Dimethylzinc-mediated, oxidatively promoted Reformatsky reaction of ethyl iodoacetate with aldehydes and ketones

Article abstract of DOI:10.1002/adsc.200700572

A practical and general Reformatsky reaction, promoted by oxidants and mediated by dimethylzinc, is described. The reaction is fast and runs at 0°C with aldehydes and ketones, under mild reaction conditions. Preliminary results obtained for the enantioselective version show that inexpensive chiral amino alcohols could be used in the challenging formation of enantioenriched quaternary stereogenic centers.

Full text of DOI:10.1002/adsc.200700572

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DOI: 10.1002/adsc.200700572
Dimethylzinc-Mediated, Oxidatively Promoted Reformatsky
Reaction of Ethyl Iodoacetate with Aldehydes and Ketones
Pier Giorgio Cozzi,a,* Alessandro Mignogna,a and Paola Vicennatia
a
Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
Fax : (+39)-051-209-9456; e-mail: piergiorgiogcozzi@.unibo.it
Received: December 7, 2007; Published online: April 11, 2008
Dedicated to Professor Andreas Pfaltz on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A practical and general Reformatsky re-
action, promoted by oxidants and mediated by di-
methylzinc, is described. The reaction is fast and
runs at 08C with aldehydes and ketones, under mild
reaction conditions. Preliminary results obtained for
the enantioselective version show that inexpensive
chiral amino alcohols could be used in the challeng-
ing formation of enantioenriched quaternary stereo-
genic centers.
mild formation of the enolate and its successive reac-
tion with electrophiles. In this contribution, we report
a practical and straightforward formation of zinc eno-
lates promoted by air, their effective use in Reformat-
sky reactions with aldehydes and ketones, and pre-
liminary results towards the development of the cor-
responding enantioselective variants.
The addition of Me2Zn to aldehydes is scarcely de-
veloped, due to the lower reactivity of Me2Zn that is
well documented in the literature.[10] Following our
studies in imino-Reformatsky reactions, we have dis-
covered that the transmetallation of iodoacetate and
Me2Zn is accelerated by the presence of air,[9] through
a cycle in which Me2Zn is acting as a source of Me
radicals, and as a source of zinc (Figure 1).
Keywords: aldehydes; dimethylzinc; enantioselec-
tive; ephedrine; ketones; Reformatsky reaction
The Reformatsky reaction[1] represents a valuable
tool for the synthetic chemist as it allows the facile
addition of zinc enolates to aldehydes, ketones, or
imines.[2] In general the reaction is heterogeneous,
and efficient methodology has been introduced for
the activation of the zinc. A great advance in the Re-
formatsky-type reaction was realized by Honda[3] and
Adrian[4] who have suggested using Me2Zn and transi-
tion metals (Rh, Ni) for the homogeneous preparation
of zinc enolates. On the other hand, zinc enolates
could be obtained by transmetallation of Et2Zn[5] and
i-Pr2Zn[6] with iodoacetate, or by the reaction of a
silyl-enolate with ZnF2.[7] In addition, many other
metals have been considered in the Reformatsky-type
reaction, and the corresponding enolates have been
formed via transmetallation with alkylmetals or by
the use of the metal in low oxidation state.[1,2] Recent-
ly, we have shown that an enantioselective Reformat-
sky reaction in the presence of a catalytic amount of
metal complexes[8] or ligands,[9] could be effectively
realized with a simple concept: performing the tras-
metallation reaction between iodoacetate and Me2Zn
Figure 1. Proposed catalytic cycle for the oxidatively pro-
in the presence of a chiral ligand able to control the moted Reformatsky reactions.
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For this reason, we have investigated, with a model work of Shibasaki12, Ph3P=O and Ph3P=S are suitable
reaction (Scheme 1, Table 1), whether oxidizing additives for reactions conducted in the presence of
agents were able to accelerate the iodo-zinc exchange, zinc reagents. In fact, we found the admission of 30
mol% of Ph3P=O in the reaction mixture considera-
bly accelerates the Reformatsky reaction (Scheme 2,
Table 2).
Two general protocols were investigated, and al-
lowed good to excellent yields to be obtained in 2 h
at 08C (Table 1). For non-enolizable aldehydes the
addition of the carbonyl substrate was performed
after 30–40 min from the mixing at 08C of iodoacetate
and Me2Zn, connecting the reaction flask to air
Scheme 1. Model reaction performed with benzaldehyde in
the presence of different oxidants.
Table 1. Oxidatively promoted Reformatsky reaction with
benzaldehyde.
Entry[a]
Oxidant
Yield[b] [%]
1
2
3
4
5
6
7
8
9
air
88
73
91
20
89
40
61
33
91
Scheme 2. Reformatsky reaction promoted by air.
H2O2/Urea
t-BuOOH[c]
DDQ
Table 2. Me2Zn-mediated Reformatsky reaction promoted
by air, with different aldehydes and ketones.
Fe+Cp2BF4
À
Oxone
PhI(OAc)2
PhI=O
CAN
Entry[a]
RCOR1
Yield [%][b]
E
1
2
3
PhCHO
94
90
90
77
77
92
89
98
98
93
92
77
95
90
66
95
FerrocenylCHO
4-MeOC6H4CHO
4-BrC6H4CHO
3-BrC6H4CHO
2-IC6H4CHO
4-PhC6H4CHO
4-MeC6H4CHO
FurfuralCHO
2-ThiopheneCHO
3-ThiopheneCHO
(E)-PhCH=CHCHO
n-C8H17CHO
CyclohexylCHO
t-ButylCHO
PhCOCH3
PhCOCH2B
4-ClPhCOCH2Cl
[a]
All the reactions were carried out in anhydrous Et2O on
a 0.2 mmol scale at 08C for 4 h employing 2 equiv. of
Me2Zn (commercially available 2M solution in toluene)
and 20 mol% of the oxidant. In the case of entry 1, air
was allowed to enter in the reaction flask via a CaCl2
drying tube.
Isolated yield after chromatographic purification.
A commercially available 5–6M solution of t-BuOOH in
decane was used for the reaction.
4[c]
5[c]
6
7
8
[b]
[c]
9[c]
10[c]
11[c]
12[c]
13[c,d]
14[d]
15[d]
16[d]
17[d]
18[d]
19[d]
20[d]
making our reaction conditions suitable for the addi-
tion of zinc enolate to carbonyls. Benzaldehyde
(1 equiv.), ethyl iodoacetate (2 equiv.) and Me2Zn
(2 equiv.) were reacted in a flask in diethyl ether at
08C in the presence of many different oxidants.
r
97
92
93
80
AHCTREUNG
In general, good isolated yields were obtained with
t-BuOOH, air[11] and CAN (cerium ammonium ni-
trate). No by-products derived from the addition of
Me2Zn to aldehyde were detected. From the point of
view of the simplicity of the reaction, opening the re-
action to the air represents an effective and economic
methodology for promoting the homogeneous Refor-
matsky reaction, as nickel or rhodium metal com-
plexes are absent. Therefore, these reaction condi-
tions were tested with a variety of aromatic, heterocy-
clic, and aliphatic aldehydes. However, we found
quite a slow reaction with electron-rich aromatic alde-
hydes, and, in order to accelerate the reaction and im-
prove yields, we studied the model reaction in the
presence of different additives. As suggested by the
[a]
All the reactions were performed at 08C , on a 0.2–
0.3 mmol scale for 2 h following the procedure
A
(Me2Zn mixed with iodoacetate in Et2O and air allowed
to enter in the reaction flask at room temperature, fol-
lowed after 30 min by the addition of the carbonyl sub-
strates at 08C; see Supporting Information for further
details), and employing 30 mol% of Ph3P=O as the addi-
tive.
Isolated yield after chromatographic purification
Three equivalents of Me2Zn and three equivalents of io-
doacetate were used in the reaction.
The reaction was carried out employing procedure B
(which consists of the rapid and consecutive addition of
all the reagents at 08C; see Supporting Information for
further details).
[b]
[c]
[d]
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Dimethylzinc-Mediated, Oxidatively Promoted Reformatsky Reaction
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(Method A, see Supporting Information for details). tained with acetophenone, which indicate that, with a
Instead, in Method B, all reagents are added consecu- fine tuning of the amino alcohol ligand and of the re-
tively in the reaction flask. This method is more ap- action conditions, it will be possible to achieve a
propriate for aliphatic enolizable aldehydes and ke- straightforward access to enantioenriched quaternary
tones, and avoids the formation of by-products de- stereogenic centers.[14] Work towards these goals is
rived from the enolization of the carbonyl and their presently in progress in our laboratory.
successive reaction with themselves. Not only does
To summarize, we have developed a simple, direct
the addition of Ph3P=O shorten the reactions, but it and effective Reformatsky reaction mediated by
permits the use of the rather unreactive and challeng- Me2Zn and promoted by air, with aldehydes and ke-
ing ketones with our reaction conditions.[8]
tones employing commercially available reagents. The
We have also evaluated the possibility of perform- enantioselective variant of these reactions looks quite
ing an oxidative catalytic enantioselective Reformat- promising, allowing the simple addition of acetate for
sky reaction, by adding a chiral ligand in a catalytic solving difficult synthetic problems using inexpensive
amount. The lower reactivity of Me2Zn,[13] compared and commercially available amino alcohols as chiral
to i-Pr2Zn, and the controlled transmetallation, are ligands.[15] The facility of execution makes this reac-
key points for these enantioselective variants. After tion adapt to became a benchmark reaction for the
an extensive evaluation of chiral amino alcohols as li- evaluation of newly synthesized chiral amino alcohols
gands, and of the reaction conditions, (see Supporting for asymmetric catalysis.
Information for details), we performed the reactions
with benzaldehyde and acetophenone between 0 and
À258C, stirring the reaction mixture in the presence
Experimental Section
of 25 mol% of (1R,2S)-N-pyrrolidinylephedrine
(Scheme 3).
Method B (for Enolizable Aldehydes and Ketones)
The desired products were isolated in moderate to
good yields, and in good enantiomeric excesses.[13]
A flame-dried, 25-mL, two-necked, round-bottom flask,
Particularly promising appear to be the results ob- equipped with magnetic stirring bar and nitrogen inlet was
Scheme 3. Examples of catalytic enantioselective Reformatsky reaction performed with 25 mol% of pyrrolidinylephedrine
with PhCHO and PhCOCH3.
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Pier Giorgio Cozzi et al.
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charged with Et2O (3 mL), THF (2 mL), Me2Zn (150 mL,
1,5 equiv.) The mixture was then cooled to 08C in an ice-
water bath and aldehyde or ketone (0.2 mmol), ethyl iodo-
[8] P. G. Cozzi, Angew. Chem. 2006, 118, 3017–3020;
Angew. Chem. Int. Ed. 2006, 45, 2951–2954.
[9] P. G. Cozzi, Adv. Synth. Catal. 2006, 348, 2075–2079.
[10] For enantioselective addition of Me2Zn, see: a) L. C.
Wieland, H. Deng, M. L. Snapper, A. H. Hoveyda, J.
Am. Chem. Soc. 2005, 127, 15453–15456; b) G. Blay, I.
Fernàndez, V. Hernàndez-Olmos, A. Marco-Aleixan-
dre, J. R. Pedro, Tetrahedron: Asymmetry 2005, 16,
1953–1958; c) A. E. Lurain, A. Maestri, A. R. Kelly,
P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc. 2004, 126,
13608–13609; d) P. G. Cozzi, P. Kotrusz, J. Am. Chem.
Soc. 2006, 128, 4240; e) M. Kitamura. S. Okada, S.
Suga, R. Noyori, J. Am. Chem. Soc. 1989, 111, 4028–
4036.
A
11.2 mg) were added in sequence. The flask was connected
to air through a calcium chloride drying tube and the mix-
ture was stirred for 24 h, then quenched with 1N HCl and
diluted with Et2O. The phases were separated, and the aque-
ous phase was extracted with Et2O (3”3 mL). The organic
phases were reunited, dried over Na2SO4 and evaporated
under reduced pressure to give a pale yellow pale oil that
was purified by chromatography (Et2O:cyclohexane).
[11] No Reformatsky reaction is taking place in a mixture
of iodoacetate, Me2Zn and benzaldehyde in de-oxygen-
ated and anhydrous solvents; P. G. Cozzi, unpublished
observations. The reaction of oxygen with R2Zn has
Acknowledgements
We thank CNR (Rome), MIUR (Rome) “Progetto Stereose-
lezione in Chimica Organica Metodologie ed Applicazioni”
and University of Bologna (funds for selected research
topics) for the financial support of this research.
´
been recently studied; see: a) J. Lewinski, W. Bury, M.
Dutkiewicz, M. Maurin, I. Justyniak, J. Lipkowski,
Angew. Chem. 2008, 120, 583-585; Angew. Chem. Int.
´
´
´
Ed. 2008, 47, 573-576; b) J. Lewinski, W. Sliwinski, M.
Dranka, I. Justyniak, J. Lipkowski, Angew. Chem. 2006,
118, 4944–4947; Angew. Chem. Int. Ed. 2006, 45, 4826–
4829.
References
[1] P. G. Cozzi, Angew. Chem. 2007, 119, 2620–2623;
Angew. Chem. Int. Ed. 2007, 46, 2568–2570, and refer-
ences cited therein.
[2] a) R. Ocampo, W. R. Dolbier Jr. , Tetrahedron 2004,
60, 9325–9374; b) A. Fürstner, Synthesis 1989, 571–
590; c) A. Fürstner, in: Organozinc Reagents, (Eds.: P.
Knochel, P. Jones), Oxford University Press, New York,
1999; pp 287–305.
[3] a) K. Kanai, H. Wakabayashi, T. Honda, Org. Lett.
2000, 2, 2549–2551; b) K. Kanai, H. Wakabayashi, T.
Honda, Heterocycles 2002, 58, 47–51.
[4] J. C. Adrian Jr. , M. L. Snapper, J. Org. Chem. 2003,
68, 2143–2150.
[5] K. Maruoka, N. Hirayama, H. Yamamoto, Polyhedron
1990, 9, 223–226.
[6] I. Sato, Y. Takizawa, K. Soai, Bull. Chem. Soc. Jpn.
2000, 73, 2825–2826.
[7] T. Hama, D. A. Culkin, J. F. Hartwig, J. Am. Chem.
Soc. 2006, 128, 4976–4985.
[12] N. Yoshikawa, N. Kumagai, S. Matsunaga, G. Moll, T.
Ohshima, T. Suzuki, M. Shibasaki, J. Am. Chem. Soc.
2001, 123, 2466–2467.
[13] The reaction of benzaldehyde with iodoacetate, per-
formed with 2 equiv. of Et2Zn at À258C in the presence
of (1R, 2S)-N-pyrrolydinylephedrine for 96 h afforded
the desired products in 94% yield and in 26% ee.
[14] a) K. Oisaki, D. Zhao, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2006; 128, 7164–7165; b) P. G. Cozzi, R.
Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007,
5969–5994, and references cited therein.
[15] While our manuscript was under review, Feringa dis-
closed a catalytic enantioselective Reformatsky reac-
tion with aldehydes performed with Me2Zn/air, and
promoted by BINOL derivatives: M. A. Fernµndez-
IbµÇez, B. Marciµ, A. J. Minnaard, B. L. Feringa,
Angew. Chem. 2008, 120, 1337-1339; Angew. Chem. Int.
Ed. 2008, 47, 1317-1319.
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