Enantioselective nickel-catalyzed conjugate addition of dialkylzinc to chalcones using chiral α-amino amides

Article abstract of DOI:10.1016/j.tetlet.2008.09.120

A series of α-amino amides derived from natural amino acids (alanine, valine, phenylalanine, isoleucine, and phenylglycine) have been synthesized and fully characterized. Their Ni(II) complexes prepared from Ni(acac)₂ catalyze the enantioselective conjugate addition of diethylzinc to chalcones in high yields and in good enantioselectivities (up to 84%). The side chain of the amino acid and the substituents in the amide nitrogen govern the enantioselectivity of the catalytic process.

Full text of DOI:10.1016/j.tetlet.2008.09.120

Tetrahedron Letters 49 (2008) 6885–6888
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective nickel-catalyzed conjugate addition of dialkylzinc
to chalcones using chiral a-amino amides
*
*
Jorge Escorihuela, M. Isabel Burguete , Santiago V. Luis
Departamento de Química Inorgánica y Orgánica, Unidad Asociada de Materiales Orgánicos Avanzados (UAMOA),
Universitat Jaume I-CSIC, Avda. Sos Baynat, s/n, 12071 Castellón, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of a-amino amides derived from natural amino acids (alanine, valine, phenylalanine, isoleucine,
Received 5 September 2008
Revised 15 September 2008
Accepted 17 September 2008
Available online 23 September 2008
and phenylglycine) have been synthesized and fully characterized. Their Ni(II) complexes prepared from
Ni(acac)2 catalyze the enantioselective conjugate addition of diethylzinc to chalcones in high yields and
in good enantioselectivities (up to 84%). The side chain of the amino acid and the substituents in the
amide nitrogen govern the enantioselectivity of the catalytic process.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective catalysis
Amino amides
Nickel complexes
Conjugate addition
Alkyl zinc
Development of catalytic processes for enantioselective C–C
bond formation is of great interest,1 and the 1,2-addition of
organozinc reagents to aldehydes is one of such processes.2 The
gated for the enantioselective addition of Grignard and dialkylzinc
reagents to enones.5 In the case of nickel, a variety of amino alco-
hols,6 pyridine,7 borneol,8 proline,9 and pyrrolidine derivatives,10
and other ligands11 have been used (Fig. 1). Nitrogen-containing li-
gands have recently gained increasing importance in this area.12
Recently, we reported that Ni(II) complexes derived from chiral
conjugate addition of dialkylzinc reagents to a,b-unsaturated pro-
chiral enones is also of importance for the synthesis of optically
active b-substituted carbonyl compounds,3 and it has allowed the
successful synthesis of biologically active compounds.4 Copper
and nickel chiral complexes have been the most widely investi-
a-amino amides are very versatile catalysts for the 1,2-enantio-
selective addition of dialkylzinc reagents to aldehydes.13 Those
Me
Ph
Ph
N
N
R
N
N
Me
H
N
t
Bu
HO
C5H11
HO
)
HO
SBn
86% (
82 (
S
)
86% (
S
)
85% (S)
Me
-Bu)2N
Ph
(CH2)3Si-support
N
H
NMe
OH
N
H
N
(n
OH
Me
83% (
90% (R)
S
)
91%
Figure 1. Ligands reported for the nickel-catalyzed conjugate addition of dialkylzinc to a,b-unsaturated prochiral enones.
* Corresponding author. Tel.: +34 964 72 8239; fax: +34 964 72 8214.
E-mail address: luiss@qio.uji.es (S. V. Luis).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.120

6886
J. Escorihuela et al. / Tetrahedron Letters 49 (2008) 6885–6888
ligands (2) are promising as they (i) can be easily prepared; (ii)
contain two nitrogen atoms with different coordination capabili-
ties connected through a chiral backbone; (iii) their properties
can be tuned by the selection of the substituents; (iv) can form ro-
bust metal complexes with transition metals under the appropriate
conditions. However, only a few nickel,9,13 copper,14 and ruthe-
nium15 complexes of some
for different applications.
a-amino amides have been reported
1,4-Additions to cyclic enones using Grignard or dialkylzinc re-
agents can occur with high enantioselectivity in the presence of Cu
complexes. Nevertheless, reports on the successful Et2Zn addition
to acyclic enones are less common giving lower enantioselectivi-
ties. Here, we report on the use of
a-amino amides for the enantio-
selective Ni-catalyzed conjugate addition of Et2Zn to chalcones.
a
-Amino amide ligands 2 were prepared using previously
reported procedures for related systems.16 Initial formation of
the activated N-hydroxysuccinimide ester of the Cbz-(S)-amino
acid followed by coupling with a variety of aliphatic, aromatic,
and benzylic amines and final N-deprotection, using HBr/AcOH,
Figure 2. Correlation between the ee of ligand 2a and the ee of 4a.
of the N-protected
70–85% overall yields after purification (Scheme 1).
a-amino amides 1, afforded compounds 2 in
enantioselectivity and yield.18 In order to optimize the reaction
time, the kinetic profile was studied under the former conditions.
Samples of the reaction mixture were taken at various intervals
of time, and the conversions were determined by GC analysis,
revealing that just 6 h at ꢀ20 °C in CH3CN was necessary to achieve
an almost complete conversion (97% yield). According to this
study, all subsequent reactions were carried out for 6 h.
In order to examine the efficiency of those ligands for the nick-
el-catalyzed enantioselective conjugate addition of diethylzinc to
a
,b-unsaturated ketones, the chiral ligand 2a (R = Phe, R0 = Phe)
was initially selected, and chalcone (3, R1 = R2 = Phe) was used as
a model substrate. In this case, best results were obtained when
Ni(acac)2 was used as the nickel source at a 2:1 ligand:Ni ratio.
From the different solvents assayed, the use of CH3CN at ꢀ20 °C
was selected.17 Thus, when a solution of 5 mol % of Ni(acac)2 and
10 mol % of the chiral ligand 2a in CH3CN was heated at reflux
for 1 h, and the chalcone was added at rt followed by the slow
addition of a solution of Et2Zn in hexane (1 M) at ꢀ20 °C, 1,3-
diphenylpentan-1-one (4a, R1 = R2 = Phe) was isolated by standard
techniques in 99% yield after 18 h. The enantiomeric excess was
determined to be 75% (77% at ꢀ50 °C, but at the expenses of
reducing the yield below 70%) by chiral HPLC analysis (Chiralcel
OD column) (Scheme 2).
The use of NiBr2, instead of Ni(acac)2, resulted in a significant
decrease of yield and enantioselectivity. This can be associated to
the low solubility of NiBr2 in CH3CN and to the lower basicity of
bromide for deprotonating the NH amide moiety, reducing the ini-
tial formation of the active complex. The order of addition of the
reactants is also important. If the order of addition of Et2Zn and
chalcone is reversed, a significant amount of Ni(II) is reduced
decreasing the amount of active chiral complex and reducing the
The study of nonlinear effects in enantioselective catalysis has
become an important mechanistic tool.19 In order to understand
the nature of the catalytic species, we examined the relationship
between the enantiomeric composition of the chiral ligand 2a
and that of the resulting product 4a. The positive nonlinear effect
(asymmetric amplification) found in this system (Fig. 2) can be ex-
plained by the difference in chemical properties of diastereomeric
complexes.7a It is reasonable to assume that 2 equiv of
a-amino
amide ligand replaces acetylacetonate anions from Ni(acac)2, form-
ing diastereomeric homochiral or heterochiral nickel complexes of
general structure NiL2. Replacement of one of those ligands by the
chelating substrate should occur for the reaction to take place.
A positive nonlinear relationship can be explained by a greater
stability of the meso complex compared to its chiral diastereoiso-
mers.20 Thus, the minor enantiomer of the ligand is trapped in this
meso complex (S/R)-2a, and it becomes less available for the cata-
lytic conjugate addition. This is corroborated by DFT studies that
reveal that the meso 2:1 (R/S) complex from 2a is slightly more sta-
ble (1.3 kcal molꢀ1) than either the R/R or the S/S complex.21 The
structure calculated for the 2:1 complexes was suggested experi-
mentally to be the most stable, in the case of 2b, as suitable crys-
tals for X-ray analysis were only obtained for the meso complex
from a mixture containing the (S)-2b ligand contaminated with a
minor amount of the R-enantiomer (Fig. 3).
O
R
O
O
THF
R
O
+
N
HO
CbzHN
O N
1) DCC, 0 °C
2) rt, 18h
CbzHN
OH
O
O
In an attempt to improve the efficiency of the conjugate
addition to chalcone, we synthesized a library of
derived from (S)-phenylalanine by modification of the amine used
in the -amino amide synthesis. The results are summarized in
Table 1.
a-amino amides
1) HBr/HOAc
2) NaOHaq
R
O
R
O
R'-NH2
H2N HN R'
a
CbzHN HN R'
Δ
THF, , 12h
2
1
In all cases, (S)-4a was the major enantiomer obtained with 2a
being superior to other ligands. Yields and enantioselectivities
decreased, in some cases very significantly, for ligands 2k and 2l
derived from aliphatic amines (entries 11 and 12) and in the case
of ligands derived from bulky amines. This is particularly true for
R0 substituents such as naphthyl (2e), anthryl (2f), or tert-butyl
(2l) (entries 5, 6, and 10). Substituents in the para position of the
phenyl group of the amide moiety had only a minor influence on
the outcome of the reaction, except in the case of the tert-butyl
substituent (2b, entry 2).
Scheme 1. Synthesis of a-amino amides.
Ni(acac)2
O
O
ligand
Et2Zn
R1
R2
R1
R2
*
3
4
Scheme 2. Ni-catalyzed conjugate addition of diethylzinc to chalcones.

J. Escorihuela et al. / Tetrahedron Letters 49 (2008) 6885–6888
6887
Figure 3. Optimized geometries of S/S and S/R Ni(II) complexes.
Table 1
2m, 2n, 2o, and 2p (derived from alanine, valine, isoleucine and
phenylglycine). Table 2 summarizes the results, and as can be seen,
no significant differences in ee values could be detected for the li-
gands with bulky side chains (entries 1, 3, and 4). Nevertheless, a
slight decrease in the enantioselectivity was observed for the li-
Effect of the amine in the Et2Zn conjugate addition to chalcone
Entrya
Ligand
R0
Yield (%)
97
eeb (%)
1
2a
75 (S)
gand derived from L-alanine (entry 2) containing the less bulky side
chain. The best result was obtained when phenyglycine (entry 5)
was used.
2
3
2b
2c
83
96
23 (S)
67 (S)
Using the conditions established, we explored the scope of Ni-
catalyzed conjugate addition of Et2Zn to various substituted
a,b-
OCH3
CH3
unsaturated chalcones using ligand 2p. The results are summarized
in Table 3. Substituted chalcones were alkylated with good yields
and interestingly, the stereoselectivity was affected by the elec-
tronic nature of the substituent. Chalcones with an electron-donat-
ing group (OMe) at the 4-position of one of the aromatic rings
afforded the highest enantioselectivities (84% and 81% ee, entries
2 and 4), while chalcones with an electron-withdrawing group
(Cl) gave slightly lower enantioselectivities (70% and 67% ee, en-
tries 3 and 5). It is worth mentioning that the enantioselectivities
obtained (ranging from 67% to 84% ee) are within the best ee up
4
5
2d
2e
89
63
35 (S)
15 (S)
6
2f
60
6 (S)
Table 2
7
8
9
2g
2h
2i
95
91
87
66 (S)
64 (S)
65 (S)
Effect of the steric bulk of the amino acid residue
Entrya
Ligand
R
Yield (%)
eeb (%)
1
2
3
4
5
2a
CH2Ph
CH3
CH(CH3)2
CH(CH3)CH2CH3
Ph
97
95
96
96
97
75 (S)
51 (S)
69 (S)
68 (S)
78 (S)
2m
2n
2o
2p
OCH3
a
All reactions were carried out at ꢀ20 °C for 6 h.
b
Determined by HPLC analysis (Chiralcel OD column).
10
11
2j
83
86
81
33 (S)
43 (S)
29 (S)
2k
2l
Table 3
Scope of the conjugate Et2Zn addition to substituted a,b-unsaturated chalcones using
ligand 2p
12
Entrya
R1
R2
Yield (%)
eeb (%)
a
1
2
3
4
5
6
Ph
Ph
Ph
Ph
97
99
96
95
93
99
78 (S)
84 (S)
70 (S)
81 (S)
67 (S)
75 (S)c
All reactions were carried out at ꢀ20 °C for 6 h.
b
Determined by HPLC analysis (Chiralcel OD column).19
4-CH3OC6H4
4-ClC6H4
Ph
Ph
Ph
4-CH3OC6H4
4-ClC6H4
Ph
In a second step, we examined the conjugate addition to
chalcone using -amino amide ligands derived from different
a
a
All reactions were carried out at ꢀ20 °C for 6 h.
Determined by HPLC analysis (Chiralcel OD column).
Me2Zn was used.
b
c
amino acids differing on the size and nature of the side chain, while
keeping R0 = Phe. Thus, a further study was carried out with ligands

6888
J. Escorihuela et al. / Tetrahedron Letters 49 (2008) 6885–6888
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In summary, we have shown that chiral
a-amino amides de-
rived from natural amino acids catalyzed the conjugate addition
of diethylzinc to chalcones with good enantioselectivities in the
presence of Ni(acac)2. Different structural modifications were
examined in order to optimize the enantioselectivity of the nick-
el-catalyzed conjugate addition. This process resulted in the selec-
tion of phenylglycine-based ligand 2p, with a phenyl group in the
amide moiety, which catalyzed the addition of diethylzinc to
substituted chalcones with enantioselectivities up to 84%. Those
enantioselectivities can be ranged between the best obtained for
this reaction. Further studies are in progress to study the scope
and mechanism of this process, and the potential application of
these catalytic systems using other metals and for other synthetic
transformations.
Acknowledgments
13. (a) Burguete, M. I.; Collado, M.; Escorihuela, J.; Galindo, F.; García-Verdugo, E.;
Luis, S. V.; Vicent, M. J. Tetrahedron Lett. 2003, 44, 6891–6894; (b) Burguete, M.
I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed. 2007, 46, 9002–
9005.
14. Burguete, M. I.; Galindo, F.; Luis, S. V.; Vigara, L. Dalton Trans. 2007, 4027–4033.
15. (a) Pelagatti, P.; Carcelli, M.; Calbiani, F.; Cassi, C.; Elviri, L.; Pelizzi, C.; Rizzotti,
U.; Rogolino, D. Organometallics 2005, 24, 5836–5844; (b) Zaitsev, A. B.;
Adolfsson, H. Org. Lett. 2006, 8, 5129–5132.
16. (a) Becerril, J.; Bolte, M.; Burguete, M. I.; Galindo, F.; García-España, E.; Luis, S.
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17. (a) Takahashi, Y.; Tamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.;
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Financial support from the Spanish Ministerio de Educación y
Ciencia (MEC, Projects CTQ2005-08016-C03) and Fundació Caixa
Castelló-UJI (Project P1-1B2004-13) is acknowledged. J.E. thanks
MEC-CSIC and UJI for a predoctoral fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.120.
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