Fractional crystallisation of (±)-iso-amarine with mandelic acid: convenient access to (R,R)- and (S,S)-1,2-diamino-1,2-diphenylethanes

Article abstract of DOI:10.1016/j.tetasy.2006.10.044

(±)-iso-Amarine can be conveniently resolved via 1:1 salt formation with either hand of mandelic acid. Enantiopure iso-amarine can be acetylated and hydrolysed to give enantiopure 1,2-diamino-1,2-diphenylethanes.

Full text of DOI:10.1016/j.tetasy.2006.10.044

Tetrahedron: Asymmetry 17 (2006) 2935–2937
Fractional crystallisation of ( )-iso-amarine with
mandelic acid: convenient access to (R,R)- and
(S,S)-1,2-diamino-1,2-diphenylethanes
D. Christopher Braddock,a,* Stephen A. Hermitage,b Joanna M. Redmonda
and Andrew J. P. Whitea
aDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 5 October 2006; accepted 30 October 2006
Abstract—( )-iso-Amarine can be conveniently resolved via 1:1 salt formation with either hand of mandelic acid. Enantiopure iso-
amarine can be acetylated and hydrolysed to give enantiopure 1,2-diamino-1,2-diphenylethanes.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
starting with benzaldehyde and hexamethyldisilazane.1 A
1:1 salt 5 was found to precipitate from iso-propanol in
an excellent yield on treatment of ( )-iso-amarine with
one equivalent of (S)-mandelic acid 4 (Scheme 1). The 1:1
composition of the salt, and the selection of the (R,R)-hand
of iso-amarine with (S)-mandelic acid was confirmed by
X-ray crystallography (Fig. 1) after recrystallisation.
Treatment of salt 5 with base gave enantiopure (R,R)-iso-
amarine 3 in a quantitative yield. The enantiomeric purity
of resolved 3 was confirmed by DCC coupling with
(R)-acetyl mandelic acid 6 to give amide 7 as a single
We have recently described a convenient gram-scale prepa-
ration of enatiomerically pure (R,R)- and (S,S)-1,2-diamino-
1,2-diphenylethanes 1 and 2 from ( )-iso-amarine 3.1
The activation of iso-amarine for hydrolysis to the required
diamines and enantiomeric resolution was achieved simulta-
neously by the formation of two separable N-acylamidines
derived from DCC-mediated coupling with (R)-acetylman-
delic acid. Herein, we report an alternative method for
accessing the enantiopure diamines in which ( )-iso-ama-
rine 3 is resolved by fractional crystallisation with mandelic
acid. Subsequent N-acetylation of the resolved amarine and
hydrolysis provides the enantiomerically pure diamine.
Ph
,
diastereoisomer (Scheme 2).1
Resolving ( )-iso-amarine
3 with (R)-mandelic acid
instead, gave access to the (S,S)-amidine in essentially iden-
tical yields, as expected. One-pot acetylation and hydrolysis
under Lifschitz and Bos’ conditions2 gave enantiomerically
pure (S,S)-diamide 8 (Scheme 3). Further hydrolysis using
Williams and Bailar’s protocol3 gave enantiomerically pure
diamine 2.
N
NH
Ph
H2N
Ph
NH2
Ph
H2N
Ph
NH2
Ph
Ph
1
2
( )-3
Since mandelic acid is readily available in both enantio-
meric forms, the resolution procedure above therefore gives
access to both enantiopure diamines 1 and 2. Tartaric acid
2. Results and discussion
( )-iso-Amarine 3 was prepared in multi-gram quantities
as previously described in a simple two-step procedure
The diastereomeric purity of (R,R,R)-7 can be readily assessed by 1H
NMR spectroscopy, the CHOAc resonance (singlet) is at dH 5.06 ppm.
The (S,S,R) diastereoisomer that would derive from (S,S)-3 has its
corresponding resonance at 5.55 ppm.
*
Corresponding author. Tel.: +44 20 7594 5772; e-mail addresses:
c.braddock@imperial.ac.uk; c.braddock@ic.ac.uk
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.044

2936
D. C. Braddock et al. / Tetrahedron: Asymmetry 17 (2006) 2935–2937
3. Conclusion
Ph
O
Ph
iPrOH
NaOH
HN
Ph
NH
Ph
O
(4R,5R)-3
We have shown that enantiomerically pure iso-amarine can
be accessed by the fractional crystallisation of the salts
formed from racemic iso-amarine and scalemic mandelic
acid. Acetylation of the free base and subsequent hydro-
lysis provided enantiomerically pure 1,2-diamino-1,2-
diphenylethanes.
( )-3
O
OH
quantitative
Ph
HO
5; 80%
4
OH
Scheme 1.
4. Experimental
4.1. Materials and methods
CH2Cl2 was distilled from CaH2. All other reagents were
used as received. Concentrated refers to the removal of
the solvent under reduced pressure on a rotary evaporator.
Optical rotations were recorded on a Perkin–Elmer 241
polarimeter with a path length of 1 dm using the
589.3 nm D-line of sodium. Solutions were prepared using
spectroscopic grade solvents and concentrations (c) are
quoted in g/100 mL. Melting points were recorded on a
Reichart Thermovar melting point apparatus and are
uncorrected. Fourier transform infra-red (IR) spectra were
recorded through diffuse reference infra-red Fourier trans-
form spectroscopy (DRIFTS) or as thin films on NaCl
1
plates using a Mattson 500 FTIR spectrometer. H NMR
were recorded at 270 MHz on a Jeol GSX-270 spectro-
meter or at 400 MHz on a 400 MHz Bruker DRX spec-
trometer. 13C NMR were recorded at 68 and 100 MHz
on a Jeol GSX-270 spectrometer or a 400 MHz Bruker
DRX spectrometer, respectively. NMR samples were run
in the indicated solvents and were referenced internally.
All chemical shift values are quoted in parts per million
and coupling constants quoted in Hertz. The following
abbreviations are used for the multiplicity of NMR signals:
s = singlet, d = doublet, t = triplet, m = multiplet. Low
resolution mass spectra (MS) [FAB, EI & CI] and high
resolution mass spectra (HRMS) were recorded by the
Imperial College Department of Chemistry Mass Spectros-
copy Service. Elemental analyses were carried out by the
University of North London Analytical Service.
Figure 1. Molecular structure of 5. The crystal studied was enantio-
merically pure; since the absolute structure could not be determined by
purely crystallographic methods the known chirality of the (S)-mandelic
acid moiety was used as an internal reference.
Ph
O
DCC
O
Ph
N
N
(R,R)-3
OAc
Ph
Ph
Ph
HO
OAc
6
7; quantitative
Scheme 2.
4.2. (+)-(4R,5R)-4,5-Dihydro-2,4,5-triphenyl-1H-imidazole
3
Racemic iso-amarine 3 (5.00 g, 16.8 mmol) and (S)-(+)-
mandelic acid 4 (2.55 g, 16.8 mmol) were dissolved in
refluxing iso-propanol (28 mL). After refluxing for 1 h
heating was stopped, and the flask was left in the oil bath
to cool slowly to rt with gentle stirring. After 16 h, the solu-
tion was cooled to 0 °C and left to stir for a further 4 h. The
resulting white crystals were collected by filtration and
dried in vacuo. The material was recrystallised from iso-
propanol to yield the 1:1 mandelic acid–iso-amarine diaste-
O
O
1. Ac2O,
NaOAc
HBr
NH HN
Ph
(S,S)-3
2
AcOH
2. HCl,
H2O
49%
Ph
8; 95%
Ph
Scheme 3.
reomeric salt 5 (2.99 g, 80%) as a white crystalline solid:
25
has previously been used as a resolving agent for
( )-iso-amarine, but a yield was not given.4 This resolution
procedure also provides a convenient alternative to the
preparation of enantiomerically pure iso-amarines from
activated benzoic acid derivatives with (1R,2R)- or
(1S,2S)-1,2-diamino-1,2-diphenylethane.5
½aꢀD ¼ þ128:0 (c 2.3, EtOH); FT IR (NaCl, NujolÒ) mmax
3430, 3100–2100 cmꢁ1; H NMR (270 MHz, DMSO-d6) d
8.05 (d, JHH = 6.7 Hz, 2H, Ar–H), 8.62–8.52 (m, 3H,
Ar–H), 7.41–7.20 (m, 15H, Ar–H), 4.95 (s, 2H, NCH),
4.82 (s, 1H, CHCO2) ppm; 13C NMR (68 MHz, DMSO-
d6) d 174.7, 163.3, 143.1, 142.0, 132.5, 129.3, 129.3, 129.1,
1
3

D. C. Braddock et al. / Tetrahedron: Asymmetry 17 (2006) 2935–2937
2937
25
128.5, 128.4, 127.6, 127.2, 127.1, 101.8, 73.3; MS (FAB+)
299 (cation) 452 (cation+anion+2H+); MS (FABꢁ) 151
(anion); Anal. Calcd for C29H26N2O3: C, 77.31; H, 5.82;
N, 6.22. Found: C, 77.42; H, 5.91; N, 6.15. Crystal data
for 5: C29H26N2O3, M = 450.52, orthorhombic, P212121
½aꢀD ¼ þ64:9 (c 1.0, 9:1, CHCl3–MeOH); FT IR (NaCl,
NujolÒ) mmax 3314, 1651, 1633 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6) d 8.89 (d, J = 8.8 Hz, 1H, NH),
8.70 (d, J = 8.8 Hz, 1H, NH), 7.76 (d, J = 6.8 Hz, 2H,
Ar–H), 7.55–7.45 (m, 3H, Ar–H), 7.32–7.12 (m, 10H, Ar–
H), 5.46 (t, J = 8.4 Hz, 1H, NCH), 5.38 (t, J = 8.4 Hz,
1H, NCH) 1.80 (s, 3H, COOCH3) ppm; 13C NMR
(100 MHz, DMSO-d6) d 169.8, 166.9, 141.0, 141.0, 134.9,
131.8 128.8, 128.4, 127.8, 127.7, 127.4, 58.2, 57.3,
23.1 ppm; MS (CI+) 359 (M+H+); HRMS calcd for
C23H23N2O2 (M+H+) 359.1760, found 359.1771 (M+H+).
˚
(no. 19), a = 8.6149(5), b = 16.0588(8), c = 17.2764(8) A,
V = 2390.1(2) A , Z = 4, dc = 1.252 g cmꢁ3, l(CuKa) =
3
˚
0.650 mmꢁ1
,
T = 293 K, colourless prisms, Oxford
Diffraction Xcalibur PX Ultra diffractometer; 4365 inde-
pendent measured reflections, F2 refinement, R1 = 0.047,
wR2 = 0.107, 3623 independent observed absorption-
corrected reflections [jFoj > 4r(jFoj), 2hmax = 137°], 317
parameters. The absolute structure of 5 could not be
unambiguously determined by either an R-factor test
[Rþ1 ¼ 0:0472, Rꢁ1 ¼ 0:0472] or by use of the Flack para-
meter [x+ = 0.1(3), xꢁ = 0.9(3)] and so was assigned by an
internal reference. Crystallographic data (excluding struc-
ture factors) have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication
number CCDC 283433. Copies of the data can be obtained
free of charge, on application to CCDC, 12 Union road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or
4.4. (ꢁ)-(1S,2S)-1,2-Diamino-1,2-diphenylethane 2
Following the procedure of Williams and Bailar,3 starting
from diamide 8 (5.0 g, 14.0 mmol), gave diamine 2
(1.44 g, 6.8 mmol, 49%) as a colourless solid after recrystal-
25
lisation (Et2O–petroleum ether): ½aꢀD ¼ ꢁ106:0 (c 1,
EtOH); other data identical to that previously reported.1
Acknowledgements
e-mail:deposit@ccdc.cam.ac.uk]. The salt
5
(2.77 g,
6.16 mmol) was suspended in CH2Cl2 (150 mL) and 1 M
aqueous NaOH (100 mL) was added. The biphasic mixture
was stirred rapidly until all the solid had dissolved. The
organic layer was separated and the aqueous layer was re-
extracted with CH2Cl2 (100 mL). The combined organic
layers were washed with water (100 mL), dried over
MgSO4 and concentrated to give (R,R)-iso-amarine 3
We thank GlaxoSmithKline Ltd for an Industrial CASE
award (to J.M.R.) and the EPSRC.
References
1. Braddock, D. C.; Redmond, J. M.; Hermitage, S. A.; White,
A. J. P. Adv. Synth. Catal. 2006, 348, 911–916, and references
cited therein.
2. Lifschitz, I.; Bos, J. G. Recl. Trav. Chim. Pays-Bas 1940, 59,
(1.83 g, quantitative) as a white crystalline solid: mp 175–
25
178 °C [lit.6 177–180 °C]; ½aꢀD ¼ þ46:0 (c 2.0, EtOH)
20
{lit.4 ½aꢀD ¼ þ46:0 (c 1, EtOH)}. Other spectral data are
173–183.
identical to that of ( )-3.1
3. Williams, O. F.; Bailar, J. C., Jr. J. Am. Chem. Soc. 1959, 81,
4464–4469.
4.3. (+)-(1S,2S)-N-Acetyl-N0-benzoyl-1,2-diamino-1,2-
diphenylethane 8
4. Lifschitz, I.; Bos, J. G. Recl. Trav. Chim. Pays-Bas 1939, 58,
638–642.
5. For example, see: Dauwe, C.; Buddrus, J. Synthesis 1995, 171–
Following the procedure of Lifshitz and Bos,2 and starting
from (S,S)-3 (5.0 g, 16.8 mmol), gave diamide 8 (5.7 g,
15.9 mmol, 95%) as a colourless solid: mp >230 °C;
172.
6. Oi, R.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 999–
1002.