Influence of aromatic substituents on metal(II)salen catalysed, asymmetric synthesis of α-methyl α-amino acids

Article abstract of DOI:10.1016/j.tet.2004.05.023

The influence of substituents on both the aromatic rings of the catalyst, and the benzylidene unit of the substrate are investigated in the (salen)copper(II) catalysed asymmetric benzylation of alanine derivatives. Catalysts with electron-donating, and el

Full text of DOI:10.1016/j.tet.2004.05.023

Tetrahedron 60 (2004) 5919–5930
Influence of aromatic substituents on metal(II)salen catalysed,
asymmetric synthesis of a-methyl a-amino acids
a
Thierry Achard,a Yuri N. Belokon’,b Jose A. Fuentes,a Michael Northa and Teresa Parsons
,
*
aDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
bA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813, Moscow, Vavilov 28,
Russian Federation
Received 9 March 2004; revised 14 April 2004; accepted 13 May 2004
Available online 8 June 2004
Abstract—The influence of substituents on both the aromatic rings of the catalyst, and the benzylidene unit of the substrate are investigated
in the (salen)copper(II) catalysed asymmetric benzylation of alanine derivatives. Catalysts with electron-donating, and electron-withdrawing
substituents of various sizes and at various locations on the aromatic rings of the salen ligand were prepared, but all exhibited inferior
enantioselectivity to the parent (salen)copper(II) complex. In contrast, the introduction of halogenated substituents onto the aromatic ring of
the N-benzylidene alanine methyl ester substrate was found to enhance the enantioselectivity of the alkylation with a para-chloro substituent
giving optimal results. A new procedure for the preparation of the catalysts which avoids the need for chromatography on sephadex LH20 is
reported, and the optimal catalyst obtained in this way was found to be a cobalt(salen) complex.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
meric14 versions of 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
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 has increased significantly in recent years. The
most effective way of carrying out this process is to use a
chiral catalyst under phase-transfer conditions, with the
chiral catalyst also 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 glycine derived imines,
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 guani-
dinium20 salts and crown ethers.21
O’Donnell was the first to show that quaternary ammonium
salts derived from cinchona alkaloids would catalyse the
asymmetric alkylation of a glycine derived enolate, leading
to non-racemic a-amino acids.2 Recently, the groups of
Lygo3 and Corey,4 have optimized this process and shown
that the use of a 9-anthracenylmethyl group to quaternize
the cinchona alkaloid results in a highly enantioselective
catalyst which allows 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.6 Quaternized cinchona alkaloids can
also be used to catalyse the alkylation of other enolates,7
Michael additions,8,9 aldol reactions,10 and enone epoxida-
tions.11 They can also be used in conjunction with achiral
palladium complexes to induce the asymmetric allylation of
enolates.12 Recently, polymer supported9,13 and oligo-
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 reported 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
Belokon’ and Kagan have subsequently shown that the
sodium salt of NOBIN23 could act as an extremely rapid and
enantioselective phase transfer catalyst for the same
´
reaction. Najera has recently reported that the sodium
Keywords: Catalyst; Phase-transfer; Asymmetric; Copper; Amino-acid.
*
salt of BINOLAM is also an effective phase-transfer
catalyst.24
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.2004.05.023

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T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
Chiral transition metal complexes have been used to
catalyse a wide range of asymmetric transformations, and
we have developed the asymmetric alkylation of amino acid
enolates under phase transfer conditions catalysed by salen
complexes of transition metals. In 1999, we reported that
nickel(II)salen complex 1a (10 mol%) would catalyse the
asymmetric benzylation of alanine enolate 2a leading to
a-methyl phenylalanine 3a (Scheme 1) with 30% enantio-
meric excess.25 The corresponding copper(II)salen complex
1b was also studied and was found to be a far more effective
catalyst. Just 2 mol% of complex 1b was sufficient to
catalyse the formation of compound 3a with 88%
enantiomeric excess. Recently, we have screened a wide
range of other metal(salen) complexes for the alkylation of
substrate 2b, but whilst the Co(II)salen complex 1c was
found to be as active as complex 1b, no superior catalyst
was found.26
2. Results and discussion
Based on precedent from our work on asymmetric
cyanohydrin synthesis using titanium(salen) complexes,30
we expected that introduction of substituents at positions 3-
and/or 5- of the aromatic rings of catalyst 1b would enhance
the enantioselectivity of the catalyst. These two positions
(ortho and para to the phenol respectively) both allow the
substituent to exert an electronic effect on the copper ion.
However, we have previously shown that for the reaction
shown in Scheme 1, introduction of a large tert-butyl group
into the 3-position of the aromatic rings had a very negative
impact on the enantioselectivity of the resulting catalyst.25
Therefore, we initially investigated the synthesis and use of
5-substituted salen complexes 4a–e. Compounds 4a–e
were prepared from the appropriate aldehyde via the
corresponding salen ligands 5a–e as shown in Scheme 2.
Aldehydes 6b and 6c were commercially available,
aldehydes 6a and 6d were prepared by literature routes,31,
32
and aldehyde 6e33 was prepared from 4-trifluoromethyl-
phenol as shown in Scheme 3.34
Schemeþ 1. Reagents: (i) 1a–c (2–10 mol%)/NaOH (solid)/BnBr;
(ii) H3O /D; (iii) (R¼Me), MeOH/AcCl then SiO2.
Complex 1b also catalysed the asymmetric alkylation of
compound 2a 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. In subsequent work, we have
also demonstrated that under appropriate reaction con-
ditions, it is possible to use the readily available methyl
ester substrate 2b.27 In addition, 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
Scheme 2. Reagents: (i) (R,R)-cyclohexane diamine/NaOMe;
(ii) CuBr2/NaOMe.
In this paper, we report the results of a study aimed at better
understanding and optimizing the influence of various
factors on the enantioselectivity of this reaction. In
particular, the effect that substituents on the aromatic
rings of catalyst 1b have on the enantioselectivity of the
catalyst are reported25,29 In addition, the influence of the
structure of the imine within substrate 2b on the enantio-
selectivity of the reaction is studied.29 Finally, a method
for the preparation of the catalysts which avoids the use of
size-exclusion chromatography on sephadex LH20 is
described.
Scheme 3. Reagents: (i) Br2; (ii) BuLi/DMF.

T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
5921
Catalysts 4a–e were screened for catalytic activity in the
alkylation of substrate 2b with benzyl bromide to give
a-methyl phenylalanine methyl ester 3b as shown in
Scheme 1. The enantiomeric excess of compound 3b was
readily determined by 1H NMR analysis of the derived
a-methylbenzyl ureas as previously reported.25–29 The
chemical yields and enantioselectivities observed using
these catalysts are summarized in Table 1.
Scheme 4. Reagents: (i) Et3N/MgSO4.
Table 1. Effect of 5-substituents on the enantioselectivity of catalysts 4a–e
Entry
R
Yield (%)
ee (%)
Table 2. Effect of imine structure on the enantioselectivity of the alkylation
of substrates 7a–j
1
2
3
4
5
tBu (4a)
OMe (4b)
NO2 (4c)
F (4d)
39
78
60
54
68
80
45
0
42
25
Entry
Ar
Yield (%)
ee (%)
CF3 (4e)
1
2
3
4
5
6
7
8
8
9
4-O2NC6H4 (7a)
4-MeOC6H4 (7b)
4-ClC6H4 (7c)
3-ClC6H4 (7d)
2-ClC6H4 (7e)
4-FC6H4 (7f)
4-BrC6H4 (7g)
4-IC6H4 (7h)
1-Naphthyl (7i)
2-Naphthyl (7j)
50
79
71
53
43
44
95
67
89
62
65
71
92
81
70
84
81
86
79
77
The introduction of a large tert-butyl group into position 5
of the aromatic rings (4a) had no significant effect on the
level of asymmetric induction observed using the catalyst
(Table 1: entry 1). In contrast, complex 4b containing a
strongly electron donating group in the 5-position displayed
significantly reduced asymmetric induction (Table 1: entry
2). Reasoning that if electron donating groups reduced the
asymmetric induction, electron withdrawing groups might
increase the asymmetric induction, the synthesis of complex
4c containing nitro groups in the 5-position was undertaken.
Unfortunately, whilst ligand 5c could be prepared without
difficulty, copper complex 4c was totally insoluble and
impossible to purify. When the catalytic activity of the
crude complex was tested, no asymmetric induction was
observed (Table 1: entry 3). The chemical yield obtained in
this case is probably due to an uncatalysed background
reaction.
Initially, the influence of electronic effects on the enantio-
selectivity was studied by the preparation of the 4-nitro 7a
and 4-methoxy 7b substituted imines. It was anticipated that
a strongly electron withdrawing group in the 4-position
would acidify the a-proton and therefore possibly lower the
enantioselectivity by increasing the rate of the uncatalysed
background reaction. This was borne out by the observed
16% reduction in enantioselectivity (Table 2: entry 1)
compared to the use of substrate 2b under identical
conditions (81% ee). In contrast however, an electron
donating methoxy substituent was expected to increase the
enantioselectivity of the reaction by reducing the acidity of
the a-proton and hence reducing the rate of the background
reaction. A possible reduction in chemical yield as a result
of the lower acidity of the a-proton was also anticipated. In
practice however (Table 2: entry 2), the chemical yield
remained high and the enantioselectivity was reduced
compared to substrate 2b. This may indicate that the
background reaction is not a significant factor when a
catalyst is present and some other factor or factors are
responsible for controlling the asymmetric induction.
To overcome the solubility problems observed with
complex 4c, the synthesis of fluorinated complexes 4d and
4e was undertaken and both complexes were obtained
without difficulty. The 5-fluoro substituents in complex 4d
are inductively strongly electron withdrawing, but mesome-
rically strongly electron donating and the complex was
found to exhibit very similar asymmetric induction to
complex 4b (Table 1: entry 4). In contrast, the trifluor-
omethyl groups in complex 4e can only exhibit an
inductively electron withdrawing effect, and this complex
was found to be an even worse catalyst (Table 1: entry 5).
Thus, the introduction of either electron donating or electron
withdrawing substituents onto the 5-positions of complex
1b was found to be detrimental for the asymmetric induction
observed when the complexes were used as asymmetric
phase transfer catalysts.
Halo substituents offer the opportunity to introduce
inductively electron withdrawing substituents onto the
imine and to have this offset to some extent by a
mesomerically electron donating effect. Therefore, a series
of compounds 7c, f–h were prepared in which a halogen
was introduced at the 4-position of the imine. In each case,
the enantioselectivity was at least as high as that observed
using substrate 2b (Table 2: entries 3, 6–8) and in the best
case (the 4-chloro substituted derivative 7c), a 10% increase
in enantioselectivity to 91% was observed (Table 2: entry
3). The order of effectiveness of a 4-halo substituent was
Cl.I.F.Br. The reason behind this ordering is not
apparent, but the enantioselectivities observed with the
bromo-, fluoro- and iodo- substituents are all within 5% of
one another and this may be within the experimental error of
Having found no advantage in introducing substituents onto
the aromatic rings of catalyst 1b, the effect of substituents
on the imine of substrate 2b was investigated. Substrates
7a–j were prepared from (S)-alanine methyl ester and the
appropriate aldehyde as shown in Scheme 4. The alkylation
of each of these substrates was carried out using benzyl
bromide as the electrophile under the conditions shown in
Scheme 1. The chemical yields and enantiomeric excesses
of the a-methyl phenylalanine methyl ester 3b obtained in
each case are reported in Table 2.

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T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
^3%. Thus, it appears that a 4-chloro substituent provides
the optimal balance of electron withdrawing and electron
donating effects to achieve the highest enantioselectivity
and retain a good chemical yield. The importance of the
chloro-substituent being in the 4-position was demonstrated
by the preparation of the corresponding 3-chloro and
2-chloro derivatives 7d,e respectively. The 3-chloro deriva-
tive which cannot exhibit any mesomeric effect gave an
identical enantioselectivity to that observed using substrate
2b (Table 2: entry 4). The 2-chloro derivative gave a lower
enantioselectivity than that observed using substrate 2b
(Table 2: entry 5), and steric effects may be important in this
case. To further probe the influence of steric effects, the
synthesis of two naphthyl derivatives 7i,j was undertaken.
These two substrates both gave enantioselectivities that
were comparable with, or just slightly lower than, substrate
2b (Table 2: entries 8 and 9), suggesting that steric effects
(at least in the plane of the aromatic ring) are not a
significant factor in determining the enantioselectivity of the
reaction.
Based on this model and mechanistic hypothesis, we
decided to prepare a series of electron rich copper(II)salen
complexes bearing hydroxy or methoxy substituents. It was
hoped that if the substituents were located in the 3-position,
then they would be able to assist with the coordination of the
sodium ion and hence enhance the catalytic activity. In
addition, there is literature precedent for hydroxyl sub-
stituents stabilizing radical anion formation in salen
ligands.36 Therefore, complexes 8a–f were prepared and
complex 4b was also included in this study as was complex
8g. The latter complex allowed us to investigate the effect of
an alkyl group at the 4-position of the salen ring as this had
not previously been studied. All of the aldehydes needed for
the preparation of complexes 8a–g are commercially
available and were converted into the corresponding salen
ligands by the route shown in Scheme 2. Copper complexes
8a–g were then prepared by one of two methods. For
complexes 8a,d,e, the salen ligand was treated with
copper(II) bromide and the resulting copper complex
purified by gel permeation chromatography on sephadex
LH-20 in the same way as for complexes 1b and 4a,b,d,e.
However, during the course of this work the sephadex LH-
20 required for the purification of complexes prepared in
this way became commercially unavailable. Therefore, for
complexes 8,b,c,f,g, an alternative synthesis was developed
which uses copper(II) acetate as the copper source. This
method had the advantage that the copper complex could be
purified simply by washing with suitable solvents (see
Section 4 for details).
In general, the effect of introducing substituents onto the
imine on the enantioselectivity of the reaction was not as
marked as the effect of introducing substituents onto the
catalyst. However, in contrast to the results obtained with
substituted catalysts, it was possible to both increase and
decrease the enantioselectivity of the reaction compared to
substrate 2b (81% ee) by using an appropriately substituted
imine.
Having successfully optimized the structure of the substrate,
we returned to studies aimed at optimizing the structure of
catalyst 1b, this time using the benzylation of substrate 7c as
the test reaction. As a result of our related work in this
area,25–29 we have developed a working model to explain
the mode of action of catalyst 1b.25,28 This model is shown
in Figure 1. The key feature of the model is the formation of
a hetero-polymetallic complex involving both copper(II)
and sodium ions, with the latter coordinated by the salen
oxygens, a process for which there is ample literature
precedent.35 In addition, our studies on changing the nature
of the transition metal ion,26 and in particular the fact that
only the paramagnetic complexes derived from Cu(II) and
Co(II) displayed high levels of asymmetric induction
suggested that the reaction might proceed by a radical or
radical anion mechanism.
The results of catalytic studies using copper complexes
8a–g and 4b in conjunction with substrate 7c are
summarized in Table 3. Previous work had suggested that
Table 3. Effect of oxygen or methyl substituents on the enantioselectivity
of catalysts 4b and 8a–g
Entry
Complex
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
4b
8f
79
46
59
39
89
61
78
56
5
4
3
14
75
52
67
74
8g
Figure 1. A model to explain the mode of action of catalyst 1b.

T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
5923
a tert-butyl substituent in the 3-positions (R1) would have a
severely detrimental effect on the catalytic activity of the
catalyst.25 It was hoped that the much smaller size of a
hydroxy or methoxy group combined with their sodium
coordinating ability would overcome this steric effect.
However, as entries 1 and 4 in Table 3 show, complexes 8a
and 8d exhibited very poor levels of asymmetric induction.
It is likely that the chemical yield observed in these cases is
largely due to an uncatalysed alkylation as we have
previously shown that significant formation of a-methyl
phenylalanine occurs under the conditions of Scheme 1,
even if the catalyst is omitted.28
Table 4. Effect of method of preparation on the enantioselectivity of
catalysts 1b and 8e
Entry
Catalyst (mol%)
Preparation
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
1b (2)
1b (2)
1b (3)
1b (4)
1b (6)
1ba (2)
8e (2)
8e (2)
8e (3)
1c (2)
CuBr2
71
94
61
78
28
83
89
89
59
89
92
78
82
81
64
84
75
83
80
85
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr2
Cu(OAc)2
Cu(OAc)2
Co(OAc)2
a
Catalyst was additionally recrystallized from dichloromethane.
The other two catalysts containing hydroxyl groups (8b and
8c) also showed negligible levels of asymmetric induction
(Table 3: entries 2 and 3). Catalysts 8a–c will almost
certainly form bis-sodium salts in situ, and this may prevent
the formation of the bimetallic complex shown in Figure 1
and hence account for the lack of catalytic activity.
to the catalyst prepared from copper acetate being less pure
due to the lack of a chromatographic purification, and use of
an increased mol% of the catalyst did increase the
enantioselectivity slightly (Table 4: entries 3 and 4).
However, it was still not possible to match the enantio-
selectivity obtained using the catalyst prepared from copper
bromide and increasing the mol% of catalyst above 4 mol%
was severely detrimental to both the enantioselectivity and
the chemical yield (Table 4: entry 5). The enantioselectivity
of catalyst 1b prepared using copper acetate could be further
slightly increased by recrystallizing the catalyst from
dichloromethane (Table 4: entry 6). This process was used
in the literature to obtain crystals of complex 1b suitable for
X-ray analysis.37 However, the recrystallization is very slow
and low yielding and so not synthetically useful.
The methoxy containing catalysts 8d–f and 4b were all
much more enantioselective than the corresponding
hydroxy derivatives, even when the methoxy groups are in
the 3-positions (R1) (Table 3: compare entries 1 and 4).
However, the highest chemical yield and asymmetric
induction was observed with catalyst 8e in which the
methoxy groups are in the 4-positions (R2) (Table 3: entry
5). In this position, the methoxy groups cannot coordinate
the sodium ion in the model shown in Figure 1 and cannot
exert any other obvious steric or electronic effect on the
catalysis. It is notable that the second best results (Table 3:
entry 7) were obtained with catalyst 8f with the methoxy
groups in the 6-position (R4), the other position on the
aromatic ring where the substituent cannot exert an apparent
steric or electronic effect. Catalysts 8e and 8f were both
significantly more active and enantioselective than catalyst
4b (Table 3: entry 6) in which the methoxy group is para to
the coordinating oxygen and so can exert a mesomeric
electronic effect on the copper ion. Catalyst 8g with methyl
rather than methoxy groups in the R4-positions showed
essentially identical enantioselectivity to catalyst 8e,
suggesting that the enantioselectivity is not connected to
the presence of an oxygen atom.
In contrast, catalyst 8e was found to be more enantio-
selective when prepared using copper acetate than when
prepared using copper bromide (Table 4: entries 7 and 8). It
may be that the purification by washing is more successful
in the case of catalyst 8e than catalyst 1b. Increasing the
amount of catalyst 8e above the standard 2 mol% was found
to have a detrimental effect on both the enantioselectivity
and the chemical yield (Table 4: entry 9).
We have previously reported that Co(salen) complex 1c
(prepared using cobalt acetate) was as enantioselective as
copper(salen) complex 1b (prepared using copper bromide).
This comparison was carried out using substrate 2b and the
enantioselectivities were 81 and 80% for catalysts 1b and 1c
respectively.26 Therefore, we decided to see if the
enantioselectivity observed with catalyst 1c could be further
enhanced by the use of substrate 7c. Treatment of substrate
7c with benzyl bromide under the standard conditions
(Scheme 1) using 2 mol% of complex 1c as catalyst resulted
in the formation of a-methyl phenylalanine methyl ester 3b
in 89% yield and 85% enantiomeric excess (Table 4: entry
10). This result is the best obtainable with any of the
catalysts studied without the need for purification on
sephadex LH20.
Since the catalysts used during this work were prepared by
two different routes and since the method reported for the
preparation of catalyst 1b was no longer viable due to the
commercial unavailability of sephadex LH20, it was
decided to carry out a direct comparison of catalysts
prepared by both synthetic routes. Two catalysts, 1b and 8e,
were chosen for this study. Samples of both catalysts were
prepared from the appropriate salen ligand using copper
bromide/sodium methoxide followed by purification by
chromatography on sephadex LH20 and by use of copper
acetate followed by isolation of the catalyst by precipitation
and purification by washing. The results obtained when the
resulting catalysts were used to induce the asymmetric
benzylation of substrate 7c are compared in Table 4.
3. Conclusions
In the case of catalyst 1b, the catalyst prepared using the
copper acetate procedure was noticeably less enantio-
selective than the catalyst prepared by the copper bromide
procedure (Table 4: entries 1 and 2). This may be partly due
The enantioselectivity of (salen)Cu complexes as catalysts
for the asymmetric benzylation of alanine derivatives was
found to be strongly influenced by substituents on the
aromatic rings of the salen ligand. All of the substituents

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T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
studied at any location on the aromatic rings had a negative
effect on the enantioselectivity. In contrast, substituents on
the aromatic ring of the N-arylidene alanine methyl ester
substrate could have either a positive or negative effect.
Optimal results were obtained using a para-chlorobenzyl-
idene imine.
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. 2-Hydroxy-5-trifluoromethylbenzaldehyde33 6e
The mode of preparation of the catalyst was also found to
influence its enantioselectivity. The best result (92% ee) was
obtained when the catalyst was prepared using copper
bromide and purified by chromatography on sephadex
LH20. An alternative procedure using copper acetate and
purification by washing with various solvents gave a less
enantioselective (78% ee) catalyst derived from the
unsubstituted salen ligand, though the enantioselectivity of
the catalyst could be increased to 84% by further
purification by recrystallization. In contrast however, for
catalyst 8e derived from the 4-methoxy-salen ligand, the
copper acetate route was found to give a more enantio-
selective (83% ee) catalyst than the copper bromide
procedure (75% ee). The most enantioselective catalyst
(85% ee) which did not need purification by sephadex LH20
however was complex 1c derived from cobalt acetate.
In a three-neck flask under an argon atmosphere, 2-bromo-
4-trifluoromethylphenol34 (0.95 g, 4.2 mmol) was dissolved
in THF (40 mL). The resulting solution was stirred and
cooled to 260 8C and then n-BuLi (3.4 mL of a 2.5 M
solution in hexane) was added dropwise. The reaction
temperature was maintained at 260 8C for 1 h. Dimethyl
formamide (1.6 mL, 21.1 mmol) was then added dropwise
at the same temperature, stirred for another 5 min at
260 8C, and then the mixture was allowed to increase its
temperature slowly until it reached room temperature and
was stirred overnight. The reaction was hydrolysed with
diluted hydrochloric acid and extracted 3 times with
dichloromethane. The combined organic layers were dried
and evaporated in vacuo to dryness to give a yellow oil
which was chromatographed using dichloromethane/hexane
(2:1) as eluent to give aldehyde 6e (239 mg, 30%) as a white
solid. Mp 59–60 8C; nmax(CHCl3) 3156 (s), 2960 (w), 2856
(w), 1665 (s), 1632 (m), 1596 (m), and 1496 cm21 (m);
dH(CDCl3) 7.0–7.8 (3H, m, ArCH), 9.88 (1H, s, HCO),
11.23 (1H, s, OH); dC(CDCl3) 119.1 (ArCH), 120.3 (ArC),
4. Experimental
1H NMR, 13C NMR and 19F NMR spectra were recorded on
a Bruker Avance 360 Spectrometer, (1H 360 MHz, 13C
90 MHz, and 19F 338 MHz). The solvent for a particular
spectrum is given in parentheses. 1H 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 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.
122.9 (q JCF¼34 Hz, ArCCF3), 124.0 (q JCF¼272 Hz,
2
1
3
3
CF3), 131.4 (q JCF¼4 Hz, ArCH), 133.8 (q JCF¼3 Hz,
ArCH), 164.3 (ArC), 196.2 (HCO); dF(CDCl3) 262.4
(CF3); m/z (EI) 190 (Mþ, 100), 189 (100), 172 (19), 161
(27), 144 (20). Found: C, 50.70%; H, 2.70%; C8H5O2F3
requires: C, 50.54%; H, 2.65%.
4.2. General procedure for the preparation of salen
ligands
To a stirred mixture of aldehyde (20.0 mmol) and (1R,2R)-
diaminocyclohexane dihydrochloride (1.87 g, 10.0 mmol)
in methanol (37 mL) and ethanol (37 mL) was added a
solution of NaOMe (5 mL of a 4.65 N solution) at room
temperature. The resulting bright yellow solution was
stirred under reflux overnight, then allowed to cool to
room temperature, filtered and evaporated in vacuo. The
yellow residue was taken up in dichloromethane (80 mL),
filtered, then the organic layers were washed with water
(2£30 mL) and brine (30 mL). The combined aqueous layers
were back extracted with dichloromethane. The combined
organic layers were dried and evaporated in vacuo to leave the
desired ligand.
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 ionization with ammonia
as the reagent gas (CI), fast atom bombardment (FAB) or
electrospray ionization (ES). The major fragment ions are
reported and only the molecular ions are assigned.
4.2.1. (1R,2R)-[N,N0-Bis-(20-hydroxy-50-tert-butyl-
benzylidene)]-1,2-diaminocyclohexane38 5a. Obtained as
a pale yellow solid in 70% yield. Mp 115–116 8C;
[a]2D0¼2184 (c 0.9, CHCl3); nmax(KBr) 2959 (s), 2863
(m), 1632 (s), and 1492 cm21 (s); dH(CDCl3) 1.16 (9H, s,
C(CH3)3), 1.3–1.8 (4H, m, CH2CH2), 3.2–3.3 (1H, m,
CHN), 6.7–6.9 (1H, m, ArCH), 7.2–7.3 (3H, m, ArCH),
8.18 (1H, s, HCvN); dC(CDCl3) 23.2 (CH2), 30.4 (CH3),
32.2 (CH2), 32.9 (CMe3), 71.8 (CHN), 115.2 (ArCH), 116.9
(ArC), 126.9 (ArCH), 128.4 (ArCH), 140.2 (ArC), 157.6
(ArC), 164.0 (HCvN).
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.

T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
5925
4.2.2. (1R,2R)-[N,N0-Bis-(20-hydroxy-50-methoxy-benzyl-
idene)]-1,2-diaminocyclohexane 5b. Obtained as a yellow
solid in 88% yield. Mp 118–120 8C; [a]2D0¼2306 (c 1.0,
CHCl3); nmax(CHCl3) 2936 (m), 2860 (w), 1636 (s), and
1592 cm21 (s); dH(CDCl3) 1.5–2.0 (4H, m, CH2CH2), 3.3–
3.4 (1H, m, CHN), 3.72 (3H, s, OCH3), 6.66 (1H, dd
J¼2.7 Hz, ArCH), 6.85 (1H, s, ArCH), 6.86 (1H, d
J¼2.7 Hz, ArCH), 8.21 (1H, s, HCvN), 12.83 (1H, s,
OH); dC(CDCl3) 24.6 (CH2), 33.5 (CH2), 56.3 (OCH3), 73.2
(CHN), 115.2 (ArCH), 117.9 (ArCH), 118.7 (ArC), 119.8
(ArCH), 152.4 (ArC), 155.5 (ArC), 164.9 (HCvN); m/z
(CI) 383 (MHþ, 100), 249 (8). Found (ES) 383.1957,
C22H27N2O4 (MHþ) requires 383.1971.
6.32 (1H, t J¼7.75 Hz, ArCH), 6.71 (1H, dd J¼7.75,
1.6 Hz, ArCH), 6.78 (1H, dd J¼7.7, 1.7 Hz, ArCH), 8.17
(1H, s, HCvN); m/z (CI) 383 (Mþ, 10), 242 (12), 210 (100),
193 (95), 170 (50). Found (ES) 405.1805, C22H26N2O4Na
(MþNaþ) requires 405.1785.
4.2.7. (1R,2R)-[N,N-Bis-(20-hydroxy-40-methoxy-benzyl-
idene)]-1,2-diaminocyclohexane. Obtained as a yellow
gel in 92% yield using the general procedure but with only a
three hour reflux and ethyl acetate rather than dichloro-
methane used to extract the product. [a]2D0¼21477 (c 0.015,
MeOH); nmax(CHCl3) 3388 (br), 2935 (w), 1625 (s), 1580
(m), and 1514 cm21 (m); dH(CDCl3) 1.3–2.1 (4H, m,
CH2CH2), 3.2–3.3 (1H, m, CHN), 3.79 (3H, s, OCH3), 6.33
(1H, dd J¼8.6, 2.4 Hz, ArCH), 6.37 (1H, d J¼2.4 Hz,
ArCH), 7.01 (1H, d J¼8.6 Hz, ArCH), 8.11 (1H, s, HCvN),
13.83 (1H, br s, OH); dC(CDCl3) 24.6 (CH2), 33.5 (CH2),
55.7 (OCH3), 72.0 (CHN), 101.5 (ArCH), 106.6 (ArCH),
112.6 (ArC), 133.1 (ArCH), 163.8 (ArC), 164.1 (HCvN),
165.3 (ArC); m/z (CI) 383 (MHþ, 100), 249 (14), 152 (11).
Found (ES) 383.1927, C22H27N2O4 (MHþ) requires
383.1965.
4.2.3. (1R,2R)-[N,N0-Bis-(20-hydroxy-50-nitro-benzyl-
idene)]-1,2-diaminocyclohexane38,39 5c. Obtained as a
yellow solid in 77% yield. Mp 198–200 8C; [a]2D0¼227
(c 1.0, CHCl3); nmax(KBr) 2926 (m), 1639 (s), 1538 (m), and
1484 cm21 (m); dH(CDCl3) 1.4–1.5 (1H, m, CH2), 1.6–1.8
(1H, m, CH2), 1.9–2.0 (2H, m, CH2), 3.3–3.5 (1H, m, CH–
N), 6.8–6.9 (1H, m, ArCH), 8.0–8.10 (2H, m, ArCH), 8.28
(1H, s, HCvN); dC(CDCl3) 24.3 (CH2), 33.1 (CH2), 72.4
(CHN), 117.5 (ArC), 118.7 (ArCH), 128.3 (ArCH), 128.5
(ArCH), 139.9 (ArC), 164.1 (HCvN), 167.7 (ArC).
4.2.8. (1R,2R)-[N,N-Bis-(20-hydroxy-60-methoxy-benzyl-
idene)]-1,2-diaminocyclohexane. Obtained as a yellow
solid in 79% yield using the general procedure but with only
a three hour reflux and ethyl acetate rather than dichloro-
methane used to extract the product. Mp 156–157 8C;
[a]2D0¼242.5 (c 0.035, CHCl3); nmax(CHCl3) 2937 (w),
2360 (w), 2252 (w), 1624 (s), 1578 (m), and 1446 cm21 (s);
dH(CDCl3) 1.4–2.0 (4H, m, CH2CH2), 3.3–3.4 (1H, m,
CHN), 3.73 (3H, s, OCH3), 6.21 (1H, d J¼8.2 Hz, ArCH),
6.48 (1H, d J¼8.4 Hz, ArCH), 7.17 (1H, t J¼7.7 Hz,
ArCH), 8.70 (1H, s, HCvN), 14.37 (1H, s, OH); dC(CDCl3)
24.6 (CH2), 33.5 (CH2), 55.9 (OCH3), 72.5 (CHN), 99.9
(ArCH), 108.3 (ArC), 110.5 (ArCH), 133.6 (ArCH), 160.0
(ArC), 161.3 (HCvN), 164.4 (ArC); m/z (CI) 384 (MHþ,
100), 249 (17), 152 (11). Found (ES) 383.1944,
C22H27N2O4 (MHþ) requires 383.1965. Found (ES)
405.1764, C22H26N2O4Na (MþNaþ) requires 405.1784.
4.2.4. (1R,2R)-[N,N0-Bis-(20-hydroxy-50-fluoro-benzyl-
idene)]-1,2-diaminocyclohexane 5d. Obtained as yellow
crystals in 36% yield after recrystallization from hexane–
isopropanol. Mp 121–123 8C; [a]2D0¼2494 (c 0.4, CHCl3);
n
max(CHCl3) 2938 (m), 2862 (m), 1636 (s) and 1589 cm21
(m); dH(CDCl3) 1.4–1.5 (1H, m, CH2), 1.6–1.7 (2H, m,
CH2), 1.8–1.85 (2H, m, CH2), 3.2–3.3 (1H, m, CHN), 6.7–
6.9 (3H, m, ArCH), 8.12 (1H, s, HCvN), 12.90 (1H, br s,
OH); dC(CDCl3) 24.5 (CH2), 33.3 (CH2), 73.1 (CHN), 116.9
(d 2JCF¼23 Hz, ArCH), 118.2 (d 3JCF¼7 Hz, ArC), 118.7 (d
3JCF¼7 Hz, ArCH), 119.7 (d 2JCF¼23 Hz, ArCH), 155.7 (d
1JCF¼237 Hz, ArCF), 157.4 (d 4JCF¼1 Hz, ArCO), 164.1 (d
4JCF¼2 Hz, HCvN); dF(CDCl3) 2126.3 (ArC–F); m/z (CI)
359 (MHþ, 100), 237 (7). Found (ES) 381.1372, C20H20-
N2O2F2Na (MþNaþ) requires 381.1385.
4.2.5. (1R,2R)-[N,N0-Bis-(20-hydroxy-50-trifluoromethyl-
benzylidene)]-1,2-diaminocyclohexane 5e. Obtained as a
yellow solid in a yield of 77%. Mp 120–122 8C;
[a]2D0¼2250 (c 0.4, CHCl3); nmax(CHCl3) 2936 (w), 1622
(s), and 1541 cm21 (m); dH(CDCl3) 1.4–2.0 (4H, m,
CH2CH2), 3.3–3.4 (1H, m, CHN), 6.9–7.4 (3H, m, ArCH),
8.22 (1H, s, HCvN), 13.64 (1H, s, OH); dC(CDCl3) 23.0
(CH2), 31.9 (CH2), 71.5 (CHN), 116.6 (ArCH), 116.9 (ArC),
120.0 (q 2JCF¼33 Hz, ArCCF3), 123.0 (q 1JCF¼271 Hz, CF3),
4.2.9. (1R,2R)-[N,N-Bis-(20,30-dihydroxybenzylidene)]-
1,2-diaminocyclohexane. To a stirred mixture of 2,3-
dihydroxybenzaldehyde (2.0 g, 14.48 mmol) in methanol
(100 mL) was added a solution of (1R,2R)-diaminocyclo-
hexane dihydrochloride (1.35 g, 7.24 mmol) and sodium
methoxide (0.78 g, 14.48 mmol) in methanol (100 mL) at
room temperature. The resulting bright yellow solution was
stirred under reflux for 2 h. Subsequently it was allowed to
cool to room temperature and then evaporated in vacuo. The
yellow residue was dissolved in dichloromethane
(3£50 mL). The organic layers were washed with water
(4£50 mL). The combined organic layers were dried
(MgSO4) and evaporated in vacuo to give a yellow gel.
Crystallization from ethyl acetate and hexane at 4 8C
overnight, gave an orange solid which was washed with
hexane (2£10 mL) to obtain the desired compound (1.64 g
64%) as an orange solid. Mp 120–121 8C; [a]2D0¼2876 (c
0.5, CHCl3); nmax(CHCl3) 3352 (br), 2937 (w), 2253 (w),
and 1631 cm21 (s); dH(CDCl3) 1.3–2.0 (4H, m, CH2CH2),
3.3–3.4 (1H, m, CHN), 6.56 (1H, t J¼7.7 Hz, ArCH), 6.63
(1H, dd J¼7.7, 1.6 Hz, ArCH), 6.85 (1H, dd J¼7.7, 1.6 Hz,
ArCH), 8.12 (1H, s, HCvN); dC(CDCl3) 24.5 (CH2), 33.3
3
3
127.7 (q JCF¼4 Hz, ArCH), 128.1 (q JCF¼3 Hz, ArCH),
162.7 (ArC), 162.9 (HCvN); dF(CDCl3) 262.0 (CF3); m/z
(CI) 459 (MHþ, 100), 190 (6), 52 (30). Found (ES) 481.1356,
C22H20N2O2F6Na (MþNaþ) requires 481.1321.
4.2.6. (1R,2R)-[N,N-Bis-(20-hydroxy-30-methoxy-benzyl-
idene)]-1,2-diaminocyclohexane.40 Obtained as a yellow
gel in 57% yield using the general procedure but with only a
three hour reflux and ethyl acetate rather than dichloro-
methane used to extract the product. [a]2D0¼2490 (c 0.05,
CHCl3); nmax(CHCl3) 2937 (w), 2861 (w), 2254 (w), 1629
(s), and 1464 cm21 (s); dH(CDCl3) 1.4–1.9 (4H, m,
CH2CH2), 3.2–3.3 (1H, m, CHN), 3.80 (3H, s, OCH3),

5926
T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
(CH2), 71.3 (CHN), 117.2 (ArC), 117.0 (ArCH), 118.2
(ArCH), 122.7 (ArCH), 145.8 (ArC), 152.6 (ArC), 165.2
(HCvN); m/z (CI) 355 (MHþ, 3), 100 (15), 98 (100), 96
(20), 94 (12). Found (ES) 355.1653, C20H23N2O4 (MHþ)
requires 355.1652.
residue was purified by gel permeation chromatography on
LH-20 using EtOH/toluene (1:3) as eluent.
4.4. General procedure for the preparation of
copper(salen) complexes using copper acetate
4.2.10. (1R,2R)-[N,N-Bis-(20,40-dihydroxybenzylidene)]-
1,2-diaminocyclohexane. To a stirred mixture of 2,4-
dihydroxybenzaldehyde (2.0 g, 14.48 mmol) in methanol
(100 mL) was added a solution of (1R,2R)-diaminocyclo-
hexane dihydrochloride (1.35 g, 7.24 mmol) and sodium
methoxide (0.78 g, 14.48 mmol) in methanol (100 mL) at
room temperature. The resulting bright yellow solution was
stirred under reflux for 2 h. The reaction mixture was cooled
to room temperature and the yellow precipitate collected by
filtration, washed with methanol (3£10 mL) and dried in
vacuo to leave the desired compound (2.31 g, 90%) as a
yellow solid. Mp .400 8C; [a]2D0¼2139 (c 0.015, DMSO);
Solutions of the appropriate salen ligand (0.83 mmol) in
ethanol (20 mL) and cuprous acetate monohydrate (0.17 g,
0.83 mmol) in water (2 mL) were mixed and refluxed under
vigorous stirring for 2 h. After this time, the resulting
solution was cooled to room temperature, filtered and the
precipitate washed successively with water, methanol and
diethyl ether (3£10 mL) to give the desired compound.
4.4.1. [(1R,2R)-[N,N-Bis-(20-hydroxybenzylidene)]-1,2-
diaminocyclohexanato]copper(II) 1b. Obtained as a
purple solid in 82% yield using the copper acetate
procedure. Mp .400 8C; [a]2D0¼2877 (c 0.0219, CHCl3);
n
max(KBr) 2934 (w), 2524 (br), 1855 (br), and 1634 cm21
n
max(KBr) 2931 (w), 1589 (s), and 1534 cm21 (s); m/z (CI)
(s); dH(DMSO-d6) 1.4–1.9 (4H, m, CH2CH2), 3.28 (1H, m,
CHN), 6.10 (1H, d J¼2.1 Hz, ArCH), 6.21 (1H, dd J¼8.5,
2.1 Hz, ArCH), 7.08 (1H, d J¼8.5 Hz, ArCH), 8.27 (1H, s,
HCvN), 9.99 (1H, br s, OH), 13.67 (1H, s, OH);
dC(DMSO-d6) 24.1 (CH2), 33.1 (CH2), 70.9 (CHN), 101.7
(ArCH), 107.2 (ArCH), 111.5 (ArC), 133.5 (ArCH), 161.9
(ArC), 164.1 (ArC), 164.4 (HCvN); m/z (CI) 355 (MHþ,
22), 235 (35), 189 (54), 136 (29), 115 (100). Found (ES)
355.1640, C20H23N2O4 (MHþ) requires 355.1652.
384 (29), 324 (34), 323 (100), 320 (32), 239 (28), 123 (28),
94 (47), 69 (27). Found (ES) 406.0729, C20H20N2O2CuNa
(MHþNaþ) requires 406.0713.
4.4.2. [(1R,2R)-[N,N0-Bis-(20-hydroxy-50-tert-butyl-
benzylidene)]-1,2-diaminocyclohexanato]copper(II) 4a.
Obtained as a brown solid in a yield of 87% using the
copper bromide procedure. Mp .270 8C; [a]2D0¼2604 (c
0.013, CHCl3); nmax(CHCl3) 3018 (w), 2951 (s), 2861 (m),
1620 (s), 1525 (s), and 1470 cm21 (s); m/z (ES) 496 (MHþ,
100), 331 (49). Found (ES) 496.2183, C28H37N2O2Cu
(MHþ) requires 496.2151.
4.2.11. (1R,2R)-[N,N-Bis-(20,50-dihydroxybenzylidene)]-
1,2-diaminocyclohexane.41 To a stirred mixture of 2,5-
dihydroxybenzaldehyde (2.0 g, 14.48 mmol) in methanol
(100 mL) was added a solution of (1R,2R)-diaminocyclo-
hexane dihydrochloride (1.35 g, 7.24 mmol) and sodium
methoxide (0.78 g, 14.48 mmol) in methanol (100 mL) at
room temperature. The resulting bright yellow solution was
stirred under reflux for 2 h. Subsequently it was allowed to
cool to room temperature and then evaporated in vacuo. The
brown residue was dissolved in dichloromethane
(3£50 mL) and filtered. The organic layers were washed
with water (100 mL), dried (MgSO4) and evaporated in
vacuo to give a brown gel. The residue was crystallized
from diethyl ether and hexane and the yellow precipitate
was collected by filtration, washed with hexane (2£10 mL)
and dried in vacuo to give the desired compound (795 mg,
31%) as a yellow solid. Mp 123–124 8C; [a]2D0¼2312 (c
0.5, MeOH); nmax(KBr) 3363 (br), 2935 (w), 1638 (s), and
1592 cm21 (m); dH(DMSO-d6) 1.4–1.9 (4H, m, CH2CH2),
6.6–6.7 (3H, m, ArCH), 8.94 (1H, s, HCvN), 9.20 (1H, s,
OH), 12.46 (1H, s, OH); dC(CD3OD) 25.7 (CH2), 34.4
(CH2), 74.1 (CHN), 120.2 (ArC), 118.1 (ArCH), 118.4
(ArCH), 121.5 (ArCH), 150.8 (ArC), 155.8 (ArC), 166.7
(HCvN); m/z (CI) 355 (MHþ, 81), 235 (100). Found (ES)
355.1645, C20H23N2O4 (MHþ) requires 355.1652.
4.4.3. [(1R,2R)-[N,N0-Bis-(20-hydroxy-50-methoxy-
benzylidene)]-1,2-diaminocyclohexanato]copper(II) 4b.
Obtained as a brown solid in 79% yield using the copper
bromide procedure. Mp .250 8C; [a]2D0¼2600 (c 0.005,
CHCl3); nmax(CHCl3) 2931 (m), 1634 (s), 1614 (m), 1538
(m), and 1468 cm21 (s); m/z (CI) 444 (MHþ, 19), 383 (100),
232 (24), 151 (57). Found (ES) 444.1112, C22H25N2O4Cu
(MHþ) requires 444.1110.
4.4.4. [(1R,2R)-[N,N0-Bis-(20-hydroxy-50-nitro-benzyl-
idene)]-1,2-diaminocyclohexanato]copper(II) 4c. Obtained
using the copper bromide procedure without chromatography
as an insoluble solid which was used without further
purification. nmax(KBr) 3062 (w), 2940 (w), 2862 (w), 1633
(m), 1601 (s), 1550 (m), and 1494 cm21 (m).
4.4.5. [(1R,2R)-[N,N0-Bis-(20-hydroxy-50-fluoro-benzyl-
idene)]-1,2-diaminocyclohexanato]copper(II) 4d. Obtained
as a brown solid in a yield of 26% using the copper bromide
procedure. Mp .270 8C; [a]2D0¼2640 (c 0.025, CHCl3);
n
max(KBr) 2942 (w), 1632 (s), 1538 (m), and 1462 cm21 (s);
m/z (ES) 420 (MHþ, 100), 140 (7). Found (ES) 420.0700,
C20H19N2O2F2Cu (MHþ) requires 420.0711.
4.3. General procedure for the preparation of
copper(salen) complexes using copper bromide
4.4.6. [(1R,2R)-[N,N0-Bis-(20-hydroxy-50-trifluoromethyl-
benzylidene)]-1,2-diaminocyclohexanato]copper(II) 4e.
Obtained as a purple solid in a yield of 30% using the
copper bromide procedure. Mp .270 8C. [a]2D0¼2352 (c
0.013, CHCl3); nmax(KBr) 2936 (w), 2861 (w), 1633 (s),
1620 (s), and 1542 cm21 (m); m/z (FAB) 520 (Mþ, 48), 307
(19), 289 (12), 154 (100), 136 (69), 107 (27), 77 (33).
To a solution of a chiral salen ligand (1.0 mmol) in
methanol (5 mL) were added CuBr2 (0.223 g, 1.0 mmol)
and NaOMe (0.23 mL of a 4.6 N solution in MeOH). The
resulting mixture was stirred for 3 h at room temperature
and then the solvent was removed in vacuo. The crude

T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
5927
Found: C, 50.80%; H, 3.77%; N, 5.14%; C22H18N2O2F6Cu
requires C, 50.82%; H, 3.49%; N, 5.39%.
4.4.13. [(1R,2R)-[N,N-Bis-(20-hydroxy-40-methyl-benzyl-
idene)]-1,2-diaminocyclohexanato]copper(II) 8g. Obtained
as a brown solid in 64% yield using the copper acetate
procedure. Mp 195–196 8C; [a]2D0¼2704 (c 0.0135, CHCl3);
m/z (ES) 412 (MHþ, 100). Found (ES) 412. 1200,
C22H25N2O4Cu (MHþ) requires 412.1207.
4.4.7. [(1R,2R)-[N,N-Bis-(2030-dihydroxy-benzylidene)]-
1,2-diaminocyclohexanato]copper(II) 8a. Obtained as a
brown solid in 67% yield using the copper bromide
procedure. Mp .400 8C; [a]2D0¼21096 (c 0.016, CHCl3);
n
max(KBr) 3406 (br), 2927 (m), 1609 (s), and 1527 cm21 (m);
n
max(KBr) 3394 (br), 2933 (m), 2859 (w), 1626 (s), and
1551 cm21 (m); m/z (ES) 438 (MþNaþ, 100), 281 (20), 227
(22), 179 (32). Found (ES) 416.0779, C20H21N2O4Cu
(MHþ) requires 416.0797. Found (ES) 438.0601, C20H20-
N2O4CuNa (MþNaþ) requires 438.0611.
4.5. General procedure for the preparation of alanine
Schiff bases
To a stirred suspension of alanine methyl ester hydro-
chloride (1.20 g, 7.20 mmol) in dichloromethane (10 mL),
triethylamine (1.00 mL, 7.20 mmol), the appropriate alde-
hyde (7.20 mmol) and a small amount of MgSO4 were
added. The reaction mixture was stirred overnight at room
temperature after which it was filtered and the solvent
removed in vacuo. The residue was the taken up in diethyl
ether (10 mL) and washed with Na2CO3(aq) (7£5 mL). The
combined organic phases were then dried over MgSO4 and
evaporated to dryness to leave the desired product.
4.4.8. [(1R,2R)-[N,N-Bis-(2040-dihydroxy-benzylidene)]-
1,2-diaminocyclohexanato]copper(II) 8b. Obtained as a
brown solid in 83% yield using the copper acetate
procedure. Mp .400 8C; [a]2D0¼2958 (c 0.009, DMSO);
n
max(KBr) 3109 (br) 2934 (w), 1621 (s), and 1542 cm21 (s);
m/z (ES) 438 (MþNaþ, 100), 416 (MHþ, 63), 415 (86), 178
(17). Found (ES) 416.0783, C20H21N2O4Cu (MHþ) requires
416.0791. Found (ES) 438.0601, C20H20N2O4CuNa
(MþNaþ) requires 438.0611.
4.5.1. para-Nitrobenzylidene imine 7a. Obtained as an
orange oil in 85% yield. [a]2D0¼þ0.8 (c 1.0, CHCl3);
4.4.9. [(1R,2R)-[N,N-Bis-(2050-dihydroxy-benzylidene)]-
1,2-diaminocyclohexanato]copper(II) 8c. Obtained as a
green/brown solid in 74% yield using the copper acetate
procedure. Mp .400 8C; [a]2D0¼2957 (c 0.011, CHCl3);
n
max(neat) 3107 (m), 2951 (m), 2854 (m), 1732 (s), 1601 (s),
and 1518 cm21 (s); dH(CDCl3) 1.58 (3H, d J¼7 Hz, CH3),
3.79 (3H, s, OCH3), 4.25 (1H, q J¼7 Hz, NCH), 7.97 (2H, d
J¼9 Hz, ArCH), 8.28 (2H, d J¼9 Hz, ArCH), 8.44 (1H, s,
HCvN); dC(CDCl3) 15.9 (CH3), 52.6 (OCH3), 68.5 (NCH),
124.4 (ArCH), 129.6 (ArCH), 141.8 (ArC), 149.8 (ArC),
161.4 (HCvN), 173.0 (CO2); m/z (ES) 237 (MHþ, 50), 207
(100). Found (ES) 237.0873, C11H13N2O4 (MHþ) requires
237.0875.
n
max(KBr) 3375 (w), 2934 (w), 1621 (s), and 1542 cm21 (s);
m/z (ES) 416 (MHþ, 100). Found (ES) 416.0797,
C22H21N2O4Cu (MHþ) requires 416.0791.
4.4.10. [(1R,2R)-[N,N-Bis-(20-hydroxy-30-methoxy-
benzylidene)]-1,2-diaminocyclohexanato]copper(II) 8d.
Obtained as a red/brown solid in 94% yield using the
copper bromide procedure. Mp 289–290 8C; [a]2D0¼2606
(c 0.032, CHCl3); nmax(KBr) 3504 (br), 2932 (m), 1627 (s),
and 1545 cm21 (m); m/z (ES) 466 (MþNaþ, 100), 413 (10),
195 (30). Found (ES) 466.0990, C22H24N2O4CuNa
(MþNaþ) requires 466.0924.
4.5.2. para-Methoxybenzylidene imine42 7b. Obtained as a
pale yellow oil in 78% yield. dH(CDCl3) 1.44 (3H, d
J¼7 Hz, CH3), 3.67 (3H, s, OCH3), 3.75 (3H, s, OCH3),
4.02 (1H, q J¼7 Hz, NCH), 6.84 (2H, d J¼9 Hz ArCH),
7.64 (2H, d J¼9 Hz, ArCH), 8.44 (1H, s, HCvN).
4.4.11. [(1R,2R)-[N,N-Bis-(20-hydroxy-40-methoxy-
benzylidene)]-1,2-diaminocyclohexanato]copper(II) 8e.
Obtained as a brown solid in 75% yield using the copper
bromide procedure and as a dark purple solid in 64% yield
using the copper acetate procedure. Data for the product
obtained using copper bromide. Mp .400 8C; [a]2D0¼2529
(c 0.035, CHCl3); nmax(KBr) 3434 (br), 2933 (m), 1626 (s),
and 1551 cm21 (s); m/z (CI); 444 (MHþ, 52), 383 (98), 139
(100), 125 (41), 98 (96). Found (ES) 444. 1110,
C22H25N2O4Cu (MHþ) requires 444.1105. Data for the
product obtained using copper acetate. Mp .400 8C;
[a]2D0¼2968 (c 0.022, CHCl3); nmax(KBr) 2933 (w), 1605
(s), and 1530 cm21 (s); m/z (ES) 444 (MHþ, 100). Found
(ES) 444. 1100, C22H25N2O4Cu (MHþ) requires 444.1105.
4.5.3. para-Chlorobenzylidene imine43 7c. Obtained as a
yellow oil in 61% yield. dH(CDCl3) 1.47 (3H, d J¼7 Hz,
CH3), 3.70 (3H, s, OCH3), 4.11 (1H, q J¼7 Hz, NCH), 7.45
(2H, d J¼9 Hz, ArCH), 7.76 (2H, d J¼9 Hz, ArCH), 8.22
(1H, s, HCvN).
4.5.4. meta-Chlorobenzylidene imine 7d. Obtained as a
yellow oil in 68% yield. [a]2D0¼þ0.6 (c 1.0, CHCl3); nmax
(neat) 3064 (w), 2984 (m), 2953 (m), 2871 (m), 1740 (s),
1645 (s), and 1570 cm21 (s); dH(CDCl3) 1.42 (3H, d
J¼7 Hz, CH3), 3.64 (3H, s, OCH3), 4.04 (1H, q J¼7 Hz,
NCH), 7.21–7.31 (2H, m, ArCH), 7.49 (1H, m, ArCH), 7.71
(1H, s, ArCH), 8.16 (1H, s, HCvN); dC(CDCl3) 19.4 (CH3),
52.0 (OCH3), 67.7 (CH), 127.0 (ArCH), 128.0 (ArCH),
129.9 (ArCH), 131.1 (ArC), 134.8 (ArC), 137.5 (ArCH),
159.1 (HCvN), 172.7 (CO2); m/z (CI) 228 (M(37Cl)Hþ,
30), 226 (M(35Cl)Hþ, 100), 166 (18). Found (EI) 225.0555,
C11H12NO325Cl (Mþ) requires 225.0557.
4.4.12. [(1R,2R)-[N,N-Bis-(20-hydroxy-60-methoxy-
benzylidene)]-1,2-diaminocyclohexanato]copper(II) 8f.
Obtained as a brown solid in 79% yield using the copper
acetate procedure. Mp 315–316 8C; [a]2D0¼21074 (c 0.005,
CHCl3); nmax(KBr) 3424 (br), 3019 (m), 1637 (s), and
1544 cm21 (m);. m/z (CI) 444 (MHþ, 20), 383 (67), 323
(17), 145 (18). Found (ES) 466. 0938, C22H24N2O4CuNa
(MþNaþ) requires 466.0924.
4.5.5. ortho-Chlorobenzylidene imine 7e. Obtained as a
yellow oil in 67% yield. [a]2D0¼20.1 (c 1.0 CHCl3);
n
max(neat) 3067 (w), 2986 (m), 2950 (m), 2890 (m), 1743
(s), 1636 (s), and 1592 cm21 (m); dH(CDCl3) 1.45 (3H, d

5928
T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
J¼7 Hz, CH3), 3.67 (3H, s, OCH3), 4.12 (1H, q J¼7 Hz,
NCH), 7.13–7.37 (3H, m, ArCH), 8.00 (1H, d J 7 Hz,
ArCH), 8.66 (1H, s, HCvN); dC(CDCl3) 18.4 (CH3), 51.1
(OCH3), 67.9 (NCH), 126.3 (ArCH), 127.4 (ArCH), 128.6
(ArCH), 130.6 (ArCH), 131.7 (ArC), 134.0 (ArC), 158.0
(HCvN), 171.6 (CO2); m/z (CI) 226 (MHþ, 100). Found
(ES) 226.0630, C11H13NO325Cl (MHþ) requires 226.0635.
(2 mol%), dry toluene (2.5 mL) and benzyl bromide
(0.126 mL, 1.06 mmol) were added to round bottomed
flask under argon. The mixture was allowed to stir overnight
at room temperature. MeOH (2 mL) and acetyl chloride
(0.44 mL) were then added, and the reaction stirred for a
further 4 h at room temperature under argon. The solvent
was removed in vacuo and the residue was added to a silica
gel column and eluted first with ethyl acetate (3£100 mL)
and then with a mixture of ethyl acetate and ethanol (4:1) to
give a-methyl phenylalanine methyl ester. If necessary, the
amino ester was filtered through aluminium oxide to remove
the last traces of copper salts.
4.5.6. para-Fluorobenzylidene imine 7f. Obtained as a
yellow oil in 68% yield. [a]2D0¼þ26.1 (c 1.0, CHCl3);
n
max(neat) 2986 (m), 2952 (m), 2872 (m), 1740 (s), 1644 (s),
and 1501 cm21 (s); dH(CDCl3) 1.42 (3H, d J¼7 Hz, CH3),
3.64 (3H, s, OCH3), 4.03 (1H, q J¼7 Hz, NCH), 6.97 (2H, t
J¼9 Hz, ArCH), 7.7–7.8 (2H, m, ArCH), 8.18 (1H, s,
HCvN); dC(CDCl3) 20.0 (CH3), 52.7 (OCH3), 68.4 (CHN),
116.1 (ArCH), 116.3 (ArC), 131.0 (ArCH), 162.1 (HCvN),
166.3 (ArCF), 173.5 (CO2); m/z (CI) 210 (MHþ, 100), 150
(20). Found (ES) 210.0927, C11H13NO2F (MHþ) requires
210.0930.
4.7. Determination of the enantiomeric excess of
a-methyl phenylalanine methyl ester
(S)-1-Phenylethyl isocyanate (1–2 drops, excess) was
added to an NMR sample (in CDCl3) of a-methyl
phenylalanine methyl ester. The solution was left until the
reaction was complete (usually overnight). The diastereo-
meric excess of the urea and hence the enantiomeric excess
of the a-methyl phenylalanine methyl ester was determined
4.5.7. para-Bromobenzylidene imine43,44 7g. Obtained as
a yellow oil in 74% yield. dH(CDCl3) 1.42 (3H, d J¼7 Hz,
CH3), 3.65 (3H, s, OCH3), 4.04 (1H, q J¼7 Hz, NCH), 7.43
(2H, d J¼8.5 Hz, ArCH), 7.54 (2H, d J¼8.5 Hz, ArCH),
8.16 (1H, s, HCvN).
1
by integration of the methylene proton region of the H
NMR spectrum of the urea.
4.5.8. para-Iodobenzylidene imine 7h. Obtained as a
yellow oil in 72% yield from a reaction carried out
following the general procedure with exclusion of light.
[a]2D0¼20.1 (c 1.0, CHCl3); nmax(neat) 2983 (m), 2984 (m),
2870 (m), 1740 (s), 1642 (s), and 1585 cm21 (s); dH(CDCl3)
1.41 (3H, d J¼7 Hz, CH3), 3.64 (3H, s, OCH3), 4.11 (1H, q
J¼7 Hz, NCH), 7.45 (2H, d J¼9 Hz, ArCH), 7.76 (2H, d
J¼9 Hz, ArCH), 8.13 (1H, s, HCvN); dC(CDCl3) 15.7
(CH3), 52.7 (OCH3), 68.3 (NCH), 98.3 (ArC), 130.4
(ArCH), 135.5 (ArCI), 137.9 (ArCH), 162.3 (HCvN),
173.1 (CO2); m/z (CI) 318 (MHþ, 60), 192 (100). Found (EI)
316.9916 C11H12NO2I (Mþ) requires 316.9913.
Acknowledgements
The authors thank the EPSRC mass spectrometry service at
the University of Wales, Swansea for recording low and
high resolution mass spectra and the EU Descartes prize
research fund for financial support and a studentship (to
TA).
References and notes
1. Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583.
2. O’Donnell, M. J.; Drew, M. D.; Cooper, J. T.; Delgado, F.;
Zhou, C. J. Am. Chem. Soc. 2002, 124, 9348. O’Donnell, M. J.;
Delgado, F. Tetrahedron 2001, 57, 6641. O’Donnell, M. J.;
Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347.
O’Donnell, M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R.
Tetrahedron Lett. 1998, 39, 8775. O’Donnell, M. J.; Wu, Sh.;
Hauffman, J. C. Tetrahedron 1994, 50, 4507. O’Donnell, M. J.;
Bennet, W.; Wu, Sh. J. Am. Chem. Soc. 1989, 111, 2353.
3. Lygo, B.; Andrews, B. I. Tetrahedron Lett. 2003, 44, 4499.
Lygo, B.; Andrews, B. I.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 2002, 43, 8015. Lygo, B.; Humphreys,
L. D. Tetrahedron Lett. 2002, 43, 6677. Lygo, B.; Crosby, J.;
Peterson, J. A. Tetrahedron 2001, 57, 6447. Lygo, B.; Crosby,
J.; Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G.
Tetrahedron 2001, 57, 2403. Lygo, B.; Crosby, J.; Lowdon,
T. R.; Wainwright, P. G. Tetrahedron 2001, 57, 2391. Lygo,
B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40,
1385. Lygo, B. Tetrahedron Lett. 1999, 40, 1389. Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
4.5.9. 1-Naphthylidene imine 7i. Obtained as a pale yellow
oil in 90% yield. [a]2D0¼þ0.8 (c 1.0 CHCl3); nmax(neat)
3048 (m), 2984 (m), 2871 (m), 1740 (s), 1636 (s), 1590 (s),
and 1509 cm21 (s); dH(CDCl3) 1.49 (3H, d J¼7 Hz, CH3),
3.64 (3H, s, OCH3), 4.09 (1H, q J¼7 Hz, NCH), 7.35–7.81
(7H, m, ArCH), 8.82 (1H, s, HCvN); dC(CDCl3) 20.1
(CH3), 52.7 (OCH3), 69.3 (NCH), 124.7 (ArCH), 125.6
(ArCH), 126.2 (ArC), 127.4 (ArCH), 128.9 (ArC), 129.1
(ArCH), 129.7 (ArCH), 131.7 (ArCH), 135.7 (ArC), 161.4
(HCvN), 173.0 (CO2); m/z (EI) 241 (Mþ, 25), 182 (100),
166 (40), 154 (95), 139 (60), 127 (50). Found (ES)
242.1181, C15H16NO2 (MHþ) requires 242.1181.
4.5.10. 2-Naphthylidene imine45 7j. Obtained as a yellow
solid in 72% yield. dH(CDCl3) 1.69 (3H, d J¼7 Hz, CH3),
3.89 (3H, s, OCH3), 4.32 (1H, q J¼7 Hz, NCH), 7.6–7.7
(2H, m, ArCH) 8.0–8.2 (5H, m, ArCH), 8.59 (1H, s,
HCvN).
4.6. General procedure for the benzylation of
N-arylidene (S)-alanine methyl esters
4. Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
Imine 2b or 7a–j (0.88 mmol), powered sodium hydroxide
(0.146 g, 3.66 mmol), catalyst 1b,c, 4a–e, or 8a–f
5. For other work on the use of monomeric N-alkylated cinchona
alkaloid derivatives as asymmetric phase transfer catalysts

T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
5929
see: Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
Jew, S.-s.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee, Y.-J.;
Park, B.-s.; Kim, M. G.; Park, H.-g. J. Org. Chem. 2003, 68,
2054. Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K.
Angew. Chem., Int. Ed. 2002, 41, 4542.
19. Lygo, B.; Allbutt, B.; James, S. R. Tetrahedron Lett. 2003, 44,
5629. Mase, N.; Ohno, T.; Hoshikawa, N.; Ohishi, K.;
Morimoto, H.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2003,
44, 4073. Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.;
Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539.
Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43,
9535.
´
´
4514. Mazon, P.; Chinchilla, R.; Najera, C.; Guillena, G.;
Kreiter, R.; Gebbink, R. J. M. K.; Koten, G. van Tetrahedron:
Asymmetry 2002, 13, 2181. Jew, S.-s.; Yoo, M.-S.; Jeong,
B.-S.; Park, J. I.; Park, H.-g. Org. Lett. 2002, 4, 4245.
Dehmlow, E. V.; Du¨ttmann, S.; Neumann, B.; Stammler,
H.-G. Eur. J. Org. Chem. 2002, 2087.
6. For an application to alanine derived substrates see: Lygo, B.;
Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671.
7. For the alkylation of a non-amino acid derived enolate see:
Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc.
1998, 120, 13000.
20. Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa,
K. Angew. Chem., Int. Ed. 2002, 41, 2832.
21. Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.;
Yamaguchi, K. Chem. Commun. 2003, 1734.
22. Belokon’, Y.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov,
N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmer, V. S.;
Kumar, R.; Kagan, H. B. Tetrahedron: Asymmetry 1998, 9,
851. Belokon’, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Kagan,
H. B. Russ. Chem. Bull. 1999, 48, 917. Belokon’, Y. N.;
Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Chesnokov, A. A.; Larionov, O. V.; Singh, I.; Parmer, V. S.;
Vyskocil, S.; Kagan, H. B. J. Org. Chem. 2000, 65, 7041.
23. Belokon’, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Vyskocil, S.; Kagan, H. B. Tetrahedron:
Asymmetry 1999, 10, 1723. Belokon’, Y. N.; Kochetkov, K. A.;
Churkina, T. D.; Ikonnikov, N. S.; Larionov, O. V.;
Harutyunyan, S. R.; Vyskocil, S.; North, M.; Kagan, H. B.
Angew. Chem., Int. Ed. 2001, 40, 1948.
´
8. O’Donnell, M. J.; Delgado, F.; Domınguez, E.; Blas, J. de;
Scott, W. L. Tetrahedron: Asymmetry 2001, 12, 821. Zhang,
F. Y.; Corey, E. J. Org. Lett. 2000, 2, 4257. Zhang, F. Y.;
Corey, E. J. Org. Lett. 2000, 2, 1097.
9. Thierry, B.; Perrard, T.; Audouard, C.; Plaquevent, J.-C.;
Cahard, D. Synthesis 2001, 1742.
10. Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron
Lett. 1999, 40, 3843. Corey, E. J.; Zhang, F. Y. Angew. Chem.,
Int. Ed. 1999, 38, 1931.
11. Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289.
Corey, E. J.; Zhang, F. Y. Org. Lett. 1999, 1, 1287.
12. Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org.
Chem. 2002, 67, 7418. Nakoji, M.; Kanayama, T.; Okino, T.;
Takemoto, Y. Org. Lett. 2001, 3, 3329. Chen, G.; Deng, Y.;
Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan,
A. S. C. Tetrahedron: Asymmetry 2001, 12, 1567.
´ ´ ´
24. Casas, J.; Najera, C.; Sansano, J. M.; Gonzalez, J.; Saa, J. M.;
Vega, M. Tetrahedron: Asymmetry 2001, 12, 699.
´
´
13. Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asymmetry
2000, 11, 3277. Thierry, B.; Plaquevent, J.-C.; Cahard, D.
Tetrahedron: Asymmetry 2003, 14, 1671.
25. Belokon’, Y.; North, M.; Kublitski, V. S.; Ikonnikov, N. S.;
Krasik, P. E.; Maleev, V. I. Tetrahedron Lett. 1999, 40, 6105.
Belokon’, Y. N.; North, M.; Churkina, T. D.; Ikonnikov, N. S.;
Maleev, V. I. Tetrahedron 2001, 57, 2491.
14. Kim, S.; Lee, J.; Lee, T.; Park, H.-g.; Kim, D. Org. Lett. 2003,
5, 2703. Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park,
B.-s.; Kim, M. G.; Jew, S.-s. Tetrahedron Lett. 2003, 44, 3497.
26. Belokon’, Y.; Fuentes, J.; North, M.; Steed, J. W. Tetrahedron
2004, 60, 3191.
´
´
Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asymmetry
2002, 13, 927. Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee,
J.-H.; Park, M.-k.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew.
Chem., Int. Ed. 2002, 41, 3036. Park, H.-g.; Jeong, B.-s.; Yoo,
M.-s.; Park, M.-k.; Huh, H.; Jew, S.-s. Tetrahedron Lett. 2001,
42, 4645.
27. Belokon’, Y.; Davies, R. G.; North, M. Tetrahedron Lett.
2000, 41, 7245.
28. Belokon’, Y.; Bhave, D.; D’Addario, D.; Groaz, E.; Maleev,
V.; North, M.; Pertosyan, A. Tetrahedron Lett. 2003, 44, 2045.
Belokon’, Y. N.; Bhave, D.; D’Addario, D.; Groaz, E.; North,
M.; Tagliazucca, V. Tetrahedron 2004, 60, 1849.
15. Okino, T.; Takemoto, Y. Org. Lett. 2001, 3, 1515.
16. Ooi, T.; Uematsu, Y.; Maruoka, K. Tetrahedron Lett. 2004, 45,
1675. Ooi, T.; Kubota, Y.; Maruoka, K. Synlett 2003, 1931.
Hashimoto, T.; Tanaka, Y.; Maruoka, K. Tetrahedron:
Asymmetry 2003, 14, 1599. Hashimoto, T.; Maruoka, K.
Tetrahedron Lett. 2003, 44, 3313. Ooi, T.; Tayama, E.;
Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 579. Ooi, T.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139.
Ooi, T.; Uematsu, Y.; Maruoka, K. Adv. Synth. Catal. 2002,
344, 288. Ooi, T.; Doda, K.; Maruoka, K. Org. Lett. 2001, 3,
1273. Ooi, T.; Takeuchi, M.; Maruoka, K. Synthesis 2001,
1716. Ooi, T.; Takeuchi, M.; Ohara, D.; Maruoka, K. Synlett
2001, 1185. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K.
J. Am. Chem. Soc. 2000, 122, 5228. Ooi, T.; Tayama, E.;
Doda, K.; Takeuchi, M.; Maruoka, K. Synlett 2000, 1500. Ooi,
T.; Kameda, M.; Tannai, H.; Maruoka, K. Tetrahedron Lett.
2000, 41, 8339. Ooi, T.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 1999, 121, 6519.
29. For a preliminary communication of some of the results
reported in this work see: Belokon’, Y. N.; Davies, R. G.;
Fuentes, J. A.; North, M.; Parsons, T. Tetrahedron Lett. 2001,
42, 8093.
30. Belokon’, Y.; Ikonnikov, N.; Moscalenko, M.; North, M.;
Orlova, S.; Tararov, V.; Yashkina, L. Tetrahedron: Asymmetry
1996, 7, 851. Belokon’, Y.; Flego, M.; Ikonnikov, N.;
Moscalenko, M.; North, M.; Orizu, C.; Tararov, V.; Tasinazzo,
M. J. Chem. Soc., Perkin Trans. 1 1997, 1293. Tararov, V. I.;
Hibbs, D. E.; Hursthouse, M. B.; Ikonnikov, N. S.; Malik,
K. M. A.; North, M.; Orizu, C.; Belokon’, Y. N. Chem.
Commun. 1998, 387. Belokon’, Y. N.; Caveda-Cepas, S.;
Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.;
Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.;
Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem.
Soc. 1999, 121, 3968. Tararov, V. I.; Orizu, C.; Ikonnikov,
N. S.; Larichev, V. S.; Moscalenko, M. A.; Yashkina, L. V.;
North, M.; Belokon’, Y. N. Russ. Chem. Bull. 1999, 48, 1128.
Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Tararov, V. I. Tetrahedron Lett. 1999, 40, 8147. Belokon’,
Y. N.; Green, B.; Ikonnikov, N. S.; Larichev, V. S.; Lokshin,
17. Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.;
Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796.
18. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,

5930
T. Achard et al. / Tetrahedron 60 (2004) 5919–5930
Gerritsma, G. J.; Reinhoudt, D. N. Inorg. Chem. 1989, 28,
B. V.; Moscalenko, M. A.; North, M.; Orizu, C.; Peregudov,
A. S.; Timofeeva, G. I. Eur. J. Org. Chem. 2000, 2655.
Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Parsons, T.; Tararov, V. I. Tetrahedron 2001, 57, 771.
Belokon’, Y. N.; Gutnov, A. V.; Moskalenko, M. A.;
Yashkina, L. V.; Lesovoy, D. E.; Ikonnikov, N. S.; Larichev,
V. S.; North, M. Chem. Commun. 2002, 244. Belokon’, Y. N.;
Carta, P.; Gutnov, A. V.; Maleev, V.; Moskalenko, M. A.;
Yashkina, L. V.; Ikonnikov, N. S.; Voskoboev, N. V.;
Khrustalev, V. N.; North, M. Helv. Chim. Acta 2002, 85,
3301. Belokon’, Y. N.; Blacker, A. J.; Clutterbuck, L. A.;
North, M. Org. Lett. 2003, 5, 4505.
1133.
36. Lamour, E.; Routier, S.; Bernier, J.-L.; Catteau, J.-P.; Bailly,
C.; Vezin, H. J. Am. Chem. Soc. 1999, 121, 1862.
37. Bernard, K.; Leppard, S.; Robert, A.; Commenges, G.; Dahan,
F.; Meunier, B. Inorg. Chem. 1996, 35, 387.
38. Yao, X.; Qiu, M.; Lue, W.; Chen, H.; Zheng, Z. Tetrahedron:
Asymmetry 2001, 12, 197.
39. Daly, A.; Dalton, C. T.; Renehan, M. F.; Gilheany, D. G.
Tetrahedron Lett. 1999, 40, 3617.
40. Nakajima, K.; Kojima, M.; Fujita, J. Chem. Lett. 1986, 1483.
41. Charles, E.; Chia, L. M. L.; Rothery, J.; Watson, E. L.;
McInnes, E. J. L.; Farley, R. D.; Bridgeman, A. J.; Mabbs,
F. E.; Rowlands, C. C.; Halcrow, M. A. J. Chem. Soc., Dalton
Trans. 1999, 2087.
31. Lindoy, L.; Meeham, G. V.; Svenstrup, N. Synthesis 1998, 7,
1029.
32. Johannes, C.; Visser, M. S.; Weatherhead, G. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1998, 120, 8340.
42. Grundke, G.; Keese, W.; Rimpler, M. Liebigs Ann. Chem.
1987, 73. Grundke, G.; Keese, W.; Rimpler, M. Synthesis
1987, 1115.
33. Geneste, H.; Schaefer, B. Synthesis 2001, 2259.
34. Yamamoto, S.; Hashiguchi, S.; Shokyo, M.; Igata, Y.;
Watanabe, T. Chem. Pharm. Bull. 1996, 4, 734.
43. Mashchenko, N.; Matveeva, A. G.; Odinets, I. L.; Matrosov,
E. I.; Petrov, E. S.; Terekhova, M. I.; Matveev, A. K.;
Mastrukova, T. A.; Kabachnik, M. I. J. Gen. Chem. USSR
1988, 58, 1762.
35. For examples see: Zheltvai, I. I.; Siritsov, A. I.; Egorova, A. L.;
Kamalov, G. L. Russ. J. Inorg. Chem. 1985, 30, 3113.
Banerjee, A. K.; Mahapatra, B.; Roy, S. K. J. Indian Chem.
Soc. 1985, 62, 778. Beale, J. P.; Cunningham, J. A.; Phillips,
D. J. Inorg. Chim. Acta 1979, 33, 113. van Veggel, F. C. J. M.;
Harkema, S.; Bos, M.; Verboom, W.; van Staveren, C. J.;
44. Oehberg, L.; Westman, J. Synlett 2001, 1893.
45. Cooper, D.; Grigg, R.; Hargreaves, S.; Kennewell, P.;
Redpath, J. Tetrahedron 1995, 51, 7791.