J. Kannappan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
OH
chromatography on silica gel (60–120 mesh). All reactions were
carried out under an inert atmosphere (nitrogen) unless other con-
ditions are specified. NMR Spectra were recorded on a 400 MHz
spectrometer (400 MHz for 1H NMR, 100 MHz for 13C NMR) with
CDCl3 as the solvent and TMS as the internal standard. Single crys-
tal X-ray diffraction data was collected Xcalibur, Eos, Gemini
diffractometer. Mass spectra were recorded on GCMS instrument
in the direct injection EI-mode. IR Spectra were recorded as KBr
pellets and specific optical rotations were measured on JACSO P-
2000 polarimeter. Melting points were recorded in Thiele’s tube
using paraffin oil and are uncorrected.
COOH
4a
amine
precipitate
HCl aq
acetonitrile,
reflux to rt
(RS)-mandelic acid
(R)-mandelic acid
yield: 37 %
> 99% ee
Scheme 2. Resolution of mandelic acid.
5. General Procedures for the synthesis of N-benzyl amine
ligands 4a–4g
(C–O) bond length (1.22–1.25 Å) of carboxylate of mandelic acid is
shorter as in case of salt of ligand 4a with (R)-mandelic acid, thus
confirming the proton transfer from mandelic acid to ligand 4b.
The assembly in salt shows ligand 4b linked with two molecules
of mandelic acid forming a trimeric assembly via two hydrogen
In a 25 mL dry RB flask, a solution of (ꢀ)-iso-bornyl amine
(0.250 g, 1.63 mmol) was dissolved in 10 mL anhydrous toluene.
To this solution was added the appropriate aldehyde (1.8 mmol)
and the reaction mixture was allowed to reflux for nearly 2–3 h
until completion on TLC. The reaction mixture was distilled off
under vacuum to remove the toluene. The mixture was then
charged with methanol (10 mL), cooled to 0 °C and charged with
sodium borohydride (3.6 mmol) and stirred for 30–60 min. The
reaction mixture was then stirred at rt. The solvent was then evap-
orated under vacuum and the mixture was extracted from ethyl
acetate (3 ꢂ 50 mL) and the combined extracts were washed with
water (2 ꢂ 25 mL). The organic layer was dried over anhydrous
sodium sulfate, evaporated under vacuum and then subjected to
column chromatography on silica gel (ethyl acetate/hexane) to
afford the desired amine.
bonds, one CH–
p interaction and two CH–O interactions. The
two hydrogen bonds are formed between the amine and hydroxyl
group of ligand 4b and mandelic acid. The bond lengths are 1.829 Å
(NHꢁ ꢁ ꢁO2) and 1.743 Å (O–Hꢁ ꢁ ꢁO3). The ligand also shows an
intramolecular hydrogen bond with bond length 2.812 Å
(NHꢁ ꢁ ꢁO1). The assembly is further linked by CH–p interaction
between CH of phenyl ring of mandelic acid and 2-hydroxy phenyl
ring of ligand 4b with bond length of 3.242 Å. The methyl protons
of isobornyl ring form CH–O interaction with O2 of mandelic acid
having bond length of 2.671 Å also CH of 2-hydroxy-phenyl ring
shows similar CH–O interaction with O3 of mandelic acid having
bond length 2.569 Å. The hydrogen attached to chiral carbon of
(R)-mandelic acid appears to be laying on the top of the aromatic
ring of the ligand. The shortest perpendicular distance between
the plane passing through this ring and the hydrogen is 3.416 Å.
The attempts to grow crystals for salts of ligand 4a as well as for
ligand 4b with (S)-mandelic acid were unsuccessful. Repeated
attempts resulted in the formation of poor quality crystals of the
salt, and were unsuitable for the diffraction.
5.1. (1R,2R,4R)-N-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
amine 4a19
Yield 72%. [
CDCl3):
a
]
28 = ꢀ82.6 (c 1, chloroform). 1H NMR (400 MHz,
D
d
7.37–7.33 (m, 4H), 7.29–7.26 (m, 1H), 3.82 (d,
J = 13.2 Hz, 1H), 3.65 (d, J = 13.6 Hz, 1H), 2.65–2.62 (m, 1H), 1.76–
1.50 (m, 5H), 1.33–1.31 (m, 1H), 1.13 (s, 3H), 1.10 (d, J = 9.6 Hz,
2H), 0.94 (s, 3H), 0.86 (s, 3H). IR (KBr): cmꢀ1 2983, 2827, 1606,
1492, 1471, 1386, 1371, 1122, 1028, 734, 696. MS (ESI): m/z 244.4.
The easy availability by simple and practical synthesis of ligand
4a and its ability to recognize isomers of racemic mandelic acid,
encouraged us to attempt its resolution. A solution of racemic
mandelic acid was heated with ligand 4a in acetonitrile and
allowed to cool, resulting in the formation crystals of salt of (R)-
mandelic acid and amine, which was then converted to free (R)-
mandelic acid (37% Y; >99% ee) (Scheme 2).
5.2.
2-((((1R,2R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl)
amino)methyl)phenol 4b20
Compound 4b was prepared by same procedure as that of 4a.
Yield 67%. Mp 60 to 62 °C. [
a
]
D
28 = ꢀ90.5 (c 1, chloroform). 1H
3. Conclusion
NMR (400 MHz, CDCl3): d 7.18 (td, J = 8.0 Hz & 1.6 Hz, 1H), 7.01
(dd, J = 7.6 Hz & 1.6 Hz, 1H), 6.85 (dd, J = 8.4 Hz & 1.2 Hz,1 H),
6.79 (td, J = 7.6 Hz & 1.2 Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 3.79 (d,
J = 13.6 Hz, 1H), 2.63–2.60 (m, 1H), 1.80–1.69 (m, 5H), 1.16–1.10
(m, 2H), 0.99 (s, 3H), 0.97 (s, 3H), 0.86 (s, 3H). IR (KBr): cmꢀ1
3271, 2953, 2877, 2358, 2339, 1591, 1477, 1261, 1097, 748. MS
(ESI): m/z 260.3.
Herein we have discussed the preparation of a series of N-benzyl
isobornyl amines and scanned them as chiral solvating agents for
the discrimination of signals of chiral acidic compounds in 1H
NMR analysis. We were able to study the supramolecular interac-
tions between the chiral solvating agent and the acid moieties by
analyzing the crystals of salts. The measurement of the enan-
tiomeric purity of the analyte was accurate enough to be expended
as a tool to determine the enantiomeric purity of unknown samples
while the amines could be used as an effective resolving agents for
separation of isomers of mandelic acid for the practical applications.
5.3.
(1R,2R,4R)-N-(2-Methoxybenzyl)-1,7,7-trimethylbicyclo
[2.2.1]-heptan-2-amine 4c
5.3.1. Compound 4c was prepared by same procedure as that of
4a
Yield 71% [
a
]
28 = ꢀ108.0 (c 1, chloroform). 1H NMR (400 MHz,
4. Experimental
4.1. General
D
CDCl3): d 7.29 (d, J = 7.6 Hz, 1H), 7.27–7.23 (m, 1H), 6.96–6.92
(m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.80 (d, J = 13.6 Hz,
1H), 3.66 (d, J = 14.0 Hz, 1H), 2.58–2.55 (m, 1H), 1.72–1.48 (m,
5H), 1.1 (s, 3H), 1.06 (d, J = 8.0 Hz, 2H), 0.91 (s, 3H), 0.84 (s, 3H).
IR (KBr): cmꢀ1 2883, 2839, 1602, 1589, 1492, 1462, 1286, 1240,
1120, 1033, 750. MS (ESI): m/z 274.3.
Thin layer chromatography was performed on silica gel plates
quoted on aluminum sheets. The spots were visualized under UV
light or with iodine vapor. All compounds were purified by column