A catalytic, Me2Zn-mediated, enantioselective reformatsky reaction with ketones

Article abstract of DOI:10.1002/anie.200504239

(Chemical Equation Presented) Kill two birds with one ... Salen! A catalytic and practical Me₂Zn-mediated enantioselective Reformatsky reaction promoted by [ClMn(salen)] with a ketone as the electrophile is presented (see scheme). The broad scope and simple nature of this procedure, which allows the use of commercially available starting materials and leads to useful building blocks containing quaternary stereocenters, make it extremely attractive. (salen = N,N′-ethylene-bis(salicylideneamine).).

Full text of DOI:10.1002/anie.200504239

Angewandte
Chemie
b-Hydroxy Esters
DOI: 10.1002/anie.200504239
A Catalytic, Me2Zn-Mediated, Enantioselective
Reformatsky Reaction With Ketones**
Pier Giorgio Cozzi*
Dedicated to Professor Achille Umani-Ronchi
on the occasion of his 70th birthday
The Reformatsky reaction,[1] one of the classic “named”
reactions, was discovered almost 120 years ago and is still
widely used in synthesis.[2] It consists of the zinc-induced
formation of b-hydroxyalkanoates from a-halocarbonyl com-
pounds and aldehydes or ketones. Its excellent functional
group tolerance and the possibility of preparing the reagent
in situ, by activation of zinc metal following a variety of
different methods,[3] have contributed to its success. In the last
six years, homogeneous Reformatsky-type reactions based on
the use of Me2Zn or Et2Zn in the presence of nickel[4] or
rhodium[5] have been described.
Although progress has been made on an asymmetric
version of the Reformatsky reaction with the introduction of
chiral auxiliaries[6] or ligands,[7] a truly catalytic version has
still not been achieved. Very few methods have been reported
[*] Prof. Dr. P. G. Cozzi
Dipartimento di Chimica “G. Ciamician”
Università di Bologna
Via Selmi, 2, 40126 Bologna (Italy)
Fax: (+39)051-209-9456
E-mail: piergiorgio.cozzi@unibo.it
[**] Dr. Eleonora Rivalta is acknowledged for her experimental help.
Professor Giuseppe Bartoli and Dr. Paolo Melchiorre are acknow-
ledged for allowing use of their chiral GC instruments. The
European Commission (project FP6-505267-1(LIGBANK)), MIUR
(Progetto Nazionale Stereoselezioni in Chimica Organica: Meto-
dologie ed Applicazioni), and FIRB (Progettazione, preparazione e
valutazione biologica e farmacologica di nuove molecole organiche
quali potenziali farmaci innovativi) are acknowledged for their
financial support of this research.
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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for the catalytic aldol reaction of ketones,[8] although the
stereocontrolled addition of Reformatsky-type reagents to
ketones has received increased attention for the preparation
of quaternary stereocenters.[9]
Herein, we disclose the first practical catalytic enantiose-
lective Reformatsky reaction with ketones, which is based on
the use of [ClMn(salen)] as the chiral catalyst. Recently, we
reported a highly efficient, enantioselective,[10] one-pot three-
component imino-Reformatsky reaction that gives b-amino
esters in moderate to good yields. We therefore tried to use
this protocol with ketones, and obtained good conversions but
only low ee values. We reasoned that a controlled and mild
formation of the zinc reagent, using the less reactive Me2Zn in
the presence of a chiral zinc complex, should lead to the first
catalytic version of this important reaction.
Scheme 2. Iodo derivatives used in the Me2Zn-mediated Reformatsky
reaction promoted by [ClMn(salen)].
Table 1: Results of the enantioselective Reformatsky reactions shown in
Scheme 2.
Entry[a]
1
Iodo derivative[b]
Conversion [%][c]
85
ee [%][d]
46
Zinc enolates can be prepared by direct exchange of iodo
esters with Et2Zn[11] or iPr2Zn.[12] Enantioselective variants
based on the exchange between an iodoacetate and Et2Zn
have also been developed.[13] We therefore tested several
chiral ligands in the presence of Me2Zn and iodoacetate[14] in a
model reaction with acetophenone, and observed the desired
conversion only in the presence of the salen ligand (Scheme 1;
2
3
4
95 (90)
60
63
44
16
50
5
6
90
90
0
40
7
84
10
Scheme 1. The Me2Zn-mediated Reformatsky reaction promoted by
[ClMn(salen)] that was chosen as the model reaction.
[a] All the reactions were performed as shown in Scheme 2 (for
experimental details see Supporting Information). [b] All iodo derivatives
were prepared by an exchange reaction with the corresponding
bromoacetate using NaI in acetone at room temperature. [c] Conversion
evaluated by HPLC analysis of the crude reaction mixture; yield of
isolated product in parentheses. [d] Determined by chiral HPLC analysis
(Chiralcel OD column).
see Supporting Information for further details).[15,16] Among
the M(salen) complexes tested, [ClMn(salen)][17] emerged as
highest ee value. Different Mn(salen) complexes were also
prepared (see Supporting Information) and used in the model
reaction, although they proved to be no better.[19] Since the
best conversion with acetophenone was obtained in refluxing
tBuOMe for a short reaction time,[20] we tested other ketones
using this protocol. Unfortunately, although conversion was
good, the enantiomeric excesses obtained were only moder-
ate. However, to our delight, when the reaction was per-
formed at room temperature in the presence of 4-phenyl-
pyridine N-oxide (Scheme 3) the enantiomeric excesses were
substantially improved.
the most promising catalyst, and the effect of changing
various reaction parameters (solvent, temperature, mode of
addition) was therefore evaluated with this complex (see
Supporting Information). Complete conversion and a good
level of ee values were obtained when performing the reaction
at reflux temperature in tBuOMe. The enantiomeric excess
improved slightly (up to 66% ee) upon performing the
reaction in the presence of 4-phenylpyridine N-oxide, an
additive that is often used in enantioselective [ClMn(salen)]-
catalyzed epoxidations,[18] although we observed lower reac-
tivity at room temperature or under reflux conditions.
Different esters were also evaluated during the optimiza-
tion of the process (Scheme 2, Table 1). As can be seen from
these data, increasing the steric hindrance of the ester caused
a drop in enantiomeric excess, with the ethyl ester giving the
Scheme 3. Catalytic enantioselective Reformatsky reactions promoted
by [ClMn(salen)] and 4-phenylpyridine N-oxide.
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The reaction shows broad scope, since aromatic, aliphatic,
heterocyclic, and a,b-unsaturated ketones all react to give the
desired products in moderate yields (Table 2). Aromatic
ketones gave enantioselectivities in the range 69–86%;
mechanism for this reaction, the clean reaction obtained
with allyl iodoacetate (Table 1, entry 6) seems to rule out the
formation of radical intermediates.[21]
In conclusion, we have developed the first effective,
catalytic, enantioselective Reformatsky reaction based on the
use of inexpensive and readily available [ClMn(salen)][22] as
the catalyst with an iodo ester as reaction partner. The
formation of a reactive zinc enolate under mild conditions,
which is able to react in a stereoselective manner with a rather
unreactive ketone, has been realized whilst avoiding the use
of strong bases, sensitive enolates, and expensive ligands. We
believe that several interesting reactions of this Reformatsky-
type reagent with other electrophiles could be possible.[23]
Table 2: Catalytic enantioselective Reformatsky reaction witha variety of
ketones.
Entry[a] Ketone
Yield [%][b] t [h]
ee [%][c]
1[d]
2
1-tetralone
1-tetralone
1-indanone
1-indanone
65
45
75
40
64
53
73
55
53
46
48
70
51
60
54
30
3
48
69
86
3[d,e]
4[f]
5
1.50 72 (R)
1.50 78 (R)
40
30
120
72
80
30
100
20
120
48
24
24
120
24
18
24
72
72
1-indanone
84 (R)
84
80
85
82
80 (R)
81 (R)
57
40
53 (R)
49
75 (R)
96
23
26
21 (S)
28
6
7
8
2-chloroacetophenone
2-chloroacetophenone
4-chloroacetophenone
1-acetonaphthone
4-bromoacetophenone
3-methylacetophenone
acetylferrocene
2-furylacetone
propiophenone
(E)-4-phenyl-3-buten-2-one
(E)-3-penten-2-one
2,2-dimethylcyclopentanone 70
4-phenylbutan-2-one
4-phenylbutan-2-one
6-methyl-5-hepten-2-one
3-methylbutan-2-one
cyclopropylacetone
Received: November 29, 2005
Revised: January 30, 2006
Published online: March 23, 2006
9
10[e]
11[e]
12
Keywords: enantioselectivity · homogeneous catalysis · ketones ·
.
manganese · N ligands
13
14[g]
15
16[h]
17
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[a] All the reactions were performed in duplicate, at room temperature,
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with PhCOMe, iodoacetate, and Me2Zn gave no conversion after
24 h.
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comparing the optical rotation with that of a known product,
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