of 3 was developed in the present
work and is outlined in Table 1.
2. Results and discussion
It is well established that the molecule of anthracene undergoes
DielseAlder reaction with suitable dienophile in the presence of
Scheme 2. Resolution of alcohol 3 and diol 1 by enzyme mediated acylation.
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N. Jain et al. / Tetrahedron xxx (2014) 1e12
3
Table 1
The basic skeleton of the roof shape molecules offer two aro-
matic rings for possible interaction with another system. The
Optimization of conditions for resolution of (ꢀ)-3a
pep
three dimensional bicyclic shape is also quite rigid to favour and
control the intermolecular interactions and hence we have pro-
posed to develop their amino derivatives for possible CSA appli-
cations. The optically pure diol (S,S)-1 and alcohol (R)-3 were
converted to the corresponding diamines and amines15 (Schemes 4
and 5). The chiral mono alcohol (R)-3 accessed in the present work
was converted to mono tosylate (R)-10 and then to its mono bromo
analogue (R)-11 by standard conditions. The tosylate (R)-10 was
converted to the roof shape amines (R)-13, (R)-14 and (R)-15 by
treatment with piperidine, piperazine and pyrrolidine, respectively.
Similar strategy was employed to prepare a set of diamines from
the corresponding ditosylate (S,S)-12 obtained from optically pure
(S,S)-1. The three roof shape chirally pure diamines (S,S)-16, (S,S)-17,
(S,S)-18 and (S,S)-19 were prepared by substitution with piperidine,
morpholine, pyrrolidine and 1,2,3,4-tetrahydroisoquinoline, re-
spectively (Scheme 5).
No Conditions
ee (%) ee (%) Conversion E value
of 3
of 5
Steapsin lipase
1
2
3
4
VA (1.5 equiv), THF 30 ꢁC, 48 h
77
59
29
16
60
78
61
80
56
43
32
16
10
14
6
VA (1.5 equiv), THF 8e10 ꢁC, 48 h
IPA (3.0 equiv), THF 30 ꢁC, 100 h
VA (1.5 equiv), dioxane 30 ꢁC, 48 h
11
Candida rugosa lipase
VA (3.0 equiv), THF 30 ꢁC, 96 h
5
4
26
13
2
Novozyme-435 lipase
6
7
8
9
VA (1.0 equiv), DIPE 30 ꢁC, 2 h
EA (5.0 equiv), DIPE 30 ꢁC, 15 h
VA (1.0 equiv), THF 30 ꢁC, 4 h
IPA (1.0 equiv), THF 30 ꢁC, 4 h
65
21
63
>99
85
95
59
89
91
74
41
26
42
52
53
77
5
36
125
17
10 IPA (1.0 equiv), THF 8e10 ꢁC, 6 h
VA¼vinyl acetate; IPA¼iso-propenyl acetate; EA¼ethyl acetate.
a
Ratio of (ꢀ)-3 to enzyme: 1.0:1.3 (w/w) for entries 1 and 4; ratio of (ꢀ)-3 to
enzyme: 1.0:0.33 (w/w) for entries 5e10.
In order to study the effect of the rigid bicyclic frame with the
two aromatic rings and the chiral centre, an analogous molecule
was synthesized. The bromo derivative (R)-11 was coupled with
piperazine to obtain di-N-alkylated derivative (R,R)-20. All the roof
shape chiral amines and diamines were characterized by usual
spectroscopic and analytical techniques (Schemes 4e6).
The absolute configuration of enantiomerically pure 3 was
established by preparing its ester with optically pure O-acetyl
mandelic acid.19 The chirally pure alcohol 3 was converted to the
diastereomerically pure ester 7 by its reaction with (S)-O-acetyl
mandelic acid (Scheme 3). The single crystal X-ray diffraction
analysis20 of 7 clearly established the absolute configuration of the
stereogenic carbon to be ‘R’ (Fig. 2). The alcohol was also converted
to the corresponding acid 9 of the known configuration, via the
aldehyde 8 using mild oxidation reaction condition.21 The absolute
configuration was further confirmed by comparison of the sign of
its specific rotation with the known data.22
The scope of the ability of optically pure roof shape amines to
discriminate the chiral substrates such as a-substituted carboxylic
acids was investigated by performing few NMR experiments at
ambient conditions. The screening process was conducted with the
racemic sample of mandelic acid 21 as the standard substrate with
the amines or diamines and the results are presented schematically
in Fig. 3 as well as the data is summarized in Table 2. The solution of
(ꢀ)-21 in CDCl3 (20 mM) was mixed with the test amine (or di-
amine) whose solution is also prepared in the same solvent in the
same concentration. The 1H NMR of the mixture was recorded at
400 MHz at ambient conditions, the CaH of (ꢀ)-21 showed a slight
shift towards the high field region. The induced chemical shift (Dd
)
was expressed in terms of the difference between the CaH signal of
(ꢀ)-21 measured in CDCl3 and the average of the separated signals
of the two enantiomers, while the chemical shift non-equivalences
(DDd) is the difference between the two resolved peaks.
The effect of amines (R)-13 to (R)-15 on mandelic acid (ꢀ)-21
was restricted mainly to the small shift of the CaH signals to the
upfield region but failed to resolve them significantly. However,
addition of diamine (S,S)-16 considerably enhanced the induced
chemical shift of the CaH signals to the upfield region but also
caused a good separation of the signals. Similar but marginally
lower resolution of the same signals was observed with morpholine
derived diamine (S,S)-17. However, the pyrrolidine derived diamine
(S,S)-18 improved the separation to more extent. This may be at-
tributed to the envelope like, slightly rigid form of the five-mem-
bered ring as against the other two six-membered chair-like
conformations.
Scheme 3. Determination of absolute configuration of (R)-3.
The effect of concentration on the ability of molecular recogni-
tion by the present CSAs was further investigated. The molar con-
centration of (S,S)-18 and (ꢀ)-21 was varied from 5.0 to 100.0 mM
in CDCl3, where the optimum values of chemical shift non-
equivalences were observed at 20.0 mM, which were followed for
all further experiments.
The roof shape amines, which show promise for (ꢀ)-21 were
then screened for few derivatives of mandelic acid to study the
effect of substitution (Scheme 7). For most of the cases it was ob-
served that the presence of electron withdrawing group (CF3 or Br)
showed enhanced degree of the shift of the signals as well as and
the chemical shift non-equivalences compared to mandelic acid. In
most of the cases of mandelic acid derivatives the diamines were
more effective in causing discrimination between CaH signals of the
Fig. 2. ORTEP diagram of diastereomeric 7.
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4
N. Jain et al. / Tetrahedron xxx (2014) 1e12
Scheme 4. Conversion of optically pure alcohol 3 to amines.
Fig. 3. Effect of the roof shape chiral amine on the CaH of the racemic mandelic acid
recorded at 20 mM, CDCl3, 400 MHz, (a) pure (ꢀ)-21, (b) (ꢀ)-21þ(S,S)-18 (2:1).
Table 2
Effect of the roof shape chiral amines and diamines on the a-proton of the racemic
mandelic acid 21.
equivalences.]
[
Dd¼induced chemical shifta; DDd¼chemical shift non-
No Amine/diamine Ratio of amine/diamine:21 Probe signal PhCH(OH)COOH
Scheme 5. Synthesis of roof shape diamines from (S,S)-1.
Dd (ppm)
DDd (ppm)
1
2
3
4
5
6
7
8
9
(R)-13
(R)-13
(R)-14
(R)-15
(S,S)-16
(S,S)-17
(S,S)-18
(S,S)-18
(S,S)-19
1:1
2:1
1:1
1:1
1:2
1:2
1:1
1:2
1:2
1:1
ꢂ0.15
ꢂ0.33
ꢂ0.14
ꢂ0.19
ꢂ0.26
ꢂ0.15
ꢂ0.21
ꢂ0.28
ꢂ0.21
ꢂ0.18
eb
eb
eb
0.007
0.056
0.044
0.032
0.071
0.024
0.008
10 (R,R)-20
a
Scheme 6. Synthesis of bis-amine of Type C.
The difference between the signals of 21 in CDCl3 solution and the average of the
signals of the two enantiomers after the addition of the amine or diamine.
b
Not resolved.
two isomers, with the exception of (R)-15, (entries 1e8, Table 3).
The CSA was also scanned for 2-(benzo[d][1,3]dioxol-6-yl)-2-
hydroxyacetic acid 24, where the amine (S,S)-18 was found suit-
able (entry 4). It was noteworthy to observe the OeCH2eO signals
getting split into two sets of two doublets on complexation with
(S,S)-18 with coupling constant of 1.2 Hz.
Two derivatives of mandelic acid where the hydroxyl group is
blocked by methyl ether in 25 and by acetyl ester in 26, were
scanned with CSA. Both the protons of methyl ether derivative 25,
i.e., CaH and CaOCH3 showed discrimination in 1H NMR (entries 5
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N. Jain et al. / Tetrahedron xxx (2014) 1e12
5
Scheme 7. List of a-functionalized acids tested with selected CSAs.
significant to note that the proton present on the alkyl substituent
on the aromatic ring of 28 also indicated discrimination. The
methine proton (CHb of 28), which should show a multiplet in 1H
NMR showed two sets of signals with CSA (entries 13e15). This
Table 3
Screening of amines and diamines as CSA for various
a
-substituted acids. [Dd¼in-
duced chemical shifta; DDd¼chemical shift non-equivalences.]
No
DL-Acid
CSAb
Probe signal H in bold (Scheme 7)
observation is probably due to the CHbep interaction between the
Dd (ppm)
DDd (ppm)
methine proton and the aromatic ring of the CSA. We were also able
to resolve the signals CaH of tartaric acid derivative (29) with (S,S)-
18 (entry 16, Table 3).
1
2
3
4
5
6
7
8
21
22
23
24
25
25
26
26
27
27
28
28
28
28
28
29
(S,S)-18
(S,S)-18
(S,S)-18
(S,S)-18
(S,S)-18
(S,S)-18
(S,S)-18
(S,S)-18
(R)-13
(R)-13
(R)-13
(R)-15
(S,S)-16
(R)-13
ꢂ0.28
ꢂ0.36
ꢂ0.34
ꢂ0.28
ꢂ0.15
ꢂ0.07
ꢂ0.055
þ0.007
ꢂ0.051
þ0.043
ꢂ0.012
ꢂ0.015
ꢂ0.011
ꢂ0.052
ꢂ0.062
Nil
0.071
0.058
0.076
0.040
The diastereomeric complex formation of the roof-shaped chiral
receptor with carboxylic acid possibly occurs with a proton transfer.
The formation of the carboxylate anion was confirmed when the
carbonyl stretch (1716 cmꢂ1 for mandelic acid) disappeared in the
FTIR spectra of a mixture of (S,S-18)/(ꢀ)-21 (1:1), and the observed
intensities got stronger at 1615 and 1622 cmꢂ1(the COOꢂ stretch).24
This may support the hypothesis that the binding of the carboxylate
ion of the racemic acid with the chiral CSA may provide di-
astereomeric complex structure where the aromatic ring of the acid
0.074 (CaH)
0.063 (CaOCH3)
0.045 (CaH)
0.004 (COCH3)
0.015 (CaH)
0.008 (CbOCH3)
0.011 (CaCH3)
0.007 (CaCH3)
0.007 (Ha)
0.007 (Ha)
0.007 (Hb)
0.043 (CaH)
9
10
11
12
13
14
15
16
(S,S)-16
(S,S)-18
may lie over one of the aromatic rings of CSA by favouring a
interaction.
pep
a
The difference between the signals of indicated H in CDCl3 solution and the
average of the signals of the two enantiomers after the addition of the amine or
diamine.
In continuation of our study of discrimination of signals of a-
functionalized acid derivatives we further examined other nuclei,
namely 13C, 19F and 31P under the effect of CSA interactions. To the
best of our knowledge not many CSAs have been effectively in-
vestigated in detecting all the four routinely targeted NMR active
nuclei for such study, although individually their analysis is
reported.25
b
Ratio of acid/CSA was 2:1 (for entries 1e8, 13 and 15) and 1:1 (for entries 9e12,
14 and 16). All the experiments were run at 20 mM concentration.
and 6, Table 3). Similar results were observed for O-acetyl de-
rivative 26 (entries 7 and 8, Table 3). This study will establish that
our system detects discrimination of more than one sets of hy-
drogen in 1H NMR analysis.
The carbonyl carbon and aC of (ꢀ)-22, which are expected to
show single peaks in 13C NMR were observed in the presence of CSA
(S,S)-18. The signals of carbonyl and aC appear as two well-sepa-
rated peaks on treatment with CSA (Fig. 4).
The CSA system was examined for the discrimination of signals
of relatively bulky 2-hydroxy-3-methoxy-3,3-diphenyl propionic
acid (ꢀ)-27, which is an intermediate for few pharmaceutical en-
tities.23 Signals of CaH and CbOMe (ꢀ)-27 were noticed to have been
affected by the complex formation between this racemic acid and
the amines (entries 9 and 10, Table 3). Particularly, the two hy-
drogen signals of CaH showed base line separation with (S,S)-18.
The hydrogen from ‘S’ isomer of 27 could be identified when
a sample of non-racemic mixture (20% ee of ‘S-27’) was analyzed,
determining a defined control over the interactions.
The racemic sample of ibuprofen 28, a widely used non-steroi-
dal anti-inflammatory agent, was also analyzed for the chiral rec-
ognition with the synthesized roof shape amines. There are three
hydrogens of the molecule of 28, which showed shift on the rec-
ognition with the CSA. The CaMe of 28 appeared as two doublets
under the influence of (R)-13 or (R)-15 (entries 11 and 12, Table 3).
The CaHa showed slightly more resolution with (R)-13 compared
with (S,S)-18 as clearly eight lines were seen corresponding to the
two separated quartets for the enantiomers (entries 13 and 14). It is
Fig. 4. (a) Carbonyl carbon of 13C NMR of (ꢀ)-22 with CSA [DDd¼0.11 ppm]; (b) aC of
13C NMR with CSA [DDd¼0.20 ppm]; CSA¼(S,S)-18; ratio of (ꢀ)-22 to CSA (2:1).
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6
N. Jain et al. / Tetrahedron xxx (2014) 1e12
The 19F NMR of 4-trifluoromethyl mandelic acid (ꢀ)-22 in
biologically significant compounds and ligands for asymmetric
synthesis also have phosphorous, we have extended our in-
vestigations to study 31P NMR of such molecules. To assess the
ability of our systems to recognize phosphorous containing acids
we chose racemic sample of (ꢀ)-1,10-binaphthyl-2,20-diyl hydrogen
phosphate 34 and studied its 31P NMR (at 162 MHz in CDCl3). The
chiral molecule of acid 34 has recently been widely used in asym-
presence of the CSA was then examined. Such approach was not
very routinely investigated.25a,25b The 19F NMR of (ꢀ)-22 shows
a sharp, single signal without any interference or overlap as in case
of the 1H NMR. The 19F signal of (ꢀ)-22 with (S,S)-16 showed two
well separated sharp signals (Dd¼0.662 and DDd¼0.054) corre-
sponding to the two enantiomers of equal ratio (Fig. 5a).
Fig. 5. (a) 19F NMR spectrum (376 MHz) of (ꢀ)-22 with (S,S)-16 (2:1); (b) The Ar-H region of 1H NMR of (ꢀ)-22 without CSA (b-i); in presence of CSA (S,S)-18 (2:1) (b-ii).
Interestingly the signals of the aromatic protons of (ꢀ)-22 also
exhibited considerable discrimination in 1H NMR spectrum when
recorded with the CSAs of Type-B. The three representative ex-
amples of CSA were investigated. The signals with (S,S)-16
metric transformations and hence it is important to develop a re-
liable method to quickly determine its optical purity.26 To the best
of our information only few CSAs work efficiently13i for such de-
tection because the chemical shift difference was generally not
found sufficiently large for the base line separation of the signals in
31P NMR.27 Hence, we examined our most effective CSA (S,S)-18 for
the discrimination of the signal of phosphorous of the racemic
sample of 34 and found very good resolution. In order to assign the
configuration to the signals we scanned a non-racemic sample of 34
(2:1 for R isomer) with optically pure (S,S)-16 and (S,S)-18 and
detected a good separation of signals (Fig. 6b and c), though with
monoamine (R)-15, slightly less separation was observed (Fig. 6d).
In both the systems the separation of isomers was very clear and
can be quantitatively measured. Consistently good separation of
signals for 31P NMR with different CSAs was observed (Table 5)
confirming the generality of our system.
(Dd¼ꢂ0.096 and DDd¼0.197) and (S,S)-17
(Dd¼ꢂ0.082 and
DDd¼0.103) were slightly overlapping but with (S,S)-18 a clear and
complete separation for the two sets of signals (eight lines) were
seen (Dd¼ꢂ0.170 and DDd¼0.202). The comparison of aromatic
hydrogens without and with CSA (S,S)-18 is presented in Fig. 5b.
Since the 19F NMR is quite useful for quick and reliable analysis
as the spectra have few signals, we examined our roof shape
amines-based CSAs for (ꢀ)-22. In continuation of our observations
the diamines were found to be more effective compared to the
monoamine based CSA (Table 4).
Table 4
Screening of different CSAs for (ꢀ)-22 to measure shift in 19F NMR
Determination of the optical purity of natural and unnatural a-
No
CSA
DDd (ppm)
amino acids and their derivatives is of prime importance since they
are used for the synthesis of many pharmacologically active mol-
ecules. In order to develop a facile method of determining optical
purity by NMR analysis, several CSAs have been recently
screened.28 The present set of CSAs was further explored to check
the discrimination of the protons located at different positions of
1
2
3
4
(S,S)-16
(S,S)-17
(S,S)-18
(R)-15
0.054
0.039
0.052
0.010
the N-Ts derivative of a-amino acid such as phenyl glycine (Fig. 7). It
is often seen that the region of 1H NMR spectrum where the dif-
ferentiation is observed is overlapped with the area covering the
signals of CSA. The analysis will be more accurate if it is confirmed
by checking the ratio of more than one protons of the sample.
Hence it is more useful to examine different signals, which shift on
the addition of CSA for more effective analysis of the analyte. For
this study the more consistently effective diamine based CSAs (S,S)-
16, (S,S)-17 and (S,S)-18 were screened to examine chiral recogni-
tion of 30 and to examine shift of its protons. In order to correlate
the signals with the two enantiomers of 30 a sample of N-Ts phenyl
glycine was prepared by mixing its D and L isomers in a fix ratio
(2:1).
We also examined the 19F NMR of an amino acid derivative 33
(Scheme 8) with (S,S)-18 where the fluorine showed two sets of
signals with considerable separation. The chemical shift non-
equivalence DDd was recorded to be 0.017 ppm. Since many
Firstly the methyl protons of the N-Ts moiety of 30 were ob-
served with the three different CSAs in the molar ratio of 2:1 (30/
Scheme 8. Chiral acids with other nuclei for NMR detection.
CSA) (Fig. 8a). The single unresolved signal at
d 2.39 ppm of 30
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N. Jain et al. / Tetrahedron xxx (2014) 1e12
7
morpholine derived (S,S)-17 (Dd¼ꢂ0.24 and DDd¼0.038) probably
the presence of oxygen atom of the CSA is responsible for this de-
viation. The upfield shift of the CaH proton in all the cases is con-
sistent due to the deprotonation of the acid group as the shielding
effect is more in case of carboxylate ion.
In the next set of study we observed the shifting of the position
of the signal of NeH hydrogen on addition of CSA (Fig. 8c). These
are the only signals, which move to downfield region indicating
stronger intramolecular hydrogen bond with carboxylate as com-
pared to carboxylic acid in the absence of CSA.29 In this case all the
three CSAs showed more or less same effect.
The structure of the CSA for the present study was designed in
such a way as to offer a three-dimensional motif and present an
aromatic plane for the effective
pep interaction with the analyte.
Due to this interaction we expect some shift in the signals of the
aromatic protons of (ꢀ)-30. Although the protons meta to the SO2N
group of N-Ts were merged with the aromatic signals of the CSAs,
the protons ortho to SO2N group appeared separately at the
downfield region and were quite suitable for this study. These
protons appeared as a doublet and as the most downfield, well
resolved signal of the spectra. The same set of CSAs was scanned for
these protons and results clearly indicate resolution of the two
doublets for the two isomers of 30 (Fig. 8d). Since these protons are
not attached to any electronegative atoms there was no significant
shift (Dd) but reasonable base line separation of the signal was
observed for (S,S)-16 and (S,S)-18, with substantial chemical shift
non-equivalences (DDd¼0.063 and 0.064).
Further exploration of application of CSA for other amino acids,
such as N-Ts alanine 31 and N-Ts phenyl alanine 32, revealed that
the presence of a rigid p-system is required for effective interaction.
Both these showed lesser degree of discrimination compared to N-
Ts phenyl glycine 30 for all the four protons under study. In both the
cases signals of methyl protons of Ts group showed discrimination
with (S,S)-18 similar to N-Ts phenyl glycine. While the aromatic
protons of Ts moiety of 32 showed discrimination with (S,S)-18, the
corresponding protons of 31 did not resolve, probably due to the
Fig. 6. 31P NMR spectrum (174 MHz) of (ꢀ)-34 with: blank (a), with (S,S)-16 (2:1) (b),
(S,S)-18 (2:1) (c) and with (R)-15 (1:1) (d).
Table 5
lack of pep interaction in alanine.
Screening of different CSAs for (ꢀ)-34 to measure shift in 31P NMR
The stoichiometry of the complex formed between (S,S)-18 and
mandelic acid (S)-21 was determined according to Job’s method of
continuous variations.30 Equimolar solutions of (S,S)-18 and (S)-21
were prepared in CDCl3 (20 mM, 5 mL) for this study. These solu-
tions were distributed among 13 NMR tubes in such a way that the
mole fractions (X) of (S,S)-18 and (S)-21 in the resulting solutions
increased from 0,1 to 0,9. The complexation induced shifts of the
methine signal (Dd) were multiplied by the mole fraction of the acid
((S)-21) and plotted against X to obtain the Job’s plot, which showed
a maxima at 0.67 (Fig. 9). This indicates that (S,S)-18 and the (S)-21
bind in a 1:2 complex under these conditions.
No
CSA
Dd (ppm)
DDd (ppm)
1
2
3
(S,S)-16
(S,S)-18
(R)-15
ꢂ1.01
ꢂ0.79.
þ0.30
0.60
0.69
0.15
Further information about the nature of the complex between
CSA (S,S)-16 and mandelic acid (ꢀ)-21 was obtained by performing
2D NOESY experiment (Fig. 10). Analysis of the spectra clearly
showed cross peak between protons of C3eC4eC3 methylenes of
piperidine ring of (S,S)-16 with CaH of (ꢀ)-21 and its aromatic
protons. This assumption is supported by our observation when
Fig. 7. Selected protons of N-tosyl phenyl glycine 30 resolved with CSA.
these CSAs failed to recognise
a-chloro propionic acid, where there
is no interaction. These observations support the tightly held
pep
acidebase interaction between the roof-shaped diamines and car-
boxylic acid. We have also observed the role of free eOH or eNH
group attached at the stereogenic centre of the a-functionalized
acids for effective binding. The OAc derivative of mandelic acid,
PhCH(OAc)COOH (26), was tested with (S,S)-18, and the 1H NMR
showed lesser degree of chemical shift non-equivalences
shifted upfield with all the three CSAs, but most effective separation
was observed with pyrrolidine derived (S,S)-18 (Dd¼ꢂ0.11 and
DDd¼0.029). It is noteworthy to observe such pronounced effect on
the methyl protons, which are located far away from the chiral
centre of a-amino acid.
In comparison, the CaH directly attached to the chiral centre
observed a significant shift for (S,S)-18 (Dd¼ꢂ0.39 and DDd¼0.048)
and for the piperidine derived (S,S)-16 (Dd¼ꢂ0.36 and DDd¼0.036)
(Fig. 8b). It is interesting to see a small shift in the pattern for
(
DDd¼0.045 for 26 and 0.071 for 21). Compared to this the
methoxy derivative of mandelic acid 25 showed slightly better
values13q
DDd¼0.074), probably due to marginal increase in its
acidity and hence electrostatic interactions.
a-
(
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8
N. Jain et al. / Tetrahedron xxx (2014) 1e12
Fig. 8. 1H NMR spectra of 30 with three CSAs: (7a) signal for CH3 of 30 with (i) blank, (ii) (S,S)-16, (iii) (S,S)-17 and (iv) (S,S)-18; (7b) signal of CaH of 30 (D/L¼2:1) with (i) blank, (ii)
(S,S)-16, (iii) (S,S)-17 and (iv) (S,S)-18; (7c) signal of NeH of 30 (D/L¼2:1) with (i) blank, (ii) (S,S)-16, (iii) (S,S)-17 and (iv) (S,S)-18; (7d) signal of Ar-H of 30 (D/L¼2:1) with (i) blank, (ii)
(S,S)-16, (iii) (S,S)-17 and (iv) (S,S)-18.
recognition by employing other NMR active nuclei 13C, 19F, 31P to
determine the CSA efficiency of the chiral roof shape amines.
Conditions were also standardized for quantitative determination
of the ratio of enantiomers in the controlled experiment, which
opens up possibilities for this technique to be used for de-
termination of ee of unknown sample.
4. Experimental section
Thin layer chromatography was performed on silica gel plates
quoted on aluminium sheets. The spots were visualized under UV
light or with iodine vapour. All the compounds were purified by
column chromatography on silica gel (60e120 mesh) and neutral
alumina. All reactions were carried out under an inert atmosphere
(nitrogen) unless other conditions are specified. NMR Spectra were
recorded on Bruker Avance 400 Spectrometer (400 MHz for 1H
NMR, 100 MHz for 13C NMR, 376 MHz for 19F NMR and 162 MHz for
31P NMR) with CDCl3 as solvent and TMS as internal standard. Mass
Fig. 9. Job plot for (S,S)-18 with (S)-21.
spectra were recorded on Thermo-Fischer DSQ II GCeMS in-
strument. IR spectra were recorded on a PerkineElmer FTIR RXI
To demonstrate practical utility of the present CSAs for the
spectrometer as KBr pellets. Elemental analysis was recorded on
quantitative determination of enantiomeric excess (ee) of the un-
known sample of mandelic acid we performed controlled experi-
ment. A set of samples of known ee (optical purity) of mandelic acid
with 0, 20, 40, 60, 80 and 95% ee, respectively, were prepared. These
PerkineElmer EA2400 series II CHNS/O analyzer. Melting points
were recorded in Thiele’s tube using paraffin oil and are un-
corrected. Specific optical rotations were measured on JACSO P-
2000 polarimeter. For the HPLC analysis Chiralcel OD-H and Chir-
samples were analysed with 0.5 equiv of (S,S)-16 by recording their
alpak IC column were used.
1H NMR. The experimental results were in accordance with the
For the synthesis of compounds 2, 3 and ligands (S,S)-16 to (S,S)-
theoretical values as can be seen from Fig. 11.
19, see Supplementary data.15
3. Conclusion
4.1. General procedure for resolution of alcohol 3
Thus in the present work we have synthesized a series of novel
chiral roof shape amines and diamines and explored their utility as
chiral solvating agents for discrimination of enantiomers of several
To a solution of racemic alcohol (3) (0.30 g, 1.27 mmol) in dry
THF (5 mL), lipase (0.10 g, 33% w/w, Novozyme-435) and iso-pro-
penyl acetate (0.13 mL, 1.27 mmol) were added and the reaction
mixture was stirred for 4 h at 30 ꢁC. The material was filtered and
the filtrate was concentrated in vacuum. Separation was carried out
by column chromatography over silica gel using ethyl acetate and
petroleum ether as the eluent. The acetate was eluted with 10%
a
-functionalized acids. We have screened a number of different a-
functionalities and studied their correlation with the ability of
discrimination, in some cases we have noted four different types of
hydrogen being affected in the 1H NMR. We have also recorded the
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N. Jain et al. / Tetrahedron xxx (2014) 1e12
9
Fig. 10. 2D NOESY spectra of (S,S)-16 with (ꢀ)-21 (1:1 ratio at 20 mM solution in CDCl3).
Fig. 11. (a) Select region of 1H NMR spectra of (ꢀ)-21 of various ratios of optical purity in presence of (S,S)-16. Values in parenthesis are observed purity. (b) Correlation between
theoretical and observed ee values.
ethyl acetate/petroleum ether [Rf 0.5] (and alcohol [Rf 0.3]) with
1H NMR (400 MHz, CDCl3):
d
1.04e1.09 (ddd, J¼12.0, 4.8, 2.8 Hz,
28
20% ethyl acetate/petroleum ether (0.131 g, 43.5%). [
a
]
D
3.6 (c 0.7,
1H), 1.90e1.96 (m, 1H), 2.12e2.19 (m, 1H), 2.94e2.99 (dd, J¼10.4,
9.6 Hz, 1H), 3.32e3.36 (dd, J¼10.4, 5.6 Hz, 1H), 4.25e4.27
(t, J¼2.8 Hz, 1H), 4.41e4.42 (d, J¼2.0 Hz, 1H), 7.03e7.13 (m, 4H),
methanol). HPLC condition: Chiralcel OD-H column, 10% iso-prop-
anol in hexane, flow¼0.7 mL/min, UV¼215 nm, retention
time¼14.28 min for (R)-isomer, 17.64 min for (S)-isomer.
7.22e7.30 (m, 4H). 13C NMR (100 MHz, CDCl3):
d 31.0, 40.9, 44.0,
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10
N. Jain et al. / Tetrahedron xxx (2014) 1e12
45.5, 66.1, 123.2, 123.5, 123.6, 125.4, 125.6, 125.7 (2C), 126.0, 140.5,
143.8 (2C), 143.9. Mass (EI): 236 (28), 202 (26), 179 (56), 178 (100),
(d, J¼1.6 Hz, 1H). Mass (EI): 233 (9), 202 (12), 178 (72), 177 (100). IR
(KBr): 3069, 3021, 2949, 2813, 2710, 1714, 1457, 1390, 1234, 1023,
758 cmꢂ1
n
176(8). IR (KBr):
n
3433, 3069, 2945, 1637, 1461, 1370, 1333, 1166,
.
1026, 935, 750, 554 cmꢂ1
.
4.5. 9,10-Dihydroethanoanthracene-11-carboxylic acid (R)-9
4.2. 9,10-Dihydro-9,10-ethanoanthracene-11-acetate (S)-5
A solution of NaClO2 (0.23 g, 2.05 mmol, 80% purity) in water
(3 mL) was added drop wise to a stirred solution of aldehyde (R)-8
(0.400 g, 1.7 mmol) in acetonitrile (3 mL), NaH2PO4 (0.07 g
0.59 mmol) in water (3 mL) and H2O2, (30%, 11.8 mmol, 0.21 mL)
kept in ice bath (5e10 ꢁC), and stirred for 3 h. A small amount of
Na2SO3 (about 0.025 g) was added to destroy the unused HOCl and
28
Yield 0.185 g, 52%, mp¼119e120 ꢁC, (lit.31 ¼ 119 ꢁC) [
(c 0.7, methanol).
a
]
4.3
D
HPLC condition: Chiralpak IC column, 1% iso-propanol in hexane,
flow¼0.5 mL/min, UV¼210 nm, retention time 19.4 min (R), min 20.4
min (S).
1H NMR (400 MHz, CDCl3):
d
1.13e1.18 (ddd, J¼12.4, 4.8, 2.4 Hz,
H2O2. Acidification with aqueous HCl (10%) afforded off white solid
28
1H), 1.90e2.03 (m, 1H), 2.11 (s, 3H), 2.26e2.32 (m, 1H), 3.40e3.45
(dd, J¼10.8, 9.8 Hz, 1H), 3.79e3.83 (dd, J¼11.2, 6.4 Hz, 1H),
4.29e4.30 (t, J¼2.4 Hz, 1H), 4.32e4.33 (d, J¼2.0 Hz, 1H), 7.09e7.16
(m, 4H), 7.25e7.34 (m, 4H). 13C NMR (100 MHz, CDCl3): 21.0, 31.2,
37.4, 43.8, 45.8, 67.3, 123.2, 123.5, 123.6, 125.5, 125.7, 125.8, 125.9,
126.2,139.4,143.4,143.5,143.6,171.0. Mass (EI): 278 (1), 202 (2),179
(15), 178 (100). IR (KBr) cmꢂ1: 3068, 3022, 2920, 1737, 1461, 1362,
1236, 1035, 951, 754. Anal.: found C 81.83, H 6.57; required
(0.30 g, 70%). Mp¼188 ꢁC (lit.1a¼189 ꢁC). [
a
]
ꢂ7.3 (c 2, chloro-
D
form), lit.22
[
a]
20 þ7.2 (c 2, chloroform).
D
1H NMR (400 MHz, CDCl3):
d
1.98e2.04 (m, 1H), 2.09e2.14 (ddd,
J¼12.8, 5.2, 2.8 Hz, 1H), 2.88e2.93 (dd, J¼10.4, 4.8 Hz, 1H)
4.34e4.35 (t, J¼6.4 Hz, 1H), 4.68e4.76 (d, J¼2.4 Hz), 7.08e7.24
(m, 4H), 7.26e7.32 (m, 4H). 13C NMR (100 MHz, CDCl3):
d 30.5, 43.7,
43.9, 46.5, 123.3, 123.5, 123.7, 125.0, 125.8 (2C), 126.2, 126.3, 139.6,
142.3, 143.8, 143.7, 179.0. Mass (EI): 250 (4), 202 (6), 179 (91), 178
C
19H18O2: C 81.99, H 6.52.
(100). IR (KBr):
n 3311, 3024, 2972,1706, 1459, 1403, 1230, 1124, 936,
761, 599 cmꢂ1
.
4.3. (S)-((11R)-9,10-Dihydro-9,10-ethanoanthracene-11-yl)
methyl 2-acetoxy-phenylacetate 7
4.6. 9,10-Dihydro-9,10-ethanoanthracene-11
(4-methylbenzenesulfonate) (R)-10
Alcohol (R)-3 (0.40 g, 1.7 mmol), DCC (0.350 g, 1.7 mmol) and
DMAP (0.020 g 0.17 mmol) were placed in two-necked flask under
nitrogen atmosphere, were dissolved in dry dichloromethane
(10 mL) and cooled to 0 ꢁC. A solution of (þ)-O-acyl mandelic acid
(S-6) (0.33 g, 1.7 mmol) in dichloromethane (5 mL) was then added
drop wise. The reaction mixture was stirred at 0 ꢁC for 1 h after,
which it was allowed to warm to room temperature and stirred for
another 14 h. Then whole reaction mixture was passed through
Celite bed, washed with dichloromethane and purified by column
To a solution of (R)-3 (1.0 g, 4.24 mmol) in dry dichloromethane
(10 mL), triethyl amine (1.71 g, 16.94 mmol) was added under ni-
trogen atmosphere at 0 ꢁC. Then p-toluenesulfonyl chloride (1.0 g,
5.29 mmol) was added in portion wise to the reaction. The solution
was stirred for 24 h at room temperature. The reaction mixture was
poured into cold water (50 mL) and extracted with dichloro-
methane (2ꢃ50 mL). The organic phase was concentrated under
vacuum, which was purified by column chromatography over silica
gel [Rf 0.6] (10% ethyl acetate/petroleum ether) affording white
chromatography over silica gel [Rf 0.7] (10% ethyl acetate/petro-
28
leum ether) affording white solid (0.56 g, 80%) mp¼97e98 ꢁC [
63.2 (c 0.5, chloroform).
a
]
solid (1.3 g, 79%). Mp¼146e147 ꢁC (lit.33¼148e150 ꢁC) [
a]
28 5.8 (c 1,
D
D
chloroform).
1H NMR (400 MHz, CDCl3): 1.01e1.06 (ddd, J¼12.4, 4.8, 2.4 Hz,
1H), 1.84e1.90 (m, 1H), 2.22 (m, 4H), 3.39e3.45 (t, J¼10.4 Hz, 1H),
3.75e3.79 (dd, J¼6.0, 5.6 Hz, 1H), 3.95e3.96 (d, J¼2.4 Hz,
1H), 4.19e4.21 (t, J¼2.4 Hz, 1H), 5.96 (s, 1H), 6.73e6.75 (d, J¼7.2 Hz,
1H), 6.95e6.99 (td, J¼7.6, 1.2 Hz) 7.03e7.09 (m, 3H), 7.15e7.22 (m,
3H), 7.44e7.50 (m, 3H), 7.54e7.56 (m, 2H).
1H NMR (400 MHz, CDCl3):
d
0.94e0.99 (ddd, J¼12.8, 4.8, 2.4 Hz,
1H), 1.90e1.97 (m, 1H), 2.30e2.33 (m, 1H), 2.49 (s, 3H), 3.22e3.27
(dd, J¼10.4, 9.6 Hz, 1H), 3.74e3.78 (dd, J¼9.6, 5.2 Hz, 1H), 4.23e4.24
(t, J¼2.8 Hz, 1H), 4.32e4.33 (d, J¼2.4 Hz, 1H), 6.96e6.97 (m, 2H),
7.10e7.12 (m, 2H), 7.19e7.28 (m, 4H), 7.37e7.37 (d, J¼1.2 Hz, 2H),
7.79e7.98 (d, J¼1.2 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 21.7, 30.6,
13C NMR (100 MHz, CDCl3):
d
20.8, 30.7, 37.2, 43.7, 45.3, 68.0,
37.5, 43.5, 44.9, 72.5, 123.1, 123.5, 123.8, 125.6, 125.7, 125.9, 126.0,
126.2, 128.0 (2C), 129.9 (2C), 132.9, 139.2, 142.9, 143.3, 143.4, 144.9.
Mass (EI): 390 (1), 202 (2), 180 (1), 178 (100), 176 (4), 152 (1). IR
74.4, 123.1, 123.5, 123.6, 125.3, 125.7, 125.8, 125.9, 126.1, 127.8 (2C),
128.9 (2C), 129.5, 134.1, 139.5, 143.1, 143.3, 143.5, 168.6, 170.4. Mass
(EI): 412 (4), 219 (4), 203 (7), 202 (4), 179 (94) 178 (100). IR:
n
3067,
(KBr): n
3070, 2953, 2917, 2862, 2359, 1364, 1177, 713 cmꢂ1. Anal.:
3020, 2951, 1744, 1461, 1373, 1334, 1245, 1048, 971, 746, 699 cmꢂ1
.
found C 73.66, H 5.62; required C24H22O3S: C 73.82, H 5.68.
Anal.: found C 78.35, H 6.22; required C27H24O4: C 78.62, H 5.86.
4.7. 9,10-Dihydro-9,10-ethanoanthracene-11-(bromomethyl)
4.4. 9,10-Dihydro-9,10-ethanoanthracene-11-
(R)-11
carbaldehyde (R)-8
To a solution of alcohol (R)-3 (0.40 g, 1.70 mmol) in dichloro-
methane (5 mL) under nitrogen atmosphere, was added CBr4
(0.71 g, 2.13 mmol) and the mixture was stirred vigorously at room
temperature for 15 min. The mixture was cooled down to 0 ꢁC and
Ph3P (0.67 g, 2.56 mmol) was added. Then reaction mixture was
stirred for 3 h at room temperature. The solvent was distilled off
under reduced pressure and material was further purified by col-
umn chromatography over silica gel [Rf 0.75] (100% petroleum
ether) affording white solid (0.38 g, 73%).
To a solution of alcohol (R)-3 (0.30 g, 1.27 mmol) in dry
dichloromethane (10 mL) under nitrogen atmosphere was added
PDC (2.4 g, 6.35 mmol) and mixture was stirred vigorously at room
temperature (6 h). The reaction mixture was diluted with diethyl
ether (30 mL) and passed through Celite. The solvent was removed
under reduced pressure and the crude product was purified by
short column chromatography over silica gel [Rf 0.65] (5% ethyl
acetate/petroleum ether) affording white solid. Yield 0.225 g, 75%,
mp¼112 ꢁC (lit.32¼112e113 ꢁC) [
a
d
]
28 ꢂ13.4 (c 1, chloroform).
Mp¼136 ꢁC (lit.34¼138 ꢁC), [
a]
28 27.7 (c 1, chloroform).
D
D
1H NMR (400 MHz, CDCl3):
1.96e2.02 (m, 1H), 2.08e2.13
1H NMR (400 MHz, CDCl3):
d
1.18e1.23 (ddd, J¼12.8, 3.6, 2.8 Hz,
(m, 1H), 2.75e2.80 (m, 1H), 4.39e4.41 (t, J¼2.4 Hz, 1H), 4.68e4.69
1H), 2.06e2.13 (m, 1H), 2.33e2.41 (m, 1H), 2.80e2.85 (t, J¼10.0 Hz,
(d, J¼2.4 Hz, 1H) 7.08e7.14 (m, 4H), 7.25e7.33 (m, 4H), 9.41e9.42
1H), 3.09e3.13 (dd, J¼9.6, 6.4 Hz, 1H), 4.29e4.30 (t, J¼2.8 Hz, 1H),
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N. Jain et al. / Tetrahedron xxx (2014) 1e12
11
4.50e4.51 (d, J¼2.4 Hz, 1H), 7.11e7.19 (m, 4H), 7.27e7.37 (m, 4H).
13C NMR (100 MHz, CDCl3):
34.8, 38.0, 41.0, 41.1, 47.1, 123.3, 123.4,
123.8, 125.6, 125.8, 126.0, 126.3, 139.5, 143.3, 143.5. Mass (EI): 301
(4), 299 (6), 218 (5), 178 (100). IR (KBr): 3036, 2938, 1456, 1286,
1228, 1022, 758, 643, 551 cmꢂ1
dry DMF (5 mL) under nitrogen atmosphere for 48 h. The reaction
mixture was quenched with water and extracted with ethyl acetate
(3ꢃ75 mL). The organic extract was washed with water and dried
over anhydrous sodium sulfate. The crude product was purified by
column chromatography over neutral alumina [Rf 0.6, 20% ethyl
acetate/petroleum ether, silica gel TLC] (10% ethyl acetate/petro-
leum ether) affording white solid (0.09 g, 20%). Mp¼160e162 ꢁC,
d
n
.
4.8. 1-[(9,10-Dihydro-9,10-ethanoanthracen-11-yl)methyl]pi-
peridine (R)-13
[a
]
28 10.8 (c 0.5, chloroform).
D
1H NMR (400 MHz, CDCl3):
d
1.15e1.19 (ddd, J¼12.4, 4.4, 2.4 Hz,
A mixture of (R)-10 (0.40 g, 1.02 mmol), piperidine (0.43 g,
5.2 mmol) and Na2CO3 (0.54 g, 5.12 mmol) was heated at 80 ꢁC in
dry DMF (5 mL) under nitrogen atmosphere for 48 h. The reaction
mixture was quenched with water and extracted with ethyl acetate
(3ꢃ75 mL). The organic extract was washed with water and dried
over anhydrous sodium sulfate. The crude product was purified by
column chromatography over neutral alumina [Rf 0.33, 20% ethyl
1H), 1.87e1.97 (m, 3H), 2.13 (s, 1H), 2.14e2.31 (br signal, 4H),
4.25e4.26 (t, J¼2.4 Hz, 1H), 4.34e4.35 (d, J¼1.2 Hz, 1H), 7.07e7.13
(m, 4H), 7.26e7.29 (m, 4H). 13C NMR (100 MHz, CDCl3):
d 33.2, 35.6,
44.2, 46.2, 53.4, 63.7, 123.0, 123.3, 123.4, 125.4, 125.5, 125.5 (2C),
125.7, 140.9, 143.9 (2C), 144.4.
Mass (EI): 522 (12), 423 (10), 345 (10), 343 (43), 204 (13), 178
(100). IR (KBr): n 3007, 3022, 2931, 1468, 1332,1240, 1138, 1010, 819,
acetate/petroleum ether, silica gel plate] (2% ethyl acetateepetro-
752 cmꢂ1. Anal.: found C 87.21, H 7.46, N 5.55; required C38H38N2: C
87.31, H 7.33, N 5.36.
28
leum ether) affording white solid. (0.22 g, 70%) mp¼145 ꢁC, [
ꢂ3.7 (c 0.5, chloroform).
a]
D
1H NMR (400 MHz, CDCl3):
d 1.14e1.43 (br signal, 2H), 1.55e1.60
Acknowledgements
(m, 4H), 1.80e1.87 (m, 4H), 1.92e1.95 (m, 1H), 2.12e2.32 (br signal,
5H), 4.25e4.26 (t, J¼2.4 Hz, 1H), 4.36e4.37 (d, J¼2.4 Hz, 1H),
7.07e7.14 (m, 4H), 7.23e7.32 (m, 4H). 13C NMR (100 MHz, CDCl3):
We thank Council of Scientific and Industrial Research (CSIR),
New Delhi for the award of Senior Research Fellowship to one of us
(N.J.). We are grateful to Prof. N. Suryaprakash, IISc, Bangalore and
Dr. S. Sahoo of Sun Pharma Advance Research Centre, Vadodara for
their help in some NMR experiments and Novozyme, Bangalore
(India) for the generous gift of immobilized enzyme.
d
24.6, 26.1, 33.4, 35.8, 44.3, 47.2, 54.9, 64.6, 122.9, 122.9, 123.3,
123.4, 125.3, 125.5, 125.6, 125.6, 141.1, 143.9, 144.0, 145.5. Mass (EI):
304 (3), 303 (10), 203 (3), 178 (15), 98 (100). IR (KBr): 3066, 3020,
2932, 2800,1454, 1377,1330,1214,1154,1125, 1095,1005, 755 cmꢂ1
n
.
Anal.: found C 87.0, H 8.15, N 5.10; required C22H25N: C 87.08, H
8.30, N 4.62.
Supplementary data
4.9. 1-[(9,10-Dihydro-9,10-ethanoanthracen-11-yl)methyl]
piperazine (R)-14
Details of the crystal structure analysis, synthesis of some li-
gands, the copies of spectra, HPLC charts, etc. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2014.05.001.
Prepared by the method similar to the one described above. [Rf
0.3, 30% ethyl acetate/petroleum ether]. Off white solid:
0.162 g (52%) mp¼181e182 ꢁC, [
a]
28 8.4 (c 1, chloroform).
References and notes
D
1H NMR (400 MHz, CDCl3):
d 1.14e1.16 (m, 1H), 1.89e2.01
€
1. (a) Weber, E.; Csoregh, I.; Ahrendt, J.; Finge, S.; Czugler, M. J. Org. Chem. 1988, 53,
(m, 3H), 2.10 (br signal, 1H), 2.56e2.72 (br signal, 4H), 3.30e3.31
(t, J¼4.8 Hz, 4H), 4.27e4.28 (t, J¼2.4 Hz, 1H), 4.30e4.31 (d, J¼2.4 Hz,
1H), 7.10e7.26 (m, 4H), 7.27e7.29 (m, 4H). 13C NMR (100 MHz,
€
5831e5839; (b) Weber, E.; Hens, T.; Gallardo, O.; Csoregh, I. J. Chem. Soc., Perkin
Trans. 2 1996, 737e745.
2. (a) Swager, T. M. Acc. Chem. Res. 2008, 41, 1181e1189; (b) Bouffard, J.; Eaton, R.
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Chem. Commun. 2011, 1674e1688; (d) Han, Y.; Guo, J.-B.; Cao, J.; Chen, C.-F.
Tetrahedron 2013, 69, 4541e4545.
CDCl3):
d 32.7, 35.8, 44.0, 44.1, 46.5, 49.9, 123.2, 123.4, 125.3, 125.5,
125.6, 125.8, 125.9, 140.5, 143.7, 143.7, 143.8. Mass (EI): 304 (100),
261 (10), 219 (5), 202 (11), 178 (40). IR (KBr):
n 3021, 2950,
2816,1605,1457, 1288, 1174,1094,1044, 933, 753 cmꢂ1. Anal.: found
C 82.65, H 7.67, N 9.45; required C21H24N2: C 82.85, H 7.95, N, 9.20.
4.10. 1-[(9,10-Dihydro-9,10-ethanoanthracen-11-yl)methyl]
pyrrolidine (R)-15
[Rf 0.4; 30% ethyl acetate/petroleum ether]. White solid (0.218 g,
28
74%): mp¼121e122 ꢁC, [
a]
ꢂ5.6 (c 1, chloroform).
D
1H NMR (400 MHz, CDCl3):
d 1.22e1.26 (m, 1H), 1.76e1.79
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(m, 4H), 1.92e2.04 (m, 3H), 2.11e2.17 (m, 2H), 2.40e2.47 (m, 4H),
4.26e4.28 (t, J¼2.4 Hz, 1H), 4.36e4.37 (d, J¼1.2 Hz, 1H), 7.10e7.14
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d 23.5, 33.4,
37.6, 44.3, 47.3, 54.5, 62.1, 122.9, 123.4 (2C), 125.4, 125.5, 125.6,
125.7, 140.9, 143.8, 143.9, 144.0, 144.5.
Mass (EI): 289 (27), 288 (36), 256 (22),178 (14), 84 (100). IR (KBr):
n
3002, 2974, 2935, 2974, 2785,1458,1234, 758 cmꢂ1. Anal.: found C
87.18, H 8.15, N 4.82; required C22H25N: C 87.15, H 8.04, N 4.84.
4.11. 1,4-Bis (11R)-(9,10-dihydro-9,10-ethanoanthracene-11-yl)
methyl)piperazine (R,R)-20
A mixture of (R)-11 (0.25 g, 0.836 mmol), (R)-14 (0.38 g,
1.25 mmol) and Na2CO3 (0.58 g, 4.18 mmol) was heated at 80 ꢁC in
Please cite this article in press as: Jain, N.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.001

12
N. Jain et al. / Tetrahedron xxx (2014) 1e12
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