A convenient preparation of enantiomerically pure (+)-(1R,2R)- and (-)-(1S,2S)-1,2-diamino-1,2-diphenylethanes

Article abstract of DOI:10.1002/adsc.200505440

A gram-scale preparation of (1S,2S)- and (1R,2R)-1,2-diamino-1,2- diphenylethanes, (1S,2S)-1 and (1R,2R)-1, is reported via (±)-iso-amarine 4. Strategically, the activation of (±)-iso-amarine 4 for hydrolysis to the required diamines and enantiomeric resolution is achieved simultaneously by formation of two separable diastereoisomeric N-acylamidines 5 and 6 derived from direct DCC-mediated coupling of (±)-iso-amarine 4 with (R)-acetylmandelic acid. iso-Amarine 4 is conveniently obtained from amarine 3, and a one-pot synthesis of the latter is reported from benzaldehyde and hexamethyldisilazane as catalysed by benzoic acid.

Full text of DOI:10.1002/adsc.200505440

FULL PAPERS
DOI: 10.1002/adsc.200505440
A Convenient Preparation of Enantiomerically Pure (þ)-(1R,2R)-
and (À)-(1S,2S)-1,2-Diamino-1,2-diphenylethanes
D. Christopher Braddock,a,* Joanna M. Redmond,a Stephen A. Hermitage,b
Andrew J. P. Whitea
a
Synthesis Section, Department of Chemistry, Imperial College London, South Kensington, London, SW72AZ, U.K.
Fax: (þ44)-207-594-5805, e-mail: c.braddock@imperial.ac.uk
b
GlaxoSmithKlineLtd, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
Received: November 12, 2005; Accepted: March 2, 2006
Abstract: A gram-scale preparation of (1S,2S)- and of (Æ)-iso-amarine 4 with (R)-acetylmandelic acid.
(1R,2R)-1,2-diamino-1,2-diphenylethanes, (1S,2S)-1 iso-Amarine 4 is convenientlyobtained from amarine
and (1R,2R)-1, is reported via (Æ)-iso-amarine 4. 3, and a one-pot synthesis of the latter is reported
Strategically, the activation of (Æ)-iso-amarine 4 for from benzaldehyde and hexamethyldisilazane as cata-
hydrolysis to the required diamines and enantiomeric lysed by benzoic acid.
resolution is achieved simultaneouslybyformation of
two separable diastereoisomeric N-acylamidines 5 Keywords: iso-amarine; amines; asymmetric synthesis;
and 6 derived from direct DCC-mediated coupling enantiomeric resolution; fractional crystallisation
Introduction
X-raycrystallographyin 1997, and are confirmed as
2
and 3, respectively.[9] Amarine 3 can be readilyepimer-
Enantiopure C2-symmetrical 1,2-diphenylethane-1,2- ised to (Æ)-iso-amarine 4 under basic conditions.[7] In
diamines, (1S,2S)-1 and (1R,2R)-1, and their N-modified principle, direct hydrolysis of (Æ)-iso-amarine 4 should
derivatives have been widelyincorporated into diverse
liberate the desired racemic diamine 1. However, the
reagents for highly asymmetric dihydroxylation,[1a] ally- amidine functional group in iso-amarine is resistant to
lation,[1b] propargylation[1c] and aldol[1d] reactions. More- direct acid hydrolysis.[10] Instead, the conjugation in
over, theyhave been used as ligands in important cata-
the amidine sub-unit must be broken byconversion to
lytic asymmetric processes such as ruthenium-catalysed a hydrolysable N-acetylamidine, followed by a two-
hydrogenation of ketones,[1e–g] manganese-catalysed ep- step hydrolysis procedure to racemic diamine 1.[7,11]
oxidation of alkenes,[1h,i] aluminium-catalysed Diels–Al- The enantiomers can then be resolved bydiastereomer-
der reactions[1j, k] and magnesium-catalysed mergedeno- ic salt formation with tartaric acid or mandelic acid fol-
lisation-aminations.[1l] Racemic diamine (Æ)-1 can be lowed byfractional crystallisation and formation of the
resolved into its enantiomers bydiastereomeric salt for-
free bases. Notwithstanding the activation-hydrolysis
mation with tartaric[2] or mandelic[3] acids. The synthesis protocol followed bythe resolution of the racemic di-
of the racemic diamine 1 is less straightforward, howev- amine, the iso-amarine route to diamine 1 is inherently
er, and has been a long-standing problem. Reductive attractive because of the inexpensive nature of the start-
couplings of N-protected aromatic imines generally ing materials and reagents viz., benzaldehyde and am-
give mixtures of meso and racemic N-protected di- monia, the ease of conversion of amarine 3 into iso-
amines.[4] A dissolving metal reduction of a spiroimid- amarine 4, and the lack of need for anychromatographic
azole successfullygave the desired racemic diamine 1 af- purifications. In this paper, we show that amarine 3 can
ter hydrolysis.[5] Two direct asymmetric syntheses of be produced directlyin a single step from benzaldehyde
enantiopure diamine 1 starting with a Sharpless asym- and hexamethyldisilazane (an inexpensive and easily
metric dihydroxylation of stilbene have also been re- handled liquid as a replacement for ammonia) as cata-
ported.[6] The classical route to the racemic diamine 1 in- lysed bybenzoic acid. Further, we couple the activation
volves the reactionof benzaldehydeand liquid ammonia of (Æ)-iso-amarine 4 for hydrolysis with its enantiomer-
to give first “hydrobenzamide” and then “amarine”.[7] ic resolution byvirtue of forming separable diastereo-
[8]
These compounds have a long and venerable history,
but the structures were onlyunequivocallysecured by
meric N-acyl-iso-amarines from (R)-acetylmandelic
acid. Taken together, these strategies dramatically
Adv. Synth. Catal. 2006, 348, 911 – 916
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
911

D. Christopher Braddock et al.
FULL PAPERS
tatoryring-closure of 2 into 3.[14] In this context, we note
that the in situ formation of 3 from 2 under our condi-
tions is apparentlyautocatalytic: once some amarine is
formed, the amidine functional group is sufficientlyba-
sic to catalyse the reaction (for instance, in a given run
the ratio of amarine 3:hydrobenzamide 2 was deter-
1
mined to be 70:30 by H NMR after 15 h–after 18 h
the ratio was 100:0). Evidently, benzoic acid catalyses
the initial hydrobenzamide formation, and the electro-
cyclic reaction is probably initiated by excess HMDS.
Once isolated, isomerisation of amarine 3 into (Æ)-
iso-amarine 4 is readilyeffected bysodium hydroxide
in ethylene glycol (70%).[7]
Dicyclohexylcarbodiimide-mediated coupling[15] of
(Æ)-iso-amarine 4 with (R)-acetylmandelic acid gave a
quantitative yield of the two N-acyl diastereoisomers
(S,S,R)-5 and (R,R,R)-6 (Scheme 2). N-Acyl-iso-amar-
shorten the synthetic route to enantiopure diamines ine 5 was obtained as a single diastereoisomer after frac-
(1S,2S)-1 and (1R,2R)-1, and delivers both enantiomers tional crystallisation of the mixture from diisopropyl
in gram quantities.
ether. Evaporation of the mother liquor gave a 1:4 mix-
ture of 5:6. Subsequent hydrolysis of 5 in THF/H2O/HCl
gave the diamide 7 as a single diastereoisomer. The rel-
ative configurations and hence the absolute configura-
tions were assigned byX-raycrystallography(Figure 1).
Results and Discussion
The direct conversion of benzaldehyde into amarine 3 The mixture of 5 and 6 from the mother liquor was also
via 2 byheating at 120 8C with hexamethydisilazane in hydrolysed in this manner to give a 1:4 mixture of dia-
a sealed tube without a solvent has been previouslyre-
mides 7 and 8, respectively. Diamide 8 was obtained as
ported.[12] In our hands, attempts to perform this reac- a single diastereoisomer after recystallisation of this
tion using distilled benzaldehyde under an atmosphere mixture from chloroform.[16] Further hydrolysis of 7
of nitrogen led to minimal conversion. Addition of cat- and 8 with HBr in glacial acetic acid gave (1S,2S)-1
alytic quantities of benzoic acid (0.5 mol %), however, and (1R,2R)-1, respectively, as single enantiomers.
led to rapid conversion of benzaldehyde into hydrobenz- Enantiomeric purity( >98%) of the two enantiomers
[17]
amide (Scheme 1). Further heating gave amarine 3 in was established bythe NMR method of Synder.
good isolated yield (61%).
It has been previouslynoted that Lewis acids are good
reagents for the conversion of aromatic aldehydes into
methanediamines of the type 2.[13] Further, basic re-
agents are known to promote the 6p-electrocyclic disro-
Figure 1. The molecular structure of 5 (30% probabilityellip-
soids).
Scheme 1. Preparation of (Æ)-iso-amarine.
912
asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 911 – 916

EnantiomericallyPure ( þ)-(1R,2R)- and (À)-(1S,2S)-1,2-Diamino-1,2-diphenylethanes
FULL PAPERS
5 and 6. This strategyconsiderablyshortens the synthet-
ic route to (R,R)-1 and (S,S)-1 from (Æ)-iso-amarine. In
addition, we have improved the synthetic access to (Æ)-
iso-amarine 4 bydeveloping an acid-catalysed conden-
sation of readilyavailable benzaldehyde and hexame-
thyldisilazane to give amarine 3, which is readilycon-
verted into (Æ)-iso-amarine 4. All of the reagents
used in this synthesis – starting with the neat condensa-
tion of benzaldehyde and hexamethyldisilazane as cata-
lysed bybenzoic acid, followed bysodium hydroxide,
acetylmandelic acid, DCC, aqueous HCl and aqueous
HBr – are readilyavailable, inexpensive, and convenient
to handle.
Experimental Section
Methods
Melting points were recorded on a Reichart Thermovar melt-
ing point apparatus and are uncorrected. Optical rotations
were recorded on a Perkin-Elmer 241 polarimeter with a
path length of 1 dm using the 589.3 D-line of sodium. Solutions
were prepared using spectroscopic grade solvents and concen-
trations (c) are quoted in g/100 mL. Fourier transform infra-
red (IR) spectra were recorded as thin films on NaCl plates us-
ing a Mattson 500 FT IR spectrometer. 1H NMR were recorded
at270 MHzon aJeol GSX-270 spectrometer and300 MHzon a
300 MHz Bruker RX spectrometer. 13C NMR were recorded at
68 MHz or 75 MHz on a Jeol GSX-270 spectrometer or a
300 MHz Bruker DRX spectrometer respectively. NMR sam-
ples were run in the indicated solvents and were referenced in-
ternally. All chemical shift values are quoted in ppm and cou-
pling constants are quoted in Hz. The following abbreviations
are used for the multiplicityof NMR signals: br ¼broad, s¼
singlet, d¼doublet, dd¼doublet of doublets, t¼triplet. Low
resolution mass spectra (MS) [EI, CI and FAB] and high reso-
lution mass spectra (HR-MS) [CI] were recorded bythe Impe-
rial College Department of ChemistryMass Spectroscopy
Service. Microanalyses were performed by Mr. S. Boyer at
London Metropolitan University, UK.
Materials
CH2Cl2 was distilled from CaH2. Petrol refers to BDH Analꢁ
petroleum spirit 40–608C. Water refers to distilled water. Ben-
zaldehyde was distilled under N2 immediatelybefore use. ( S)-
Mandelic acid was recrystallised from CHCl3. (R)-(À)-(a)-
Acetoxyphenyl acetic acid was prepared from (R)-(À)-man-
delic acid and acetyl chloride by the published method.[18] All
other reagents and solvents were used as received.
Scheme 2. Preparation of (R,R)-1 and (S,S)-1.
Conclusion
In conclusion, we have demonstrated a convenient
gram-scale synthesis of both enantiopure diamines
(R,R)-1 and (S,S)-1 bya strategyof activation of ( Æ)-
iso-amarine 4 for hydrolysis to the required diamines
and simultaneous enantiomeric resolution via forma-
(4R*,5S*)-4,5-Dihydro-2,4,5-triphenyl-1H-imidazole
(Amarine) (3)
Benzaldehyde (96 mL, 950 mmol), hexamethyldisilazane
(240 mL, 1.15 mol) and a catalytic amount of benzoic acid
tion of two separable diastereoisomeric N-acyl amidines (575 mg, 4.7 mmol) were stirred at 1208C under nitrogen for
Adv. Synth. Catal. 2006, 348, 911 – 916
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
913

D. Christopher Braddock et al.
FULL PAPERS
24 h. The mixture was allowed to cool to room temperature, an
amorphous yellow solid formed and the entire mixture was tak-
en up in toluene (500 mL). The organic phase was washed with
saturated aqueous sodium hydrogen carbonate solution (2Â
250 mL), water (250 mL), brine (250 mL), dried (MgSO4), fil-
tered and concentrated under vacuum. The resulting yellow
residue was purified bymixed solvent recystallisation (toluene,
diethyl ether) to afford amarine 3 as a white crystalline solid;
yield: 57.2 g (191 mmol, 61%); mp 124–1278C (lit.[7] 128–
15 h, was cooled to 0 0C for further 5 h. The resulting crystals
were separated byfiltration, washed with a small amount of
cold diisoproyl ether (50 mL) and dried under reduced pres-
sure to afford the pure N-acyl-iso-amarine 5 as a white crystal-
line solid; yield: 17.2 g (68%); mp 170–1718C; [a]2D5: À107.5 (c
1
9.1, CHCl3); FT IR (NaCl): nmax ¼1737, 1707, 1626 cmÀ1; H
3
NMR (270 MHz, CDCl3): d¼7.83 (d, JH,H ¼6.5 Hz, 2H, Ar-
H), 7.51–7.12 (m, 16H, Ar-H), 6.97–6.92 (m, 2H, Ar-H), 5.55
(s, 1H, CH), 5.04 (br s 1H, NCHꢀ), 4.99 (br s, 1H, NCH), 2.03
(s, 3H, COOCH3); 13C NMR (68 MHz, CDCl3): d¼170.4,
166.2, 159.8, 140.3, 140.2, 131.8, 131.1, 130.9, 129.9, 129.5,
129.2, 128.9, 128.9, 128.6, 128.2, 127.9, 126.0, 125.3, 78.6, 75.1,
68.1, 20.7; MS (CIþ): m/z¼475 (MþHþ); HR-MS: calcd. for
C31H27N2O3: 475.2022 (MþHþ), found: 475.2030; anal. calcd.
for C31H26N2O3: C 78.46, H 5.52, N 5.90; found: C 78.53, H
5.47, N 5.94.
1318C); FT-IR (NaCl): nmax ¼3377, 1615, 1599 cmÀ1
;
1H
3
NMR (270 MHz, CDCl3): d¼7.97 (d, JH,H ¼6.9 Hz, 2H, Ar-
H), 7.49–7.47 (m, 3H, Ar-H), 7.00–6.95 (m, 10H, Ar-H), 5.45
(s, 2H, NCH), 4.75 (br s, 1H, NH); 13C NMR (68 MHz,
CDCl3): d¼164.6, 138.9, 131.2, 129.9, 128.8, 127.7, 127.6,
127.4, 126.9, 70.8 (br s); MS (CIþ): m/z¼299 (MþHþ); HR-
MS: calcd. for C21H19N2: 299.1548 (MþHþ), found: 299.1543.
The combined filtrates were concentrated under vacuum to
give an amorphous solid (yield: 37.5 g, 79.1 mmol) containing
(R,R,R) diastereomer 6 in a 4:1 excess over (R,S,S) diaster-
eomer 5. A portion of this mixture could be purified bycolumn
chromatography(petrol:ethyl acetate, gradient elution: 4:1 to
3:1) to produce pure (R,R,R) diastereomer 6: mp 67–738C;
Rf ¼0.39 (2:1, petrol:ethyl acetate); [a]2D5: À38.8 (c 2.3,
(4S*,5S*)-4,5-Dihydro-2,4,5-triphenyl-1H-imidazole
[(Æ)-iso-Amarine] (4)
Following the procedure of Williams and Bailar,[7] a stirred
mixture of amidine 3 (42 g, 141 mmol), water (6 mL), diethy-
lene glycol (35 mL) and sodium hydroxide (9.0 g, 225 mmol)
was boiled in an open beaker until the temperature reached
1558C. The temperature was maintained for 45 min, during
which time the sodium salt of the iso-amarine had precipitated
and the solution became a thick slurry. The mixture was al-
lowed to cool to room temperature and treated with glacial
acetic acid (25 mL), diluted with ethanol (125 mL) and heated
to boiling (1058C) until all remaining solid had dissolved. After
cooling, the solution was basified to pH¼9 with concentrated
aqueous ammonia solution (ca. 22 mL). The resulting tan pre-
cipitate was filtered, washed with cold ethanol, and dried under
vacuum (yield: 32.4 g). The crude product was recrystallised
from toluene to afford racemic iso-amarine 4 as a pale yellow
crystalline solid; yield: 29.3 g (70%); mp 199–2048C [lit.[7]
198–2018C]; FT IR (NaCl): nmax ¼3400–2800, 1594 cmÀ1; 1H
CHCl3); FT-IR (NaCl): nmax ¼1737, 1704, 1693 cmÀ1
;
1H
NMR (270 MHz, CDCl3): d¼7.70–6.86 (m, 20H, Ar-H), 5.83
(br s, 1H, NCHꢀ), 5.45 (br s, 1H, NCH), 5.06 (s, 1H, CH), 1.98
(s, 3H, COOCH3); 13C NMR (68 MHz, CDCl3): d¼170.7,
142.3, 140.4, 132.2, 131.3, 131.1, 129.6, 129.5, 129.0, 128.8,
128.5, 128.3, 128.0, 126.4, 125.6, 78.5 (br), 75.6, 70.7, 20.5; MS
(CIþ): m/z¼475 (MþHþ); HR-MS: calcd. for C31H27N2O3:
475.2022 (MþHþ), found: 475.2018.
Crystal data for 5
C31H26N2O3, M¼474.54, orthorhombic, P212121, (no. 19), a¼
10.1710(7), b¼14.6196(9) c¼17.2572(11) Š, V¼2566.1(3)
Š3, Z¼4, Dc ¼1.228 g cmÀ3, m(Cu-Ka)¼0.633 mmÀ1, T¼
173 K, colourless blocks, Oxford Diffraction Xcalibur PX Ultra
diffractometer; 4696 independent measured reflections, F2 re-
finement, R1 ¼0.039, wR2 ¼0.101, 4638 independent observed
3
NMR (270 MHz, CDCl3): d¼7.94 (d, JH,H ¼8.3 Hz, 2H, Ar-
H), 7.51–7.25 (m, 13H, Ar-H), 5.42 (br s, 1H, NH) 4.90 (s,
2H, NCH); 13C NMR (68 MHz, CDCl3): d¼163.1, 143.6,
131.1, 130.2, 128.8, 128.7, 127.6, 127.5, 126.9, 71.8 (br); MS
(CIþ): m/z¼299 (MþHþ); HR-MS: calcd. for C21H19N2:
299.1548 (MþHþ), found: 299.1554.
absorption-corrected reflections [jFo j >4s(jFo j), 2qmax
¼
1378], 329 parameters. The absolute structure of 5 could not
þ
be unambiguouslydetermined byeither an R-factor test [R1
À
¼0.0390, R1 ¼0.0392] or byuse of the Flack parameter [ xþ ¼
0.0(2), xÀ ¼1.1(2)] and so was assigned byinternal reference.
CCDC 283432.
(À)-(4S,5S)-1-[(R)-a-Acetoxyphenylacetyl]-4,5-
dihydro-2,4,5-triphenylimidazole (5) and (À)-(4R,5R)-
1-[(R)-a-Acetoxyphenylacetyl]-4,5-dihydro-2,4,5-
triphenylimidazole (6)
(þ)-(1S,2S)-N-[(R)-a-Acetoxyphenylacetyl]-N’-
benzoyl-1,2-diamino-1,2-diphenylethane (7)
Dicyclohexylcarbodiimide (27.0 g, 129 mmol) was added to a
stirred solution of iso-amarine 4 (32.0 g, 107 mmmol) and
(R)-a-acetoxyphenylacetic acid (25.0 g, 129 mmol) in CH2Cl2
(350 mL) at À20 0C under nitrogen, and the reaction mixture
was allowed to warm to room temperature. After 5 h a volumi-
nous white precipitate had formed. The mixture was filtered
and the filtrate was concentrated under vacuum to afford a
crude mixture of diastereoisomers 5 and 6 (yield: 58.8 g, quan-
titative) as a pale yellow solid mass. The crude mixture was tak-
en up in refluxing diisopropyl ether (1050 mL). The solution
was allowed to cool graduallyto room temperature and, after
A
stirred suspension of N-acyl-iso-amarine 5 (16.8 g,
35.4 mmol) in a mixture of THF (50 mL), water (100 mL)
and concentrated hydrochloric acid (10 mL) was heated to re-
flux for 2 h. The reaction mixture was allowed to cool to room
temperature and concentrated to 2/3 of its original volume un-
der vacuum. After standing at room temperature for 1 h, the
white precipitate was collected byfiltration, washed with
cold water and dried bydrystirring at 60 0C under vacuum to
afford diamide 7 as a fine colourless solid; yield: 16.1 g
(92%); mp>2308C; [a]2D5: þ7.3 (c 4.3, 10:1, CHCl3:MeOH);
914
asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 911 – 916

EnantiomericallyPure ( þ)-(1R,2R)- and (À)-(1S,2S)-1,2-Diamino-1,2-diphenylethanes
FULL PAPERS
1
FT-IR (NaCl): nmax ¼3308, 1731, 1668, 1641 cmÀ1; H NMR
ganic layers were combined, dried over solid NaOH, filtered
and concentrated under vacuum. The crude product was re-
crystallised from diethyl ether:petroleum ether 40–608C8C
(10 mL:20 mL) to afford diamine 1 as a colourless, crystalline
solid; yield: 1.9 g (34%); mp 81–848C [lit.[19] 83–858C]; [a]D25:
À91.0 (c 4.6, EtOH) {lit.[20] [a]2D5: À87.1 (c 2.3, EtOH)}; FT-IR
1H NMR (270 MHz, CDCl3): d¼7.27–7.25 (m, 10H, Ar-H),
4.09 (s, 2H, NCH), 1.62 (br s, 4H, NH2); 13C NMR (68 MHz,
CDCl3): d¼143.5, 128.3, 127.1, 127.0, 62.0; MS (CIþ; NH3)
213 (MþHþ); HR-MS: calcd. for C14H16N2: 213.1392 (Mþ
Hþ), found: 213.1390. The optical purity( >98%) was assessed
bythe method of Synder, [17] using 2 equivalents of (R)-mandel-
ic acid and integrating the doublet at 6.83 versus 6.78 ppm.
3
(270 MHz, DMSO-d6): d¼9.05 (d, JHH ¼7.6 Hz, 1H,
3
3
OCNH), 8.98 (d, JH,H ¼7.4 Hz, 1H, NH), 7.78 (d, JH,H
¼
6.9 Hz, 2H, Ar-H), 7.54–7.44 (m, 3H, Ar-H), 7.26–7.10 (m,
15H, Ar-H), 5.88 (s, 1H, CH), 5.47 (m, 2H, NCHÂ2) 2.11 (s,
3H, COOCH3); 13C NMR (68 MHz, DMSO-d6): d¼170.0,
168.1, 166.9, 140.9, 140.6, 136.0, 135.1, 131.8, 128.9, 128.8
(Â2), 128.4, 128.3, 128.1, 128.0, 128.0, 127.8, 127.4, 75.7, 58.2,
57.3, 21.3; MS (CIþ): m/z¼493 (MþHþ); HR-MS: calcd. for
C31H29N2O4: 493.2127 (MþHþ), found: 493.2123; anal. calcd.
for C31H28N2O4: C 75.59, H 5.73, N 5.69; found: C 75.52, H
5.80, N, 5.71.
(NaCl): nmax ¼3360 (br), 3295 (br), 3060, 3028, 2908, 2857 cmÀ1
;
(À)-(1R,2R)-N-[(R)-a-Acetoxyphenylacetyl]-N’-
benzoyl-1,2-diamino-1,2-diphenylethane (8)
(þ)-(1R, 2R)-1,2-Diamino-1,2-diphenylethane (1)
Following the procedure for the conversion of N-acyl-iso-
amarine 5 into diamide 7 above, diastereomericallyenriched
(R,R,R)-amide 6 (37.5 g, 79.1 mmol) was converted to diamide
8 as a 4:1 (R,R,R):(R,S,S) mixture of diastereomers (yield:
30.8 g, 79%). The crude solid was dissolved in refluxing
CHCl3 (1.9 L) and the hot solution was allowed to cool slowly
to room temperature. On cooling the pure (R,R,R) diamide 8
precipitated, and was collected byfiltration. Removal of a fur-
ther 600 mL of solvent under vacuum and cooling to 00C result-
ed in the precipitation of a second crop of diastereomerically
pure (R,R,R) diamide 8, which was again collected byfiltration.
The two crops were combined and dried under vacuum to af-
ford pure (R,R,R)-diamide 8 as a white crystalline solid; yield:
13.6 g (58%): mp>2308C; [a]2D5: À69.5 (c 2.3, 10:1
CHCl3:MeOH); FT-IR (NaCl): nmax ¼3305, 1739, 1667,
Following the above procedure starting from diamide 8 (12.5 g,
25.5 mmol) gave diamine 1 as a colourless, crystalline solid;
yield: 2.46 g (46%); mp 78–828C [lit.[19] 79–838C]; [a]D25:
þ90.7 (c 3.4, EtOH) {lit.[20] [a]2D5: þ90.4 (c 1.9, EtOH)}. The op-
[17]
tical purity( >98%) was assessed bythe method of Synder,
using 2 equivalents of (S)-mandelic acid and integrating the
doublet at 6.83 versus 6.78 ppm. The other spectral data are
identical to those for its enantiomer.
Acknowledgements
We thank GlaxoSmithKline Ltd and the EPSRC for an Industri-
al CASE award (to. J. M. R.).
1633 cmÀ1
;
1H NMR (270 MHz, DMSO-d6): d¼9.08 (d,
3
3JH,H ¼8.1 Hz, 1H, OCNH), 8.81 (d, JH,H ¼8.8 Hz, 1H,
3
OCNH), 7.66 (d, JH,H ¼7.4 Hz, 2H, Ar-H), 7.56–7.41 (m,
References and Notes
3H, Ar-H), 7.31–7.10 (m, 15H, Ar-H), 5.88 (s, 1H, CH), 5.45
3
3
(t, JH,H ¼8.6 Hz, 1H, NCH’), 5.32 (t, JH,H ¼8.4 Hz, 1H,
NCH), 2.01 (s, 3H, COOCH3); 13C NMR (68 MHz, DMSO-
d6): d¼170.1, 168.0, 166.6, 140.9, 140.9, 136.0, 135.0, 131.7,
128.7, 128.3, 127.9, 127.8, 127.6, 127.4, 127.3, 75.6, 57.9, 57.6,
21.1; MS (CIþ): m/z¼493 (MþHþ); HR-MS: calcd. for
C31H29N2O4: 493.2127 (MþHþ), found: 493.2148; anal. calcd.
for C31H28N2O4: C 75.59, H 5.73, N 5.69; found: C 75.64, H
5.77, N, 5.61.
[1] a) E. J. Corey, P. D. Jardine, S. Virgil, P.-W. Yuen, R. D.
Connell, J. Am. Chem. Soc. 1989, 111, 9243–9244;
b) E. J. Corey, C.-M. Yu, S. S. Kim, J. Am. Chem. Soc.
1989, 111, 5495–5496; c) E. J. Corey, C.-M. Yu, D.-H.
Lee, J. Am. Chem. Soc. 1990, 112, 878–879; d) E. J. Cor-
ey, S. S. Kim, J. Am. Chem. Soc. 1990, 112, 4976–4977;
e) R. Noyori, Angew. Chem. Int. Ed. 2002, 41, 2008–
2022 and references cited therein; f) R. Noyori, M. Ya-
makawa, S. Hashiguchi, J. Org. Chem. 2001, 66, 7931–
7944; g) M. J. Burk, W. Hems, D. Herzberg, C. Malan,
A. Zanotti-Gerosa, Org. Lett. 2000, 2, 4173–4176;
h) W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen,
J. Am. Chem. Soc. 1990, 112, 2801–2803; i) W. Zhang,
E. N. Jacobsen, J. Org. Chem. 1991, 56, 2296–2298;
j) E. J. Corey, R. Imwinkelried, S. Pikul, Y. B. Xiang, J.
Am. Chem. Soc. 1989, 111, 5493–5495; k) E. J. Corey,
N. Imai, S. Pikul, Tetrahedron Lett. 1991, 32, 7517–
7520; l) D. A. Evans, S. G. Nelson, J. Am. Chem. Soc.
1997, 119, 6452–6453.
(À)-(1S, 2S)-1,2-Diamino-1,2-diphenylethane (1)
Following a modified hydrolysis method of Williams and Bai-
lar,[7] a mixture of diamide 7 (12.8 g, 25.9 mmol), glacial acetic
acid (33 mL) and 48% aqueous hydrobromic acid (65 mL ) was
refluxed for 6 h. Further portions of HBr (15 mL) and acetic
acid (8 mL) were added, and the reaction mixture was refluxed
for further 20 h. The solution was concentrated to 1/3 its origi-
nal volume, cooled to 5 0C and allowed to stand for 15 h. The
resulting precipitate was filtered, washed with cold ether and
dissolved in 30 mL of water. The aqueous solution was filtered
to remove insoluble by-products, and aqueous sodium hydrox-
ide solution (40%, ca. 4.5 mL) was added slowlyto the filtrate
such that the temperature did not exceed 258. The mixture was
cooled to 58C for 15 min and the resulting precipitate from the
aqueous phase was extracted with ether (3Â80 mL). The or-
[2] For example, see: R. R. Fenton, R. S. Vagg, P. A. Wil-
liams, Inorg. Chim. Acta 1988, 148, 37–44 and references
cited therein.
[3] K. Saigo, N. Kubota, S. Takebayashi, M. Hasegawa, Bull.
Chem. Soc. Jpn. 1986, 59, 931–932.
Adv. Synth. Catal. 2006, 348, 911 – 916
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
915

D. Christopher Braddock et al.
FULL PAPERS
[4] An enantioselective oxazaborolidine reduction of 1,2-
bis(p-methoxyphenylimino)-1,2-diphenylethane to the
N,N’-protected diamine has been reported. Subsequent
imidazolidinone formation allows separation of the
meso-isomer. Oxidative removal of the p-anisyl groups
and aqueous hydrolysis gives enantiopure diamine 1;
a) M. Shimizu, M. Kamei, T. Fujisawa, Tetrahedron
Lett. 1995, 36, 8607–8610; a 2005 paper reports the dou-
ble addition of phenyllithium to chiral bisimines derived
from tert-butanesulfinamide to give N,N-diprotected dia-
mines in up to a 97:3 ratio dl:meso; the method requires
AlMe3 as an additive; b) X. Sun, S. Wang, S. Sun, J. Zhu,
J. Deng, Synlett 2005, 2776–2780.
[5] S. Pikul, E. J. Corey, Org. Synth. 1993, 71, 22–29.
[6] a) From a diazide: D. Pini, A. Iuliano, C. Rosini, P. Sal-
vadori, Synthesis 1990, 1023–1024; b) from a cyclic sul-
fate: R. Oi, K. B. Sharpless, Tetrahedron Lett. 1991, 32,
999–1002.
[7] O. F. Williams, J. C. Bailar, Jr., J. Am. Chem. Soc. 1959,
81, 4464–4469 and references cited therein.
[8] D. H. Hunter, S. K. Sim, Can. J. Chem. 1972, 50, 669–677
and references cited therein.
[12] a) H. Uchida, T. Shimizu, P. Y. Reddy, S. Nakamura, T.
Toru, Synthesis 2003, 1236–1240; b) for a microwave-ac-
celerated method over solid catalysts see: H. Uchida, H.
Tanikoshi, S. Nakamura, P. Y. Reddy, T. Toru, Synlett
2003, 1117–1120; c) for a one-pot synthesis of iso-amar-
ine from benzaldehyde and HMDS with LiBr in DMSO
see: E. A. Mistryukov, Mendeleev Commun. 2001, 29–
30.
[13] K. Nishiyama, M. Saito, M. Oba, Bull. Chem. Soc. Jpn.
1988, 61, 609–611.
[14] D. H. Hunter, S. K. Sim, Can. J. Chem. 1972, 50, 678–
689.
[15] J. C. Sheenan, G. P. Hess, J. Am. Chem. Soc. 1955, 77,
1067–1068; attempts to utilise the corresponding acid
chloride, led instead to the formation of racemic diaster-
eomers. Presumably, this occurs via amidine-promoted
ketene formation.
[16] The diastereomeric purityof 7 and 8 can be readilyas-
sessed by 1H NMR spectroscopy: the acetate methyl res-
onances (singlets) are at dH ¼2.11 and 2.01 ppm, respec-
tively. In each case, the diastereomers are produced
>98% pure.
[9] E. J. Corey, F. N. M. Kꢂhnle, Tetrahedron Lett. 1997, 38,
8631–8634 and references cited therein.
[10] It is also resistant to reduction with hydride-transfer re-
agents. Reduction to the desired racemic diamine 1 has
been achieved bythe action of aluminium amalgam in
moist THF (ref.[9]).
[17] S. C. Benson, P. Cai, M. Colon, M. A. Haiza, M. Tokles,
J. K. Snyder, J. Org. Chem. 1988, 53, 5335–5341.
[18] P. Saravanan, A. Bisai, S. Baktharaman, M. Chandrase-
khar, V. K. Singh, Tetrahedron 2002, 58, 4693–4706.
[19] As stated bythe Sigma-Aldrich catalogue for the enan-
tiomericallypure material.
[11] I. Lifschitz, J. G. Bos, Recl. Trav. Chim. Pays Bas 1940,
59, 173–183 and references cited therein.
[20] Reading taken from authentic enantiomericallypure
sample purchased from Sigma-Aldrich.
916
asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 911 – 916