Highly enantioselective addition of Me2Zn to aldehydes catalyzed by ClCr(Salen)

Article abstract of DOI:10.1021/ja057969d

High enantiomeric excesses are obtained in the addition of Me₂Zn catalyzed by commercially available ClCr(Salen). Broad scope, simple procedure, room temperature, low catalyst loading are the characteristics of this new enantioselective process, which uses the rather unreactive Me₂Zn. Enantiomeric excesses in the range of 71-99% are obtained with all the aldehydes tested. Copyright

Full text of DOI:10.1021/ja057969d

Published on Web 03/24/2006
2
Highly Enantioselective Addition of Me Zn to Aldehydes Catalyzed by
ClCr(Salen)
Pier Giorgio Cozzi* and Peter Kotrusz
Dipartimento di Chimica, UniVersity of Bologna, “G. Ciamician”, Via Selmi 2, 40126 Bologna, Italy
Received November 23, 2005; E-mail: piergiorgio.cozzi@unibo.it
The addition of R
benchmark reaction in which new chiral ligands are evaluated.
2
Zn reagents to aldehydes represents a
Table 1. Enantioselective Addition of Me2Zn to Benzaldehyde
Promoted by M(Salen) Complexes
2
Hundreds of successful chiral ligands based on amino alcohols or
3
4
5
related SN, SeN, and NN frameworks have been introduced in
6
recent years. Most of the ligands introduced are employed in the
7
presence of Et
small number of studies in the addition of Me
in part determined by the lower reactivity of Me
2
Zn, while Me
2
Zn was used in a few reports. The
2
Zn to aldehydes is
Zn, well
2
8
documented in the literature. However, the development of a highly
enantioselective methodology for the addition of a methyl group
is still a highly desirable process.
Herein we describe a highly efficient catalytic asymmetric
addition of Me
metal complex.
2
Zn to aldehydes promoted by a chiral Cr(Salen)
yield
ee
yield
(%)b
ee
entrya
Salen
solvent
(%)
b
(%)
c
entrya Salen
solvent
(%)
c
Salen metal complexes are useful catalysts for a variety of
asymmetric transformations. The Schiff base framework, able to
act as a bifunctional catalyst, is also well adapted to promoting the
t
t
t
t
t
t
t
t
t
9
1
2
3
4
5
6
7
8
9
ClMn
Co
Co(OTs)
Cu
AlCl
V(O)
Zn
Mn(N)
CrCl
CrCl
BuOMe
BuOMe
BuOMe
BuOMe
0
0
0
0
11
12
13
14
15
16
17
18
CrCl Et
CrCl CH
CrCl
CrCl
2
O
82 94(R)
0
BuOMe 79 94(R)
BuOMe 12
2
Cl
2
e
f
t
t
t
10
11(S)
8(R)
addition of organometallic reagents to aldehydes. Recently, we
reported that Zn(Salen) metal complexes are able to promote the
g
h
i
BuOMe 10
d
CrCl BuOMe 35
CrCl BuOMe 70 55(R)
BuOMe 90 85(R)
CrCl BuOMe 90 34(R)
t
BuOMe
BuOMe
BuOMe
0
0
0
addition of Et
2
Zn to aldehydes11 in moderate ee. Kozlowski and
CrCl
t
t
j
co-workers have exploited this concept through the tailored design
of new Salen Schiff bases, able to coordinate electrophiles and
nucleophiles in a close proximity.12 On the other hand, ClCr(Salen)
represents a privileged metal complex, able to transmit chiral
information in a variety of processes. Jacobsen has recently
reported the activation of tin enolate14 in a remarkable catalytic
alkylation, expanding the scope of ClCr(Salen)-mediated processes.
On the basis of this intriguing reactivity, we have explored the
possibility of using ClCr(Salen) catalysts in the activation of other
organometallic reagents. Particularly, we were interested in search-
ing for new promoters for the addition of the stable and rather
j,e
t
BuOMe 91 97(R) 19
toluene 90 95(R)
CrCl BuOMe 83 29(R)
10
a
Reactions were carried out on a 0.2 mmol scale at RT for 24 h
13
employing 2 equiv of Me Zn (2 M solution in toluene) and 2 mol % of
2
ClCr(Salen). b Isolated yield after chromatographic purification. Deter-
c
mined by chiral HPLC analysis. Not determined. e Reaction was performed
d
f
at 0 °C for 24 h. The reaction was performed for 48 h on 0.5 mmol scale
using 0.03 mol % of the catalyst in 1 mL of BuOMe. The reaction was
t
g
performed for 48 h on a 0.5 mmol scale using 0.03 mol % without adding
t
BuOMe. h The reaction was performed on 0.3 mmol for 48 h using 0.2
t
i
mol % of the catalyst without adding BuOMe. The reaction was performed
on 0.3 mmol for 48 h using 0.5 mol % of the catalyst without adding
tBuOMe. Et2Zn (1.1 M in hexane, 2 equiv) was used as organometallic
j
1
5
unreactive Me
presence of Me
2
Zn. Initial screens of different M(Salen) in the
Zn and benzaldehyde (Table 1) revealed the unique
reagent in this reaction.
2
properties of Cr(Salen) in this transformation. While different metal
Salen complexes did not produce a reaction after 24 h, 2% of
commercially available ClCr(Salen) was able to promote the
catalytic process was extended to other aldehydes (Table 2). As
reported in Table 2, aliphatic, aromatic, R,â-unsaturated, and
heterocyclic aldehydes are good substrates for this process.
It is particularly worth noting that in the case of aromatic
aldehydes the enantiomeric excesses obtained are in the range of
92-99%. Yields are generally from good to excellent, and the
purification of the reaction mixture consists of a rapid chromato-
graphy in order to eliminate the metal complex. Electron-rich
aromatic substrates require 4 mol % of the catalyst to produce a
good yield.
As increasing sterical hindrance in the proximity of the carbonyl
group normally gives lower yield and lower enantiomeric excess
in the catalytic addition of alkyl zinc reagents, we have studied
our system using concentrated conditions with challenging hindered
aldehydes (Table 2, entries 14-21), obtaining good results in terms
of yield and enantiomeric excesses.17 While with ClCr(Salen) it
was possible to perform the reaction even with 1% of the catalyst
(Table 1, entry 17), it is worth noting that the reported methodolo-
2
addition of Me Zn at room temperature, and a remarkable enan-
tiomeric excess of 97% was obtained in this model reaction.
Decreasing the reaction temperature makes no difference to the
selectivity. Different solvents were employed and, in general,
ethereal solvents, or toluene, gave high ee, while the reaction was
2 2
not promoted in CH Cl . Levels of less than 1% of the catalyst
can be employed at room temperature (Table 1, entries 16 and 17),
but a lower enantiomeric excess was observed. However, in the
presence of 0.5 mol % of the catalyst, in concentrated conditions,
good yield and ee of 85% was obtained in the model reaction with
benzaldehyde (Table 1, entry 17).16 The more reactive Et
2
Zn reacted
smoothly with benzaldehyde at room temperature, but the product
was isolated with low enantiomeric excess. The reaction was
performed at 0 °C, but a decreasing enantiomeric excess was
observed (Table 1, entry 19). This quite efficient and straightforward
4940
9
J. AM. CHEM. SOC. 2006, 128, 4940-4941
10.1021/ja057969d CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Addition of Me2Zn to Aldehydes
Promoted by ClCr(Salen)
oni in Chimica Organica: Metodologie ed Applicazioni), and FIRB
(Progettazione, preparazione e valutazione biologicae farmacologica
di nuove molecole organiche quali potenziali farmaci innovativi)
are gratefully acknowledged.
Supporting Information Available: Representative experimental
1
13
procedure, and details for H and C NMR and chiral HPLC analysis
of enantiomerically enriched alcohols. This material is available free
of charge via the Internet at http://pubs.acs.org.
entrya
RCHO
yieldb
ee (%)c
1
2-naphthylCHO
3-BrC6H4CHO
3-thiophenylCHO
4-MeSC6H4CHO
4-CF3C6H4CHO
4-PhC6H4CHO
91
86
86
88
95
89
87
80
89
95
81
68
82
75
73
78
57
56
49
40
65
93
96
99
98
94
94
96
95
96
92
89
82
80
97
80
73
76
79
82
71
77
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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t
1- Bu-dimethylsilyloxy-2-methyl-propanal
a
Reactions were carried out on a 0.3 mmol scale at RT for 24 h
b
employing 2 mol % of ClCr(Salen). Isolated yield after chromatographic
purification. Determined by chiral HPLC analysis unless noted otherwise.
Absolute configuration was established by comparison with the reported
optical rotation for known alcohols. Reaction carried out for 48 h using 4
mol % of catalyst. Volatile product. Yield calculated on the corresponding
,5-dinitrobenzoate prepared from the crude reaction mixture. Determined
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% of ClCr(Salen) was dissolved in the 2 M toluene solution of Me2Zn,
then the aldehyde was added neat by syringe at 0 °C. The reaction was
c
(
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(
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3
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4
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h
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7
b
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i
6b
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4
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0,11
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tallic reagents,
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(
(
(
2
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2
reactivity towards aldehydes: Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby,
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evaluated in more comprehensive studies.
To summarize, we have developed a highly enantioselective
addition of Me Zn to aldehydes employing the commercially
2
available ClCr(Salen), which provides high selectivity for aromatic
and hindered aliphatic aldehydes or R,â-unsaturated aldehydes with
a simple reaction procedure. Further work in our laboratory will
be directed toward exploiting the use of Cr(Salen) metal complexes
in the catalytic addition of other organometallic reagents to
aldehydes and ketones.19
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8
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(
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Acknowledgment. Financial support from the European Com-
munity (IBAAC Project), MIUR (Progetto Nazionale Stereoselezi-
JA057969D
J. AM. CHEM. SOC.
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VOL. 128, NO. 15, 2006 4941