Influence of the metal and chiral diamine on metal(II)salen catalysed, asymmetric synthesis of α-methyl α-amino acids

Article abstract of DOI:10.1016/j.tet.2004.02.025

The influence of the metal ion and chiral diamine used to form a metal(salen) complex on the catalytic activity of the complex in the asymmetric benzylation of an alanine enolate was investigated. Only metal ions which could form square-planar complexes g

Full text of DOI:10.1016/j.tet.2004.02.025

Tetrahedron 60 (2004) 3191–3204
Influence of the metal and chiral diamine on metal(II)salen
catalysed, asymmetric synthesis of a-methyl a-amino acids
a
Yuri N. Belokon,b Jose Fuentes,a Michael Northa and Jonathan W. Steed
,
*
aDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
bA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, Vavilov 28, 117813 Moscow, Russian Federation
Received 24 November 2003; revised 16 January 2004; accepted 12 February 2004
Abstract—The influence of the metal ion and chiral diamine used to form a metal(salen) complex on the catalytic activity of the complex in
the asymmetric benzylation of an alanine enolate was investigated. Only metal ions which could form square-planar complexes gave
catalytically active complexes, and best results were obtained with metal ions from the first row of transition metals, particularly copper(II)
and cobalt(II). Salen ligands derived from acyclic, chiral 1,2-diamines were found to generate poor catalysts, an effect which seems to
correlate with the ability of the substituents within the diamine to adopt a conformation in which they are anti to one another. Complexes
derived from a variety of 5- and 6-membered cyclic 1,2-diamines did form active catalysts, but the enantioselectivity was always far lower
than that of the parent cyclohexane-1,2-diamine derived complex.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reactions,10 and enone epoxidations.11 It can also be used in
conjunction with achiral palladium complexes to induce the
asymmetric allylation of enolates.12 Recently, polymer
supported9,13 and oligomeric14 versions of the cinchona
derived phase transfer catalysts have been developed and
used for asymmetric amino acid synthesis. The catalysts
have also been used under micellar conditions.15
There is currently considerable interest in the asymmetric
synthesis of a-amino acids and a,a-disubstituted amino
acids by the alkylation of a prochiral enolate derived from
glycine or an a-substituted amino acid in the presence of a
chiral catalyst. Most of this work is carried out under phase-
transfer conditions, with the chiral catalyst acting as a phase
transfer catalyst.1
Synthetic quaternary ammonium salts derived from
binaphthol have been developed by Maruoka.16 These
salts have been shown to act as asymmetric phase transfer
catalysts for both the alkylation and dialkylation (with two
different alkylating agents) of a glycine derived imine,
leading to both a-amino acids and a,a-disubstituted amino
acids with excellent enantiomeric excesses. The asymmetric
alkylation of b-keto-esters17 and aldol reactions are also
catalysed by these chiral ammonium salts.18 Other groups
have also investigated the use of synthetic phase transfer
catalysts derived from ammonium19 or guanidinium20 salts
and crown ethers.21
The first results in this area came from the group of
O’Donnell and used quaternary ammonium salts derived
from cinchona alkaloids to catalyse the asymmetric
alkylation of a glycine derived enolate, leading to
a-amino acids with moderate enantiomeric excesses.2 The
main problem with this chemistry was the inadequate
enantioselectivity, but recently the groups of Lygo3 and
Corey,4 have shown that the use of a 9-anthracenylmethyl
group to quaternize the cinchona alkaloid resulted in a
catalyst that exhibited significantly enhanced enantio-
selectivity, and allowed the synthesis of a-amino acids
with .95% enantiomeric excess.5 Attempts to extend this
chemistry to enolates derived from other amino acids, thus
allowing the synthesis of a,a-disubstituted amino acids
were less successful due to the lower enantioselectivity
observed.6 The same catalyst can also be used to catalyse
the alkylation of other enolates,7 Michael additions,8,9 aldol
All the above work is based on the use of purely organic
catalysts as asymmetric phase transfer catalysts. It was not
until 1998 that Belokon’ and Kagan first demonstrated that a
metal complex could act as an asymmetric phase transfer
catalyst. The sodium salt of TADDOL was found to catalyse
the alkylation of alanine derivatives leading to a-methyl-a-
amino acids with up to 82% enantiomeric excess.22 It was
subsequently shown that the sodium salts of both NOBIN23
and BINOLAM24 could act as asymmetric phase transfer
catalysts for the same reaction.
Keywords: Phase-transfer-catalysis; a-Amino acid; Alkylation; Diamine.
*
Corresponding author. Tel.: þ44-207-848-1164; fax: þ44-870-131-3783;
e-mail address: michael.north@kcl.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.025

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Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
Chiral transition metal complexes have been used to
catalyse a wide range of asymmetric transformations, and
we have shown that they can be used to catalyse the
asymmetric alkylation of amino acid enolates under phase
transfer conditions. In 1999, we reported that nickel(II)salen
complex 1a (10 mol%) would catalyse the asymmetric
benzylation of alanine enolate 2 leading to a-methyl
phenylalanine 3 (Scheme 1) with 30% enantiomeric
excess.25 The corresponding copper(II)salen complex 1b
was found to be a far more effective catalyst and 2 mol% of
this complex was sufficient to catalyse the formation of
compound 3 with 88% enantiomeric excess. Complex 1b
also catalysed the asymmetric alkylation of compound 2
with other alkyl halides, giving a-methyl a-amino acids
with 75–90% enantiomeric excess.25 These reactions are
carried out under solid–liquid phase transfer conditions
with solid sodium hydroxide as the base, and both
enantiomers of catalyst 1b are equally readily available,
thus allowing the synthesis of either enantiomer of an
a-methyl a-amino acid.
2. Results and discussion
The first factor that we studied was the effect of the central
transition metal. Since the nickel(II) and copper(II) com-
plexes 1a,b had already been found to be catalytically
active,25 a range of other (salen)M2þ complexes were
prepared and tested for catalytic activity in the model
reaction shown in Scheme 2. The substrate 4 used in this
work does not have the optimized para-chlorobenzylidene
imine as this optimisation had not been discovered at the
start of this project.26 Substrate 4 was subsequently used
throughout the work described in this paper to allow the
results to be compared. The enantiomeric excess of the
a-methyl-phenylalanine methyl ester product 5 was deter-
mined by reaction with an excess of (S)-a-methyl
benzylisocyanate to give a pair of diastereomeric ureas 6.
The diastereotopic benzylic protons (PhCH2) of compounds
6 give rise to a series of four well resolved doublets in the 1H
NMR spectrum. Integration of these doublets allowed the
diastereomeric excess of ureas 6 and hence the enantiomeric
excess of amine 5 to be determined once the conversion of 5
to 6 had gone to completion.
Scheme 2. Reagents: (i) 1a-l (2 mol%)/NaOH (solid)/BnBr; (ii) MeOH/
AcCl; (iii) SiO2; (S)-PhCH(Me)NvCvO.
Initially, first row transition metal complexes were studied.
Complexes 1c-e could be prepared and isolated by reaction
of the salen ligand with the appropriate metal acetate.
However, all attempts to isolate complex 1f using zinc
bromide or diethylzinc (in thf, toluene or hexane) as the
metal source were completely unsuccessful.29 Therefore,
this complex was prepared in situ from the salen ligand and
diethylzinc. Manganese(II)salen30,31 and iron(II)salen31,32
complexes 1c and 1d were found to be catalytically inactive
(Table 1: entries 1 and 2). These complexes would not be
Schemeþ 1. Reagents: (i) 1a,b (2–10 mol%)/NaOH (solid)/BnBr;
(ii) H3O /D.
Table 1. The effect of the metal in complexes 1 on enantioselectivitya
In subsequent work, we have studied the effect that
substituents on the aromatic rings of catalyst 1b have on
the enantioselectivity of the catalyst,25,26 and optimized the
reaction conditions and the structure of the imine within
substrate 2.26 We have also demonstrated that under
appropriate reaction conditions, it is possible to use the
readily available methyl ester analogue 4 of substrate 2.27
Most recently, we have shown that the chemistry shown in
Scheme 1 can be applied to amino acids other than alanine,
thus allowing the synthesis of a range of non-racemic a,a-
disubstituted a-amino acids.28
Entry
Metal
Complex
Yield (%)
Enantioselectivity (%)b
1
2
Mn2þ
Fe2þ
Co2þ
Ni2þ
Cu2þ
Zn2þ
Rh2þ
Pd2þ
Pt2þ
1c
1d
1e
1a
1b
1f
1g
1h
1i
15
34
83
34
91
39
92
56
55
46
66
21
1
3
80
30
81
1
14
1
0
3
4c
5
6
7
8
9
10
11
12
Co3þ
Co3þ
Co1þ
1j
1k
1l
7
0
0
In this paper, we report the results of a study aimed at better
understanding the influence of various factors on the
enantioselectivity of this reaction. In particular, we have
prepared catalysts from a range of transition metals and
from both cyclic and acyclic chiral diamines.
a
Reactions were carried out under the conditions described in Scheme 2.
The error in this measurement is estimated to be ^3%.
Data taken from Ref. 25 for substrate 2 and using 10 mol% of complex
1a.
b
c

Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
3193
expected to be square-planar. The 15–34% yield of
essentially racemic compound 5 obtained in these reactions
presumably arises from an uncatalysed background reaction
as we have previously shown that even in the absence of any
catalyst, racemic a-methyl-phenylalanine is formed under
the reaction conditions.33
The results from the first row of transition metal M2þ(salen)
complexes clearly show that a square-planar complex is
essential for catalytic activity. It is also notable that
complexes 1b and 1e which are both paramagnetic (17e2
and 15e2 systems respectively) are significantly more
active than the nickel(II)salen complex 1a which is
diamagnetic (16e2 system), despite the fact that all three
complexes are known to be square-planar.36,38 This suggests
that the mechanism may involve a single electron transfer
process.
Cobalt(II)salen complex34 1e was found to be as active a
catalyst as the copper(II)salen complex 1b (Table 1: entries
3 and 5), which is the best previously known salen complex
for this reaction. To further investigate the relationship
between complexes 1e and 1b, the X-ray structure35 of
complex 1e was obtained for comparison with the known
structure of complex 1b.36 The structure of complex 1e is
shown in Figure 1, and as expected the complex was found
to be square-planar.37 Comparison of the bond lengths and
bond angles within the X-ray structures of complexes 1b
and 1e revealed that the structures were essentially super-
imposable. The asymmetric unit of compound 1e contains
two essentially identical, independent, homochiral
molecules that form discrete, face-to-face dimers in the
Three other M2þ(salen) complexes were prepared from
group 9/10 metals in the second and third rows of transition
metals. Rh(II)salen complex 1g was prepared from
rhodium(II) acetate and was found to be catalytically active,
but gave product 5 with only 14% enantiomeric excess
(Table 1: entry 7). An attempt to increase the enantio-
selectivity by using 10 mol% of catalyst 1g was unsuccess-
ful, giving product 5 with an unchanged 13% enantiomeric
excess. Interestingly however, complex 1g gave the (S)-
enantiomer of compound 5 as the major product, whilst
every other complex tested gave predominantly the (R)-
enantiomer of the product. The reason for this difference in
enantioselectivity is not known, but it may be relevant that
rhodium(II)salen complexes are known to be bimetallic
with a Rh–Rh bond.39 Palladium(II)salen complex40,41 1h
(prepared from palladium(II) acetate) and platinum(II)salen
complex41,42 1i (prepared from platinum(II) chloride) were
both catalytically inactive, giving racemic product 5
(Table 1: entries 8 and 9). These three results again show
the superiority of complexes from group 9 over complexes
from group 10 as asymmetric phase transfer catalysts.
Complexes 1h and 1i were also tested as catalysts in
conjunction with potassium hydroxide rather than sodium
hydroxide as the base. Our model to explain the asymmetric
induction in these reactions25,28 envisages the formation of a
bimetallic complex, with the alkali metal coordinated
between the oxygen atoms of the salen ligand. Increasing
the size of the transition metal within the salen complex was
anticipated to increase the distance between these two
oxygen atoms so that they would prefer to coordinate to a
larger alkali metal. However, palladium complex 1h gave
just a 13% yield of racemic 5 under these conditions, and
platinum complex 1i gave no product. As a result of these
results we concluded that only first row transition metal
complexes formed useful catalysts and our subsequent work
was concentrated on these species.
˚
solid state with a Co· · ·Co distance of 3.326(1) A.
Symmetry-related dimers interact via CH· · ·O hydrogen
bonds.
All of the above work was carried out with metal ions in the
þ2 oxidation state. Two Co(III) complexes were also
prepared and tested. Iodo complex 1j was prepared by
treatment of Co(II)salen complex 1e with iodine in
dichloromethane as reported for the preparation of other
iodocobalt(III)salen complexes.43 Complex 1k was
obtained by treatment of complex 1e with ferrocinium
hexafluorophosphate in acetonitrile.44 By analogy with the
known X-ray structures45 of other 5-coordinate Co(III)salen
complexes, complex 1j is expected to have a square-based
pyramidal structure with the salen ligand forming the square
base. Complex 1k, with a non-coordinating anion will
however be square-planar.46 Both of these complexes
displayed little or no catalytic activity (Table 1, entries 10
and 11).
Figure 1. The X-ray structure of complex 1e.
In situ prepared zinc(II)salen complex 1f did not give an
active catalyst (Table 1: entry 6). A survey of the Cambridge
X-ray database revealed that Zn(salen) complexes tend not
to be four-coordinate in the solid state. Instead, trigonal
bipyramidal, five-coordinate complexes are formed by
intermolecular association involving the salen oxygen
atoms.29

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Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
Finally, the use of salen complexes of metals in the þ1
oxidation state was investigated. Attempts to prepare the
Cu(I)salen complex from copper(I) acetate and the salen
ligand were unsuccessful as only the Cu(II)salen complex
1b could be isolated from these reactions. The preparation
of Co(I)salen complexes by the reduction of the correspond-
ing Co(II)salen complexes using sodium amalgam is
however a well known process.47 Cobalt(I)salen complexes
are known to be square-planar and to be capable of
coordinating a sodium ion between the two phenolic
oxygens.48 Therefore, complex 1e was treated with sodium
amalgam in thf to generate the corresponding Co(I)salen
complex34 1l This complex was used without purification
due to the known sensitivity of Co(I)salen complexes to air,
but was not found to display any catalytic activity.
Reactions involving complex 1l were far less clean than
those involving complexes 1b,e, produced only a small
amount of product and gave only racemic product (Table 1:
entry 12).
The R-groups in complexes 7a-d can adopt locations which
are either gauche- or anti- to one another as shown by the
Newman projections in Figure 2. Cyclic diamines (such as
(R,R)-cyclohexane-1,2-diamine) can only adopt the gauche-
conformation, but for acyclic diamines the anti-confor-
mation is generally thermodynamically more stable as it
minimizes steric repulsions between the R-groups. The
X-ray structure of the square-planar cobalt(II) complex
derived from ligand 7a has previously been determined53
and shows that the methyl groups are indeed anti to one
another.
Having determined that Co2þ and Cu2þ were the optimal
metals, the structure of the diamine was next investigated.
Four complexes (7a-d) derived from three C2-symmetric
acyclic diamines with different steric properties were
prepared. The (R,R)-1,2-diphenyl-ethane-1,2-diamine
needed for the preparation of complexes 7b,c was
commercially available49,50 and the corresponding diamines
needed for the preparation of complexes 7a,d were prepared
by a literature route involving the addition of the appropriate
Grignard reagent to imine 8 (Scheme 3).51,52 As the results
in Table 2 show, all of these ligands formed copper(II)
complexes which were less catalytically active than
complex 1b. The most active of these complex was 7a
(Table 2: entry 1) derived from (R,R)-butane-2.3-diamine,
and complex 7d was catalytically inactive (Table 2: entry 4)
as indicated by the absence of any enantioselectivity. The
chemical yield in this case is probably due to the
uncatalysed background reaction.33
Figure 2. gauche- and anti-Conformations of salen complexes.
Complex 7b derived from (R,R)-1,2-diphenyl-ethane-1,2-
diamine was less active than complex 7a (Table 2: compare
entries 1 and 2). X-ray structures of square-planar
nickel(II)salen complexes derived from this ligand have
been reported in which the phenyl rings are gauche- or anti-
to one another.54,55 In contrast, the X-ray structure of the
square-planar cobalt(II) complex analogous to 7c shows that
the phenyl rings on the ethylenediamine unit are in this case
locked into the anti-conformation to avoid steric inter-
actions with the two additional phenyl rings on the imine
part of the ligand.56 Complex 7c was found exhibit only a
very low enantioselectivity (Table 2: entry 3).
To investigate why complex 7d was totally inactive, an
X-ray structure analysis of this complex was undertaken.57
This compound also contains two independent molecules in
the asymmetric unit, although a face-to-face interaction as
in 1e is precluded by the bulk of the tert-butyl substituents.
Intermolecular association is again via CH· · ·O interactions
and, as in 1e, the geometry at both independent Cu(II) ions
is square-planar. The structure also revealed (Fig. 3) that the
tert-butyl groups adopted anti-positions on the five-
membered chelate ring to minimize steric repulsions
between them. The effect of this is that the tert-butyl
groups extend over and below the copper ion as shown in
the space filling model illustrated in Figure 4. This would
prevent substrate 4 from complexing to the copper ion, and
hence prevent complex 7d from exhibiting any catalytic
activity.
Scheme 3. Reagents: (i) RMgBr then H3Oþ; (ii) Pd(OH)2/HCO2NH4/
EtOH/D.
Table 2. The effect of acyclic diamines on catalytic activitya
Entry
Complex
Yield (%)
Enantioselectivity (%)
1
2
3
4
7a
7b
7c
7d
73
21
54
27
36
25
5
0
The results obtained with complexes 7a-d strongly suggest
that for a complex to be catalytically active, the substituents
a
Reactions were carried out under the conditions described in Scheme 2.

Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
3195
To restrict the ligands to a gauche-conformation whilst
varying the size of the substituents within the ethylene-
diamine unit, a series of complexes derived from cyclic
diamines was prepared. First, the systematic replacement of
the cyclohexyl ring within catalyst 1b with cyclopropyl,
cyclobutyl- and cyclopentyl- rings to give complexes 9a-c
was investigated. The enantiomerically pure diamines
required for this work were prepared by literature pro-
cedures.58,59 The catalytic activity observed which should
be with each of these complexes is presented in Table 3.
Figure 3. The X-ray structure of complex 7d.
Table 3. The effect of cyclic diamines on catalytic activitya
Entry
Complex
Yield (%)
Enantioselectivity (%)
Figure 4. A space-filling model of complex 7d showing the tert-butyl group
protruding over the copper ion.
1
2
3
4
5
6
9a
9b
9c
9d
9e
9f
69
60
84
59
52
85
0
0
25
37
32
32
on the ethylenediamine part of the salen ligand must adopt a
gauche-conformation. Complexes 7c,d where this is not
possible are inactive, whilst complexes 7a,b which are
expected to exist as an equilibrium mixture of anti- and
gauche-conformations are active. Complex 7a with small
methyl substituents would be expected to have a greater
percentage of molecules in the gauche-conformation than
complex 7b and hence to be more catalytically active. This
matches the observed results.
a
Reactions were carried out under the conditions described in Scheme 2.
In the case of compounds 9a and 9b, whilst we were able to
prepare the required enantiomerically pure 1,2-diamines,
and the salen ligand, it was not possible to isolate the copper

3196
Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
complexes 9a,b. It may be that the torsional angles around
the 3- or 4-membered ring prevent the heteroatoms within
the salen ligand from adopting suitable locations to form a
square-planar complex. However, the crude product
obtained by mixing the ligand and copper(II) bromide was
tested, though no enantioselectivity was observed (Table 3:
entries 1 and 2).
to imine 8 gave diamine63 10 as shown in Scheme 4.
Treatment of diamine 10 with butylmagnesium chloride and
catalytic bis-(cyclopentadienyl)zirconium dichloride
resulted in reductive cyclisation to cyclohexane derivative64
11. However, the order of addition of the reagents was found
to be critical to control the stereochemistry of the
cyclisation. Only when the butylmagnesium chloride and
(cyclopentadienyl)zirconium dichloride were premixed
followed by addition of diamine 10 was compound 11
obtained as the major stereoisomer. In our hands, all other
conditions gave unreacted starting material. Hydrogenolysis
of compound 11 was carried out using 20% Pd(OH)2 on
carbon at three atmospheres pressure of hydrogen for 24 h,
and gave the partially deprotected compound 12. Compound
12 was resubjected to the same hydrogenolysis conditions to
give diamine 13. Treatment of diamine 13 with salicyl-
aldehyde gave the required salen ligand 14 which could be
complexed to copper to give complex 9e.
Cyclopentane derivative 9c was prepared by the literature
route,59 and the corresponding N-benzyl pyrrolidine derived
ligand was also prepared by a modification of the literature
procedure.60 Thus, N-benzyl-(3S,4S)-3,4-dihydroxy-
pyrrolidine was prepared from (R,R)-tartaric acid. However,
in our hands the conversion of this diol into the
corresponding bis-azide by a Mitsunobu procedure60 was
problematic. In contrast, conversion of the diol to the
corresponding bis-mesylate61 and then conversion to the
bis-azide using the procedure reported for 1,2-diazido-
cyclopentane62 worked smoothly. Subsequent reduction of
the bis-azide to the corresponding diamine, formation of the
salen ligand and synthesis and isolation of complex 9d
occurred as expected. However, whilst complexes 9c and 9d
did form active catalysts (Table 3: entries 3 and 4), the
asymmetric induction observed with them was only about
one third that observed with the corresponding cyclohexane
derivative 1b.
In complex 9e, the formation of the chelate forces both
amino groups to adopt equatorial positions on the
cyclohexane ring, and this in turn means that both methyl
groups are in axial positions. It was hoped that the methyl
groups would be able to interact with a coordinated
substrate, but disappointingly, complex 9e only exhibited
32% enantioselectivity (Table 3: entry 5), compared to 81%
for complex 1b (Table 1: entry 5) which does not have the
two methyl groups on the cyclohexane ring. The acyclic
diamine derived ligands 7a-d demonstrated that axial
groups on the carbon adjacent to the nitrogen atoms were
detrimental to the enantioselectivity of the catalysts. The
result obtained with complex 9e suggests that this effect
extends all the way across the cyclohexane ring.
The 1,2-diamino-4,5-dimethylcyclohexane required for the
synthesis of complex 9e was prepared by a modification of a
literature procedure. Addition of allylmagnesium bromide
The enantiomerically pure anthracene derived diamine
required for the preparation of complex 9f was prepared
from anthracene and fumaric acid by the literature route.65
Condensation of this diamine with salicylaldehyde gave the
required salen ligand49 which could be complexed to copper
to give complex 9f. In complex 9f, the cyclohexane ring is
forced to adopt a boat conformation, and this was found to
have a detrimental effect on the enantioselectivity of the
catalyst (Table 3: entry 6) as the complex converted
compound 4 into product 5 with just 32% enantiomeric
excess.
3. Conclusions
Of the metal(salen) complexes studied as asymmetric phase
transfer catalysts in this work, only the Cu(II) and Co(II)
complexes were found to give high levels of asymmetric
induction. These two complexes are both square-planar and
paramagnetic. Variation of the original cyclohexane-1,2-
diamine derived salen ligand did not increase the asym-
metric induction. Complexes derived from acyclic diamines
exist predominantly in an anti-conformation which may
account for their reduced catalytic activity. It was not
possible to isolate copper complexes of cyclopropyldiamine
and cyclobutyldiamine derived ligands. The cyclopentyl-
diamine and cyclohexyldiamine derived ligands studied,
were catalytically active, but gave lower asymmetric
Scheme 4. Reagents: (i) allylMgBr then H3Oþ; (ii) BuMgBr (5 equiv.)/Cp2-
ZrCl2 (20 mol%); (iii) Pd(OH)2/C/H2, 3 atm; (iv) salicylaldehyde.

Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
3197
induction than the parent cyclohexane diamine derived
complex.
DENZO-SMN package67 and positional data were refined
along with diffractometer constants to give the final unit cell
parameters. Integration and scaling (DENZO-SMN, Scale-
pack67) resulted in unique data sets corrected for Lorentz
and polarisation effects and for the effects of crystal decay
and absorption by a combination of averaging of equivalent
reflections and an overall volume and scaling correction.
Structures were solved using SHELXS-9768 and developed
via alternating least squares cycles and difference Fourier
synthesis (SHELXL-9768) with the aid of the program
XSeed.69 All non-hydrogen atoms were modelled aniso-
tropically, while hydrogen atoms are assigned an isotropic
thermal parameter 1.2 times that of the parent atom (1.5 for
terminal atoms) and allowed to ride. All calculations were
carried out with IBM compatible PCs.
4. Experimental
4.1. General
1H NMR, 13C NMR, 19F NMR and 31P NMR spectra were
recorded on a Bruker Avance 360 Spectrometer, (1H
360 MHz, 13C 90 MHz, 19F 338 MHz and 31P 145 MHz).
The solvent for a particular spectrum is given in
1
parentheses. H and 13C NMR Spectra were referenced to
TMS and chemical-shift (d) values, expressed in parts per
million (ppm), are reported downfield of TMS. Chemical-
shift values for 31P spectra are reported downfield of
phosphoric acid, and chemical-shift values for 19F spectra
are relative to CFCl3. The multiplicity of signals is reported
as singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), broad (br) or a combination of any of these. For 13C
NMR spectra, the peak assignments were made with the
assistance of DEPT experiments.
4.1.1. Manganes0e(II)salen complex 1c. To a solution of
(R,R)-[N,N0-bis-(2 -hydroxybenzylidene)]-1,2-diamino-cyclo-
hexane (476 mg, 1.48 mmol) in ethanol (15 ml), was added
KOH (166 mg, 2.96 mmol) dissolved in ethanol (4 ml). To the
resulting yellow solution was added a suspension of anhydrous
manganese acetate (256 mg, 1.48 mmol) in ethanol (4 ml) and
the reaction was refluxed at 100–120 8C for 2 h under a
nitrogen atmosphere. The solution was allowed to reach room
temperature and then concentrated in vacuo. The resulting
black solid was taken up with dichloromethane, filtered and
evaporated in vacuo to leave a black solid which was
recrystallized from dichloromethane/hexane to afford com-
pound 1c (461 mg, 83%) as black crystals. Mp .250 8C.
[a]2D0¼21233 (c 0.012, CHCl3); nmax (KBr) 3022 (w), 2934
(m), 2859 (w), 1632 (s), 1600 (s) and 1537 cm21 (s); m/z (ESI)
375 (Mþ, 100). Found (ESI) 375.0900 (Mþ), C20H20N2O2Mn
requires 375.0880.
Infrared spectra were recorded on a Perkin–Elmer FT-IR
Paragon 1000 spectrometer, as a thin film between NaCl
plates in the reported solvent, or as KBr disks. The
characteristic absorption is reported as broad (br), strong
(s), medium (m) or weak (w). Low and high resolution mass
spectra were recorded at the EPSRC national service at the
University of Wales, Swansea, or on a Bruker Apex III
FTMS or Jeol AX505W spectrometer within the chemistry
department at King’s College. The sample was ionized by
electron ionization (EI), chemical ionisation (CI) fast atom
bombardment (FAB) or electrospray ionization (ESI). The
major fragment ions are reported and only the molecular
ions are assigned.
4.1.2. Iron(II)salen complex 1d.32 (R,R)-[N,N0-Bis-(20-
hydroxybenzylidene)]-1,2-diamino-cyclohexane (847 mg,
2.63 mmol) and anhydrous iron(II) acetate (457 mg,
2.63 mmol) were stirred in ethanol (8 ml) at 75 8C for 1 h
under a nitrogen atmosphere A dark orange solid pre-
cipitated. The mixture was allowed to cool to room
temperature and then filtered and washed with hexane
under a nitrogen atmosphere. The orange precipitate was
purified by suspension in refluxing ethanol under a nitrogen
atmosphere, followed by filtration and washing with hexane
to give compound 1d (494 mg, 50%) as an orange solid. Mp
.270 8C; [a]2D0¼2714 (c 0.017, CHCl3); nmax (KBr) 3024
(w), 2926 (m), 2855 (w), 1614 (s) and 1539 cm21 (s); m/z
(ESI) 376 (Mþ, 100). Found (ESI) 376.0846 (Mþ),
C20H20N2O2Fe requires 376.0869.
Optical rotations were recorded on a Perkin–Elmer 343
polarimeter in a thermostated cell of length 1 dm at 20 8C
using the sodium D-line, and a suitable solvent that is
reported along with the concentration (in g/100 ml). Melting
points were determined with a Buchi Melting Point
apparatus N8 520092 and are uncorrected. Elemental
analyses were performed by the London School of
Pharmacy.
Chromatographic separations were performed with silica
gel 60 (230–400 mesh) and thin-layer chromatography was
performed on polyester backed sheets coated with silica gel
60 F254, both supplied by Merck. Toluene was distilled
from sodium prior to use.
4.1.3. Cobalt(II)salen complex 1e.34 (R,R)-[N,N0-Bis-(20-
hydroxybenzylidene)]-1,2-diamino-cyclohexane (1.61 g,
5.0 mmol) and anhydrous cobalt(II) acetate (1.25 g,
5.0 mmol) were stirred in ethanol (16 ml) at 70 8C for 1 h
under an argon atmosphere. During this time an orange solid
precipitated. The reaction was allowed to cool to room
temperature and then filtered and washed with hexane under
a nitrogen atmosphere. The orange precipitate was purified
by suspension in refluxing ethanol under an argon
atmosphere, followed by filtration and washing with hexane
to obtain a crimson solid (543 mg, 29%). Crystals suitable
for X-ray analysis were obtained by recrystallisation from
hexane/dichloromethane. Mp .270 8C; [a]2D0¼21420 (c
Crystals were mounted on a thin glass fibre using epoxy
resin and cooled on the diffractometer to 120 K using an
Oxford Cryostream low temperature attachment. Approxi-
mate unit cell dimensions were determined by the Nonius
Collect program66 from 5 index frames of width 28 in f
using a Nonius KappaCCD diffractometer, with a detector to
crystal distance of 30 mm. The Collect program was then
used to calculate a data collection stratgey to 99.5%
completeness for u¼27.58 using a combination of 28 f
and v scans of 10–120 s deg21 exposure time (depending
on crystal quality). Crystals were indexed using the

3198
Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
0.050, CHCl3); nmax (KBr) 3019 (w), 2930 (w), 2855 (w),
1603 (s) and 1531 cm21 (m); m/z (FAB) 380 (MHþ, 70%),
379 (Mþ, 66), 307 (26), 154 (100), 136 (69). Crystal data:
C20H20CoN2O2, M¼379.31, red cube, 0.30£0.30£
0.30 mm3, monoclinic, space group P21 (No. 4),
chromatography on LH-20 using EtOH/toluene (1:3) as
eluent to give a mixture of complex 1i and unreacted ligand.
The mixture was washed with diethyl ether (3£4 ml) to
leave complex 1i (60 mg, 19%) as a yellow solid. Mp 180–
190 8C (decomp.); [a]2D0¼2192 (c 0.017, CHCl3); nmax
(KBr) 2932 (m), 1607 (s) and 1535 cm1 (m); dH (CDCl3)
1.3–2.4 (4H, m, CH2CH2), 3.6–3.7 (1H, m, CH–N), 6.4–
7.4 (4H, m, ArCH), 7.63 (1H, s, H–CN); dC (CDCl3) 25.0
(CH2), 28.1 (CH2), 74.1 (CH), 116.2 (ArCH), 122.5 (ArC),
122.7 (ArCH), 134.1 (ArCH), 134.3 (ArCH), 151.2
(CHvN), 163.8 (ArC); m/z (ESI) 538 (MþNaþ). Found
(ESI) 1053.2262 (2MþNaþ), C40H40N4O4Pt2Na requires
1053.2237.
˚
a¼11.1089(7), b¼12.3377(6), c¼12.3903(10) A, b¼
3
3
˚
97.133(3)8, V¼1685.05(19) A , Z¼4, Dc¼1.495 g/cm ,
˚
F000¼788, KappaCCD, Mo Ka radiation, l¼0.71073 A,
T¼120(2) K, 2umax¼55.08, 10999 reflections collected,
6940 unique (Rint¼0.0610). Final GooF¼0.996,
R1¼0.0534, wR2¼0.0871, R indices based on 5011
reflections with I.2s(I) (refinement on F 2), 452
parameters, 1 restraint. Lp and absorption corrections
applied,
parameter¼20.009(17).70
m¼1.034 mm21
.
Absolute
structure
4.1.7. Cobalt(III)salen complex 1j. To a solution of
complex 1e (100 mg, 0.26 mmol) in dichloromethane
(53 ml) was added a solution of iodine (34 mg,
4.1.4. Rhodium(II)salen complex 1g. (R,R)-[N,N0-Bis-(20-
hydroxybenzylidene)]-1,2-diamino-cyclohexane (116 mg,
0.36 mmol) and sodium methoxide (39 mg, 0.72 mmol)
were dissolved in methanol (7 ml). The yellow solution was
stirred at room temperature for 5 min, then [Rh(OAc)2]2·
2H2O (86 mg, 0.18 mmol) was added as a slurry in MeOH
(2 ml). The resulting green solution was stirred and heated
to 60 8C for 4 h, under an argon atmosphere. Subsequently,
the dark brown mixture was allowed to cool to room
temperature and then evaporated in vacuo. The crude
product was dissolved in dichloromethane (7 ml) and
diethyl ether (10 ml) was added until a pale brown solid
precipitated. The precipitate was collected by suction
filtration, washed with diethyl ether (5 ml) and dried in
vacuo to leave complex 1g (150 mg, 98%) as a pale brown
solid. Mp .270 8C; [a]2D0¼28 (c 0.025, MeOH); nmax
(CHCl3) 2942 (m), 2863 (w), 1635 (s), 1602 (s) and
1536 cm21 (w); m/z (ESI) 423 (Mþ, 100). Found (ESI)
423.0572 (Mþ), C20H20N2O2Rh requires 423.0574.
0.13 mmol) in dichloromethane (1 ml). The mixture was
stirred at room temperature for 1 h during which time the
red colour of the solution disappeared and a brown solid
precipitated. The solution was evaporated to dryness to give
complex 1j (128 mg, 96%) as a brown solid which was used
without further purification. Mp 260 8C; [a]2D0¼21000 (c
0.001, CHCl3); nmax (KBr) 3052 (w), 2933 (w), 2859 (w),
1628 (s), 1595 (s) and 1535 cm21 (m); dH (DMSO-d6)
1.5–3.1 (4H, m, CH2CH2), 3.6–3.7 (1H, m, CHN), 6.5–7.6
(4H, m, ArCH), 8.03 (1H, s, HCvN); dC (DMSO-d6) 24.5
(CH2), 29.8 (CH2), 69.9 (CH), 115.5 (ArCH), 119.3 (ArC),
123.0 (ArCH), 135.1 (ArCH), 135.5 (ArCH), 164.4
(CHvN), 165.6 (ArC). Found (ESI) 379 (M2Iþ, 100).
Found (ESI) 379.0831 (M2Iþ), C20H20N2O2Co requires
379.0857.
4.1.8. Cobalt(III)salen complex 1k. A solution of ferro-
cenium hexafluorophosphate (66 mg, 0.20 mmol) in aceto-
nitrile (4 ml) was added to a solution of complex 1e (75 mg,
0.20 mmol) in acetonitrile (4 ml) at room temperature. The
mixture was stirred for 19 h and then was concentrated in
vacuo. The crystalline residue was washed with hexane to
remove ferrocene and dried in vacuo to afford complex 1k
(104 mg, 99%) as a black crystalline solid. Mp .250 8C;
[a]2D0¼23005 (c 0.033, MeOH); nmax (KBr): 2939 (w),
1637 (s), 1604 (m), and 1544 cm21 (m); dH (DMSO-d6)
1.6–2.1 (4H, m, CH2CH2), 3.0–3.1 (1H, m, CHN), 6.7–7.6
(4H, m, ArCH), 8.02 (1H, s, HCvN); dC (DMSO-d6) 24.5
(CH2), 29.8 (CH2), 69.8 (CH), 115.5 (ArCH), 119.2 (ArC),
123.0 (ArCH), 135.1 (ArCH), 135.5 (ArCH), 164.4
(CHvN), 165.6 (ArC); dF (DMSO-d6) 270.5 (d
4.1.5. Palladium(II)salen complex 1h.40 (R,R)-[N,N0-Bis-
(20-hydroxybenzylidene)]-1,2-diamino-cyclohexane (122 mg,
0.378 mmol) andsodiummethoxide(49 mg,0.91 mmol)were
dissolved in methanol (29 ml). The yellow solution was stirred
at room temperature for 5 min, then anhydrous palladium
acetate (85 mg, 0.378 mmol) was added and the reaction
stirred for 2 h. The precipitate was collected by vacuum
filtration, washed with cold methanol and dried in vacuo with
gentle heating for several hours to provide complex 1h
(127 mg, 79%) as a yellow solid. Mp .270 8C; [a]2D0¼2504
(c 0.025, CHCl3); nmax (KBr) 3045 (w), 2932 (m), 2857 (w),
1632(s),1601(s)and1531 cm21 (s); dH (CDCl3)1.3–2.4(4H,
m, CH2CH2), 3.6–3.7 (1H, m, CH–N), 6.4–7.3 (4H, m,
ArCH), 7.31 (1H, s, HCvN); dC (CDCl3) 24.9 (CH2), 28.8
(CH2), 72.7 (CH), 115.0 (ArCH), 121.2 (ArC), 122.2 (ArCH),
135.0 (ArCH), 135.2 (ArCH), 155.6 (CHvN), 165.9 (ArC);
m/z (ESI) 426 (Mþ, 100). Found (ESI) 426.0644 (Mþ),
C20H20N2O2Pd requires 426.0648. Found: C, 56.4%; H, 4.5%;
N, 6.3%. C20H20N2O2Pd requires: C, 56.3%; H, 4.7%; N,
6.6%.
1
1JPF¼711 Hz, PF6); dP(DMSO-d6) 2143 (hept. JPF¼
711 Hz, PF6); m/z (ESI) 379 (M2PF6)þ. Found (ESI)
379.0821 (M2PF6)þ, C20H20N2O2Co requires 379.0851.
4.1.9. Copper(II)salen complex 7a. (þ)-[N,N0-Bis-(20-
hydroxybenzylidene)]-2,3-diamino-butane53
(80 mg,
0.3 mmol), copper(II) bromide (67 mg, 0.3 mmol) and
sodium methoxide (33 mg, 0.6 mmol) were dissolved in
methanol (5 ml) and stirred for 18 h at room temperature.
The solvent was evaporated in vacuo and the residue was
purified by chromatography on LH-20 using EtOH/toluene
(1:3) to give complex 7a (74 mg, 69%), as a dark brown
solid. Mp 258–260 8C; [a]2D0¼2582 (c 0.014, CHCl3); nmax
(CHCl3) 2964 (w), 1622 (s), 1600 (m) and 1536 cm21 (m);
m/z (CI) 358 (MHþ, 55), 297 (63), 148 (89), 122 (100), 72
4.1.6. Platinum(II)salen complex 1i.41 (R,R)-[N,N0-Bis-(20-
hydroxybenzylidene)]-1,2-diamino-cyclohexane (200 mg,
0.62 mmol), PtCl2 (165 mg, 0.62 mmol) and NaOMe
(67 mg, 1.24 mmol) were added to methanol (5 ml) stirred
for 4 h at room temperature and then the solvent was
removed in vacuo. The residue was first purified by

Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
3199
(61). Found (ESI) 358.0743 (MHþ), C18H19N2O2Cu
requires 358.0737.
0.6 mmol) were dissolved in methanol (8 ml) and stirred
for 3 h at room temperature. The solvent was evaporated in
vacuo and the residue was purified by chromatography on
LH-20 using EtOH/toluene (1:3) to give complex 7c
(186 mg, 98%), as a brown solid. Mp .270 8C; [a]2D0¼260
(c 0.025, CHCl3); nmax (KBr) 3057 (w), 2926 (w), 1600 (m),
1568 (s) and 1521 cm21 (s); m/z (CI) 634 (MHþ, 100), 573
(33), 286 (56), 106 (92). Found (ESI) 634.1680 (MHþ),
C40H31N2O2Cu requires 634.1676.
4.1.10. [N,N0-Bis-(20-hydroxyphenyl)phenylmethyl-
idene]-(R,R)-1,2-diamino-1,2-diphenylethane and
[N-(20-hydroxyphenyl)phenylmethylidene]-(R,R)-1,2-
diamino-1,2-diphenylethane. To a solution of (R,R)-1,2-
diamino-1,2-diphenylethane (220 mg, 1.04 mmol) in
ethanol (10 ml), 2-hydroxybenzophenone (410 mg,
2.07 mmol) was added at room temperature. The resulting
bright yellow solution was stirred under reflux for 44 h, then
it was allowed to cool to room temperature and allowed to
stand overnight. The resulting precipitate was filtered,
washed with cold ethanol (2 ml), dried by suction filtration
and then in vacuo to leave [N,N0-bis-(20-hydroxyphenyl)-
phenylmethylidene]-(R,R)-1,2-diamino-1,2-diphenylethane71
(300 mg, 51%) as a yellow solid. Mp 215–217 8C;
[a]2D0¼þ178 (c 0.55, CHCl3); nmax (CHCl3) 3064 (w), 3032
(w), 2913 (w) and 1606 cm21 (s); dH (CDCl3) 4.68 (1H, s,
CH), 6.50–7.37 (14H, m, ArCH), 15.42 (1H, s, OH); dC
(CDCl3) 72.5 (CH), 117.9 (ArCH), 118.4 (ArCH), 120.4
(ArC), 127.4 (ArCH), 127.7 (ArCH), 128.0 (ArCH), 128.3
(ArCH), 128.5 (ArCH), 128.7 (ArCH), 128.9 (ArCH), 129.2
(ArCH), 132.4 (ArCH), 132.9 (ArCH), 134.3 (ArC), 140.3
(ArC), 163.2 (ArC), 175.4 (CvN); m/z (CI) 573 (MHþ, 5),
286 (31), 198 (73), 106 (100). Found (ESI) 573.2549 (MHþ),
C40H33N2O2 requires 573.2536. The mother liquors from the
crystallisation were evaporated in vacuo, and the resulting
yellow residue was purified by chromatography using Et2-
O/hexane (3:7) to give [N-(20-hydroxyphenyl)phenylmethyl-
idene]-(R,R)-1,2-diamino-1,2-diphenylethane (142 mg, 35%)
as a yellow solid. Mp 61–64 8C; [a]2D0¼þ48 (c 0.5, CHCl3);
4.1.13. [N,N0-Bis-(20-hydroxybenzylidene)]-(R,R)-3,4-
diamino-2,2,5,5-tetramethylhexane. To a solution of
(R,R)-3,4-diamino-2,2,5,5-tetramethyl-hexane52 (270 mg,
1.6 mmol) in ethanol (20 ml), was added salicylaldehyde
(380 mg, 3.2 mmol). The resulting bright yellow solution
was stirred under reflux for 5 h. Subsequently the solution
was allowed to reach room temperature and then evaporated
in vacuo. The residue was recrystallized from hexane-
isopropanol to leave the desired product (340 mg, 56%) as
yellow crystals. Mp 117–119 8C; [a]2D0¼þ185 (c 0.083,
CHCl3); nmax (CHCl3) 3060 (w), 2963 (s), 2871 (m), 1626
(s) and 1582 cm21 (m); dH (CDCl3) 0.83 (9H, s, C(CH3)3),
3.31 (1H, s, CH–N), 6.8–7.3 (4H, m, ArCH), 8.30 (1H, s,
HCvN), 13.58 (1H, s, OH); dC (CDCl3): 28.0 (CH3), 36.3
(CMe3), 77.7 (CHN), 118.0 (ArCH), 118.6 (ArCH), 118.9
(ArC), 131.7 (ArCH), 132.8 (ArCH), 162.3 (ArC), 165.8
(CHvN); m/z (CI) 381 (MHþ, 100), 262 (8), 122 (12).
Found (ESI) 381.2541 (MHþ), C24H33N2O2 requires
381.2542. Found: C, 75.9%; H, 8.6%; N, 7.2%.
C24H32N2O2 requires: C, 75.8%; H, 8.5%; N, 7.4%.
4.1.14. Copper(II)salen complex 7d. [N,N0-Bis-(20-
hydroxybenzylidene)]-(R,R)-3,4-diamino-2,2,5,5-tetramethyl-
hexane (140 mg, 0.37 mmol), copper(II) bromide (82 mg,
0.37 mmol) and sodium methoxide (40 mg, 0.74 mmol) were
added to methanol (2 ml) and stirred for 3 h at room
temperature. The solvent was evaporated in vacuo and the
residue was purified by chromatography on LH-20 using
EtOH/toluene (1:3) to give complex 7d as a black solid.
Recrystallisation from hexane-dichloromethane gave complex
7d (111 mg, 68%) as black crystals. Mp .270 8C;
[a]2D0¼21200 (c 0.025, CHCl3); nmax (KBr) 3021 (w), 2963
(s), 2870 (w), 1614 (s), and 1533 cm21 (s); m/z (FAB) 464
(MþNaþ, 100), 442 (MHþ, 66), 350 (24), 328 (52). Found
(ESI) 442.1682 (MHþ), C24H31N2O2Cu requires 442.1681.
Found: C, 65.1%; H, 7.0%; N, 6.2%. C24H30N2O2Cu requires:
C, 65.2%; H, 6.8%; N, 6.3%. Crystal data: C24H30CuN2O2,
M¼442.04, blue needle, 0.40£0.15£0.15 mm3, monoclinic,
nmax (CHCl3) 3384 (w), 3062 (m), 3030 (m), 2908 (w), 1607
(s) and 1572 cm21 (m); dH (CDCl3) 1.55 (2H, brs, NH2), 4.32
(1H, d J¼5.5 Hz, CH), 4.39 (1H, d J¼5.5 Hz, CH), 6.51–7.31
(19H, m, ArCH), 15.90 (1H, s, OH); dC (CDCl3) 62.8 (CH),
72.7 (CH), 117.9 (ArCH), 118.4 (ArCH), 120.3 (ArC), 127.6
(ArCH), 127.7 (ArCH), 127.5 (ArCH), 127.9 (ArCH), 128.1
(ArCH), 128.5 (ArCH), 128.6 (ArCH), 128.8 (ArCH), 129.3
(ArCH), 132.3 (ArCH), 133.1 (ArCH), 133.9 (ArC), 141.0
(ArC), 142.6 (ArC), 163.7 (ArC), 175.4 (CvN); m/z (CI) 393
(MHþ, 20), 287 (100), 270 (99), 167 (15), 106 (55). Found
(ESI) 393.1961 (MHþ), C27H25N2O requires 393.1961.
4.1.11. Copper(II)salen complex 7b.50 (R,R)-[N,N0-Bis-
(20-hydroxybenzylidene)]-1,2-diamino-1,2-diphenylethane,
(140 mg, 0.33 mmol), CuBr2 (74 mg, 0.33 mmol) and
NaOMe (36 mg, 0.67 mmol) in methanol (4 ml) were
stirred for 4 h at room temperature and then the solvent
was removed in vacuo. The crude residue was purified by
chromatography on LH-20 using EtOH/toluene (1:3) to give
complex 7b (109 mg, 69%) as a purple solid. Mp .270 8C;
[a]2D0¼2310 (c 0.010, CHCl3); nmax (CHCl3) 3028 (w),
1619 (s), and 1535 cm21 (m); m/z (FAB) 504 (MþNaþ,
100%), 482 (MHþ, 69), 481 (Mþ, 21). Found (ESI)
482.1053 (MH)þ, C28H23N2O2Cu requires 482.1056.
Found: C, 70.0%; H, 4.4%; N, 5.5%. C28H22N2O2Cu
requires: C, 69.8%; H, 4.6%; N, 5.8%.
space group P21 (No. 4), a¼11.2350(4), b¼18.1208(5),
3
˚
˚
c¼11.5127(4) A, b¼108.019(2)8, V¼2228.88(13) A , Z¼4,
Dc¼1.317 g/cm3, F000¼932, KappaCCD, Mo Ka radiation,
˚
l¼0.71073 A, T¼120(2) K, 2umax¼55.08, 14897 reflections
collected, 8895 unique (Rint¼0.0872). Final GooF¼1.012,
R1¼0.0527, wR2¼0.1067, R indices based on 7186 reflections
with I.2s(I) (refinement on F 2), 535 parameters, 1 restraint.
Lp and absorption corrections applied, m¼1.001 mm21
.
Absolute structure parameter¼20.007(12).70
4.1.15. (2)-(R,R)-[N,N0-Bis-(20-hydroxybenzylidene)]-
1,2-diaminocyclopropane. To a solution of (2)-trans-
1,2-diaminocyclopropane dihydrochloride58 (190 mg,
1.3 mmol) in dichloromethane (10 ml), salicylaldehyde
(351 mg, 2.9 mmol) was added at room temperature. The
4.1.12. Copper(II)salen complex 7c. [N,N0-Bis-(20-
hydroxyphenyl)phenylmethylidene]-(R,R)-1,2-diamino-1,2-
diphenylethane71 (173 mg, 0.3 mmol), copper(II) bromide
(67 mg, 0.3 mmol) and sodium methoxide (33 mg,

3200
Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
resulting bright yellow solution was stirred at reflux for
23 h, and then evaporated in vacuo to give a dark yellow
syrup. The residue was dissolved in dichloromethane and
hexane was added to precipitate impurities. The solution
was filtered and evaporated in vacuo to give the desired
compound72,73 (148 mg, 40%) as a bright yellow solid. Mp
109–111 8C; [a]D20¼2563 (c 1.6, CHCl3); nmax (CHCl3)
3057 (w), 2986 (w), 2883 (w), 1625 (s) and 1580 cm21 (m);
dH (CDCl3) 1.59 (2H, t J¼6.3 Hz, CH2), 3.32 (1H, t
J¼6.3 Hz, CH), 6.8–6.9 (2H, m, ArCH), 7.1–7.3 (2H, m,
ArCH), 8.40 (1H, s, H–CN), 12.37 (1H, brs, OH); dC
(CDCl3) 20.4 (CH2), 50.6 (CHN), 117.3 (ArCH), 119.3
(ArC), 119.4 (ArCH), 131.5 (ArCH), 132.5 (ArCH), 160.7
(ArC), 164.0 (CHvN); m/z (FAB) 281 (MHþ, 50), 160
(55), 148 (100), 132 (72), 105 (80). Found (ESI) 281.1286
(MHþ) C17H17N2O2 requires 281.1290.
(w), 1639 (s), 1601 (m) and 1534 cm21 (m); m/z (ESI) 370
(MHþ). Found (ESI) 739.1402 (2MþHþ), C38H37N4O4Cu2
requires 739.1401.
4.1.19. Copper(II) complex 9d. (3R,4R)-[N,N0-Bis-(20-
hydroxybenzylidene)]-1-benzyl-3,4-diaminopyrrolidine60
(65 mg, 0.16 mmol), CuBr2 (36 mg, 0.16 mmol) and
NaOMe (18 mg, 0.33 mmol) were added to methanol
(6 ml) and stirred at room temperature for 3 h. The solvent
was evaporated in vacuo and the residue was purified by gel
permeation chromatography on LH-20 using EtOH/toluene
(1:3) as eluent to give complex 9d (34 mg, 45%) as a dark
green solid. Mp 236–238 8C; [a]2D0¼230 (c 0.023, CHCl3);
nmax (KBr) 1637 (s) and 1536 cm21 (m); m/z (ESI) 461
(MHþ, 55), 412 (100), 387 (31). Found (ESI) 461.1158
(MHþ), C22H25N2O2Cu requires 461.1159.
4.1.16. (1)-[N,N0-Bis-(20-hydroxybenzylidene)]-1,2-dia-
minocyclobutane. To a solution of (þ)-trans-1,2-diamino-
cyclobutane59 (112 mg, 1.3 mmol) in dichloromethane
(10 ml), salicylaldehyde (317 mg, 2.6 mmol) was added at
room temperature. The resulting bright yellow solution was
stirred at room temperature for 19 h, and then evaporated in
vacuo to give the desired product73 (233 mg, 61%) as a
yellow gel. [a]D20¼þ565 (c 1.2, CHCl3); nmax (CHCl3) 3057
(w), 2990 (w), 2948 (w), 2875 (w), 1625 (s) and 1580 cm21
(m); dH (CDCl3) 1.9–2.3 (2H, m, CH2CH2), 4.0–4.1 (1H,
m, CH), 6.8–7.3 (4H, m, ArCH), 8.21 (1H, s, HCvN),
13.21 (1H, brs, OH); dC (CDCl3) 24.4 (CH2), 69.5 (CHN),
117.4 (ArCH), 119.0 (ArC), 119.2 (ArCH), 132.1 (ArCH),
132.9 (ArCH), 161.4 (ArC), 164.2 (CHvN); m/z (CI) 295
(MHþ, 100), 191 (10), 148 (6), 122 (6). Found (ESI)
317.1243 (MþNa)þ, C18H18N2O2Na requires 317.1261.
4.1.17. (2)-(R,R)-[N,N0-Bis-(20-hydroxybenzylidene)]-
1,2-diaminocyclopentane. To a solution of (2)-(R,R)-
trans-1,2-diaminocyclopentane59 (179 mg, 1.8 mmol) in
dichloromethane (10 ml), salicylaldehyde (437 mg,
3.6 mmol) was added at room temperature. The resulting
bright yellow solution was stirred at room temperature for
21 h, then evaporated in vacuo, and dried in vacuo with
gentle heating for several hours to give the desired product
(433 mg, 78%) as a yellow gel. [a]2D0¼2467 (c 0.535,
CHCl3); nmax (neat) 3057 (w), 2959 (m), 2873 (m), 1626 (s)
and 1580 cm21 (m); dH (CDCl3) 1.8–2.2 (3H, m, CH2CH2-
CH2), 3.6–3.7 (1H, m, NCH), 6.8–7.2 (4H, m, ArCH), 8.19
(1H, s, HCvN), 13.24 (1H, s, OH); dC (CDCl3) 22.3 (CH2),
33.4 (CH2), 76.9 (CHN), 117.2 (ArCH), 119.0 (ArC), 119.1
(ArCH), 131.8 (ArCH), 132.7 (ArCH), 161.3 (ArC), 165.1
(CHvN); m/z (CI) 308 (Mþ, 56), 187 (100), 147 (14), 122
(22). Found (ESI) 309.1593 (MHþ) C19H21N2O2 requires
309.1598.
4.1.20. N,N0-Bis-[(S)-10-phenylethyl]-(1R,2R,4R,5R)-1,2-
diamino-4,5-dimethyl-cyclohexane.64
Bis-(cyclopenta-
dienyl)zirconium dichloride (224 mg, 0.76 mmol) and dry
diethyl ether (70 ml) were added to a three necked flask
under a N2 atmosphere. n-Butylmagnesium chloride (2 M in
Et2O, 9.4 ml, 18.7 mmol) was added with stirring and the
mixture was allowed to react for 30 min. N,N0-Bis-[(S)-10-
phenylethyl]-(R,R)-4,5-diamino-1,7-octadiene
(1.3 g,
3.74 mmol) dissolved in dry diethyl ether (5 ml) was then
added dropwise and the resulting mixture was allowed to
react for 44 h at room temperature. The reaction was
quenched with saturated aqueous ammonium chloride
(40 ml). The aqueous layer was extracted with diethyl
ether (3£40 ml) and the combined organic layers were
washed with brine (70 ml), dried over magnesium sulphate
and concentrated in vacuo to give an orange oil (1.3 g)
which contained a 6:1 ratio of the 4,5-(R,R) and 4,5-(R,S)-
diastereomers. The diastereomers were separated by column
chromatography using EtOAc/hexane (1:3) as eluent. The
4,5-(R,R)-diastereomer (790 mg, 60%) eluted first as a
yellow oil, followed by the 4,5-(R,S)-diastereomer (134 mg,
10%) as a yellow oil. Spectroscopic data for both
diastereomers were consistent with the literature data.64
4.1.21. N-[(S)-10-Phenylethyl]-(1R,2R,4R,5R)-1,2-dia-
mino-4,5-0dimethyl cyclohexane 12. A solution of N,N0-
bis-[(S)-1 -phenylethyl]-(1R,2R,4R,5R)-1,2-diamino-4,5-
dimethyl cyclohexane (350 mg, 1.0 mmol) in methanol
(20 ml) was hydrogenated in the presence of 20% Pd(OH)2
on carbon (150 mg) under hydrogen at three atmospheres
pressure for 24 h. The reaction was filtered through Celite
and concentrated in vacuo The resulting pale yellow residue
was purified by chromatography using ethyl acetate/
methanol (5:1) to give compound 12 (115 mg, 47%) as a
colourless oil. [a]D20¼296.7 (c 0.55, CHCl3); nmax (neat)
3301 (s), 3025 (w), 2960 (s), 2923 (s), 2872 (m) and
1584 cm21 (m); dH (CDCl3) 0.79 (3H, d J¼6.3 Hz, CH3),
0.88 (3H, d J¼6.3 Hz, CH3), 1.27 (3H, d J¼6.6 Hz, CH3),
1.3–1.5 (4H, m, 2£CH2), 1.75 (2H, brs, NH2), 1.77 (1H, s,
NH), 2.1–2.2 (1H, m, CH), 2.6–2.7 (1H, m, CH), 3.82 (1H,
q J¼6.6 Hz, CH), 7.1–7.3 (5H, m, ArCH); dC (CDCl3) 20.4
(CH3), 20.5 (CH3), 25.6 (CH3), 32.9 (CH), 33.5 (CH2), 33.8
(CH), 37.1 (CH2), 51.3 (CH), 55.3 (CH), 56.5 (CH), 127.1
(ArCH), 127.2 (ArCH), 128.8 (ArCH), 146.3 (ArC); m/z
(CI) 247 (MHþ, 100), 174 (10), 120 (43). Found (ESI)
247.2174 (MHþ), C16H27N2 requires 247.2174.
4.1.18. Copper(II) complex 9c. (2)-(R,R)-[N,N0-Bis-(20-
hydroxybenzylidene)]-1,2-diamino-cyclopentane (213 mg,
0.69 mmol), CuBr2 (154 mg, 0.69 mmol) and NaOMe
(75 mg, 1.38 mmol) were added to methanol (5 ml) and
stirred for 5 h at room temperature. The solvent was
evaporated in vacuo and the residue was purified by gel
permeation chromatography on LH-20 using CH2Cl2 as
eluent. Recrystallization from dichloromethane gave
complex 9c (104 mg, 41%) as small green needles. Mp
.270 8C; [a]2D0¼2177.8 (c 0.016, CHCl3); nmax (KBr) 2933

Y. N. Belokon et al. / Tetrahedron 60 (2004) 3191–3204
3201
4.1.22. (1R,2R,4R,5R)-1,2-Diamino-4,5-dimethyl cyclo-
hexane 13. solution of compound 12 (236 mg,
solution was added 6 N HCl (6 ml). The mixture was stirred
and heated to 80 8C for 3 h and stirred at room temperature
overnight. The two layers were separated and the aqueous
phase was washed with toluene (2£10 ml). The aqueous
phase was then concentrated in vacuo to give (þ)-
(11S,12S)-diamino-9,10-dihydro-9,10-ethano-anthracene
dihydrochloride (970 mg, 40%) as a brownish solid. Mp
.250 8C; [a]D20¼þ14 (c 0.25, CHCl3); nmax (KBr) 3406
(m), 2878 (br), 1578 (m) and 1527 cm21 (m); dH (CD3OD)
3.66 (1H, brs, CH), 4.79 (1H, brs, CH), 7.3–7.4 (2H, m,
ArCH), 7.5–7.6 (2H, m, ArCH); dC (CD3OD) 48.0 (CH),
56.6 (CH), 126.8 (ArCH), 127.9 (ArCH), 129.5 (ArCH),
129.7 (ArCH), 138.1 (ArC), 141.3 (ArC); m/z (EI) 237
((M2HCl–Cl)þ, 100).
A
0.96 mmol) in methanol (6 ml) was hydrogenated in the
presence of 20% Pd(OH)2 on carbon (150 mg) under
hydrogen at three atmospheres pressure for 90 h. The
reaction was filtered through Celite and concentrated in
vacuo. The resulting pale yellow residue was purified by
chromatography using dichloromethane/methanol (3:1) to
give compound 13 (45 mg, 33%) as a colourless oil.
Spectroscopic data were consistent with the literature
data.64
4.1.23. (1R,2R,4R,5R)-[N,N0-Bis-(20-hydroxybenzyl-
idene)]-1,2-diamino-4,5-dimethylcyclohexane 14. To a
solution of (1R,2R,4R,5R)-4,5-dimethyl-cyclohexane-1,2-
diamine64 (35 mg, 0.25 mmol) in ethanol (6 ml), salicyl-
aldehyde (61 mg, 0.50 mmol) was added at room tempera-
ture. The resulting bright yellow solution was refluxed for
19 h, then allowed to cool to room temperature and
evaporated in vacuo. The residue was purified by column
chromatography using ethyl acetate/hexane (1:2) as eluent
to afford compound 14 (26 mg, 30%) as a yellow solid. Mp
93–95 8C; [a]D20¼þ245 (c 1.3, CHCl3); nmax (CHCl3) 2957
(w), 2926 (m), 2875 (m), 1630 (s) and 1582 cm21 (m); dH
(CDCl3) 0.95 (3H, d J¼6.0 Hz, CH3), 1.5–1.7 (2H, m,
CH2), 1.7–1.9 (1H, m, CH), 3.4–3.5 (1H, m, CH), 6.8–6.9
(2H, m, ArCH), 7.1–7.3 (2H, m, ArCH), 8.32 (1H, s,
HCvN), 13.51 (1H, brs, OH); dC (CDCl3) 20.4 (CH3), 33.8
(CH), 37.2 (CH2), 70.0 (CHN), 117.3 (ArCH), 119.1
(ArCH), 119.2 (ArC), 131.8 (ArCH), 132.8 (ArCH), 161.5
(ArC), 164.6 (CHvN); m/z (CI) 351 (MHþ, 100%), 247 (9),
232 (10), 122 (39). Found (ESI) 351.2063 (MHþ),
C22H27N2O2 requires 351.2067.
4.1.26. (11S,12S)-[N,N0-Bis-(20-hydroxybenzylidene)]-
11,12-diamino-9,10-dihydro-9,10-ethanoanthracene. To
a solution of (þ)-(11S,12S)-11,12-diamino-9,10-dihydro-
9,10-ethanoanthracene dihydrochloride (280 mg, 0.9 mmol)
in ethanol (20 ml), were added sodium methoxide (98 mg,
1.8 mmol) and salicylaldehyde (221 mg, 1.8 mmol). The
resulting solution was stirred under reflux for 3 h. The
solution was allowed to cool to room temperature and then
evaporated in vacuo. The yellow residue was taken up in
dichloromethane (20 ml) and washed with water (15 ml)
and brine (15 ml). The organic layer was dried over
anhydrous magnesium sulphate and evaporated to dryness
to leave the desired compound (220 mg, 54%) as a yellow
solid. Mp 102–104 8C; [a]2D0¼þ250 (c 1.4, CHCl3); nmax
(CHCl3) 3024 (w), 2879 (w), 1628 (s) and 1579 cm21 (m);
dH (CDCl3) 3.45 (1H, s, CH), 4.23 (1H, s, CH), 6.7–6.8 (2H,
m, ArCH), 7.1–7.3 (6H, m, ArCH), 8.21 (1H, s, HCvN),
12.41 (1H, s, OH); dC (CDCl3) 52.0 (CH), 77.5 (CH), 117.5
(ArCH), 118.9 (ArC), 119.2 (ArCH), 124.6 (ArCH), 126.1
(ArCH), 127.1 (ArCH), 127.2 (ArCH), 131.9 (ArCH), 133.0
(ArCH), 140.2 (ArC), 140.7 (ArC), 161.2 (ArC), 164.9
(CHvN); m/z (ESI) 445 (MHþ, 100). Found (ESI)
445.1907 (MHþ), C30H25N2O2 requires 445.1911.
4.1.24. Copper(II) complex 9e. Ligand 14 (25 mg,
0.07 mmol), CuBr2 (16 mg, 0.07 mmol) and NaOMe
(8 mg, 0.142 mmol) were added to methanol (2 ml) and
stirred at room temperature for 5 h. The solvent was
evaporated in vacuo and the residue was purified by gel
permeation chromatography on LH-20 using CH2Cl2/
MeOH (1:1) as eluent. Recrystallization from dichloro-
methane/methanol gave complex 9e (28 mg, 96%) as small
purple needles. Mp .250 8C; [a]2D0¼2451 (c 0.014,
CHCl3); nmax (CHCl3) 2931 (w), 1630 (s), 1602 (m) and
1540 cm21 (m); m/z (EI) 411 (Mþ, 2), 132 (25), 91 (22), 44
(100). Found (ESI) 412.1204 (MHþ), C22H25N2O2Cu
requires 412.1207.
Acknowledgements
The authors thank the EPSRC mass spectrometry service at
the University of Wales, Swansea for recording low and
high resolution mass spectra.
4.1.25. (1)-(11S,12S)-11,12-Diamino-9,10-dihydro-9,10-
ethano-anthracene dihydrochloride.65 (11S,12S)-9,10-
Dihydro-9,10-ethanoanthracene-11,12-diacid
References and notes
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