Catalytic enantioselective Reformatsky reaction with aldehydes

Article abstract of DOI:10.1002/anie.200704841

(Chemical Presented) 120 years after the discovery of the Reformatsky reaction, the first effective catalytic enantioselective Reformatsky reaction with aldehydes using a binol derivative as a chiral catalyst is presented (see scheme; TMS = trimethylsilyl

Full text of DOI:10.1002/anie.200704841

Angewandte
Chemie
DOI: 10.1002/anie.200704841
Asymmetric Catalysis
Catalytic Enantioselective Reformatsky Reaction with Aldehydes**
M. ngeles Fernµndez-Ibµæez, Beatriz Maciµ, Adriaan J. Minnaard, and Ben L. Feringa*
[
1]
The classical Reformatsky reaction, introduced for the first
time in 1887, consists of the zinc-induced formation of b-
hydroxyesters by the reaction of a-halogenated esters with
[
2]
aldehydes or ketones. Currently, Reformatsky reactions are
defined as transformations that result from metal insertions
into carbon–halogen bonds activated by carbonyl groups and
subsequent addition of different kinds of electrophiles.The
Reformatsky reaction is among the most useful methods for
the formation of carbon–carbon bonds and an important
alternative to the base-induced aldol reaction.Its excellent
functional-group tolerance and mild reaction conditions have
contributed to its success.The reaction is typically heteroge-
neous in nature; however, in recent years homogeneous
Reformatsky reactions based on the use of Me Zn or Et Zn
Scheme 1. Model reaction using chiral binol derivatives. TMS=trime-
thylsilyl, TBDMS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
2
2
[
3]
have been described.
The asymmetric version of the Reformatsky reaction has
[
4]
[5]
been achieved using chiral auxiliaries or ligands. Recently,
a catalytic enantioselective version of this transformation has
been reported by Cozzi, employing ketones or imines as
(S)-L2 as the chiral ligand.Full conversion was obtained in
these cases although the enantioselectivity dropped to 26 and
8% ee, respectively.Addition of catalytic amounts of [NiCl 2-
(PPh ) ] or [RhCl(PPh ) ], which are expected to give faster
[
6]
electrophiles. High enantioselectivities have been reached
using chiral [MnCl(salen)] complexes (20 mol%) in the
reaction with ketones and N-methylephedrine (20–
3
2
3 3
halogen–zinc exchange compared to the direct insertion of
[
3]
3
0 mol%) in the imino-Reformatsky reaction.However,
Me Zn, gave nonreproducible results in the addition of
2
[
7]
both methods provide low levels of enantioselectivity in the
reaction with benzaldehyde.
Herein, we report the first effective catalytic enantiose-
lective Reformatsky reaction with aldehydes using a catalyst
based on binol derivatives as the chiral ligand.
ethyl bromoacetate to benzaldehyde using (S)-L2 as the
chiral ligand.Finally, to activate the Me 2Zn reagent, we
decided to exchange the nitrogen atmosphere with air.It is
known that Me Zn in the presence of oxygen forms the more
2
[
8]
reactive alkyl peroxides (RZnOOR), which are able to
initiate radical reactions.
[6b,8,9]
Several chiral ligands (10 mol%) were tested in a model
Under these conditions, by
reaction with benzaldehyde in the presence of Me Zn and
using 10 mol% of (S)-L2, complete conversion and a
promising level of enantioselectivity (58% ee) were obtained
(Table 1, entry 1).It is important to note that the reaction was
complete in less than 1 h, in sharp contrast with the reaction
under nitrogen.Lower and higher temperatures and different
additives and iodoacetates were evaluated, and in all cases
lower enantioselectivities were obtained.
2
ethyl iodoacetate in a nitrogen atmosphere (Scheme 1).
Chiral ligands (S)-L1, (S)-L2, and (S)-L3 gave the highest
enantioselectivities (62–69% ee), but unfortunately the con-
version into the desired product 1 was only 10–20%.The
remaining starting material was recovered, and no 1,2-
addition product of Me Zn to benzaldehyde was detected.
2
Therefore, we initially focussed our efforts on the key issue of
conversion and chemoselectivity.
Table 1: Effect of the amount of ligand on the enantioselectivity.
To increase the conversion, the more reactive Et Zn and
2
iPr Zn were used as the zinc source in the model reaction with
2
[*] Dr. M. . Fernµndez-Ibµæez, Dr. B. Maciµ, Prof. Dr. A. J. Minnaard,
Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry
University of Groningen Nijenborgh 4
[a]
Entry
Ligand (L*)
mol% L*
ee [%]
9747 AG, Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: b.l.feringa@rug.nl
1
2
3
4
5
6
(S)-L2
(S)-L2
(S)-L2
(S)-L2
(S)-L1
(S)-L1
10
20
30
50
10
20
58
70
80
74
62
74
[
**] This research was financially supported by the Dutch Ministry of
Economic Affairs. M.A.F.-I. thanks the Spanish Ministry of Educa-
tion and Science for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
[a] Determined by chiral HPLC analysis (Chiralcel OD-H).
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Next, the effect on the enantioselectivity of different
by-products were detected by NMR or GC–MS analysis.
Aromatic aldehydes with electron-poor and electron-rich
substituents at the para position gave enantioselectivities in
the range 76–80% ee (Table 2, entries 2–6).The bulky
mesitaldehyde provided 76% ee (Table 2, entry 7).The
enantioselectivity of the reaction using 2-furaldehyde was
modest (54% ee; Table 2, entry 8), in contrast with 2-thie-
nylaldehyde, which gave 84% ee (Table 2, entry 9).The
reaction with cinnamic aldehyde provided a moderate
enantioselectivity (Table 2, entry 10), whereas 2-naphthalde-
hyde gave 80% ee and a slightly lower conversion compared
to other aldehydes (Table 2, entry 11).The lowest enantiose-
lectivity was observed with the linear aliphatic aldehyde n-
octanal (Table 2, entry 12).However, the use of more-
hindered aliphatic aldehydes (isobutyraldehyde and pivalde-
hyde) gave an increase in the enantioselectivity (30% and
50% ee, respectively; Table 2, entries 13 and 14) compared to
the linear substrate.
catalyst loadings was studied (Table 1).We found that the
enantioselectivity increased to 80% ee when the amount of
ligand was raised (Table 1, entries 1–3).This effect might be
explained by competition between catalytic and uncatalyzed
reactions.Surprisingly, with 50 mol% of ( S)-L2 the enantio-
selectivity did not improve, but dropped to 74% ee.Both
ligands (S)-L1 and (S)-L2 gave very similar results under the
same conditions, but enantioselectivities were slightly higher
for (S)-L1 (Table 1, entries 5 and 6).
To suppress the uncatalyzed reaction we decided to adopt
a slow-addition protocol for benzaldehyde in this reaction.
Thus, the addition of benzaldehyde over 3 h to the reaction
mixture using 10 mol% of (S)-L2, ethyl iodoacetate, and
Me Zn in Et O provided 1 with high enantioselectivity
2
2
(
86% ee).Unfortunately, the conversion dropped dramati-
cally.Analysis of the reaction mixture by GC–MS showed the
formation of diethyl succinate (see Figure 1).The presence of
this product can be attributed to homocoupling of two ethyl
acetate radicals, which in the absence of an electrophile are
engaged in the termination step, thus explaining the low
To explain the results obtained in this work we suggest a
possible mechanism for our catalytic system that is based on a
catalytic cycle proposed by Cozzi for the imino-Reformatsky
[
10]
[6b,11]
[12]
conversion observed.
reaction
(Figure 1).
and the zinc species proposed by Noyori
To solve the problem of competing reactions, different
addition rates of RCHO were evaluated.Finally, the optimal
reaction conditions were obtained by using 20 mol% of (S)-
L1 while adding benzaldehyde over 10 min.Gratifyingly,
these conditions provided nearly full conversion into 1 and an
enantioselectivity of 84% ee (Table 2, entry 1).
The scope of the reaction was examined with several
aldehydes (Table 2).The new catalytic asymmetric version of
the Reformatsky reaction proceeded with good yields, and no
Table 2: Catalytic enantioselective Reformatsky reaction with various
aldehydes.
[
a]
[c]
Entry
R
Product
Yield [%]
ee [%]
[
b]
(
Conversion) [%]
[
[
[
d]
d]
d]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
phenyl
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
72 (87)
75 (81)
70 (83)
72 (98)
87 (98)
73 (84)
72 (86)
75 (88)
69 (86)
82 (95)
61 (76)
56 (75)
87 (n.d.)
70 (n.d.)
84 (R)
80 (R)
80 (R)
76
80
80 (R)
76
54 (R)
84
42 (R)
80
Figure 1. Proposed catalytic cycle for the Reformatsky reaction in air.
4-chlorophenyl
4-bromophenyl
4-cyanophenyl
4-isopropylphenyl
4-methoxyphenyl
mesityl
2-furyl
2-thienyl
2-phenylvinyl
2-naphthyl
n-heptyl
In conclusion, we have developed the first catalytic
chemo- and enantioselective Reformatsky reaction with
aldehydes, proceeding with high levels of asymmetric induc-
tion in several cases.A readily available binol derivative was
used as a chiral catalyst, and the reaction was performed with
[
[
d]
d]
[
d]
d]
0
1
2
3
4
ethyl iodoacetate and Me Zn as the zinc source.The presence
2
of air was found to be crucial, presumably to initiate a radical
mechanism.Currently, efforts are directed towards expanding
the scope and elucidating the mechanism of this new
asymmetric transformation.
7
[
isopropyl
tert-butyl
30 (R)
[
e]
50
[
a] Yield of isolated product. [b] Determined by GC–MS. [c] Determined
by chiral GC or HPLC (see the Supporting Information for further
details). [d] Absolute stereochemistry was determined by comparison of
the sign of specific rotation with those of literature values (see the Experimental Section
Supporting Information for further details). [e] Determined by formation
In a two-neck, 100-mL round-bottom flask equipped with a CaCl2
of the corresponding Mosher esters. n.d.=not determined.
tube, Et O (5 mL), (S)-L1 (0.025 mmol, 20 mol%), and ethyl
2
1
318
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Angewandte
Chemie
iodoacetate (0.5 mmol, 2 equiv) were added at room temperature.
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Me Zn (1 mmol, 4 equiv, 2m in toluene) was added, and immediately
16, 1913 – 1918.
2
a solution of aldehyde (0.25 mmol) in Et O (1 mL) was added over a
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2
1
0-min period by using a syringe pump.At the same time that the
addition of aldehyde was started, again Me Zn (1 mmol, 4 equiv, 2m
2
in toluene) was added.The resulting solution was stirred for 1 h and
quenched with aqueous HCl (1m).The organic phase was separated,
and the aqueous phase was extracted with Et O (5 mL).The
2
combined organic phases were dried over MgSO , and the solvent
4
was evaporated under reduced pressure to give b-hydroxyesters 1.
The products were purified by flash chromatography (see the
Supporting Information for further details).
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Published online: January 4, 2008
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[7] These experiments were carried out with ethyl bromoacetate
instead of ethyl iodoacetate in order to follow faithfully the
procedure described in the literature (see reference [3]).
Keywords: enantioselectivity · O ligands · oxygen ·
´
.
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