Stereospecific synthesis of C2 symmetric diamines from the mother diamine by resonance-assisted hydrogen-bond directed diaza-cope rearrangement

Article abstract of DOI:10.1021/ja803951u

Sixteen diphenylethylenediamine analogues including those with electron donating, electron withdrawing, and sterically bulky substituents have been prepared in good overall yields (70-90%) and in enantiomerically pure form (>99% ee) by diaza-Cope rearrangement reaction. A single chiral mother diamine, ((R,R)-1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane), is reacted with appropriate aldehydes to form the initial diimines that rearrange to give all the product diimines in the (S,S) form. The daughter diamines are obtained by hydrolysis of the product diimines. Density functional theory computation shows that resonance-assisted hydrogen-bond is the main driving force behind all the rearrangement reactions. Chiral high performance liquid chromatography and circular dichroism spectroscopy show that the highly stereospecific rearrangement reactions take place with apparent inversion of stereochemistry.

Full text of DOI:10.1021/ja803951u

Published on Web 08/14/2008
Stereospecific Synthesis of C2 Symmetric Diamines from the
Mother Diamine by Resonance-Assisted Hydrogen-Bond
Directed Diaza-Cope Rearrangement
Hyunwoo Kim, Yen Nguyen, Cindy Pai-Hui Yen, Leonid Chagal, Alan J. Lough,
B. Moon Kim,* and Jik Chin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto, Ontario, M5S
3H6, Canada, and School of Chemistry, Seoul National UniVersity, Seoul, 151-747, Korea
Received June 3, 2008; E-mail: jchin@chem.utoronto.ca
Abstract: Sixteen diphenylethylenediamine analogues including those with electron donating, electron
withdrawing, and sterically bulky substituents have been prepared in good overall yields (70∼90%) and in
enantiomerically pure form (>99% ee) by diaza-Cope rearrangement reaction. A single chiral mother
diamine, ((R,R)-1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane), is reacted with appropriate aldehydes to form
the initial diimines that rearrange to give all the product diimines in the (S,S) form. The daughter diamines
are obtained by hydrolysis of the product diimines. Density functional theory computation shows that
resonance-assisted hydrogen-bond is the main driving force behind all the rearrangement reactions. Chiral
high performance liquid chromatography and circular dichroism spectroscopy show that the highly
stereospecific rearrangement reactions take place with apparent inversion of stereochemistry.
Scheme 1
Introduction
Chiral diamines may be regarded as privileged structures for
making stereoselective catalysts and drugs.1,2 Some of the most
interesting and effective chiral catalysts developed to date (Chart
1) are based on C2 symmetric chiral diamines like 1,2-
diaminocyclohexane (dach) and 1,2-diphenylethylenediamine
(dpen).2 These include oxidation3 and reduction4 catalysts as
well as hydrolysis5 and C-C bond forming catalysts6 (Chart
1). Diamines are useful not only for making metal-based
catalysts but also for making organocatalysts.7 While dach and
dpen are popular diamine ligands, there is no particular reason
why they should be the best for making all diamine-based
catalysts. Steric and electronic tuning of chiral catalysts in
general can give higher reactivity and stereoselectivity.8 Tuning
of chiral diamine ligands has been shown to provide interesting
mechanistic insights9 as well as to yield more effective
catalysts.10 There is much current interest in developing
synthetic methods2 for building chiral diamine libraries. Such
libraries would be useful for the tuning of known catalysts (Chart
1) and receptors as well as for generating new ones.11 In
addition, chiral diamine libraries are of considerable interest
for developing bioactive compounds.1b,12 It is generally difficult
to synthesize a wide variety of dpen analogues with electron
(1) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (b) Kim,
H.; So, S. M.; Kim, B. M.; Chin, J. Aldrichimica Acta 2008, in press.
(c) Nieto, S.; Lynch, V. M.; Anslyn, E. V.; Kim, H.; Chin, J. J. Am.
Chem. Soc. 2008, 130, 9232.
(2) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580.
donating, electron withdrawing, or sterically hindered substit-
uents. Resolution of each new chiral diamine often requires
tedious optimization.13,14 Over thirty years ago Vo¨gtle and
(3) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801. (b) McGarrigle, E. M.; Gilheany, D. G.
Chem. ReV. 2005, 105, 1563. (c) Wang, X.; Reisinger, C. M.; List, B.
J. Am. Chem. Soc. 2008, 130, 6070.
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R. Chem. ReV. 2006, 106, 2912.
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9
12184 J. AM. CHEM. SOC. 2008, 130, 12184–12191
10.1021/ja803951u CCC: $40.75
2008 American Chemical Society

Stereospecific Synthesis of C2 Symmetric Diamines
A R T I C L E S
Chart 1. Diamine Based Catalysts
Goldschmitt showed that a diaza-Cope rearrangement reaction
can be used to synthesize meso-vicinal diamines by a unified
approach.15 This elegant reaction has since been widely used
to synthesize bioactive compounds based on meso-vicinal
diamines.16 More recently we showed in a preliminary com-
munication that the chiral version of the rearrangement reaction
goes even faster and with excellent stereospecificity.17 Here we
examine the scope of this resonance assisted hydrogen bond
(RAHB)17-19 directed diaza-Cope rearrangement (DCR) reac-
tion for making enantiopure “daughter” diamines from a single
“mother” diamine (Scheme 1).
Scheme 2
Results and Discussion
NMR Scale Reactions. To test the scope of the rearrangement
reaction for making chiral vicinal diamines, we studied the
reaction of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (hpen,
1) with a wide variety of aryl aldehydes including those with
electron withdrawing (2a-g) and donating (2h-k) groups at
the para position. In addition, we also studied the reaction of 1
with sterically bulky aryl aldehydes (2l-p). In all cases, the
progress of the rearrangement reaction in DMSO-d6 can be
conveniently monitored by 1H NMR. In a typical reaction, 2.5
equiv of an aldehyde is added to a solution of 1 (50 mM)
dissolved in DMSO-d6. The mother diamine (1) reacts with the
aldehydes (2a-p) to form the initial diimines (4a-p Scheme
2).20 In general the initial diimines are not isolated since they
rearrange to the product diimines (5) at ambient temperature.
The rearrangement reaction is considerably slower when alde-
hydes with strongly electron donating groups (2k) are used. In
(6) Allylic alkylation: (a) Trost, B. M.; Machacek, M. R.; Aponick, A.
Acc. Chem. Res. 2006, 39, 747. (b) Trost, B. M.; Crawley, M. L. Chem.
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Int. Ed. 2007, 46, 7803. Aldol reaction: (h) Denmark, S. E.; Stavenger,
R. A. Acc. Chem. Res. 2000, 33, 432. Mannich reaction: (i) Kobayashi,
S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am.
Chem. Soc. 2003, 125, 2507. (j) Handa, S.; Gnanadesikan, V.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900.
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Chem. Soc. 2005, 127, 14223. (l) Trost, B. M.; Fandrick, D. R. J. Am.
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2007, 107, 5471. (d) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007,
107, 5713. (e) Lelais, G.; MacMillan, D. W. C. Adrichimica Acta 2006,
39, 79. (f) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138. (g) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis:
Wiley-VCH: Weinheim, Germany, 2005.
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(10) (a) Taran, F.; Gauchet, C.; Mohar, B.; Meunier, S.; Valleix, A.; Renard,
P. Y.; Créminon, C.; Grassi, J.; Wagner, A.; Mioskowski, C. Angew.
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Stavenger, R. A.; Su, X.; Wong, K.-T.; Nishigaichi, Y. J. Org. Chem.
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Figure 1. Partial 1H NMR spectra for conversion of (a) 4k to (b) 5k taken
in DMSO-d6.
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A R T I C L E S
Kim et al.
Figure 2. Solid state molecular structures of (a) (S,S)-5b and (b) (S,S)-5l with 50% probability thermal ellipsoids and global minimum structures of (c)
(S,S)-5b and (d) (S,S)-5l at the molecular mechanics level. All hydrogens except for the ones in the phenol, imine, and diamine backbone have been omitted
for clarity.
Table 1. Computed Energies of Diaza-Cope Rearrangement
Reactions
are used. The key signal for all the rearrangement reactions is
the phenolic H NMR peaks of the product diimines (5). This
1
RAHB signal appears as a singlet far downfield (δ 12.4-13.7)
of any other peaks. Figure 1 shows a typical 1H NMR spectrum
taken after the rearrangement reaction is complete.
Computation. Molecular mechanics and density functional
theory (DFT) computation provide valuable insight into the
(11) Kim, H.-J.; Kim, W.; Lough, A. J.; Kim, B. M.; Chin, J. J. Am. Chem.
Soc. 2005, 127, 16776.
R
∆E (kcal/mol)a
K (calcd)b
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67, 101.
NO2
Cl
-9.9
-7.6
-6.8
-4.6
-4.7
-2.2
1.7 × 107
3.8 × 105
9.3 × 104
2.6 × 103
2.5 × 103
4.4 × 102
(13) Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.; Minami, S.; Ema, T.
Bull. Chem. Soc. Jpn. 2004, 77, 1001.
H
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Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008, 73,
133.
OMe
OH
NMe2
(15) Vo¨gtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1.
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Gust, R.; Niebler, K.; Scho¨nenberger, H. J. Med. Chem. 2005, 48,
7132. (c) von Rauch, M.; Schlenk, M.; Gust, R. J. Med. Chem. 2004,
47, 915. (d) Karl, J.; Gust, R.; Spruss, T.; Schneider, M. r.;
Scho¨nenberger, H.; Engel, J.; Wrobel, K.-H.; Lux, F.; Haeberlin, S. T.
J. Med. Chem. 1988, 31, 72. (e) Vassilev, L. T.; Vu, B. T.; Graves,
B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.;
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(f) Fotouhi, N.; Haley, G. J.; Simonsen, K. B.; Vu, B. T.; Webber,
S. E. U.S. Patent Appl. US 20070167437, 2007. (g) Chin, J.; Mancin,
F.; Thavarajah, N.; Lee, D.; Lough, A.; Chung, D. S. J. Am. Chem.
Soc. 2003, 125, 15276.
a DFT at the B3LYP/6-31G(d) level. b Gas phase at 25 °C.
Table 2. Circular Dichroism Cotton Effects of Diimines
1st Cotton
effect (nm)
2nd Cotton
effect (nm)
isosbetic
point (nm)
λmax
(nm, UV-vis)
compound
5a
5b
5i
338
341
333
335
312
316
308
313
320
334
322
326
326
330
322
317
5p
(17) Kim, H.-J.; Kim, H.; Alhakimi, G.; Jeong, E. J.; Thavarajah, N.;
Studnicki, L.; Koprianiuk, A.; Lough, A. J.; Suh, J.; Chin, J. J. Am.
Chem. Soc. 2005, 127, 16370.
this case, heating the reaction solution (DMSO-d6) at 50 °C for
2 h provides the rearranged diimine. Thus, the rearrangement
reaction takes place whether benzaldehydes with electron
donating, electron withdrawing, or sterically bulky substituents
(18) (a) Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc.
2000, 122, 10405. (b) Jeffrey, G. A. An Introduction to Hydrogen
Bonding; Oxford University Press: New York, 1997.
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Scheme 3. Calculated Activation Enthalpies for Possible Chairlike Transition States (ts)
a DFT at the B3LYP/6-31G(d) level.
Figure 3. Circular dichroism spectra of 5a, 5b, 5i, and 5p, (100 µM in THF at 25 °C, 1 cm cell) and their UV-vis spectra.
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Table 3. Stereospecific Synthesis of Daughter Diamines
a >99% ee of 5 is obtained when >99% ee of 1 is used. b Isolated yield.
diaza-Cope rearrangement reaction. The product diimines
(5a-p) formed from the reaction of 1 and aryl aldehydes
(2a-p) all have at least 11 freely rotating single bonds
leading to hundreds of possible conformers. Interestingly,
the global energy minimum conformers for 5b and 5l obtained
by molecular mechanics computation closely match the
corresponding crystal structures (Figure 2). While computed
structures do not always correspond to crystal structures
because of solvent effects and crystal packing, molecular
mechanics computation provides a fast and reliable method
for finding the global energy minimum conformers in our
system.
(19) (a) Park, H.; Kim, K. M.; Lee, A.; Ham, S.; Nam, W.; Chin, J. J. Am.
Chem. Soc. 2007, 129, 1518. (b) Kim, K. M.; Park, H.; Kim, H.-J.;
Chin, J.; Nam, W. Org. Lett. 2005, 7, 3525. (c) Chin, J.; Kim, D. C.;
Kim, H.-J.; Panosyan, F. B.; Kim, K. M. Org. Lett. 2004, 6, 2591.
Although molecular mechanics computation is useful for
obtaining the global energy minimum conformer for the product
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Stereospecific Synthesis of C2 Symmetric Diamines
A R T I C L E S
ts-1 is expected to be the most stable since all aryl substituents
are in pseudoequatorial positions. DFT computation shows that
ts-1 is more stable than ts-2 and ts-3 by about 7.7 and 15.3
kcal/mol, respectively. Thus one phenyl group in the pseudoaxial
position (ts-2) should result in about 4 × 105-fold decrease in
the rate of rearrangement at ambient temperature. Reaction of
(R,R)-4 through ts-1 is expected to produce (S,S)-5. In contrast,
reactions of (R,R)-4 through ts-2 or ts-3 are expected to produce
meso-5 or (R,R)-5 respectively (Scheme 3). Thus DFT computa-
tion indicates that the rearrangement should take place exclu-
sively by ts-1 with apparent inversion in stereochemistry. Indeed,
chiral high performance liquid chromatography (HPLC) and
cicular dichroism (CD) spectroscopy show that there is inversion
of stereochemistry with all our rearrangement reactions (see
below). We do not detect any meso-5 or (R,R)-5 by chiral HPLC.
Interestingly, there is a high degree of preorganization for the
rearrangement reaction as the computed and crystal structures
of 5b and 5l (Figure 2) all resemble the chairlike transition state
(ts). Combination of computation, X-ray crystallography, chiral
HPLC, and CD spectroscopy can be used to support our
proposed mechanism for the rearrangement reaction.
Chiral HPLC. The stereospecificity of the rearrangement
reaction was determined by chiral HPLC. In general, chiral
diamines are derivatized before introduction into the HPLC
column.23 In our case, the product diimine can be directly
injected into the column without derivatization. All of our
rearrangement reactions (4 to 5) go to completion with excellent
stereospecificity. There is no observable loss in enantiopurity
on going from the initial diimines to the product diimines. This
provides a convenient route to enantiopure daughter diamines
(>99% ee) without the need for tedious and time-consuming
optimization of resolution conditions for individual diamines.
It has been shown that diamines like 3a are diffiult to purify
even after many cycles of resolution.13 All of our rearrangement
reactions take place with apparent inversion of stereochemistry
as expected from the chairlike transition state with all pseu-
doequatorial substituents. This has been further confirmed by
CD spectroscopy.
Circular Dichroism Spectroscopy. To verify inversion of
stereochemistry for the rearrangement reaction, absolute ster-
eochemistry of the rearranged diimines (5) was determined by
the exciton chirality method.24 Space coupling of chromophores
in a chiral molecule gives rise to bisignate CD curves (Cotton
effect) which enables one to determine absolute configuration
and conformation of small molecules. Figure 3 shows CD and
UV-vis spectra of 5a, 5b, 5i, and 5p. In all cases, there are
two strong Cotton effects of the same amplitude but of opposite
signs in (R,R)-5 and (S,S)-5. The first Cotton effect at 333-341
nm is followed by the second Cotton effect at 308-316 nm
(Table 2). According to the exciton chirality analysis, (R,R)-5
is expected to give a negative first Cotton effect followed by a
positive second Cotton effect. Similarly (S,S)-5 is expected to
give a positive first Cotton effect followed by a negative second
Cotton effect. Thus the CD spectra show that the diaza-Cope
rearrangementreactionstakeplacewithinversionofstereochemistry.
Synthetic scale reactions. A variety of organic solvents can
be used for the synthesis of the rearranged diimines (5). In some
cases, the rearranged diimine precipitates out of ethanol as a
yellow solid in 70-80% yield (method A). The rearranged
Figure 4. Crystal structures of sterically hindered diamines (3n and 3o,
30% thermal ellipsoid). Chloride counteranion is not shown for clarity.
diimine (5), it is not so useful for predicting the values of the
equilibrium constants for the rearrangement reaction (Scheme
2). In contrast to the experimental results, molecular mechanics
computation shows that the initial diimines (4) are much more
stable than the corresponding rearranged diimines (5). However,
DFT computation shows that the rearrangement reactions with
electron donating or withdrawing groups (Table 1) are all
thermodynamically favorable in agreement with experimental
results. DFT computation further shows that the reaction
becomes increasingly less favorable with more electron donating
substituents. This computational result is consistent with the
observation that the rearrangement reaction takes place more
slowly with electron donating substituents (e.g., 4k). Compared
to the electron withdrawing substituents, electron donating
substituents are better able to stabilize the starting diimine (4)
by conjugation. Thus the kinetics and thermodynamics of the
rearrangement reaction (Scheme 2) are expected to become less
favorable with electron donating substituents on the aryl ring.
DFT computation and experimental results clearly show that
5 is more stable than 4. This is presumably due to the stronger
hydrogen bonds in 5 than in 4.17,18 It is interesting to consider
why the RAHBs in 5 should be stronger than regular hydrogen
bonds in 4. Charged hydrogen bonds are known to be stronger
than neutral hydrogen bonds.18b Thus hydrogen bond between
ammonium and acetate is stronger than that between ammonia
and acetic acid. In charged hydrogen bonds, the hydrogen bond
is reinforced by favorable electrostatic interactions. It appears
that in 5, delocalization of the lone pair electrons on the oxygen
through to the nitrogen results in charge separation and
strengthening of the hydrogen bond. Such delocalization is not
possible in 4. Resonance-assisted hydrogen bonds play an
important role not only in chemistry but also in biology. RAHBs
may be found in Watson-Crick base pairing of DNA, R-helical
and ꢀ-sheet structures of protein, and pyridoxal phosphate
dependent enzymatic processes.21
It has been shown that there is excellent agreement between
the experimental and DFT computational activation enthalpies
for the highly stereospecific sigmatropic rearrangement reac-
tions.22 To understand the origin of the stereospecificity, we
considered three chairlike transition states for the diaza-Cope
rearrangement reaction (Scheme 3). Among these structures,
(20) The imidazolidine intermediate can also be observed by 1H NMR.
This five-membered ring intermediate is stabilized by electron
withdrawing substituents.
(21) Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry, 6th ed.; Freeman,
W. H. 2006.
(22) Hrovat, D. A.; Chen, J.; Houk, K. N.; Borden, W. T. J. Am. Chem.
Soc. 2000, 122, 7456.
(23) Zhong, Y.-W.; Izumi, K.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6,
4747.
(24) Circular Dichroism: Principles and Applications, 2nd ed.; Berova,
N., Nakanishi, K., Woody, R. W., Eds.; Wiley-VCH: New York, 2000.
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Scheme 4. Synthesis of Chiral Vicinal Diamines
diimine can also be prepared in DMSO (method B). Once the
rearrangement is complete in DMSO, extraction was used to
isolate the product diimine. The extract was dried and hydro-
lyzed (3% concd HCl in THF) without further purification to
the diamine dihydrochloride salt as a white powder in good
yields (90-99%). The diamine dihydrochloride salt can be
converted to the neutral form by extraction under basic
conditions. Table 3 shows that a wide variety of diamines (3)
can be prepared in high overall yields (70-90%) and excellent
enantiopurity (>99% ee). Crystal structures of two of the bulky
diamines are shown in Figure 4.
4) without the need for chiral resolution.27 This method has the
advantage of being catalytic although scale up may be difficult
with one of the steps requiring sodium azide.
Conclusion
A wide variety of chiral vicinal diamines were prepared by
diaza-Cope rearrangement (DCR) reaction. This method has now
been commercialized.28 DFT computational studies show that
RAHB is the main driving force for all the rearrangement
reactions regardless of the electron withdrawing, electron
donating, or sterically bulky substituents. This method has
several advantages compared to other methods for making chiral
diamines. First, enantiopure mother diamine (hpen, 1, >99%
ee) provides enantiopure daughter diamines (3, >99% ee) in
high overall yields (70-90%) without the need for individual
resolution. Second, the rearrangement reaction can be easily
scaled up as it takes places under mild conditions without the
need for any catalysts or additives. Third, the enantiomeric
excess as well as absolute configuration of the new diamines
can be conveniently determined from the intermediate diimines
(5) by using chiral HPLC and CD spectroscopy. This simple
and general process may be valuable not only for steric and
electronic tuning of diamine-based catalysts but also for
developing novel ligands and catalysts.
Comparison of the DCR Method with Other Methods. Some
of the diamines in Table 3 were previously synthesized by other
methods. Two of the most widely used methods for making
chiral vicinal diamines are (a) Corey’s25 reductive amination
of benzil analogues (Scheme 4) and (b) Pedersen’s26 reductive
coupling of imines (Scheme 4). Corey et al. showed that C2
symmetric chiral vicinal diaryl diamines can be prepared as
racemic mixtures in good to excellent yields (85% to 100%)
from the corresponding benzil analogues. However, the yields
for resolution of the diamines with tartaric acid were generally
low (36% to 64% of theoretical yield). Denmark10b and
Busacca’s10c groups used the reductive coupling method for
making a variety of chiral vicinal diamines as a racemic mixture.
Although the reductive coupling reaction has the advantage of
being simple, the yield for the coupling step is only around 14%
to 50% and the reaction requires 2 equiv of niobium.10b,c Tartaric
acid resolution gave acceptable separation of some diamine
enantiomers,10,23 but it failed to give satisfactory results for
separation of others like 4a13 and 4k14 even after many
recrystallizations. In such cases, various chiral acids were
screened for resolution14 or the diamines were derivatized with
a chiral reagent and separated by column chromatography.10b,13
Thus the overall yields for the synthesis of enantiopure diamines
are often low (10% of theoretical yield).10
Experimental Section
Procedure A. To a cloudy solution of 2.2 g (10 mmol) of 1,2-
bis(2-hydroxylphenyl)-1,2-diaminoethane (1) in 33 mL of ethanol
was added 24 mmol of aryl aldehyde. The resulting clear reaction
mixture was stirred for 1 h at room temperature to give 5 as a
yellow precipitate. The solid was filtered, washed with 10 mL of
ethanol, and dried in vacuum.
(25) (a) Pikul, S.; Corey, E. J. Org. Synth. 1993, 71, 22. (b) Corey, E. J.;
Lee, D.-H.; Sarshar, S. Tetrahedron: Asymmetry 1995, 6, 3.
(26) Roskamp, E. J.; Pedersen, S. F. J. Am. Chem. Soc. 1987, 109, 3152.
(27) (a) Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483. (b) Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.;
Katsuki, T. Tetrahedron 1994, 50, 11827. (c) Hilgraf, R.; Pfaltz, A.
AdV. Synth. Catal. 2005, 347, 61.
One way to avoid tedious resolution of racemic diamines is
to synthesize diamine enantiomers stereoselectively. Recently,
samarium-mediated reductive coupling of chiral sulfinyl imines
has been reported by Xu and co-workers23 as a direct approach
to synthesize enantiomerically pure diaryl vicinal diamines
(Scheme 4). This method gave diamine enantiomers with
variable yields (25% to 99%). Sharpless asymmetric dihydroxy-
lation of alkenes can also lead to enantiopure diamines (Scheme
(28) Alfa Aesar, DiaminoPharm, Sigma-Aldrich, Strem. HPEN is available
from DiaminoPharm and Sigma-Aldrich. It can also be prepared according
to: Bernhardt, G.; Gust, R.; Reile, H.; vom Orde, H.-D.; Müller, R.;
Keller, C.; Spruss, T.; Schönenberger, H.; Burgemeister, T.; Mannschreck,
A.; Range, K.-J.; and Klement, U. J. Cancer Res. Clin. Oncol. 1992,
118, 201.
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12190 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Stereospecific Synthesis of C2 Symmetric Diamines
A R T I C L E S
Procedure B. To a clear solution of 2.2 g (10 mmol) of 1,2-
bis(2-hydroxylphenyl)-1,2-diaminoethane (1) in 50 mL of DMSO
was added 24 mmol of aryl aldehyde. The resulting mixture was
stirred overnight at room temperature, and then the mixture was
poured into 150 mL of distilled water. The aqueous layer was
extracted with diethyl ether. The combined organic layer was
washed with distilled water, and dried over sodium sulfate. After
evaporation of the solvent, the residue was dried in vacuum.
Hydrolysis of Diimines (5). To a clear solution of 5 (10 mmol)
in 100 mL of THF was added 3.0 mL of 37% HCl solution. Stirring
the reaction mixture at ambient temperature for 3 h afforded the
product as a white precipitate. The solid was filtered and washed
with THF to afford analytically pure 3 as the dihydrochloride salt.
Crystal Parameters. 5b: C28H22N4O6, T ) 150(2) K, mono-
clinic, P21/n, Z ) 4, a ) 16.4941(7) Å, b ) 8.9269(5) Å, c )
17.8748(9) Å, R ) 90°, ꢀ ) 106.919(3)°, γ ) 90°, V ) 2518.0(2)
Å3, R1 ) 0.0558, wR2 ) 0.1390 for I > 2σ(I), GOF on F2 ) 1.014.
3n: C16H24.25Cl2N2O1.125, T ) 150(2) K, monoclinic, C2, Z ) 16,
a ) 30.0290(11) Å, b ) 15.9190(7) Å, c ) 19.3815(6) Å, R )
90°, ꢀ ) 127.4090(17)°, γ ) 90°, V ) 7359.3(5) Å3, R1 ) 0.0785,
wR2 ) 0.2020 for I > 2σ(I), GOF on F2 ) 1.019. 3o:
C70H82Cl16N6O4, T ) 150(1) K, orthorhombic, C2221, Z ) 4, a )
15.6507(7) Å, b ) 22.6708(7) Å, c ) 19.8315(10) Å, R ) 90°, ꢀ
) 90°, γ ) 90°, V ) 7036.5(5) Å3, R1 ) 0.0652, wR2 ) 0.1608
for I > 2σ(I), GOF on F2 ) 0.995.
Computational Methods. All calculations were carried out with
Spartan ’06 from Wavefunction Inc. DFT computation at B3LYP/
6-31G(d) level was used to calculate the optimized geometry and
vibrational frequencies. A vibrational analysis was performed at
each stationary point to confirm its identity as an energy minimum
or a transition structure. The gas-phase enthalpy was calculated as
∆H298 ) ∆ZPVE + ∆∆H0f298K + ∆E0. Zero-point vibrational
energy (ZPVE) and enthalpy change (∆∆H0f298K) from 0 to 298
K at 1 atm were obtained from vibrational frequencies.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada for financial support. BMK
acknowledges financial support from the Strategic Technology
Development Program from the Ministry of Knowledge Economy
of Korea.
Supporting Information Available: Characterization data,
calculation results (PDF) and X-ray structural data for 3n, 3o,
and 5b (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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