Nickel complexes from α-amino amides as efficient catalysts for the enantioselective Et2Zn addition to benzaldehyde

Article abstract of DOI:10.1016/S0040-4039(03)01705-2

Ni²⁺ complexes derived from simple α-amino amides catalyze very efficiently the addition of Et₂Zn to benzaldehyde, giving (S)-1-phenylethanol as the major isomer in most cases (94% yield, 97% ee for R=Bn). The nature of the substituent on the amide nitrogen atom seems to play a key role in determining the asymmetric induction observed.

Full text of DOI:10.1016/S0040-4039(03)01705-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6891–6894
Nickel complexes from a-amino amides as efficient catalysts for
the enantioselective Et2Zn addition to benzaldehyde
M. Isabel Burguete,* Manuel Collado, Jorge Escorihuela, Francisco Galindo,
Eduardo Garc´ıa-Verdugo, Santiago V. Luis* and Mar´ıa J. Vicent
Department of Inorganic and Organic Chemistry, ESTCE, University Jaume I, E-12080 Castello´n, Spain
Received 20 June 2003; accepted 9 July 2003
Abstract—Ni2+ complexes derived from simple a-amino amides catalyze very efficiently the addition of Et2Zn to benzaldehyde,
giving (S)-1-phenylethanol as the major isomer in most cases (94% yield, 97% ee for R=Bn). The nature of the substituent on
the amide nitrogen atom seems to play a key role in determining the asymmetric induction observed.
© 2003 Elsevier Ltd. All rights reserved.
Vicinal diamines represent a very interesting class of
organic compounds that have found important applica-
tions in different fields.1 The 1,2-diamino moiety can be
found in many natural products such as biotin, and
different synthetic compounds of this class have been
developed for biomedical applications, in particular in
chemotherapy since the initial studies with cisplatin-
related compounds.2 On the other hand, chiral 1,2-
diamines are receiving increasing attention as starting
materials for stereoselective synthesis and as chiral
metal ligands and organocatalysts.3 In connection with
this target, most efforts have been devoted to the
preparation and study of chiral vicinal diamines having
C2 symmetry. However, the preparation of enantiopure
compounds of this class is not a trivial task and
requires carefully controlled synthetic strategies and, in
many cases, racemate separation. This has limited the
general use of those chiral auxiliaries to a reduced
number of structures, in particular 1,2-diphenyl-1,2-
ethanediamine and 1,2-cyclohexanediamine.4
some cases, can be even more efficient than related C2
systems.7
Catalytic properties of metal complexes derived from
amide or sulfonamide derivatives of C2 symmetric 1,2-
diamines, such as 5 and 6, have been reported8 (Fig. 1).
Nevertheless, complexes 4 derived from the general
structure 2 have not been very much studied in asym-
metric catalysis, except, perhaps, some proline deriva-
tives.9 As a matter of fact, a-amino amides 2 present
some structural features that make them very attractive
in this respect. The presence of two nitrogen atoms with
different coordination capabilities and the relative acid-
ity of the NꢀH amide functionality can favor the for-
mation of strong metal complexes with a very tightly
defined steric and electronic environment that can be
easily optimized through the appropriate selection of R
On the contrary, simple C1 symmetric enantiomerically
pure 1,2-diamines (3) can be efficiently prepared from
easily available a-amino acids 1 according to the gen-
eral route outlined in Scheme 1.5 The presence of C2
symmetry is generally considered an advantageous
structural feature,6 but many recent examples have
shown the potential of C1 symmetric ligands that, in
Scheme 1. Preparation of a-amino amides and diamines.
* Corresponding authors. Tel.: +34 964 72 8239; fax: +34 964 72
8214; e-mail: luiss@mail.uji.es
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01705-2

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M. I. Burguete et al. / Tetrahedron Letters 44 (2003) 6891–6894
N-hydroxy succinimide 8 in the presence of DCC (87%
yield). Reaction of the intermediate 9 with different
aliphatic and aromatic amines afforded N-protected
a-amino amides 10, in general in excellent yields.
Deprotection using HBr/AcOH was almost quantitative
and allowed us to obtain the desired products 11 with
the overall yields shown in Table 1.
As can be seen in Table 1, yields were similar for
aromatic and aliphatic amines and additional func-
tional groups such as alcohol or ester can be present.
The addition of Et2Zn to benzaldehyde in the presence
of catalytic amounts of compounds 11 was selected as a
well-known benchmark reaction to explore their poten-
tial in enantioselective catalysis. A wide range of chiral
ligands such as b-amino alcohols, amino sulfur com-
pounds, diols and some chiral amines has shown to act
as efficient catalysts for this reaction.11,12
Scheme 2. Synthesis of a-amino amides
Table 1. Results for the synthesis of a-amino amides 11
Preliminary experiments were carried out with ligand
11h, a compound having two stereocenters with abso-
lute configuration S. The results are gathered in Table
2 (entries 1–4). As can be seen in entry 1, no catalytic
activity was observed when the ligand was added to the
Table 2. Results for the Et2Zn addition to benzaldehyde
in the presence of metal complexes of 11
and R% groups, a behavior comparable to that found in
b-amino alcohols.
As a part of our efforts to develop chiral catalysts
based on cheap and easily available chiral sources and
according to the former considerations,10 a series of
a-amino amides derived from L-phenylalanine were pre-
pared as described in Scheme 2.
Taking into account our previous experience with
related systems, the N-cbz protected amino acid 7 was
converted into the activated ester 9 by reaction with

M. I. Burguete et al. / Tetrahedron Letters 44 (2003) 6891–6894
6893
detail,11c,16 and several mechanistic studies have been
carried out for the Ti mediated catalytic reaction,11d,17
but much less is known for the mechanism involved in
the reaction catalysed by Ni2+ complexes. In our case,
all data indicate that upon addition of Et2Zn the blue–
green paramagnetic Ni2+ octahedral complex initially
formed with UV–vis bands at 390, 650 and 1020 nm, is
transformed into an orange diamagnetic Ni2+ square-
planar complex with a maximum absorbance at 445
nm. Deprotonation of the amide hydrogen is required
for this change, and this takes place even with weaker
bases as shown in IR experiments by the significant
shift of the CꢁO band to lower frequencies, but depro-
tonation of the primary amino group can also take
place in the presence of Et2Zn as has been observed in
other related systems.18,19
Figure 2.
reagent’s mixture, and the same happened when 11h
was first stirred in the presence of Zn(OAc)2 (entry 2).
It is not easy to rationalize this behavior, but, most
likely, it can be ascribed to the formation of oligomeric
complex species of low activity. A similar situation has
been described, for instance, when comparing the activ-
ity of soluble and supported catalysts derived from
compounds with partly related structures.13 In the same
way, it has been observed that N-alkylated and steri-
cally constrained b-amino alcohols show, in general, the
higher activities for the same reaction.11 A completely
different behavior was observed, however, when 11h
was allowed to react first with Cu(OAc)2 or Ni(OAc)2
in a 1:1 ratio (entries 3 and 4) In both cases, a clear
catalytic activity was observed.14 This can be ascribed
to the formation of the corresponding Cu or Ni com-
plexes 4h. The catalytic activity of some metal com-
plexes, in particular Ti(IV) and Cu(II) complexes, for
R2Zn additions is well documented, and Ni(II) com-
plexes have been used for conjugate carbonyl
additions.9c,15
Initially, the stereochemical outcome of the reaction
can be rationalized in terms of a transition state (14)
(Fig. 2) related to that generally accepted for the addi-
tion of diethylzinc to benzaldehyde in the presence of
b-amino alcohols.15 Coordination of benzaldehyde to
the Ni atom should take place at the position more
distant from the substituent on the amide nitrogen
atom and using the lone pair of the oxygen anti to the
Cꢀaryl bond. From the two possible arrangements of
this class, the anti TS 14 seems to be the most stable in
agreement with theorical calculations,16 giving place to
the formation of the S-13 enantiomer, the major isomer
observed in most cases. The nature of the N-sub-
stituents at the amide group can affect to the energy
differences between syn and anti TS, but, alternatively,
a change in the conformation of the five-membered ring
from envelope to planar could allow considering a
six-membered chair TS similar to that recently reported
by Norrby that would give place to the formation of
the R-13 enantiomer.16d As can be seen in Table 2, the
bulkier N-substituents are those for which the preva-
lence of S-13 as the major isomer is lower.
In the case of the copper complex, no asymmetric
induction was observed, but a reasonable selectivity
(85%) and enantioselectivity was obtained (67% ee,
(R)-1-phenylpropanol 13 as the major isomer) when the
nickel complex was used.
In view of the former results, other ligands were tested
using similar conditions. As shown in Table 2, results
obtained are dependent on the nature of the R% sub-
tituent at the amide nitrogen atom. Very good activities
and enantioselectivities were achieved for ligands 11b
(85% ee) and 11k (97% ee) derived from simple amines
containing an unsubstituted aromatic ring. The use of
ligands derived from more bulky amines (11c, 11d, 11i)
always gave complexes with lower activities and enan-
tioselectivities. A remarkable result was that observed
when using a-amino amide 11i prepared from 4-t-butyl-
aniline. In this case, the observed asymmetric induction
was low (17% ee), but the major isomer obtained had
an absolute configuration (R), opposite to that
observed in other cases. Even if this ee value is low, this
result opens the way to consider that a dual enantio-
selective control can be achieved with ligands 3 through
an appropriate balance of the R and R% groups, a
situation of great interest in the development of
efficient chiral catalysts.
Nevertheless, the situation is more complicated. A spec-
trophotometric study was carried out using amino
amide 11e as a model, since it contains the strongly
absorbing chromophore anthracene (m=6.6×105 M−1
cm−1 at u=365 nm in methanol). The formation of the
11e–Ni(II) complex in MeOH containing NaOH can be
followed through the shift of its UV–vis absorption
spectrum to longer wavelengths. In order to ascertain
the stoichometry of the complex(es) formed in solution,
the method of continuous variations (Job method) was
applied,20 monitoring the absorbance increment at u=
400 nm versus the molar fraction ( f ) of ligand. Prelim-
inary results show that
a
stable 1:2 complex
(metal:ligand) is formed in solution and actually it is
the prevalent species at elevated concentrations. How-
ever at much lower concentrations there is an equi-
librium between the 1:1 and the 1:2 complexes. Further
work is presently being carried out to determine the
role played by both species in the addition reaction, but
the present results clearly reveal the very high potential
of those simple a-amino amides as chiral auxiliaries in
enantioselective catalysis.
The mechanism of the Et2Zn addition to benzaldehyde
in the presence of b-amino alcohols has been studied in

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12. For some recent examples see, for instance: (a) Liu,
Acknowledgements
D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.;
Wang, R.; Choi, M. C. K.; Chan, A. C. S. Org. Lett.
2001, 3, 2733; (b) Lake, F.; Moberg, C. Tetrahedron:
Asymmetry, 2001, 12, 755; (c) Shintani, R.; Fu, G. C.
Org. Lett. 2002, 4, 3699; (d) Ko, D.-H.; Kim, K.-H.; Ha,
D.-C. Org. Lett. 2002, 4, 3759; (e) Priego, J.; Mancheno,
O. G.; Cabrera, S.; Carretero, J. C. J. Org. Chem. 2002,
67, 1346; (f) Fontes, M.; Verdaguer, X.; Sola, L.; Vidal-
Ferran, A.; Reddy, K. S.; Riera, A.; Perica`s, M. A. Org.
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We thank the Spanish MCYT (project PPQ2002-04012-
C03-02) and Bancaixa (project P1-1B 2001-12) for
financial support.
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