Stereoselective olefination reactions promoted by Rieke manganese

Article abstract of DOI:10.1055/s-0029-1216880

A study of the advantages of using manganese, an inexpensive and nontoxic metal, to perform stereoselective β-elimination reactions and to promote sequential olefination reactions of aldehydes to obtain α,β- unsaturated esters and amides is presented. Various elimination reactions, all of them characterized by occurring with complete stereoselectivity and in high yields, were performed using active manganese (Mn*) as metalating agent. This ability of manganese has been applied to develop a novel and direct synthesis of (E)-α,β-unsaturated esters or amides and (Z)-α,β-unsaturated α-halo esters and α-choroamides through a Mn*-mediated sequential olefination protocol of aldehydes with dichloro esters or amides and trihalo esters or trichloroamides, respectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216880

2634
FEATURE ARTICLE
Stereoselective Olefination Reactions Promoted by Rieke Manganese
S
tereosele
o
ctive
O
lefina
s
tions
P
rom
é
otedbyRieke
M
M
anganese . Concellón,* Humberto Rodríguez-Solla, Vicente del Amo, Pamela Díaz
Dpto. Química Orgánica e Inorgánica, Universidad de Oviedo, C/ Julián Clavería, 8, 33071 Oviedo, Spain
Fax +34(985)103448; E-mail: jmcg@uniovi.es
Received 13 May 2009; revised 20 May 2009
ing a large number of contributions reporting the synthesis
Abstract: A study of the advantages of using manganese, an inex-
pensive and nontoxic metal, to perform stereoselective b-elimina-
tion reactions and to promote sequential olefination reactions of
aldehydes to obtain a,b-unsaturated esters and amides is presented.
of a,b-unsaturated esters10,11 or amides,11,12 some of these
methods take place without complete stereoselectivity
(particularly when the double bond is trisubstituted) and
Various elimination reactions, all of them characterized by occur- are either tedious (multistep procedures) or imply the use
ring with complete stereoselectivity and in high yields, were per-
of expensive starting materials.
formed using active manganese (Mn*) as metalating agent. This
Based on these precedents, we reported the first transfor-
ability of manganese has been applied to develop a novel and direct
mation of 2-bromo-3-hydroxy esters into a,b-unsaturated
esters with complete stereoselectivity promoted by com-
mercial manganese activated by chlorotrimethylsilane.13
Later, we described a novel manganese-mediated olefina-
tion reaction of aldehydes to obtain (E)-a,b-unsaturated
esters or amides14 and (Z)-a-halo-a,b-unsaturated esters
or amides,15 in all cases, with complete diastereoselectiv-
ity.
synthesis of (E)-a,b-unsaturated esters or amides and (Z)-a,b-unsat-
urated a-halo esters and a-choroamides through a Mn*-mediated
sequential olefination protocol of aldehydes with dichloro esters or
amides and trihalo esters or trichloroamides, respectively.
Key words: manganese, elimination reactions, stereoselectivity,
a,b-unsaturated esters, a,b-unsaturated amides, metalation
Manganese is a nontoxic1 and inexpensive2 metal and the
reduction potential of Mn2+/Mn0 system (–1.03 V)3 is ad-
equate to reduce an important number of organic func-
tions. According to these properties, extensive use of
manganese in organic synthesis might be expected. How-
ever, in contrast to other metals, such as lithium, magne-
sium, zinc, or samarium, the application of manganese in
organic synthesis has been scarcely developed. Among
the main reasons for this lack of development are the in-
ability of commercially available manganese to react di-
rectly with organic compounds as consequence of its
passivity,4 mainly because of the formation of an oxide
layer on its surface. To overcome the lack of reactivity of
manganese metal, different procedures have been de-
scribe to obtain active manganese (Mn*) by Rieke5 and
Fürstner6 in 1996, by Oshima7 in 1998, and by Cahiez8 in
1999. Since then the number of reported transformations
promoted by Mn* have increased.9 It is important to note
that all these transformations take place with high selec-
tivity. Combining the aforementioned properties of man-
ganese (reduction potential, selectivity, low price, and
toxicity) with our interest in the development of novel
highly selective organic reagents, including the use of se-
Herein, we present a study of the advantages of using
manganese to perform stereoselective b-elimination reac-
tions and to promote sequential olefination reactions of al-
dehydes to obtain a,b-unsaturated esters and amides.
Manganese-Promoted b-Elimination Reactions
Our first aim was to test the ability of manganese to pro-
mote highly stereoselective b-elimination reactions. The
starting materials to carry out this study were a-bromo-b-
hydroxy esters as a consequence of their ready availability
and the easy metalation of the C–Br bond of these esters.
To perform the metalation we used commercial manga-
nese activated by chlorotrimethylsilane.
Treating a solution of a-bromo-b-hydroxy esters 1 and
chlorotrimethylsilane (1.75 equiv) in anhydrous tetrahy-
drofuran with commercially available manganese gran-
ules (325 mesh, Aldrich, 1.5 equiv) for five hours at reflux
temperature afforded, after appropriate workup, the corre-
sponding a,b-unsaturated esters 2 with total E-stereose-
lectivity and in high yields (Table 1).
lective metals, has prompted us to develop new synthetic The starting materials 1 were easily prepared, as mixtures
applications of manganese.
of diastereoisomers (~1:1), by reaction of the correspond-
ing lithium enolates of a-bromo esters (generated by treat-
ment of a-bromo esters 3 with lithium diisopropylamide
at –85 °C) with aldehydes at the same temperature
(Scheme 1).
We decided to test the ability of manganese to promote
highly stereoselective elimination reactions towards the
synthesis of a,b-unsaturated esters or amides, based on:
(a) the use of manganese to carry out elimination reactions
has not been previously reported, and (b) despite there be- It is noteworthy that the a,b-unsaturated esters 2 were ob-
tained with total stereoselectivity from diastereoisomeric
mixtures of compounds 1.
SYNTHESIS 2009, No. 15, pp 2634–2645
x
x.
x
x
.
2
0
0
9
Advanced online publication: 29.06.2009
DOI: 10.1055/s-0029-1216880; Art ID: Z09909SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Stereoselective Olefinations Promoted by Rieke Manganese
2635
Professor José M. Con- 1998 to 2009. He became a areas of this research inter-
cellón was born in Zaragoza full Professor in 2006 and est are the b-elimination,
in 1950 and graduated from currently he is the Head of deuteration, and cyclopro-
the University of Zaragoza the Department of Organic panation reactions of unsat-
in 1973, obtaining his Ph.D. and Inorganic Chemistry at urated acid derivatives. His
from the University of Oviedo University. He current research interest
Oviedo in 1977. He became worked in the synthetic ap- also includes the synthetic
Associate Professor in 1983 plications of functionalized applications of enantiopure
at the University of Oviedo. organometallic compounds a-amino ketones and the de-
He was Vice-Dean of the derived from lithium and velopment of new synthetic
Faculty of Chemistry of magnesium until 1996. In methodologies based on the
Oviedo University for four that year, he started his work use of chromium dichloride
years until March 1998, and in the field of organic trans- and active manganese. He is
Dean of the Faculty of formations promoted by sa- the co-author of more than
Chemistry of Oviedo from marium diiodide. Specific 125 papers.
Dr. Humberto Rodríguez- ing his Ph.D., he developed terests are focused on the
Solla was born in Gijón new methodologies to carry development of new meth-
(Asturias) in 1975 and grad- out b-elimination, reduc- odologies using organome-
uated from the University of tion, and cyclopropanation tallic compounds based on
Oviedo in 1998. He ob- reactions using samarium samarium diiodide, chromi-
tained his Ph.D. at the same diiodide or samarium car- um dichloride, and active
university in 2002 super- benoids. During his post- manganese and their appli-
vised by Prof. José M. Con- doctoral research he worked cation in asymmetric syn-
cellón. In that year he in the area of organometallic thesis. He was awarded with
moved to Oxford (UK) compounds and the use of the Ph.D. Prize (Colegio
where he was a postdoctoral samarium diiodide with ox- Oficial de Químicos de
researcher in the Chemistry azolidinone chiral auxilia- Asturias y León) in 2003
Research Laboratory (Uni- ries or DKP templates. and with the Ph.D. Extraor-
versity of Oxford) under the Currently, he has a Ramón y dinary Prize (University of
supervision of Prof. Stephen Cajal contract at University Oviedo) in 2004.
G. Davies until 2005. Dur- of Oviedo. His research in-
Dr. Vicente del Amo was Concellón. In November is currently working under
born in Madrid in 1978. He 2005, after receiving a pres- the supervision of Prof.
attended the Universidad tigious Alexander von Douglas Philp. Vicente’s re-
Autónoma de Madrid from Humboldt fellowship, he search interests are based on
which he graduated in 2001. moved to the Ludwig- exploiting
In 2005 he was awarded Maximilians-Universität molecular recognition inter-
non-covalent
with Ph.D. from the Univer- (Munich, Germany) to work actions on catalytic process-
sity of Bristol (UK) where for 14 months, as a postdoc- es and the control of
he worked under the super- toral research fellow in the chemical reactions and also
vision of Prof. Anthony P. group of Prof. Paul Knochel. on developing novel syn-
Davis. The same year he Finally, in March 2007 he thetic applications of orga-
moved to the University of took up a research assistant nometallic reagents.
Oviedo to work for five position at the University of
months in the group of Prof. St. Andrews (UK) where he
Pamela Díaz was born in Dr. Humberto Rodríguez- reactions towards the stere-
Gijón (Asturias) in 1982. Solla. In 2006, she obtained oselective synthesis of a,b-
She graduated in chemistry her Master’s degree from unsaturated ketones. Her
from the University of the same University work- current research interest is
Oviedo in 2004 and started ing on the use of samarium focused on the development
her Ph.D. in organic chemis- diiodide and chromium of new methodologies based
try under the supervision of dichloride to promote se- on the use of active manga-
Prof. José M. Concellón and quential aldolic/elimination nese.
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

2636
J. M. Concellón et al.
FEATURE ARTICLE
Table 1 Synthesis of a,b-Unsaturated Esters 2 with Manganese/Chlorotrimethylsilane
OH
Mn (0)
CO2Et
CO2Et
Br R2
R1
R1
TMSCl, THF
reflux
R2
1
2
Entry
Product
R1
R2
Yielda (%)
Mn
b
c
SmI2
70
CrCl2
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
n-C7H15
H
82
85
51
75
83
90
78
91
65
Cy
H
4-MeOC6H4
n-C7H15
CH(Ph)Me
Ph
H
Me
75
87
86
90
64
n-C6H13
n-C6H13
n-C6H13
n-C6H13
2g
2h
(E)-CH=CHMe
(E)-CH=CHPh
a Isolated yield after column chromatography based on compounds 1; all products were isolated with >98% de determined by 1H NMR and/or
GC-MS of the crude products 2.
b Isolated yield obtained using SmI2.16
c Isolated yield obtained using CrCl2.10e
h). On the other hand, when the reaction was carried out
O
OH
R2
1) LDA
in the absence of chlorotrimethylsilane, no reaction was
found. These observations suggest that chlorotrimethylsi-
lane plays some role as manganese activating agent4 but
does not interfere with the b-elimination reaction.
CO2Et
R1
OEt
2) R1CHO
3) H3O+
Br
Br R2
3
1
Obtaining the (E)-alkene as major diastereoisomer could
be justified based on thermodynamic arguments as the E-
diastereoisomer is thermodynamically more stable than
the Z-diastereoisomer. However, the higher thermody-
namic stability of the E-diastereoisomer could not explain
the total diastereoselectivity observed for this reaction.
We then proposed a mechanism to explain the high levels
of stereoselectivity shown in this reaction (>98% de)
based on a chelation control model (Scheme 2), similar to
that proposed for other published b-elimination reac-
tions.11
Scheme 1 Preparation of starting compounds 1
The diastereoisomer purities of compounds 2 were deter-
1
mined on the crude reaction products by H NMR spec-
troscopy (300 MHz). The E-stereochemistry of the C=C
bond in products 2 was assigned on the basis of the value
1
of the H NMR coupling constants between the olefinic
protons of esters 2a–c (Table 1), in which the C=C bond
was disubstituted, and by comparison of the spectroscopic
data of esters 2a–h (Table 1) with those values previously
reported the same compounds obtained by other meth-
ods.16
Thus, a manganese enolate intermediate 4 could be
generated17 after metalation of the C–Br bond of com-
pound 1. Chelation of the manganese(II) center with the
oxygen atom of the alcohol group could generate a six-
membered cyclic transition state.18 Tentatively, we sur-
mise that the chairlike transition state model A might be
involved, with the R1 group in an equatorial orientation.
As depicted in B (Newman projection of A through atoms
C2 and C3), R1 and R2 have a cis relationship. A concerted
elimination process through this proposed transition state
could afford the (E)-a,b-unsaturated esters 2. In addition,
the chelation of the manganese(II) center with the oxygen
atom of the alcohol group could increase the ability of the
hydroxy group as a leaving group. The generation of a
manganese enolate in the presence of an hydroxy group
It is remarkable that the manganese/chlorotrimethylsi-
lane-promoted elimination reaction of a-halo-b-hydroxy
esters afforded the corresponding a,b-unsaturated esters
in higher yields than those obtained from analogous reac-
tions mediated by samarium diiodide11,16 or chromium
dichloride.10e In addition, the results shown in Table 1,
demonstrate the generality of this method. The reaction is
robust and can be used to obtain di- or trisubstituted a,b-
unsaturated esters 2, which can display a wide variety of
R1 and R2 substituents: aliphatic (linear, branched, or cy-
clic), unsaturated, or aromatic.
When lower quantities of chlorotrimethylsilane (0.4
equivalents) were employed the b-elimination reaction
also took place although it required longer times (ca. 12
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Olefinations Promoted by Rieke Manganese
2637
MnBr
OH
OH
H
O
O
Mn/TMSCl
CO2Et
CO2Et
2
R1
R1
R1
OEt
BrMn R2
Br R2
R2
H
1
4
H
O
R1
R2
O
O
R1
MnII
O
R2
OEt
MnII
OEt
H
H
A
B
Scheme 2 Chelation control model for the conversion of 1 into 2
can be rationalized assuming that the elimination process Previously, our group and other laboratories have reported
takes place faster than the competing hydrolysis of the C– similar synthesis of a,b-unsaturated esters or amides pro-
Mn(II) bond, moreover when the elimination is assumed moted by samarium diiodide, zinc, or chromium dichlo-
to go through a rigid chelated transition state.
ride through sequential processes21 involving dihalo-
acetates or dihaloacetamides and aldehydes. However, the
cost of samarium diiodide or chromium dichloride is a
drawback and inexpensive reagents, such as manganese,
are desirable to promote stereoselective sequential reac-
tions.
This mechanism could also justify the synthesis of com-
pounds 2 in a diastereopure form, from a mixture of dia-
stereoisomers of 1. We assumed that after the reaction of
1 with manganese, only one stereoisomer could be ob-
tained with the appropriate relative configuration for the
coordination of the manganese center with the oxygen
atom from the free alcohol. In this sense, the two starting
diastereoisomers 1 are transformed into two enantiomeric
enolates, which afford a single E-stereoisomer through a
b-elimination reaction.
Sequential Synthesis of (E)-a,b-Unsaturated Esters 2
and Amides 5
Initially, the olefination of aldehydes was attempted with
ethyl dibromoacetate using commercial manganese acti-
vated by chlorotrimethylsilane, under different reaction
conditions. However, no reaction took place as a conse-
quence of the passivity of commercial manganese.
Rieke Manganese-Promoted Sequential Olefination
Reactions
Consequently, active manganese (Mn*) was used to pro-
Once the ability of manganese to promote stereoselective mote the sequential olefination protocol. Active manga-
elimination reactions was proven, we decided to investi- nese was readily prepared by the method described by
gate the use of manganese on the olefination reaction of Cahiez.8 Thus, treatment of a solution of lithium tetrachlo-
aldehydes with dihalo- or trihalo esters or amides. This romanganate(II) (or MnCl2·2 LiCl) (13 mmol) in tetrahy-
process could take place throughout two sequential reac- drofuran (20 mL) with a mixture of lithium (26 mmol) and
tions, both promoted by Mn*: an aldol-type reaction in the catalytic amounts of 2-phenylpyridine (4 mmol) in tet-
first step, followed by a b-elimination reaction as the sec- rahydrofuran (20 mL) at room temperature for three
ond step.
hours, afforded active manganese as a black slurry.
Sequential reactions are those in which compounds are We evaluated the efficiency of the olefination method on
formed in a sequence of events without the isolation of suitable aldehydes to obtain the a,b-unsaturated esters
any intermediate. These methods hold an enormous po- 2a–d, which were previously prepared from compounds 1
tential in organic synthesis, due to their simplicity and be- (Table 1). When the olefination was carried out with Mn*
cause considerably less time, effort, and materials are at room temperature long reaction times were necessary to
required to obtain organic compounds when compared to complete the reaction. To overcome this drawback, the
more traditional multistep procedures. In addition, the metalation was performed in tetrahydrofuran at reflux
starting materials used in sequential transformations are temperature. The best results were obtained after treating
simple, typically commercial compounds. An important a solution of aldehydes 6a–c (1 equiv) and the corre-
requirement to perform sequential reactions is that the sponding dichloro ester 7 (1.2 equiv) in tetrahydrofuran at
yield and selectivity of each individual transformation in reflux with active manganese (5 equiv) for five hours
a multistep sequence must be exceedingly high to avoid (Scheme 3). The corresponding (E)-a,b-unsaturated es-
the generation of complex product mixtures. Thus, to ters 2a–d were obtained with total stereoselectivity and in
date, only samarium diiodide19 or chromium dichloride20 similar yields (Table 2) to those obtained from com-
have been found to be suitable to promote sequential reac- pounds 1 (Table 1). In order to establish a fair comparison
tions.
of the yields gathered in Tables 1 and 2 it is necessary to
take into account that Table 1 contains yields of a single
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

2638
J. M. Concellón et al.
FEATURE ARTICLE
O
reaction, (the b-elimination reaction of compounds 1),
while Table 2 outlines the overall yields of two successive
transformations (nucleophile addition of enolate to alde-
hyde and elimination reaction).
O
5 Mn*
R2
Cl
R1CHO
OR3
R1
OR3
THF, Δ
Cl
R2
6a R1 = n-C7H15
6b R1 = Cy
6c R1 = 4-MeOC6H4
2a–d
7 R2 = H, Me
R3 = Me, Et
To study the generality of this olefination reaction of alde-
hydes, we prepared a,b-unsaturated esters 2a–x (Table 2),
which were obtained in all cases with complete E-stereo-
selectivity (>98% de). Table 2 also compares the yields of
esters 2a,b,k,q,s with those obtained when these com-
pounds were prepared by the olefination reaction of the
corresponding aldehydes, but this time using either samar-
ium diiodide19d or chromium dichloride19d to promote the
reaction. The yields of the Mn*-mediated olefination re-
actions are higher, or at least similar, than those obtained
using samarium diiodide or chromium dichloride.
Scheme 3 Sequential olefination reactions of aldehydes 6a–c and
ethyl dichloroacetate promoted by Mn*
Motivated by our positive results, our interest shifted to
generalize the sequential olefination protocol to the prep-
aration of a,b-unsaturated amides. These compounds be-
long to an important class of natural products with both
biological and insecticide properties.22
Similarly to the olefination reaction with dihalo esters,
initially, the synthesis of amides was carried out using the
Table 2 Sequential Synthesis of (E)-a,b-Unsaturated Esters 2 Promoted by Mn*
O
O
5 Mn*
R2
R1CHO
OR3
R1
OR3
THF, Δ
R2
Cl Cl
6
7
2
Entry
Ester 2
Yielda (%)
Mn*
R1
R2
H
OR3
OEt
OMe
OEt
OEt
OEt
OEt
OMe
OMe
Ot-Bu
OEt
OEt
OEt
OMe
OEt
OEt
OEt
OEt
OEt
SmI2
CrCl2
75
b
c
1
2
2a
2b
2c
2d
2i
n-C7H15
Cy
83
87
92
73
89
92
85
89
78
88
90
81
72
88
85
70
68
88
66
H
60
84d
3
4-MeOC6H4
n-C7H15
H
4
Me
H
5
i-Bu
6
2j
s-Bu
H
7
2k
2l
CH(Me)Ph
CH2CH2Ph
CH2CH2Ph
H
69d
88d
8
H
9
2m
2o
2p
2q
2r
2s
H
10
11
12
13
14
15
16
17
18
(CH2)8CH=CH2
H
(E)-CH=CHPh
H
Ph
H
81
70
95
72
Ph
H
4-ClC6H4
n-C7H15
Cy
H
2t
Bn
Me
Me
Bn
2u
2v
2x
i-Bu
i-Bu
a Isolated yield after column chromatography based on aldehydes 6; all products were isolated with E/Z >98:2 determined by 1H NMR and/or
GC-MS of the crude products.
b Isolated yield obtained using Sml2.21d
c Isolated yield obtained using CrCl2.21d
d The reaction was carried out with the ethyl ester instead of the methyl ester.
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Olefinations Promoted by Rieke Manganese
2639
O
Table 3 Synthesis of (E)-a,b-Unsaturated Amides 5 Promoted by
Mn*
O
5 Mn*
R2
R1CHO
R1
NEt2
NEt2
THF, Δ
O
O
R2
Cl Cl
5 Mn*
R2
R1CHO
NR3
R1
NR3
2
6a R1 = n-C7H15
6b R1 = Cy
6c R1 = 4-MeOC6H4
2
THF, Δ
5a R1 = n-C7H15; R2 = H; 87%
5h R1 = Cy; R2 = H; 85%
5n R1 = 4-MeOC6H4; R2 = H; 82%
5q R1 = n-C7H15; R2 = Me; 75%
R2
Cl Cl
8 R2 = H, Me
5
6
8
Entry Amide R1
R2
NR3
Yielda
(%)
2
Scheme 4 Sequential syntheses of (E)-a,b-unsaturated amides
5a,h,n,q by the olefination reaction of aldehydes promoted by Mn*
1
2
5a
5b
5c
5d
5e
5f
n-C7H15
n-C7H15
s-Bu
H
NEt2
87
84
78
84
83
81
80
85
85
77
82
71
79
82
83
80
75
73
77
78
76
71
73
same reaction conditions as those used to obtain esters 2,
from octanal (6a), cyclohexanecarbaldehyde (6b), or 4-
methoxybenzaldehyde (6c) and N,N-diethyldichloroacet-
amide or 2,2-dichloro-N,N-diethylpropanamide (8, R2 =
H, Me). The a,b-unsaturated amides 5a,h,n,q were pre-
pared (Scheme 4 and Table 3) with total stereoselectivity
and in high yields, comparable to those obtained in the
synthesis of a,b-esters (Scheme 3 and Table 2).
H
morpholino
NEt2
3
H
4
i-Bu
H
NEt2
5
i-Bu
H
morpholino
NEt2
6
(CH2)8CH=CH2
(CH2)8CH=CH2
Cy
H
7
5g
5h
5i
H
morpholino
NEt2
To probe the generality of this method a range of a,b-un-
saturated amides 5a–w were prepared (Table 3). In all
cases only the E-diastereoisomer of compounds 5 was ob-
tained in high yields (≥71%).
8
H
9
Cy
H
Ni-Pr2
NEt2
The diastereoisomeric purity of esters 2 and amides 5 was
determined by 1H NMR spectroscopy (300 MHz) and GC-
MS on the crude reaction products. In all cases, the (E)-
olefins were obtained as the sole isomer; other isomers
were not detected in the crude reaction mixtures.23 The
relative E-configuration of the C=C bond of esters 2 and
amides 5 was established based on: (a) the value of the 1H
NMR coupling constants between the olefinic protons of
esters (Table 2, entries 1–3 and 5–14) and amides
(Table 3, entries 1–16);24 (b) by comparison between their
spectroscopic data with those previously reported for the
same esters16,21d or amides12j,k,21d prepared by other syn-
thetic methods, or (c) the results of NOESY experiments
on ester 2b or amides 5r,t,v, in which the C=C bond are
trisubstituted.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5j
CH(Me)Ph
CH2CH2Ph
Ph
H
5k
5l
H
NEt2
H
NEt2
5m
5n
5o
5p
5q
5r
5s
Ph
H
morpholino
NEt2
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
n-C7H15
s-Bu
H
H
Ni-Pr2
NEt2
H
Me
Me
Me
Me
Me
Bn
Bn
NEt2
morpholino
NEt2
i-Bu
From the results shown in Tables 2 and 3, the following
features could be drawn for this reaction: (a) Esters 2 and
amides 5 can be obtained from aromatic (containing either
donor and withdrawing substituents), or aliphatic (linear,
branched, or cyclic) aldehydes, including also readily
enolizable aldehydes such as 2-phenylpropanal, in con-
trast to other reported methods.25 (b) No appreciable dif-
ferences in the selectivity and yields of this sequential
5t
CH2CH2Ph
Ph
NEt2
5u
5v
5w
morpholino
NEt2
n-C7H15
(CH2)8CH=CH2
NEt2
a Isolated yield after column chromatography based on aldehydes 6;
all products were isolated with E/Z >98:2 determined by 1H NMR
process were detected when varying the alcohol of esters and/or GC-MS of the crude products.
7 or the amine of amides 8 (Table 2, entries 8/9 and 12/13;
tolerates the presence of some functional groups, such as
Table 3, entries 1/2, 4/5, 6/7, 8/9, 12/13, and 14/15). Espe-
cially important is the chance of preparing a,b-unsaturat-
ed amides derived from morpholine (Table 3, entries 2, 5,
7, 13, 18, and 21), as they can be easily transformed into
synthetically valuable ketones.26 (c) Esters 2 or amides 5,
bearing a trisubstituted C=C bond, were obtained with
complete stereoselectivity. It is, however, known from the
literature that when the substitution around the C=C bond
increases it is difficult to obtain this type of compounds
with high stereoselectivity.27 (d) The olefination reaction
other additional double bonds (Table 2, entries 10 and 11;
Table 3, entries 6, 7, and 23), alkoxy groups (Table 2, en-
try 3; Table 3, entries 14 and 15) or chlorine atoms
(Table 2, entry 14; Table 3, entry 16).
When the sequential olefination reaction was carried out
employing ketones instead of aldehydes no reaction took
place.
As an extension of the sequential olefination reaction of
aldehydes and based on the good results obtained in the
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

2640
J. M. Concellón et al.
FEATURE ARTICLE
synthesis of a,b-unsaturated esters or amides, we applied
this method to the preparation of other interesting synthet-
ic compounds such as a-halo-a,b-unsaturated esters or
amides.
Table 4 Synthesis of (Z)-a,b-Unsaturated a-Halo Esters 9 and a-
Chloroamides 10 Promoted by Mn*
O
O
5 Mn*
THF, Δ
Hal
Hal
R1CHO
R1
Y
Y
Hal
9/10
Hal
Synthesis of (Z)-a-Haloacrylic Acid Derivatives 9 and
10
6
11/12
Entry Product R1
Hal
Y
Yielda
(%)
a-Halo-a,b-unsaturated acid derivatives are precursors of
relevant organic derivatives such as a-halo-a,b-unsaturat-
ed ketones,28 carboxylic acids,29 2-haloallylic alcohols,30
a-amino acids,31 various heterocycles including
aziridines2,32 or trisubstituted alkenes33 In addition, natu-
ral products or pharmaceutical drugs34 have been prepared
from these compounds.
1
2
9a
n-C7H15
n-C7H15
Cy
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Fc
Fc
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OEt
89
88
95
89
92
85
87
48
71
74
69
64
62
88
86
9b
Oi-Pr
OEt
3
9c
4
9d
Cy
Oi-Pr
OEt
In general, the preparation of (Z)-a-halo-a,b-unsaturated
esters or amides has been scarcely reported. The methods
published so far are based on classical methodologies:
Wittig, Horner–Wadsworth–Emmons, Julia, or Peterson
olefination reactions. More recently, the synthesis of (Z)-
a-halo-a,b-unsaturated carbonyl compounds by the reac-
tion of dihalo acid derivatives with aldehydes promoted
by chromium dichloride,20f,35 iron,21b or samarium
diiodide36 have also been published. All these contribu-
tions present serious drawbacks such as limited generali-
ty, low stereoselectivity, poor yields, the necessity of
using expensive reagents, or tedious experimental work.
Thus, finding an easy highly selective olefination method
would be ideal.
5
9e
i-Bu
6
9f
s-Bu
OEt
7
9g
(CH2)8CH=CH2
4-MeOC6H4
OEt
8
9h
OEt
b
9
9i
n-C7H15
OEt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
9j
Cyb
Oi-Pr
OEt
9k
i-Bub
9l
Cyb
OEt
9m
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
s-Bub
OEt
On the synthesis of a-chloro-a,b-unsaturated esters by the
sequential reaction of aldehydes with trichloro esters pro-
moted by Mn*, we first attempted the same reaction con-
ditions used to obtain unsaturated esters 2 or amides 5.
The best results were obtained after the addition of Mn*
(5 equiv) to a solution of the corresponding aldehyde 6 (1
equiv) and trichloroacetate 11 (1.1 equiv) in tetrahydrofu-
ran at room temperature. The reaction mixture was then
stirred at reflux temperature for five hours. After standard
work-up, the corresponding a-chloro-a,b-unsaturated es-
ters 9a–h were isolated with total Z-stereoselectivity and
in high yields (Table 4).
n-C7H15
n-C7H15
n-C7H15
Cy
NEt2
Ni-Pr2
morpholino 84
NEt2 80
morpholino 75
NEt2 82
morpholino 79
Cy
i-Bu
i-Bu
s-Bu
NEt2
NEt2
NEt2
NEt2
Ni-Pr2
79
86
73
81
86
Under analogous reaction conditions a-bromo- or a-fluo-
ro-a,b-unsaturated esters were not obtained, isolating the
nonhalogenated esters of type 2 instead of the expected
compounds. To overcome the dehalogenation process, the
reaction was performed at room temperature for 12 hours.
So, the a-bromo-a,b-unsaturated esters 9i–k and a-fluoro-
a,b-unsaturated esters 9l,m shown in Table 4, entries 9–
11 and 12, 13, respectively, were prepared with complete
(CH2)8CH=CH2
CH(Me)Ph
4-MeOC6H4
4-MeOC6H4
a Isolated yield after column chromatography based on aldehydes 1;
all products were isolated with Z/E >98:2 as determined by 1H NMR
Z-stereoselectivity and in good to higher yields (>69%, and/or GC-MS on the crude products.
bromo derivatives or >62%, fluoro esters).
b In this case, r.t. and 12 h reaction time were required to avoid isolat-
ing the corresponding nonhalogenated product.
c In this case ethyl dibromofluoroacetate was employed instead of the
corresponding trichloro- or tribromoacetate.
Similarly, stereoisomerically pure (Z)-a-chloroacryla-
mides 10 were obtained in high yields (≥73%) after stir-
ring
a mixture containing Mn* (5 equiv), the
corresponding aldehyde 6 (1 equiv), and the trichloroace-
tamide 12 (1.1 equiv) in tetrahydrofuran at refluxing tem-
perature for five hours. However, all attempts to gain
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Olefinations Promoted by Rieke Manganese
2641
access to bromo- or fluoroacrylamides, including the use
of milder reaction conditions (r.t., 12 h), were unsuccess-
ful and a complex mixture of compounds was obtained.
OMnII
Y
MnIIO
R1
O
6
Mn*
Hal
7, 8, 11 or 12
Y
R2 Hal
R2
13
Y= OR3, NR3
The nature of the single Z-stereoisomer obtained for com-
1
pounds 9 and 10 was unambiguously established by H
14
NMR spectroscopy (300 MHz) and/or GC-MS on the
crude reaction products. On compounds 9b,c,e,i–l and
10d,f,k,l the Z-configuration of the C=C bond 10 was es-
tablished by NOESY experiments and by comparison
with the NMR data previously described in the literature
for compound 9c.36 In the case of the fluoro derivatives
9l,m, the configuration was established based on the value
of 1H NMR coupling constants between the olefinic pro-
ton and the fluorine atom (3JHF = 34 and 33 Hz, for 9l and
9m, respectively).37
2
R2 = H, alkyl or Hal
Mn*
MnII
O
MnIIO
R1
O
MnIIO
R1
O
R1
Y
Y
R2
Y
R2 MnII
R2
2, 5, 9 or 10
15
MnII
O
R1
O
Isolated yields for the a-halo-a,b-unsaturated esters 9 and
a-chloroacrylamides 10 are summarized in Table 4. It can
be observed that the synthesis of both 9 and 10 could be
carried out from a broad range of linear, branched, or cy-
clic aliphatic aldehydes. When aromatic aldehydes were
employed, a complex mixture of products was obtained,
except in the case of 4-methoxybenzaldehyde, in which
the corresponding ester 9h or amides 10k,l were obtained,
also with complete stereoselectivity (Table 4, entries 8,
24, 25).
H
R2
MnII
Y
C
Scheme 5 Proposed mechanism to explain the olefination reactions
of aldehydes 6
urated a-halo esters or a-chloroamides 9 or 10, respective-
ly.
To show the synthetic applications of esters 2 and 9 and
amides 5 or 10 we have reported some transformations of
these compounds into other relevant unsaturated com-
pounds.
Similarly to compounds 2 and 5, a-halo-a,b-unsaturated
esters 9 derived from hindered alcohols (Table 4, entries
2, 4, and 9) and a-chloroacrylamides 10 from hindered
amines (Table 4, entries 15, and 25) or morpholine were
available (Table 4, entries 16, 18, and 20). In our hands,
no sequential olefination reaction could be carried out em-
ploying ketones instead of aldehydes.
Transformation of Esters 9 and Amides 5 or 10 into
Unsaturated Ketones 16, Carboxylic Acids 17 or
Aldehydes 18 and Allylic Alcohols 19
Table 5 shows various a,b-unsaturated ketones or a-chlo-
ro-a,b-unsaturated ketones 16 which were obtained, in
very high yields (>77%), from amides derived from mor-
pholine 5 or 10. The reaction of compounds 5b,e,r, or
10e,c,g with organolithium compounds at –78 °C for 30
minutes afforded the corresponding ketones 16 in high
yields (Table 5).26 Three characteristics of this transfor-
mation are worth of mention: (a) The integrity of the C=C
bond was unaffected by this transformation. (b) Alkyl alk-
1-enyl ketones 16, in which R3 is an aliphatic group (such
as 16a,c,e,f,h)38 and chloromethyl ketones39 16d,g, are
difficult to prepare by other alternative methods. Remark-
ably, employing morpholine amides as starting materials
for the transformation of this class of compounds into ke-
tones, is more advantageous than using the corresponding
Weinreb derivatives as the morpholine derivatives are less
expensive.
Mechanism
Accordingly our sequential procedure for obtaining (E)-
a,b-unsaturated esters or amides and (Z)-a,b-unsaturated
a-halo esters or a-chloroamides with complete stereose-
lectivity could be rationalized and justified on the basis of
the following steps. Firstly, metalation of the dihalo or tri-
halo acid derivatives with Mn* takes place, affording the
corresponding halogenated manganese enolate 13, which
reacts with the aldehyde 6 to give the corresponding alco-
holate 14. In a second step, an elimination reaction, after
a second metalation of the alcoholate 14 by manganese,
occurs to afford 15. The complete stereoselectivity could
be then justified assuming a similar chelated transition
state to that previously proposed to explain the transfor-
mation of 1 into 2. Thus, we suggest that the chelation of
the manganese(II) center with the oxygen atom of the al-
coholate group generates a six-membered cyclic transi-
tion state C (Scheme 5). The elimination reaction takes
place on this intermediate, in the conformation in which
the substituents occupy an adequate position to obtain the
thermodynamically most stable chairlike transition state
structure. This concerted elimination process gives (E)-
a,b-unsaturated esters or amides 2 or 3, or (E)-a,b-unsat-
The unsaturated carboxylic acids 17 (Table 6) were also
prepared from either amides 5 or esters 9. In this case, the
treatment of the morpholine amides 5b,u, or the N,N-di-
ethylamide 5l, with potassium tert-butoxide in a mixture
of water–tetrahydrofuran40 at reflux afforded the corre-
sponding (E)-a,b-unsaturated carboxylic acids 17a–c in
nearly quantitative yields (92–97%) and without loss of
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

2642
J. M. Concellón et al.
FEATURE ARTICLE
O
Table 5 Synthesis of a,b-Unsaturated Ketones 16
O
LiAlH4
R1
N
O
O
R1
H
R3Li
–78 °C, THF, 12 h
R2
O
R2
R1
N
R1
R3
–78 °C, THF, 30 min
18a R1 = n-C7H15; R2 = H; 85%
18b R1 = Ph; R2 = H; 91%
18c R1 = Ph; R2 = Me; 93%
R2
O
R2
5b
5m
5u
5/10
16
Entry Substrate Product R1
R2
R3
Yielda
(%)
Scheme 6 Synthesis of a,b-unsaturated aldehydes 18
tion of the unsaturated morpholine-based amides 5 with
lithium aluminum hydride at low temperature (–78 °C).41
Compounds 18 were isolated in nearly quantitative yields
(>85%) and as a single E-diastereoisomer (Scheme 6).
1
2
3
4
5
6
7
8
5b
5e
16a
16b
16c
16d
16e
16f
n-C7H15
i-Bu
H
Me
Ph
98
94
89
H
5r
s-Bu
Me
Me
Cl
Cl
Cl
Cl
Bu
(Z)-Chloroallylic alcohols 19a and 19b were obtained in
high yields and without losing their stereochemical integ-
rity by reduction of a-chloroacrylates 9b and 9c with lith-
ium aluminum hydride at room temperature for 12 hours
(Scheme 7).
5r
s-Bu
CH2Cl 83
10c
10c
10e
10g
n-C7H15
n-C7H15
Cy
Me
Bu
97
90
16g
16h
CH2Cl 79
allyl 77
The diastereoisomeric purity of all compounds 16–19 was
1
determined by H NMR spectroscopy on the crude reac-
tion products.
i-Bu
a Isolated yield after column chromatography based on compounds 1;
all products were isolated with >98% de as determined by 1H NMR
and/or GC-MS on the crude materials.
O
LiAlH4
R1
OH
R1
OR2
r.t., THF, 12 h
Cl
Cl
9b
Table 6 Synthesis of a,b-Unsaturated Carboxylic Acids 17
19a R1 = n-C7H15; 80%
19b R1 = Cy; 83%
O
O
9c
different
R1
OH
R1
Y
conditions
Scheme 7 Synthesis of (Z)-haloallylic alcohols 19
R2
R2
5/9
17
Conclusion
Entry Substrate Product R1
R2
Y
Yielda
(%)
Novel synthetic applications of manganese, an inexpen-
sive and nontoxic metal, have been reported. Various
elimination reactions, all of them characterized by occur-
ring with complete stereoselectivity and in high yields,
were performed using active manganese (Mn*) as meta-
lating agent. This ability of manganese has been applied
in our laboratory to develop a novel and direct synthesis
of (E)-a,b-unsaturated esters 2 or amides 5 and (Z)-a,b-
unsaturated a-halo esters 9 and a-choroamides 10,
through a Mn*-mediated sequential olefination protocol
of aldehydes with dichloro esters or amides and trihalo es-
ters or trichloroamides, respectively. Taking into account,
on the one hand, the low price of manganese metal and its
low toxicity, and on the other, the fantastical stereochem-
ical outcome and the high yields obtained in manganese-
mediated transformations, these novel olefination pro-
cesses can certainly constitute the method of choice in the
preparation (E)-a,b-unsaturated esters 2 or amides 5 and
(Z)-a,b-unsaturated a-halo esters 9 and a-chloroamides
10. Moreover, we have demonstrated that the sequential
olefination reaction of aldehydes combined with other re-
actions constitutes an efficient access to (E)-a,b-unsatur-
ated ketones or carboxylic acids, (Z)-a-chloro-a,b-
unsaturated ketones or carboxylic acids, carboxylic acids,
(E)-a,b-unsaturated aldehydes or (Z)-haloallylic alcohols,
all of them in diastereopure form.
1
2
3
4
5
5b
5u
5l
17ab
17bb
17cb
17dc
17ec
n-C7H15
Ph
H
morpholino 92
morpholino 97
Me
H
Ph
NEt2
Oi-Pr
OEt
95
89
91
9d
9f
Cy
Cl
Cl
s-Bu
a Isolated yield after column chromatography based on compounds 1;
all products were isolated with >98% de as determined by 1H NMR
and/or GC-MS on the crude materials.
b Reaction conditions: t-BuOK, H2O, THF, reflux 12 h.
c Reaction conditions: KOH, MeOH, r.t., 12 h.
stereochemistry. These carboxylic acids were also isolat-
ed from the reaction of a-chloro esters 9d,f with potassi-
um hydroxide in methanol at room temperature for 12
hours. From this procedure (Z)-a,b-unsaturated a-chloro-
carboxylic acids 17d and 17e were obtained in 89% and
91% yields, respectively. All the acids 17a–e were ob-
tained in diastereopure form.
The a,b-unsaturated acid derivatives prepared could be
also reduced to the corresponding aldehydes or alcohols
without jeopardizing their stereochemistry. Accordingly,
a,b-unsaturated aldehydes 18a–c were obtained by reduc-
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Olefinations Promoted by Rieke Manganese
2643
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under an N2 or argon atmosphere using
standard vacuum-line techniques and glassware that was flame
dried and cooled under N2 before use. THF was distilled from Na/
benzophenone ketyl immediately prior to use. All other solvents
were used as supplied (analytical or HPLC grade) without prior pu-
rification. All reagents were purchased in the highest quality avail-
able and were used without further purification. Organic layers
were dried over Na2SO4. TLC was performed on aluminum plates
coated with 60 F254 silica. Plates were visualized using UV light
(254 nm), I2, 1% aq KMnO4, or 10% ethanolic phosphomolybdic
acid. Flash column chromatography was performed on Kieselgel 60
silica. NMR spectra were recorded in the deuterated solvent stated
and the field was locked by external referencing to the relevant deu-
terium resonance. 1H NMR spectra were recorded on spectrometers
at 300 or 400 MHz. 13C NMR spectra and DEPT experiments were
determined at 75 or 100 MHz. Unless otherwise noted NMR spectra
are recorded at r.t. Chemical shifts are given in ppm relative to
TMS, which is used as an internal standard. GC-MS and HRMS
were measured at 70 eV. Only the most important IR absorptions
and the molecular ions and/or base peaks in MS are given.
the combined organic extracts were washed sequentially with 3 M
HCl (2 × 10 mL), sat. NaHCO3 (2 × 20 mL), sat. Na2S2O3 (2 × 20
mL), and brine (2 × 20 mL) and dried (Na2SO4). Solvents were re-
moved in vacuo. Purification by flash column chromatography (sil-
ica gel, hexane–EtOAc, 3:1) provided pure compounds 5.
a-Halo-a,b-unsaturated Esters 9 or Amides 10; General Proce-
dure
The slurry of Mn* (8.5 mL, 2.5 mmol) in THF was added to a stirred
soln of the trihalo ester or amide (0.6 mmol) 11, or 12, respectively
and the corresponding aldehyde (0.5 mmol) in THF (2 mL) under
inert atmosphere. The mixture was heated at reflux for 5 h before it
was quenched with 3 M HCl. The organic material was extracted
with Et2O (3 × 20 mL), the combined organic extracts were washed
successively with 3 M HCl (2 × 10 mL), sat. NaHCO3 (2 × 20 mL),
and H2O (2 × 20 mL) and dried (Na2SO4). Solvents were removed
in vacuo. Purification by flash column chromatography (silica gel,
compounds 9: hexane–EtOAc, 10:1; compounds 10: hexane–
EtOAc, 3:1) provided pure compounds 9 and 10. In the particular
case of the synthesis of a-bromo or a-fluoro derivatives, instead at
reflux for 5 h, the reaction was carried out at r.t. for 12 h.
a,b-Unsaturated esters 2,13,14a and 9,15 amides 5,14b and 10,15 ketones
16,14b,15 carboxylic acids 17,14b,15b aldehydes 18,14b and a-haloallylic
alcohols 1915b have been fully characterized in the corresponding
references.
a-Halo-a,b-unsaturated Ketones 16; General Procedure
The requisite organolithium compound (3.0 mmol) was added drop-
wise to the corresponding morpholine amide 5 or 9 (1.0 mmol) in
THF (4 mL) at –78 °C. After stirring for 30 min the reaction was
quenched with aq sat. NH4Cl (10 mL), followed by extraction with
Et2O (3 × 10 mL). Usual workup provided crude products 16, which
were purified by flash column chromatography (silica gel, hexane–
EtOAc, 10:1).
a,b-Unsaturated Esters 2 Promoted by Mn/TMSCl; General
Procedure
A mixture of 1 (0.4 mmol, 1 equiv) in anhyd THF (2.5 mL), Mn
granules (325 mesh, 0.6 mmol, 1.5 equiv), and TMSCl (0.7 mmol,
1.75 equiv) was refluxed for 5 h. Then the mixture was quenched
with aq 0.1 M HCl (10 mL) and extracted with Et2O (3 × 10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo. The crude a,b-unsaturated esters were puri-
fied by flash column chromatography (silica gel, hexane–EtOAc,
10:1) provide pure compounds 2.
a,b-Unsaturated Acids 17; General Procedure
From amides 5: A slurry of t-BuOK (3.0 mmol), H2O (1.0 mmol),
and the corresponding a,b-unsaturated amide (0.5 mmol) in THF (4
mL) was stirred vigorously at reflux for 12 h. After that time, the
mixture was cooled with an ice bath and a mixture ice-water (10
mL) was added. The organic layer was separated and the aqueous
layer extracted with Et2O (2 × 10 mL). Usual workup provided
crude products 17, which were purified by flash column chromatog-
raphy (silica gel, hexane–EtOAc, 1:1).
Preparation of Highly Active Manganese (Mn*)
A mixture of Li (0.18 g, 26 mmol) and 2-phenylpyridine (0.98 mL,
4 mmol) in THF (20 mL) under N2 atmosphere was stirred for 1 h.
In a separate flask a soln of the complex Li2MnCl4 was prepared by
stirring a suspension of anhyd MnCl2 (1.62 g, 13 mmol) and LiCl
(1.10 g, 26 mmol) in THF (20 mL) for 30 min. Then, this yellow
soln was added at r.t. with a syringe to the 2-phenylpyridine/Li soln
previously prepared and was stirred, under an N2 atmosphere at r.t.
for 1 h. The black slurry was allowed to stir at r.t. for 3 h.
From esters 9: To a soln of the corresponding a,b-unsaturated ester
9 (1.0 mmol) in MeOH (2 mL) under an N2 atmosphere was added
KOH (3.0 mmol). After stirring the mixture at r.t. for 12 h the reac-
tion was quenched by the addition of 1 M HCl (5 mL). The organic
material was then extracted with Et2O (3 × 10 mL) and dried
(Na2SO4). Solvents were removed in vacuo. Purification by flash
column chromatography (silica gel, hexane–EtOAc, 1:1) afforded
pure compounds 17.
a,b-Unsaturated Esters 2 Promoted by Active Manganese; Gen-
eral Procedure
The slurry of Mn* (8.5 mL, 2.5 mmol) in THF was added to a stirred
soln of ethyl 1,1-dichloroacetate (0.08 g, 0.6 mmol) and the corre-
sponding aldehyde (0.5 mmol) in THF (2 mL) under an N2 atmo-
sphere. The mixture was refluxed for 3 h before it was quenched
with 3 M HCl. The organic material was extracted with Et2O (3 × 20
mL), the combined organic extracts were washed sequentially with
3 M HCl (2 × 10 mL), sat. NaHCO3 (2 × 20 mL), sat. Na2S2O3
(2 × 20 mL), and brine (2 × 20 mL) and dried (Na2SO4). Solvents
were removed in vacuo. Purification by flash column chromatogra-
phy (silica gel, hexane–EtOAc, 10:1) provided pure compounds 2.
a,b-Unsaturated Aldehydes 18; General Procedure
A 1.5 M soln of LiAlH4 in THF (1.0 mmol) was added dropwise to
a mixture of the corresponding morpholine amide 5 (1 mmol) in
THF (4 mL) at –78 °C. Then the mixture was stirred for 12 h and
quenched with an ice-water mixture (10 mL), followed by extrac-
tion with Et2O (2 × 10 mL). Usual workup provided crude products
18, which were purified by flash column chromatography (silica
gel, hexane–EtOAc, 10:1).
a-Haloallylic Alcohols 19; General Procedure
To a suspension of LiAlH4 (1.0 mmol) in THF was added dropwise
to the corresponding compound 9 (1.0 mmol) in THF (1 mL) at 0
°C. After stirring the mixture at r.t. for 12 h the reaction was
quenched by addition of a mixture of ice-water and extracted with
Et2O. The combined organic phases were dried (Na2SO4) and the
solvents were removed under reduced pressure. The crude products
19 were purified by flash column chromatography (silica gel, hex-
ane–EtOAc, 3:1).
a,b-Unsaturated Amides 5 Promoted by Active Manganese;
General Procedure
The slurry of Mn* (8.5 mL, 2.5 mmol) in THF was added to a stirred
soln of 1,1-dichloroacetamide (0.6 mmol) and the corresponding al-
dehyde (0.5 mmol) in THF (2 mL) under an inert atmosphere. The
mixture was heated at reflux for 5 h before it was quenched with 3
M HCl. The organic material was extracted with Et2O (3 × 20 mL),
Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York

2644
J. M. Concellón et al.
FEATURE ARTICLE
(13) Concellón, J. M.; Rodríguez-Solla, H.; del Amo, V. Synlett
2006, 315.
Acknowledgment
We acknowledge Ministerio de Ciencia e Innovación (MICINN
CTQ2007-61132) and Principado de Asturias (FICYT IB08-08) for
financial support. J.M.C. thanks his wife Carmen Fernández-Flórez
for her time. H.R.S. and P.D. thank MICINN for a Ramón y Cajal
Contract (Fondo Social Europeo), and Principado de Asturias
(FICYT) for a predoctoral fellowship, respectively.
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FEATURE ARTICLE
Stereoselective Olefinations Promoted by Rieke Manganese
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Synthesis 2009, No. 15, 2634–2645 © Thieme Stuttgart · New York