Stereoselective synthesis of (Z)-α-haloacrylic acid derivatives, and (Z)-haloallylic alcohols from aldehydes and trihaloesters or amides promoted by Rieke manganese

Article abstract of DOI:10.1039/b803449d

A Mn*-promoted sequential process directed toward the synthesis of (Z)-α-halo-α,β-unsaturated esters or amides is described. In both cases, the process takes place with complete Z-stereoselectivity. In addition, (Z)-α-chloro-α,β-unsaturated ketones and carboxylic acids, and (Z)-haloallylic alcohols were readily prepared from (Z)-α-halo-α,β-unsaturated amides derived from morpholine, or esters. A mechanism has been proposed to explain the sequential process and the stereoselectivity observed. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803449d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of (Z)-a-haloacrylic acid derivatives, and
(Z)-haloallylic alcohols from aldehydes and trihaloesters or amides promoted
by Rieke manganese†
Jose´ M. Concello´n,* Humberto Rodr´ıguez-Solla and Pamela D´ıaz
Received 28th February 2008, Accepted 16th May 2008
First published as an Advance Article on the web 18th June 2008
DOI: 10.1039/b803449d
A Mn*-promoted sequential process directed toward the synthesis of (Z)-a-halo-a,b-unsaturated esters
or amides is described. In both cases, the process takes place with complete Z-stereoselectivity. In
addition, (Z)-a-chloro-a,b-unsaturated ketones and carboxylic acids, and (Z)-haloallylic alcohols were
readily prepared from (Z)-a-halo-a,b-unsaturated amides derived from morpholine, or esters. A
mechanism has been proposed to explain the sequential process and the stereoselectivity observed.
with a,a-dihaloesters13 or amides,14 yielding (E)-a,b-unsaturated
Introduction
esters or amides, respectively. Very recently we communicated
(Z)-a-Halo-a,b-unsaturated acid derivatives are useful building
our first examples of the stereoselective synthesis of (Z)-a-halo-
a,b-unsaturated esters and amides.15 The good results reported
in this communication prompted us to study the generality and
drawbacks of this method. Thus, we report herein full studies
concerning the Mn*-promoted sequential process directed toward
the stereoselective synthesis of (Z)-a-halo-a,b-unsaturated esters
and amides, giving special attention to the generality and main
limitations of this process. A mechanism is proposed to explain the
experimental results obtained. Finally some synthetic applications
of the obtained (Z)-a-halo-a,b-unsaturated esters and amides are
demonstrated: the syntheses of various compounds, such as (Z)-
a,b-unsaturated a-halo ketones and carboxylic acids, and (Z)-
haloallylic alcohols are reported.
blocks from a synthetic point of view. These compounds have
been used as starting materials for the synthesis of important
organic compounds such as trisubstituted alkenes with complete
stereospecificity,1 a-aminoacids,2 a variety of heterocycles includ-
ing aziridines,2b,3 and natural or pharmaceutical products.4 These
compounds are also interesting since they can be employed as key
intermediates in the preparation of other functionalities, inter alia
(Z)-a-halo-a,b-unsaturated ketones5 and carboxylic acids,6 and
(Z)-haloallylic alcohols.7
The most important well-known methods of generating C–
C double bonds (Wittig, Horner-Wadsworth-Emmons, Julia or
Peterson olefination reactions) have been applied to the synthesis
of (Z)-a-halo-a,b-unsaturated acid derivatives.8 Nevertheless these
methods often present some of the following drawbacks: poor
yields, low stereoselectivity, lack of generality, the employment of
expensive reagents or tedious experimental work.
Results and discussion
Recently, the synthesis of (Z)-a-halo-a,b-unsaturated com-
pounds by the reaction of dihaloacid derivatives with aldehydes
Synthesis of (Z)-a-haloacrylates and a-chloroacrylamides
promoted by CrCl2,9 Fe,10 and SmI2 has been published.
11
The active manganese was readily prepared using the method de-
scribed by Cahiez et al.16 Thus, treatment of Li2MnCl4 (13 mmol)
(prepared from 1 equivalent of MnCl2 and 2 equivalents of LiCl)
with 26 mmol of lithium in the presence of catalytic amounts of
2-phenylpyridine (4 mmol) at room temperature for 3 h, afforded
active manganese cheaply as a black slurry.17
As part of our interest in the development of new selective
syntheses of unsaturated compounds, and motivated by our
studies on the synthetic applications of metalation reactions using
different active metals, we tested the possibility of using manganese
to perform 1,2-elimination processes.
To 5 equiv. of the black slurry of active manganese (Mn*), a
solution of 1 equiv. of the corresponding aldehyde 1 and 1.1 equiv.
of trichloroacetate 2 in THF was added and then stirred at reflux
for 5 h. After that time, the corresponding a,b-unsaturated a-
haloesters 3 were isolated with total stereoselectivity and in high
yields (Table 1).
The reaction showed general tolerance towards a variety of
substrates. Thus, linear, branched or cyclic aliphatic aldehydes gave
the corresponding 2-chloroalk-2-enoates 3 in high yields (>85%,
after purification by column chromatography) and with complete
Z-stereoselectivity as shown in Table 1 (entries 1–7). The process
was also tolerant of the presence of other double bonds in the
aliphatic chain, as demonstrated by the synthesis of compound
3g. Nevertheless, when aromatic aldehydes were used as starting
Although manganese has been scarcely used in organic syn-
thesis, it is cheaper and less toxic than other metals. Therefore,
we developed a novel and totally stereoselective b-elimination
reaction of 2-bromo-3-hydroxyesters promoted by the Mn–
TMSCl system to obtain (E)-a,b-unsaturated esters.12 More
recently our laboratory has demonstrated the utility of Rieke-
Mn (Mn*) to promote the sequential reaction of aldehydes
Dpto. de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad
de Oviedo, 33071 Oviedo, Spain. E-mail: jmcg@uniovi.es; Fax: +34 98 510
34 46; Tel: +34 98 510 34 57
† Electronic Supplementary Information (ESI) available: Copies of 1H
and 13C NMR spectra for all new compounds 3, 5 and 9–11. See DOI:
10.1039/b803449d
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Table 1 Synthesis of aliphatic (Z)-a,b-unsaturated a-haloesters 3
Table 2 Synthesis of (Z)-a,b-unsaturated a-chloroamides 5
Entry
3
R1
R2
Hal
Z : E
Yield (%)a
Entry
5
R1
R2
Et
Z : E
Yield (%)a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
n-C7H15
n-C7H15
Cy
Cy
i-Bu
s-Bu
CH2=CH(CH2)8
p-MeOC6H4
n-C7H15
Cy
i-Bu
Cy
Et
i-Pr
Et
i-Pr
Et
Et
Et
Et
Et
i-Pr
Et
Et
Et
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
F
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
89
88
95
89
92
85
87
48
71
74
69
64
62
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
n-C7H15
n-C7H15
n-C7H15
Cy
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
98 : 2
88
86
84
80
75
82
79
79
86
73
81
86
i-Pr
b
Et
b
Cy
i-Bu
Et
b
i-Bu
s-Bu
Et
Et
Et
Et
9
9
CH2=CH(CH2)8
Ph(CH3)CH
p-MeOC6H4
p-MeOC6H4
10
11
12
13
3j
3k
3l
10
11
12
5j
5k
5l
i-Pr
3m
s-Bu
F
a Yield of the isolated product after column chromatography based on
a Yield of the isolated product after column chromatography based on
compound 1.
compound 1. b Derived from morpholine.
obtained in high yield and with complete stereoselectivity (Table 2,
entries 11 and 12).
materials, a complex mixture of products was obtained and no
unsaturated compounds 3 or 5 were obtained except in the case of
p-methoxybenzaldehyde in which the corresponding unsaturated
ester 3 was obtained with complete stereoselectivity and in low
yield (Table 1, entry 8).
All attempts to access bromo- or fluoroacrylamides were
unsuccessful. Thus, under milder reaction conditions (room
temperature, 12 h), neither a-bromo- nor fluoroacrylamides were
obtained and a mixture of debrominated byproducts or a complex
mixture of compounds was afforded.
In contrast to other olefination methodologies such as the
Wittig reaction,18 it is noteworthy that no significant differences
were observed in the stereoselectivity and/or yield of this process
when hindered trihaloacetates 2 or trichloroacetamides 4 (Ta-
bles 1 and 2, respectively) were employed. Thus, no differences
were observed between the reactions of ethyl and isopropyl
trihaloacetates (Table 1, entries 1–2, 3–4 and 10) and ethyl and
isopropyl trichloroacetamides (Table 2, entries 1–2, and 11–12).19
In addition, acrylamides derived from morpholine were also
available (Table 2, entries 3, 5 and 7).
The Z : E ratios of compounds 3 and 5 were determined for
the crude reaction products by 1H NMR spectroscopy (300 MHz)
and/or GC-MS, showing the presence of single stereoisomers. The
Z-stereochemistry of the C–C double bond of both a-haloacrylates
3 and a-haloacrylamides 5 was established by NOESY experiments
in the case of compounds 3b, 3c, 3e, 3i–k, 3l, 5d, 5f, 5k, 5l and
by comparison with the NMR data previously described in the
literature for compound 3c.11 In the case of the fluoro derivatives
3l and 3m, the configuration was established based on the value of
1H NMR coupling constants between the olefinic proton and the
fluorine atom (3JHF = 34 and 33 Hz, for 3l and 3m respectively).20
The Z-configuration of the other compounds 3 or 5, different from
those mentioned above, was established by analogy.
When the same reaction conditions were used on trihaloacetates
other than trichloroacetate (tribromoacetate or dibromofluoroac-
etate), completely dehalogenated compounds 3 were obtained.
Nevertheless, when 5 equiv. of the black slurry of Mn*, 1 equiv. of
the corresponding aldehyde 1 and 1.1 equiv. of the corresponding
tribromo- or dibromofluoroacetate 2 in THF was stirred under
milder reaction conditions (room temperature, 12 h), bromo or
fluoro derivatives were obtained in an efficient manner. Thus,
the reaction of tribromo or dibromofluoroacetates with the
corresponding aldehyde afforded 2-bromoacrylates 3i–k (Table 1,
entries 9–11) or 2-fluoroacrylates 3l and 3m in good yields and
with complete Z-stereoselectivity (Table 1, entries 12 and 13).
When this reaction was carried out employing ketones instead of
aldehydes (acetophenone and 4-methyl-2-pentanone), no reaction
took place and only unreacted ketone and byproducts from
metalation of the trihaloesters or amides were isolated.
Based on the results of the syntheses of the (Z)-a-
chloroacrylates, we tested the performance of the same reaction
conditions in the synthesis of (Z)-a-chloroacrylamides. Hence,
compounds 5 were obtained after stirring 5 equiv. of the black
slurry of Mn*, 1 equiv. of the corresponding aldehyde 1 and
1.1 equiv. of the trichloroacetamide 4 in THF at reflux for 5 h.
The results are summarized in Table 2 and it can be observed
that the method is general. Thus, a range of amides derived
from aliphatic (linear, branched or cyclic, Table 2, entries 1–
8), functionalized (entry 9), and readily enolizable aldehydes
(entry 10) were obtained in high yields (ranging between 73–
88%) and with complete Z-stereoselectivity (Table 2). When
aromatic aldehydes were used as starting materials, the results
obtained were similar to those observed in the synthesis of the
esters. So, no acrylamides were obtained except in the case of p-
methoxybenzaldehyde in which the corresponding product 5 was
Mechanism
To rationalize the synthesis of compounds 3 or 5, we propose
a similar mechanism to that previously used to explain the
preparation of a,b-unsaturated esters13 or amides14 through a
sequential reaction promoted by Mn* (Scheme 1). Thus, a
sequential reaction is proposed to explain the formation of
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Table 3 Synthesis of (Z)-a,b-unsaturated a-chloroketones 9
Entry
5
9
R1
R3
Z : E
Yield (%)a
1
2
3
4
5c
5c
5e
5g
9a
9b
9c
9d
n-C7H15
n-C7H15
Cy
Me
n-Bu
CH2Cl
CH2CH CH2
98 : 2
98 : 2
98 : 2
98 : 2
97
90
79
77
=
i-Bu
a Yield of the isolated product after column chromatography based on the
corresponding compound 5.
The Z-configuration of the alkene function was established by
a NOESY experiment, with a nuclear Overhauser effect being
observed between the olefinic proton and n-PrCH2 on ketone
9b. This assignment allowed indirect determination of the Z-
configuration of the starting unsaturated amide 5c, which could
not be established directly by a NOESY experiment.
The synthesis of alkyl alk-1-enyl ketones, 9 (R3 = aliphatic) by
other alternative methods is difficult to achieve,24 and it is worth
mentioning the synthesis of the chlorinated ketone 9c, by reaction
with chloromethyllithium generated in situ.25 Remarkably, the use
of morpholine amides as starting materials, to transform amides
derived from morpholine into ketones, is more advantageous than
using the corresponding Weinreb derivatives since the morpholine
derivatives are cheaper.
(Z)-a-Chloro-a,b-unsaturated carboxylic acids 10a and 10b can
be obtained by basic hydrolysis of the a-chloroacrylates 3d and
3f respectively, with potassium hydroxide in methanol at room
temperature for 12 h. Compounds 10 were obtained in high yield
(>89%) and as single Z-stereoisomers (1H NMR of the crude
reaction products). No important differences in the yields of the
acids obtained were observed when different (ethyl or isopropyl)
esters 3 were employed as starting compounds (Scheme 2).
Scheme 1 Proposed mechanism.
products 3 or 5. In the first stage an aldolic reaction between the
enolate obtained by the metalation of trihaloesters 2 or amides
4 took place. The Reformatsky adduct 7 was metalated by Mn*
to give the organomanganese intermediate 8 which undergoes a
spontaneous b-elimination affording the unsaturated ester 3 or
amide 5. The complete Z-stereoselectivity of this process can be
explained by assuming the transition state I, which is generated
as a consequence of the coordination between the manganese(II)
and the oxygen atom of the alcoholate group in the enolate
8.21 In this chair-like transition state the R1 group occupies
a pseudoequatorial position to reduce the 1,3-steric hindrance.
Elimination through this transition state I, such as that depicted
in 8, would afford the Z-stereoisomer. Indirect support for this
mechanism was given by the isolation of the corresponding 2,2-
dichloro-3-hydroxyester or amide, (obtained by hydrolysis of the
intermediates 7) from the crude reaction during the synthesis of
compounds 3d and 5c.22 When these isolated intermediates 7 were
treated with 2.5 equiv. of Mn*, compounds 3d and 5c were also
stereoselectively obtained.
Synthetic applications of (Z)-a-haloacrylates 3 and
a-chloroacrylamides 5
To demonstrate the synthetic applications of the a-haloacrylates
and a-chloroacrylamides obtained, selected examples were readily
transformed into various unsaturated compounds, such as (Z)-
a-chloro-a,b-unsaturated ketones 9 and carboxylic acids 10, and
(Z)-haloallylic alcohols 11.
Scheme 2 Synthesis of (Z)-a,b-unsaturated-a-chlorocarboxylic acids 10.
Finally the treatment of a-chloroacrylates 3b and 3c with lithium
aluminium hydride at room temperature for 12 h afforded the
corresponding (Z)-haloallylic alcohols 11a and 11b (Scheme 3)
in high yield and without loss of the diastereoisomeric purity
(1H NMR of the crude reaction products). Again, no differences
As has been reported,23 amides derived from morpholine
(Table 2, entries 3, 5, and 7) are especially useful. Thus, the
reaction of different (Z)-a,b-unsaturated a-haloamides derived
from morpholine 5 with various organolithium compounds at
−78 ◦C for 30 min afforded the corresponding unsaturated ketones
9 in high yields (>77%) (Table 3).
The transformation seems to be general and a range of
morpholine-based unsaturated amides and organolithium com-
pounds can be used. It is noteworthy that the integrity of the C–C
double bond was unaffected under the reaction conditions used to
perform this transformation, with the ketone being obtained as a
single Z-stereoisomer (1H NMR of the crude reaction products).
Scheme 3 Synthesis of (Z)-chloroallylic alcohols 11.
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were observed when this transformation was performed using the
different ethyl or isopropyl a-chloroacrylates.
The mixture was heated at reflux for 5 h before it was quenched
with HCl 3 M. The organic material was extracted with diethyl
ether (3 × 20 mL), the combined organic extracts were washed
successively with HCl 3 M (2 × 10 mL), saturated NaHCO3
(2 × 20 mL), and water (2 × 20 mL) and dried over Na2SO4.
Solvents were removed in vacuo. Purification by flash column
chromatography on silica gel (compounds 3: hexane–EtOAc 10 :
1; compounds 5: hexane–EtOAc 3 :1) provided pure compounds
3 and 5. In the particular case of the synthesis of a-bromo or
a-fluoro derivatives, instead of refluxing for 5 h the reaction was
carried out at room temperature for 12 h.
Conclusion
In conclusion, a simple, straightforward and general sequential
method has been developed to synthesize a,b-unsaturated a-
haloesters (bromo, chloro, and fluoro) 3 and a-chloroamides 5 with
total Z-stereoselectivity, through a sequential process promoted by
the non-toxic and cheap Mn*. This reported synthesis of (Z)-a-
halo-a,b-unsaturated esters or amides, combined with their trans-
formation into different halounsaturated compounds, constitutes
easy and efficient access to (Z)-a-chloro-a,b-unsaturated ketones
and carboxylic acids, and (Z)-haloallylic alcohols.
Ethyl (Z)-2-chlorodec-2-enoate (3a). 1H NMR (300 MHz,
CDCl3): d 7.08 (t, J = 6.8 Hz, 1 H), 4.29 (q, J = 7.0 Hz, 2 H),
2.42–2.32 (m, 2 H), 1.69–1.48 (m, 2 H), 1.37–1.24 (m, 11 H), 0.89
(t, J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d 162.8 (C),
142.8 (CH), 125.9 (C), 63.0 (CH2), 32.6 (CH2), 30.3 (CH2), 30.2
(CH2), 29.9 (CH2), 28.6 (CH2), 23.5 (CH2), 15.3 (CH3), 14.9 (CH3);
MS (70 eV, EI) m/z (%) 232 [M+, 5], 137 (32), 135 (100), 122 (58),
107 (73); HRMS (70 eV) calc. for C12H21ClO2 232.1230, found
232.1227; IR (neat): m 2928, 1750, 1267 cm−1; Rf = 0.5 (hexane :
EtOAc 10:1).
Experimental
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum-line techniques and glassware that was
flame dried and cooled under nitrogen before use. THF was
distilled from sodium–benzophenone ketyl immediately prior to
use. All other solvents were used as supplied (analytical or HPLC
grade) without prior purification. All reagents were purchased
in the highest quality available and were used without further
purification. Organic layers were dried over Na2SO4. Thin layer
chromatography was performed on aluminium plates coated with
60 F254 silica. Plates were visualized using UV light (254 nm),
iodine, 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 deuteron 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 were recorded at room temperature. Chemical
shifts are given in ppm relative to tetramethylsilane (TMS), which
was used as an internal standard. GC-MS and HRMS were
measured at 70 eV. Only the most important IR absorptions
(in cm−1) and the molecular ions and/or base peaks in the MS
are given.
Isopropyl (Z)-2-chloro-3-cyclohexylacrylate (3d). 1H NMR
(400 MHz, CDCl3): d 6.86 (d, J = 9.3 Hz, 1 H), 5.18–5.02 (m,
1 H), 2.69–2.52 (m, 1 H), 1.81–1.72 (m, 2 H), 1.39–1.18 (m, 8 H),
1.31 (d, J = 6.4 Hz, 6 H); 13C NMR (100 MHz, CDCl3): d 162.3
(C), 146.3 (CH), 123.2 (C), 69.8 (CH), 38.5 (CH), 30.9 (2 × CH2),
25.7 (CH2), 25.3 (2 × CH2), 21.7 (2 × CH3); MS (70 eV, EI) m/z
(%) 230 [M+, 2], 188 (64), 82 (100), 67 (66), 55 (16); HRMS (70 eV)
calc. for C12H19ClO2 230.1074, found 230.1084; IR (neat): m 2982,
1729, 1628, 1145 cm−1; Rf = 0.39 (hexane : EtOAc 20 : 1).
Ethyl (Z)-2-chloro-4-methylhex-2-enoate (3f). 1H NMR
(300 MHz, CDCl3): d 6.87 (d, J = 9.6 Hz, 1 H), 4.29 (q, J =
7.1 Hz, 2 H), 2.87–2.59 (m, 1 H), 1.49–1.33 (m, 2 H), 1.23 (t, J =
7.0 Hz, 3 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.91 (t, J = 7.4 Hz, 3 H); 13
C
NMR (75 MHz, CDCl3): d 163.9 (C), 147.4 (CH), 130.6 (C), 62.1
(CH2), 35.9 (CH), 28.9 (CH2), 18.6 (CH3), 14.1 (CH3), 11.6 (CH3);
MS (70 eV, EI) m/z (%) 190 [M+, 8], 225 (36), 179 (28), 69 (100);
HRMS (70 eV) calc. for C9H15ClO2 190.0761, found 190.0769; IR
(neat): m 3415, 1645, 1263 cm−1; Rf = 0.37 (hexane : EtOAc 10 : 1).
Ethyl (Z)-2-chlorotrideca-2,12-dienoate (3g). 1H NMR
(300 MHz, CDCl3): d 7.07 (t, J = 7.5 Hz, 1 H), 5.97–5.74 (m,
1 H), 5.04–4.93 (m, 2 H), 4.14 (q, J = 6.9 Hz, 2 H), 2.43–2.24 (m,
2 H), 2.10–2.00 (m, 2 H), 1.70–1.55 (m, 2 H), 1.44–1.25 (m, 13 H);
13C NMR (75 MHz, CDCl3): d 161.7 (C), 142.4 (C), 139.1 (CH),
126.7 (CH), 114.1 (CH2), 60.1 (CH2), 33.7 (CH2), 29.3 (CH2),
29.2 (CH2), 29.1 (CH2), 29.0 (CH2), 28.8 (CH2), 28.6 (CH2), 24.9
(CH2), 14.2 (CH3); MS (70 eV, EI) m/z (%) 272 [M+, 8], 135 (100),
107 (66), 69 (86); HRMS (70 eV) calc. for C15H25ClO2 272.1543,
found 272.1524; IR (neat): m 2928, 2853, 1737, 1641 cm−1; Rf =
0.42 (hexane : EtOAc 10 : 1).
General procedure for the preparation of Rieke-manganese.
A
mixture of lithium (26 mmol) and 2-phenylpyridine (4 mmol)
in THF (20 mL) under a nitrogen atmosphere was stirred for
1h. In a separate flask a solution of the Li2MnCl4 complex was
prepared by stirring a suspension of anhydrous MnCl2 (13 mmol)
and LiCl (26 mmol) in THF (20 mL) for 30 min. Then, this yellow
solution was added at room temperature with a syringe to the
2-phenylpyridine–lithium solution previously prepared, and was
stirred under a nitrogen atmosphere at room temperature for 1 h.
The black slurry was allowed to stir at room temperature for 3 h.
Ethyl (Z)-2-chloro-3-(4-methoxyphenyl)acrylate (3h). 1H
NMR (300 MHz, CDCl3): d 7.89 (d, J = 8.6 Hz, 2 H), 7.89 (s,
1 H), 6.96 (d, J = 8.7 Hz, 2 H), 4.36 (q, J = 7.1 Hz, 2 H), 3.90
(s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3):
d 163.7 (C), 161.6 (C), 136.4 (CH), 132.6 (2 × CH), 130.2 (C),
126.9 (C), 113.9 (2 × CH), 62.3 (CH2), 55.3 (CH3), 14.2 (CH3);
General procedure for the synthesis of a-halo-a,b-unsaturated
esters 3 or amides 5. The slurry of Mn* (2.5 mmol, 8.5 mL)
in THF was added to a stirred solution of the trihaloester or
amide (0.6 mmol) 2, or 4, respectively and the corresponding
aldehyde (0.5 mmol) 1 in THF (2 mL) under an inert atmosphere.
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MS (70 eV, EI) m/z (%) 240 [M+, 100], 177 (20), 132 (70), 89 (10);
HRMS (70 eV) calc. for C12H13ClO3 240.0553, found 240.0505;
IR (neat): m 3055, 1717, 1603, 738 cm−1; Rf = 0.32 (hexane :
EtOAc 10 : 1).
4-[(Z)-(1-Chlorocyclohex-1-en-1-yl)carbonyl]morpholine (5e).
1H NMR (300 MHz, CDCl3): d 5.86 (d, J = 9.0 Hz, 1 H),
3.72–3.60 (m, 4 H), 3.54–3.44 (m, 4 H), 1.91–1.81 (m, 1 H),
1.71–1.60 (m, 2 H), 1.33–1.11 (m, 4 H), 1.03–0.91 (m, 4 H); 13C
NMR (75 MHz, CDCl3): d 165.1 (C), 137.8 (CH), 122.4 (C),
66.6 (CH2), 66.4 (CH2), 47.4 (CH2), 45.9 (CH2), 41.6 (CH), 32.9
(4 × CH2), 25.7 (CH2); MS (70 eV, EI) m/z (%) 257 [M+, 14],
135 (26), 86 (50), 56 (88), 41 (100); HRMS (70 eV) calc. for
C13H20ClNO2 257.1183, found 257.1139; IR (neat): m 2926, 1712,
1642, 1448 cm−1; Rf = 0.57 (hexane : EtOAc 10 : 1).
Isopropyl (Z)-2-bromo-3-cyclohexylacrylate (3j). 1H NMR
(400 MHz, CDCl3): d 7.04 (d, J = 7.8 Hz, 1 H), 5.17–5.09 (m,
1 H), 2.60–2.51 (m, 1 H), 1.75–1.66 (m, 2 H), 1.37 (d, J = 6.0 Hz,
6 H), 1.35–1.14 (m, 8 H); 13C NMR (100 MHz, CDCl3): d 162.0
(C), 149.7 (CH), 114.6 (C), 70.0 (CH), 40.9 (CH), 30.5 (2 × CH2),
25.6 (CH2), 25.1 (2 × CH2), 21.5 (CH3), 21.3 (CH3); MS (70 eV,
EI) m/z (%) 274 [M+, <1], 225 (42), 183 (100), 165 (68), 101 (27);
HRMS (70 eV) calc. for C12H19BrO2 274.0568, found 274.0659;
IR (neat): m 2929, 1726, 1450, 1264 cm−1; Rf = 0.62 (cyclohexane :
EtOAc 30 : 1).
4-[(Z)-(1-Chloro-4-methylpent-1-en-1-yl)carbonyl]morpholine
(5g). 1H NMR (400 MHz, CDCl3): d 6.07 (t, J = 7.4 Hz, 1 H),
3.72–3.53 (m, 8 H), 2.14 (apparent t, J = 7.2 Hz, 2 H), 1.78–1.68
(m, 1 H), 0.89 (d, J = 6.6 Hz, 6 H); 13C NMR (100 MHz, CDCl3,
233 K): d 165.0 (C), 132.5 (CH), 124.3 (C), 66.5 (CH2), 66.3 (CH2),
47.2 (CH), 42.1 (CH2), 36.7 (CH2), 27.6 (CH2), 22.3 (2 × CH3);
MS (70 eV, EI) m/z (%) 231 [M+, 20], 216 (32), 196 (36), 174 (86),
86 (100); HRMS (70 eV) calc. for C11H18ClNO2 231.1020, found
231.1021; IR (neat): m 2959, 1641, 1439, 1116 cm−1; Rf = 0.25
(hexane : EtOAc 3 : 1).
Ethyl (Z)-2-bromo-5-methylhex-2-enoate (3k). 1H NMR
(300 MHz, CDCl3): d 6.77 (t, J = 7.5 Hz, 1 H), 4.24 (q, J =
7.2 Hz, 2 H), 2.22–2.02 (m, 1 H), 1.87–1.72 (m, 2 H), 1.33 (t, J =
7.2 Hz, 3 H), 0.97 (d, J = 5.7 Hz, 3 H), 0.95 (d, J = 5.6 Hz, 3 H);
13C NMR (100 MHz, CDCl3): d 167.6 (C), 142.2 (CH), 134.0 (C),
60.5 (CH2), 42.5 (CH2), 28.3 (CH), 22.6 (CH3), 22.4 (CH3), 14.1
(CH3); MS (70 eV, EI) m/z (%) 205 [M+ − Et, 10], 139 (77), 118
(72), 69 (100), 55 (32); HRMS (70 eV) calc. for [C9H15BrO2 – Et]
204.9864, found 204.9888; IR (neat): m 2995, 1745, 1472 cm−1; Rf =
0.55 (cyclohexane : EtOAc 30 : 1).
(Z)-2-Chloro-N,N-diethyl-4-methylhex-2-enamide (5h). 1H
NMR (300 MHz, CDCl3): d 5.73 (d, J = 9.4 Hz, 1 H), 3.41 (q, J =
7.1 Hz, 4 H), 2.71–2.61 (m, 1 H), 1.48–1.39 (m, 2 H), 1.19 (t, J =
7.1 Hz, 6 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.93 (t, J = 7.4 Hz, 3 H);
13C NMR (100 MHz, CDCl3, 233 K): d 164.1 (C), 136.0 (CH),
123.8 (C), 42.9 (CH2), 39.1 (CH2), 34.6 (CH), 29.1 (CH2), 19.2
(CH3), 14.0 (CH3), 12.4 (CH3), 11.9 (CH3); MS (70 eV, EI) m/z
(%) 217 [M+, 50], 182 (99), 160 (100), 145 (68); HRMS (70 eV)
calc. for C11H20ClNO 217.1233, found 217.1222; IR (neat): m
3511, 2949, 1643, 1458 cm−1; Rf = 0.41 (hexane : EtOAc 3 : 1).
Ethyl
(Z)-2-fluorocyclohexyl-2-enoate
(3l). 1H
NMR
(400 MHz, CDCl3): d 6.01 (dd, J = 34.2, 9.6 Hz, 1 H),
4.43 (q, J = 6.8 Hz, 2 H), 2.61–2.53 (m, 1 H), 1.94–1.84 (m, 2 H),
1.74–1.63 (m, 4 H), 1.41 (t, J = 6.8 Hz, 3 H), 1.34–1.11 (m, 4 H);
13C NMR (100 MHz, CDCl3): d 161.9 (C), 146.5 (d, J = 253.5 Hz,
C), 125.5 (d, J = 11.7 Hz, CH), 64.7 (CH2), 33.9 (CH), 31.9 (2 ×
CH2), 25.7 (CH2), 25.3 (2 × CH2), 13.6 (CH3); MS (70 eV, EI)
m/z (%) 200 [M+, 28], 81 (100), 67 (83), 55 (59); HRMS (70 eV)
calc. for C11H17FO2 200.1213, found 200.1223; IR (neat): m 1729,
1265, 740 cm−1; Rf = 0.20 (hexane : EtOAc 20 : 1).
(Z)-2-Chloro-N,N-diethyldec-2-enamide (5a). 1H NMR
(400 MHz, CDCl3): d 5.96 (t, J = 7.1 Hz, 1 H), 3.41–3.33 (m,
4 H), 2.24 (apparent q, J = 7.2 Hz, 2 H), 1.41–1.39 (m, 2 H),
1.25–1.15 (m, 8 H), 1.19 (t, J = 7.1 Hz, 3 H), 1.15 (t, J = 7.1 Hz,
3 H), 0.85 (t, J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3,
233 K): d 165.8 (C), 131.0 (CH), 124.3 (C), 42.8 (CH2), 38.8
(CH2), 31.7 (2 × CH2), 29.1 (CH2), 27.8 (CH2), 22.6 (2 × CH2),
14.2 (CH3), 13.9 (CH3), 12.3 (CH3); MS (70 eV, EI) m/z (%) 259
[M+, 15], 224 (100), 187 (32), 160 (79); HRMS (70 eV) calc. for
C14H26ClNO 259.1703, found 259.1727; IR (neat): m 3451, 2974,
1642, 1460 cm−1; Rf = 0.52 (hexane : EtOAc 3 : 1).
(Z)-2-Chloro-N,N-diisopropyldec-2-enamide (5b). 1H NMR
(400 MHz, CDCl3, 233 K): d 5.81 (t, J = 7.2 Hz, 1 H), 4.02–
3.95 (m, 1 H), 3.80–3.40 (m, 1 H), 2.11 (apparent q, J = 6.8 Hz,
2 H), 1.40–1.09 (m, 10 H), 1.30 (d, J = 5.8 Hz, 6 H), 1.17 (d, J =
6.0 Hz, 6 H), 0.81 (m, 3 H); 13C NMR (100 MHz, CDCl3, 233
K): d 165.4 (C), 129.3 (CH), 126.7 (C), 48.0 (CH), 44.2 (CH), 31.6
(CH2), 29.5 (CH2), 29.0 (CH2), 28.8 (CH2), 22.5 (CH2), 20.5 (2 ×
CH3), 20.2 (CH2), 20.0 (2 × CH3), 13.9 (CH3); MS (70 eV, EI)
m/z (%) 287 [M+, 8], 252 (100), 201 (41); HRMS (70 eV) calc. for
C16H30ClNO 287.2016, found 287.2025; IR (neat): m 3444, 2927,
1643, 1431 cm−1; Rf = 0.55 (hexane : EtOAc 10 : 1).
(Z)-2-Chloro-N,N-diethyltrideca-2,12-dienamide
(5i). 1H
NMR (400 MHz, CDCl3): d 5.94 (t, J = 7.1 Hz, 1 H), 5.84–5.75
(m, 1 H), 5.01–4.89 (m, 2 H), 3.42–3.30 (m, 4 H), 2.25–2.20 (m,
2 H), 2.04–1.96 (m, 2 H), 1.42–1.10 (m, 12 H), 1.17 (t, J = 6.9 Hz,
3 H), 1.13 (t, J = 7.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3, 233
K): d 166.2 (C), 139.8 (CH), 131.3 (CH), 124.7 (C), 114.4 (CH2),
43.2 (CH2), 39.2 (CH2), 34.2 (CH2), 29.8 (CH2), 29.7 (CH2), 29.5
(CH2), 29.4 (CH2), 29.0 (CH2), 28.3 (2 × CH2), 14.3 (CH3), 12.7
(CH3); MS (70 eV, EI) m/z (%) 299 [M+, 6], 264 (100), 160 (94),
41 (72); HRMS (70 eV) calc. for C17H30ClNO 299.2016, found
299.2022; IR (neat): m 3440, 2927, 1659, 1462 cm−1; Rf = 0.42
(hexane : EtOAc 3 : 1).
(Z)-2-Chloro-N,N-diethyl-4-phenylpent-2-enamide
(5j). 1H
NMR (400 MHz, CDCl3, 233 K): d 7.42–7.10 (m, 5 H), 5.94
(d, J = 9.2 Hz, 1 H), 3.93–3.84 (m, 1 H), 3.28–3.19 (m, 2 H),
3.15–3.06 (m, 2 H), 1.29 (d, J = 6.8 Hz, 3 H), 0.98 (t, J = 6.8 Hz,
3 H), 0.96 (t, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3, 233
K): d 165.2 (C), 143.1 (C), 134.4 (CH), 128.4 (2 × CH), 127.2 (C),
126.5 (2 × CH), 123.0 (CH), 42.7 (CH), 38.9 (CH2), 38.0 (CH2),
20.2 (CH3), 13.6 (CH3), 12.1 (CH3); MS (70 eV, EI) m/z (%) 265
[M+, 47], 230 (100), 158 (98), 129 (89), 72 (71); HRMS (70 eV)
calc. for C15H20ClNO 265.1233, found 265.1191; IR (neat): m
3425, 1615, 1451, 701cm−1; Rf = 0.35 (hexane : EtOAc 3 : 1).
General procedure for the synthesis of a-halo-a,b-unsaturated
ketones 9. The requisite organolithium compound (3.0 mmol)
was added dropwise to the corresponding morpholine amide 3
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(1.0 mmol) in THF (4 mL) at −78◦C. After stirring for 30 min
the reaction was quenched with an aqueous saturated solution of
NH4Cl (10 mL), followed by extraction with diethyl ether (3 ×
10 mL). The usual workup provided crude products 9, which were
purified by flash column chromatography on silica gel (hexane :
EtOAc 10 : 1).
pressure. The crude products 11 were purified by flash column
chromatography on silica gel (hexane : EtOAc 3 : 1).
Compound 11a has been previously described.26
(Z)-2-Chloro-3-cyclohexylprop-2-en-1-ol (11b). 1H NMR
(300 MHz, CDCl3): d 5.64 (d, J = 9.0 Hz, 1 H), 4.17 (s, 2 H),
2.54–2.44 (m, 1 H), 2.08 (br s, 1 H), 1.82–1.52 (m, 6 H), 1.35–1.16
(m, 4 H); 13C NMR (75 MHz, CDCl3): d 132.5 (CH), 131.1 (C),
67.4 (CH2), 34.3 (CH), 33.6 (2 × CH2), 32.1 (2 × CH2), 31.8
(CH2); MS (70 eV, EI) m/z (%) 174 [M+, 4], 159 (59), 123 (100), 81
(85), 55 (55); HRMS (70 eV) calc. for C9H15ClO 174.0811, found
174.0817; IR (neat): m 3357, 2924, 1449 cm−1; Rf = 0.46 (hexane :
EtOAc 5 : 1).
(Z)-1,3-Dichloro-4-cyclohexylbut-3-en-2-one (9c). 1H NMR
(300 MHz, CDCl3): d 6.92 (d, J = 9.3 Hz, 1 H), 4.56 (s, 2 H),
2.71–2.59 (m, 1 H), 1.79–1.59 (m, 4 H), 1.43–1.17 (m, 6 H); 13C
NMR (75 MHz, CDCl3): d 186.4 (C), 147.5 (CH), 128.2 (C), 46.4
(CH2), 38.6 (CH), 30.7 (2 × CH2), 25.6 (CH2), 25.1 (2 × CH2);
MS (70 eV, EI) m/z (%) 220 [M+, 18], 151 (10), 89 (15), 81 (100);
HRMS (70 eV) calc. for C10H14Cl2O 220.0422, found 220.0413; IR
(neat): m 2932, 1711, 1266, 739 cm−1; Rf = 0.22 (hexane : EtOAc
20 : 1).
Acknowledgements
We acknowledge MEC (CTQ2007-61132) for financial sup-
port. J.M.C. thanks his wife Carmen Ferna´ndez-Flo´rez for her
time. H.R.S. and P.D. thank MEC for a Ramo´n y Cajal Con-
tract and Principado the Asturias for a predoctoral fellowship,
respectively. Our thanks to Euan C. Goddard (CRL, University
of Oxford) for his revision of the English.
(Z)-5-Chloro-8-methylnona-1,5-dien-4-one (9d). 1H NMR
(300 MHz, CDCl3): d 7.02 (t, J = 7.2 Hz, 1 H), 6.05–5.91 (m,
1 H), 5.25–5.15 (m, 2 H), 3.56 (d, J = 7.2 Hz, 2 H), 2.31 (apparent
t, J = 7.2 Hz, 2 H), 1.92–1.82 (m, 1 H), 0.98 (d, J = 6.9 Hz, 6 H);
13C NMR (75 MHz, CDCl3): d 192.3 (C), 140.6 (CH), 133.3 (C),
130.4 (CH), 118.9 (CH2), 43.4 (CH), 38.4 (CH2), 27.9 (CH2), 22.4
(2 × CH3); IR (neat): m 3055, 1726, 1266, 739 cm−1; Rf = 0.42
(hexane : EtOAc 10 : 1).
Notes and references
1 (a) F.-L. Quing and X. Zhang, Tetrahedron Lett., 2001, 42, 5029–
5032; (b) K. Tanaka and S. Katsumura, Org. Lett., 2000, 2, 373–375;
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Synlett, 1998, 198–200; (e) T. Rossi, F. Bellina, C. Bechini, L. Mannina
and P. Vergamini, Tetrahedron, 1998, 54, 135–156.
2 (a) M.-Y. Chang, P.-P. Sun, S.-T. Chen and N.-C. Chang, Tetrahedron
Lett., 2003, 44, 5271–5273; (b) S. N. Filigheddu and M. Taddei,
Tetrahedron Lett., 2002, 43, 3857–3860.
3 (a) H. Dollt and V. Zabel, Aust. J. Chem., 1999, 52, 259–270; (b) A.
Kakehi and S. Ito, J. Org. Chem., 1974, 39, 1542–1545.
4 E. Mironiuk-Puchalska, E. Kołaczkowska and W. Sas, Tetrahedron
Lett., 2002, 43, 8351–8354.
5 (a) L. C. Larock, Comprehensive Organic Transformations, Wiley-VCH,
New York, 2nd edn, 1999, p. 715; (b) C. R. Johnson and M. P. Braun,
J. Am. Chem. Soc., 1993, 115, 11014–11015; (c) C. R. Johnson, L. S.
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7738.
6 (a) W. Li, J. Li, Z.-K. Wan, J. Wu and W. Massefski, Org. Lett., 2007,
9, 4607–4610; (b) F. Effenberger and G. Zoller, Tetrahedron, 1988, 44,
5573–5582.
7 Y. Oda, S. Matsuo and K. Saito, Tetrahedron Lett., 1992, 33, 97–100.
8 The most important methods to prepare a,b-unsaturated haloesters are
reported in references 6a, and 9.
9 (a) D. K. Barma, A. Kundu, H. Zhang, C. Mioskowski and J. R.
Falck, J. Am. Chem. Soc., 2003, 125, 3218–3219; (b) J. R. Falck, A.
Bandyopadhyay, D. K. Barma, D.-S. Shin, A. Kundu and R. V. Krishna
Kishore, Tetrahedron Lett., 2004, 45, 3039–3042.
10 J. R. Falck, R. Bejot, D. K. Barma, A. Bandyopadhyay, S. Joseph and
C. Mioskowski, J. Org. Chem., 2006, 71, 8178–8182.
11 J. M. Concello´n, M. Huerta and R. Llavona, Tetrahedron Lett., 2004,
45, 4665–4667.
General procedure for the synthesis of a-halo-a,b-unsaturated
acids 10. To a solution of the corresponding compound 3
(1.0 mmol) in MeOH (2 mL) under a nitrogen atmosphere was
added KOH (3.0 mmol). After stirring the mixture for 12 h at
room temperature the reaction was quenched by the addition of
HCl 1M (5 mL). The organic material was then extracted with
diethyl ether (3 × 10 mL) and dried over Na2SO4. Solvents were
removed in vacuo. Purification by flash column chromatography
on silica gel (hexane : EtOAc 1 : 1) afforded pure compounds 10.
(Z)-2-Chloro-3-cyclohexylacrylic acid (10a). 1H NMR
(300 MHz, CDCl3): d 7.26 (br s, 1 H), 7.07 (d, J = 9.3 Hz, 1 H),
2.66 (m, 1 H), 1.79–1.66 (m, 4 H), 1.43–1.15 (m, 6 H); 13C NMR
(75 MHz, CDCl3): d 167.6 (C), 149.8 (CH), 122.0 (C), 38.8 (CH),
30.7 (2 × CH2), 25.7 (CH2), 25.2 (2 × CH2); MS (70 eV, EI) m/z
(%) 188 [M+, 11], 107 (17), 82 (100), 67 (74), 41 (22); HRMS
(70 eV) calc. for C9H13ClO2 188.0604, found 188.0608; IR (neat):
m 3430, 2925, 1692, 1624 cm−1; Rf = 0.17 (hexane : EtOAc 1 : 1).
(Z)-2-Chloro-4-methylhex-2-enoic acid (10b). 1H NMR
(300 MHz, CDCl3): d 10.37 (br s, 1 H), 7.27 (t, J = 7.4 Hz, 1 H),
2.31 (t, J = 7.2 Hz, 2 H), 1.94–1.81 (m, 1 H), 0.98 (d, J = 6.6 Hz,
3 H), 0.97 (d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3):
d 167.7 (C), 144.6 (CH), 124.3 (C), 38.5 (CH), 27.7 (CH2), 22.3
(2 × CH3); MS (70 eV, EI) m/z (%) 162 [M+, 8], 120 (100), 69
(15), 56 (25); HRMS (70 eV) calc. for C7H11ClO2 162.0448, found
162.0450; IR (neat): m 3426, 1630, 1466, 1266 cm−1; Rf = 0.17
(hexane : EtOAc 3 : 1).
12 J. M. Concello´n, H. Rodr´ıguez-Solla and V. del Amo, Synlett, 2006,
315–317.
13 J. M. Concello´n, H. Rodr´ıguez-Solla, P. D´ıaz and R. Llavona, J. Org.
Chem., 2007, 72, 4396–4400.
General procedure for the synthesis of a-haloallylic alcohols 11.
To a suspension of LiAlH4 (1.0 mmol) in THF was added dropwise
the corresponding compound 3 (1.0 mmol) in THF (1 mL) at
0 ◦C. After stirring the mixture for 12 h at room temperature the
reaction was quenched by the addition of a mixture of water–
ice and extracted with ether. The combined organic phases were
dried over Na2SO4 and the solvents were removed under reduced
14 J. M. Concello´n, H. Rodr´ıguez-Solla and P. D´ıaz, J. Org. Chem., 2007,
72, 7974–7979.
15 J. M. Concello´n, H. Rodr´ıguez-Solla and P. D´ıaz, Org. Biomol. Chem.,
2008, 6, 451–453.
16 G. Cahiez, A. Mart´ın and T. Delacroix, Tetrahedron Lett., 1999, 40,
6407–6410.
17 Aldrich Catalogue (2007–2008): 1 mmol SmI2 (prepared by the method
described in: J. M. Concello´n, H. Rodr´ıguez-Solla, E. Bardales and M.
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Huerta, Eur. J. Org. Chem., 2003, 1775–1778)—1.2 €; 1 mmol CrCl2—
6.33 €; 1 mmol Mn* (prepared by the method described in reference
16)— 0.30 €.
1.71–1.61 (m, 4 H), 1.44–1.21 (m, 6 H), 1.35 (d, J = 6.3 Hz, 6 H);
13C NMR (75 MHz, CDCl3): d 165.2 (C), 104.2 (C), 80.4 (CH), 72.2
(CH), 40.5 (CH), 28.0 (CH2), 26.3 (CH2), 26.0 (CH2), 25.8 (CH2),
25.6 (CH2), 21.2 (CH3), 21.1 (CH3). 4-(1,1-Dichloro-2-hydroxynonan-
18 B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863–927.
19 All the starting materials were commercially (ethyl trichloro- or
dibromofluoroacetate, and aldehydes) or readily (ethyl tribromoacetate
or trichloroacetamides from tribromoacetyl chloride or trichloroacetyl
chloride and the corresponding alcohol or amine, respectively) available
compounds.
20 R. M. Silverstein, G. C. Bassler, and T. C. Morrill, in Spectrometric
Identification of Organic Compounds, John Wiley and Sons, New York,
1991, chapter 4, appendix F, p. 221.
21 Manganese(II) enolates and related species have been proposed as
intermediates in other manganese-promoted transformations, see:
(a) G. Dessole, L. Bernardi, B. F. Bonini, E. Capito`, M. Fochi, R. P.
Herrera, A. Ricci and G. Cahiez, J. Org. Chem., 2004, 69, 8525–8528;
(b) J. Tang, H. Shinokubo and K. Oshima, Tetrahedron, 1999, 55, 1893–
1904; (c) K. Oshima, J. Organomet. Chem., 1999, 575, 1–20; (d) G.
Cahiez, B. Figade`re and P. Cle´ry, Tetrahedron Lett., 1994, 35, 6295–
6298 and reference 12.
22 Isopropyl 2,2-dichloro-3-cyclohexyl-3-hydroxypropanoate (intermedi-
ate from 3d): 1H NMR (300 MHz, CDCl3): d 9.5 (br s, 1 H), 5.13
(hp, J = 6.3 Hz, 1 H), 4.49 (d, J = 4.5 Hz, 1 H), 1.85–1.77 (m, 1 H),
1
1-carbonyl)morpholine (intermediate from 5c): H NMR (300 MHz,
CDCl3): d 4.27–4.21 (m, 2 H), 4.10–3.98 (m, 2 H), 3.81–3.65 (m, 5 H),
1.98–1.86 (m, 1 H), 1.77–1.62 (m, 2 H), 1.50–1.25 (m, 9 H), 0.90 (t, J =
6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3): d 164.9 (C), 85.0 (C), 77.7
(CH), 65.5 (CH2), 66.0 (CH2), 48.6 (CH2), 43.9 (CH2), 31.7 (CH2), 29.8
(CH2), 29.3 (CH2), 29.1 (CH2), 26.0 (CH2), 22.5 (CH2), 14.0 (CH3).
23 Amides derived from morpholine can be readily transformed into;
(a) ketones: R. Mart´ın, P. Romea, C. Tey, F. Urp´ı and J. Vilarrasa,
Synlett, 1997, 1414–1416; (b) aldehydes: C. Douat, A. Heitz, J. Martinez
and J.-A. Fehrentz, Tetrahedron Lett., 2000, 41, 37–40; (c) carboxylic
acids: P. G. Gassman, P. K. G. Hodgson and R. J. Balchunis, J. Am.
Chem. Soc., 1976, 98, 1275–1276.
24 (a) A. P. Duncan and J. L. Leighton, Org. Lett., 2004, 6, 4117–4119;
(b) R. R. Huddleston and M. J. Krische, Org. Lett., 2003, 5, 1143–
1146.
25 J. Barluenga, B. Baragan˜a, A. Alonso and J. M. Concello´n, J. Chem.
Soc., Chem. Commun., 1994, 969–970.
26 S. Nakatsu, A. T. Gubaidullin, V. A. Mademov and S. Tsuboi,
Tetrahedron, 2004, 60, 2337–2349.
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