Synthesis of β-hydroxy esters using highly active manganese

Article abstract of DOI:10.1016/j.tetlet.2003.11.045

A modified Reformatsky reaction is reported using highly reactive manganese (Mn*). The active manganese was found to readily react with α-haloester in the presence of aldehydes and ketones to yield the corresponding β-hydroxy esters. The reaction is carried out at room temperature in the absence of Lewis acid or trapping agents.

Full text of DOI:10.1016/j.tetlet.2003.11.045

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1807–1809
Synthesis of b-hydroxy esters using highly active manganeseq
YoungSung Suh and Reuben D. Rieke*
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA
Received 7 October 2003; revised 5 November 2003; accepted 6 November 2003
Abstract—A modified Reformatsky reaction is reported using highly reactive manganese (MnÃ). The active manganese was found to
readily react with a-haloester in the presence of aldehydes and ketones to yield the corresponding b-hydroxy esters. The reaction is
carried out at room temperature in the absence of Lewis acid or trapping agents.
ꢀ 2003 Published by Elsevier Ltd.
O- Mn2+
The Reformatsky reaction is one of the standard
methods for preparing b-hydroxy esters1. The reaction
typically utilized refluxing benzene or benzene/ether
solvents and is characterized by difficulty of initiation
and modest yields. Another major problem is the con-
trol of the very exothermic reaction. Several attempts
have been put forth2 to improve the reaction condition
including use of Rieke zinc,3 trimethyl borate/THF, or
continuous-flow procedure requiring refluxing ben-
zene.4;5 Most recently, high intensity ultrasound-pro-
moted Reformatsky reactions using a-bromoester, zinc
dust and a catalytic amount of iodine were reported in
high yields of b-hydroxy esters.6 Moreover, a variety of
metals or metal salts other than zinc have been studied
in order to extend the scope and selectivity.7–13
Mn*
H5C2OC=CHR + Br-
Br-CH-COOC2H5
R
THF, RT
R'
O
R"
H3O+
R = H, alkyl
P
Scheme 1.
The active manganese was prepared following the pro-
cedure published previously.15;16 The basic procedure
involves the reduction of an anhydrous manganese salt
with lithium and naphthalene in THF under argon
atmosphere at room temperature.
However, the study of the reaction using manganese has
been limited. In fact, there was only one report,14 where
the employed procedure required the presence of a
stoichiometric amount of a trapping agent such as acetic
anhydride and Lewis acid such as zinc chloride. In the
absence of acetic anhydride or Lewis acid, the yields are
very low. Therefore, in the course of our studies on the
chemistry of active manganese, we attempted to study
the reaction in detail using manganese (Scheme 1). We
now wish to report our positive results and improve-
ments on the Reformatsky reaction using active man-
ganese.
Initially, active manganese was simply treated with a
a-bromoester followed by addition of the carbonyl
compound at room temperature. But the results were
found to be disappointing. Once the reaction started,
there was considerable difficulty in moderating the
exothermic reaction as expected. Also, the reaction was
complicated by the formation of homo-coupling prod-
ucts. Lowering the reaction temperature resulted in
lower yields. However, we found that the activated
manganese would react rapidly with the a-bromoester in
the presence of the carbonyl compounds in THF pro-
ducing high yields of the corresponding addition prod-
uct.17 The reaction was completed in 1–2 h at room
temperature. The results are summarized in Table 1.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.045
* Corresponding author. Tel.: +1-402- 472-3501/472-2930; fax: +1-402-
472-9402; e-mail addresses: rrieke1@unl.edu, rrieke@unlserve.unl.
edu
Active manganese (MnÃ) prepared from MnBr2 or
MnCl2 is extremely reactive towards ketones and alde-
hydes yielding pinacols. This precluded its use in this
0040-4039/$ - see front matter ꢀ 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.11.045

1808
Y. S. Suh, R. D. Rieke / Tetrahedron Letters 45 (2004) 1807–1809
Table 1. Reactions of a-bromoester with carbonyl compounds using MnÃ
Entry
1
a-Bromoesters
Carbonyl compound
Producta
OH O
Yield (%)b
O
OEt
H
BrCH2COOEt I
90
(II)
1a
O
H
OH O
2
3
4
I
I
I
85
86
82
OEt
1b
O
OH O
OEt
OEt
CH3
CH3
1c
O
OH
O
Ph
1d
OEt
O
5
6
I
I
91
79
O
OH
1e
O
H
OH O
OEt
BnO
OMe
BnO
OMe
1f
Br
O
O
Ph
7
8
II
90
86
O
O
1g
O
OH O
I
OEt
H
NC
NC
Ph
1h
O
O
9
C2H5O2C(CH2)6Br
68
70
CH2(CH2)4CO2Et
Cl
1i
O
OH O
OEt
10
II
II
OEt
Br
1j
OH O
OEt
11
58
CO2Et
Br
1k
a All products are fully characterized (1H, 13C NMR and MS) and match literatures.
b Isolate yield (based on electrophiles).
reaction. However, Mnà prepared from MnI2 is much
less reactive allowing the formation of the Reformatsky
reagent in preference to pinacol formation. Accordingly,
MnI2 proved to be ideal for this reaction (Table 2).

Y. S. Suh, R. D. Rieke / Tetrahedron Letters 45 (2004) 1807–1809
Table 2. Reactivity study of Mnà on halides
1809
Acknowledgements
OH
We gratefully acknowledge the financial support pro-
vided by the National Science Foundation.
MnX2 (1 equiv)
PhCHO
Li(2.0 equiv)
OH
dl/meso
/ Np(0.2 equiv)
Yielda (%)
References and notes
MnX2
Conditions (ꢁC/time)
MnCl2
MnBr2
MnI2
rt/30 min
rt/overnight
rt/24 h
86
89
80
1. Shriner, R. L. Org. React. 1942, 1, 1.
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366.
7. For review on C8K and metal–graphite combinations,
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8. (a) Moriwake, T. J. Org. Chem. 1966, 31, 983; (b)
Mladenova, M.; Blagoev, B.; Kurtev, B. Bull. Soc. Chim.
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155.
12. Imamto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.;
Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem.
1984, 49, 3904.
13. Villieras, J.; Perriot, P.; Bourgain, M.; Normant, J. F.
J. Organomet. Chem. 1975, 102, 129.
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7373.
a Isolate yield (based on aldehyde).
The reactivity of the organomanganese reagents was
examined with several aldehydes and ketones. The cor-
responding b-hydroxyester products were obtained in
high yields (entries 1–8). It is noteworthy that this
reaction exhibits tolerance of functional groups on the
aromatic ring including cyano and methoxy. Signifi-
cantly, a a-bromolactone was also found to readily react
and undergo a mixed aldol condensation (entry 7). For
all cases, the reaction was conducted in absence of any
Lewis acid, which is required for zinc enolates prepared
from a-haloketones. Organomanganese compounds in
which the ester group is farther removed from the
carbanion centre can also be prepared and the reaction
with benzoyl chloride gave a modest yield (entry 9). This
would not be possible for the lithium or magnesium
reagents. Secondary and tertiary manganese enolates
were also tested with aldehydes and were shown to
provide the corresponding products readily (entries 10
and 11). The activated manganese will also react with
a-chloroesters in THF. However, the yields are only in
the modest range.
15. (a) Kim, S.-H.; Hanson, M. V.; Rieke, R. D. Tetrahedron
Lett. 1996, 37, 2197; (b) Kim, S.-H.; Rieke, R. D. Synth.
Commun. 1997, 28, 1065; (c) Kim, S.-H.; Rieke, R. D.
Tetrahedron Lett. 1997, 38, 993.
16. (a) Rieke, R. D.; Kim, S.-H.; Wu, X. J. Org. Chem. 1996,
37, 2197; (b) Kim, S.-H.; Rieke, R. D. J. Org. Chem. 1998,
63, 6766; (c) Kim, S.-H.; Rieke, R. D. J. Org. Chem. 1998,
63, 5235.
In summary, manganese ester enolates were readily
prepared for the Reformatsky reaction via direct oxi-
dative addition of highly active Rieke manganese to
a-haloesters, lactone and alkyl halides with remote ester
groups. The resulting reagents demonstrated excellent
addition reactions with various electrophiles such as
aldehydes and ketones. The employed procedure does
not require any special preparation or complicated
work-up process. The wide range of haloesters that can
be used in this reaction offers the synthetic chemist an
important new tool.
17. The following is
a representative procedure: Ethyl
a-bromoacetate (60 mmol) and benzaldehyde (58 mmol)
were weighed separately. To the black slurry of active
manganese in THF (30 mL) was added the mixture of
benzaldehyde and ethyl a-bromoacetate drop by drop
over 25 min. The addition was conducted at 0 ꢁC and the
entire system was kept under argon. The reaction mixture
was stirred at room temperature for about an hour after
the addition was completed. The reaction was then
quenched with 2 N hydrochloric acid (20 mL) or saturated
ammonium chloride and the organic layer was separated
from the acidic aqueous layer. The aqueous layer was
extracted with ether (3 · 20 mL) and the combined organic
phase was washed twice with saturated sodium hydrogen
carbonate (10 mL) and water (10 mL). The ether extract
was dried over anhydrous magnesium sulfate, filtered and
the solvent was evaporated, resulting in a pale yellow
liquid. The crude product was subjected to GLC, which
showed no by-products. The crude product was purified
by vacuum distillation or column chromatography yield-
ing 90% of the corresponding compound.
Supporting Information
Typical procedure for synthesis of b-hydroxy esters
using active manganese. Characterization information
1
including H NMR, 13C NMR spectra and/or MS/IR
data for all products (1a–k). The supplementary data is
available online with the paper in ScienceDirect.