Stereoselective synthesis of (Z)-α-halo-α,β-unsaturated esters, and amides from aldehydes and trihaloesters or amides promoted by manganese

Article abstract of DOI:10.1039/b717513b

Preliminary results of a Mn-promoted sequential process directed toward the stereoselective synthesis of different (Z)-α-halo-α,β- unsaturated compounds are described. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b717513b

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Stereoselective synthesis of (Z)-a-halo-a,b-unsaturated esters, and amides
from aldehydes and trihaloesters or amides promoted by manganese†
Jose´ M. Concello´n,* Humberto Rodr´ıguez-Solla and Pamela D´ıaz
Received 13th November 2007, Accepted 11th December 2007
First published as an Advance Article on the web 21st December 2007
DOI: 10.1039/b717513b
Preliminary results of a Mn-promoted sequential process
directed toward the stereoselective synthesis of different (Z)-
a-halo-a,b-unsaturated compounds are described.
to the inherent passivity exhibited by this metal, which is coated by
an outer shell of oxide. This drawback could be overcome by using
active manganese (Mn*), such as that reported by Cahiez et al.14
Thus, very recently, we developed a Mn*-mediated sequential reac-
tion of aldehydes with a,a-dihaloesters15 or amides16 to obtain (E)-
a,b-unsaturated esters or amides, respectively, in high yields and
with total E-stereoselectivity. These precedent results, prompted us
to attempt the preparation of the scarcely reported aliphatic (Z)-
a,b-unsaturated a-haloesters 3 and aliphatic or aromatic amides
5 by the Mn*-mediated reaction of aldehydes with different
trihaloacetates or acetamides, and the transformation of amides
derived from morpholine into (Z)-a,b-unsaturated a-haloketones
9 by reaction with organolithium compounds.17 Thus, the obtained
previous results are described in this communication.
a-Halo-a,b-unsaturated esters are useful synthetic building blocks.
Thus, these compounds have been used as starting materials to
access important organic compounds, inter alia, trisubstituted
alkenes with complete stereospecificity,1 a-amino acids,2 a variety
of heterocycles including aziridines2b,3 and natural or pharmaceu-
tical products.4 They can also serve as the functionalized vinyl
halide in transition metal-mediated coupling reactions.5 As a
consequence of their importance, the most important classical
methodologies to generate C–C double bonds (Wittig, Horner–
Wadsworth–Emmons, Julia or Peterson olefination reactions) have
been applied to their synthesis.6 These methods often present
some drawbacks. Thus, in some cases the former compounds are
obtained in poor yields, low stereoselectivity, and the generality of
other methods is scarce. Indeed, some reagents are expensive or
the experimental work tedious.
Recently, a synthesis of (Z)-a-halo-a,b-unsaturated esters
(chloro, bromo and fluoro) through a sequential reaction of
trihaloacetates with various aldehydes promoted by CrCl2 with
total stereoselectivity and in high yields was described by Falck
and Mioskowski et al.7 A similar methodology was also applied
to prepare two examples of (Z)-a-chloro-a,b-unsaturated amides,8
but generality of the process was not demonstrated.9 The main
drawbacks of both syntheses could be the high price10 and the
relative toxicity of the chromium salts.
Later on, to overcome these drawbacks the same authors
reported the preparation of (Z)-a-halo-a,b-unsaturated esters by
using the cheaper and non-toxic Fe(0) instead of CrCl2.11 However,
this objective was not completely attained due to: (a) in some
cases the reaction was not completely stereoselective and Z–
E mixtures of esters were obtained; and (b) when bromoacry-
lates were prepared, debrominated byproducts (ranging between
15%–20%) contaminated the corresponding a,b-unsaturated bro-
moester crude mixtures. In addition, only three examples of
aliphatic a-halo-a,b-unsaturated esters by using CrCl2 or Fe(0)
were reported in the corresponding papers.7,11
Synthesis of aliphatic (Z)-a,b-unsaturated a-haloesters 3
The best results were obtained after the addition of 5 equiv. of
the black slurry of active manganese to a solution of 1 equiv. of
the corresponding aldehyde 1 and 1.1 equiv. of trichloroacetate
2 in THF at room temperature which afforded, after refluxing
for 5 h, the corresponding aliphatic a,b-unsaturated a-haloester 3
with total stereoselectivity and in high yields (Table 1). The active
manganese was readily prepared by using the method described
by Cahiez.14‡
The reaction is general. Linear, branched or cyclic aliphatic
aldehydes gave the corresponding 2-chloroalk-2-enoates 3 in high
yields (>88%, after purification by column chromatography) and
with complete Z-stereoselectivity as shown in Table 1 (entries 1–
3). In contrast to other olefination reactions such as the Wittig
reaction,18 the yield and the stereoselectivity of the reaction
was unaffected when a highly hindered trichloroacetate (Table 1,
entry 3), was employed. All the starting materials were commer-
cially (ethyl trichloro- or dibromofluoroacetate and aldehydes)
Table 1 Synthesis of aliphatic (Z)-a,b-unsaturated a-haloesters 3
On the other hand, although the reduction potential of the
Mn+2/Mn(0) system12 is adequate to reduce an important number
of organic functions, and the manganese is non-toxic and very
cheap, it has been scarcely used in organic synthesis13 possibly due
Entry
3
R1
R2
Hal
Z–E
Yield (%)a
1
2
3
4
5
3a
3b
3c
3d
3e
i-Bu
Cy
C7H15
C7H15
s-Bu
Et
Et
i-Pr
Et
Et
Cl
Cl
Cl
Br
F
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
92
95
88
71
62
Departamento de Qu´ımica Orga´nica e Inorga´nica, Universidad de Oviedo,
Julia´n Claver´ıa 8, 33071 Oviedo, Spain. E-mail: jmcg@uniovi.es
† Electronic supplementary information (ESI) available: General proce-
dures, spectroscopic data, and copies of 1H and 13C NMR spectra for
compounds 3, 5 and 9. See DOI: 10.1039/b717513b
a Yield of the isolated product after column chromatography based on
compound 1.
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or readily (ethyl tribromoacetate from tribromoacetyl chloride)
available compounds.
assume that the synthesis of 3 or 5 took place through a sequential
reaction in two steps (Scheme 1). Initially, a manganese enolate 6
was generated by metalation of one C–Hal bond of 2 or 4 with
2 equiv. of Mn*. Thus, a Reformatsky-type process takes place
initially to afford the dihaloester or amide 7. A metalation of a
C–Hal of 7 afforded the manganese enolate 8, which underwent a
spontaneous 1,2-elimination reaction to give 3 or 5.
Under milder reaction conditions (room temperature, 12 h),
bromo or fluoro derivatives could be also obtained in an efficient
manner in which debrominated byproducts were not detected.
Thus, the reaction of ethyl tribromoacetate or dibromofluoroac-
etate with the corresponding aldehyde afforded 2-bromoacrylate
3d or 2-fluoroacrylate 3e in good yields and with complete Z-
stereoselectivity (Table 1, entries 4 and 5). The Z–E ratio of
compounds 3 was determined on the crude reaction products by
1H NMR spectroscopy (300 MHz) and/or GC-MS, showing the
presence of a single stereoisomer. The Z-stereochemistry of the C–
C double bond of a-halo-a,b-unsaturated esters 3 was established
by NOESY experiments and by comparison with the NMR data
previously described in the literature for compound 3c.19 The
trans configuration of the fluoro derivative 3e was established
1
based on the value of the H NMR coupling constant between
the olefinic proton and the fluorine atom (JHF = 34 Hz).20 The
configurations of other esters were established by analogy to the
preceding determinations.
Synthesis of (Z)-a,b-unsaturated a-haloamides 5
Scheme 1 Proposed mechanism.
After testing several reaction conditions, a,b-unsaturated a-
haloamides were prepared by treatment of a solution of the
corresponding aldehyde and trichloroacetamide in THF with 5
equiv. of Mn* at reflux for 5 hours. Hence, a range of amides,
aliphatic (linear, branched or cyclic) and aromatic were obtained in
high yields (>80%), after purification by column chromatography
and with complete Z-diastereoselectivity (Table 2).
Similarly to esters 3, the amides were obtained with complete Z-
stereoselectivity (1H NMR spectroscopy and GC-MS on the crude
reaction products), the Z configuration of the C–C double bond
of amides 5 being determined by performing NOESY experiments
on compounds 5a, 5b, 5d, and 5e.
It is noteworthy that this process was not affected by the
use of trichloroacetamides derived from different amines. In
turn, the starting amides were readily obtained by reaction of
trichloroacetyl chloride with the corresponding amine.
These obtained results could be explained by the same mech-
anism previously proposed to explain the synthesis of a,b-
unsaturated esters15 or amides16 promoted by Mn*. Thus we
This elimination could take place through a chelation-control
model (Scheme 1), in which the Mn(II) center is coordinated with
the oxygen atom of the alcoholate group in the enolate 8, to
produce a six-membered ring.21 Tentatively we propose a chair
transition state model I to justify the configuration of the alkene
function on the obtained esters or amides 3 or 5. Thus, in the
more stable chair transition state, the R1 group would adopt a
pseudo-equatorial position to avoid 1,3-diaxial interactions. A
1,2-elimination reaction from I such as that depicted in 8, would
afford the Z-stereoisomer. An indirect support for this mechanism
is given by the detection of the corresponding 2,2-dichloro-3-
hydroxyester or amide (obtained by hydrolysis of the intermediates
7) on the crude reaction of compounds 3b and 5c.
The synthesis of (Z)-a,b-unsaturated a-haloamides derived
from morpholine are of special interest due to their synthetic
applications.22 Therefore, taking into account the important appli-
cations of a-haloenones in the preparation of different important
substrates, and biologically active products,23 the amide 5c was
readily transformed into ketones 9a and 9b, as shown in Scheme 2.
◦
Thus the reaction of 5c with methyl- or butyllithium at −78 C
Table 2 Synthesis of (Z)-a,b-unsaturated a-haloamides 5
for 1 h afforded the corresponding ketone 9a or 9b. This transfor-
mation took place without loss of the diastereoisomeric purity of
the C–C double bond (1H NMR of the crude reaction products)
and in nearly quantitative yields (97 and 90%, respectively).
The Z-configuration of the alkene function was established by
a NOESY experiment on ketone 9b. Hence the assignment of the
Z-stereochemistry of 9b allowed the indirect determination of the
Entry
5
R1
R2
Et
Z–E
Yield (%)a
1
2
3
4
5
5a
5b
5c
5d
5e
i-Bu
Cy
C7H15
p-MeOC6H4
p-MeOC6H4
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
82
80
84
81
86
Et
b
Et
i-Pr
a Yield of the isolated product after column chromatography based on
compound 1. b From morpholine.
Scheme 2 Synthesis of (Z)-a,b-unsaturated a-chloroketones 9.
452 | Org. Biomol. Chem., 2008, 6, 451–453
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Z-configuration of the starting a,b-unsaturated amide 5c, which
could not be established directly by a NOESY experiment. It is
noteworthy that the prepared ketones 9a and 9b (R3 = aliphatic)
are difficult to achieve by using other reported methods.
In conclusion, an easy, straightforward and general sequential
method has been developed to synthesize aliphatic a,b-unsaturated
a-haloesters (bromo, chloro, and fluoro) 3 and chloroamides 5 with
total Z-stereoselectivity, through a sequential process promoted
by the non-toxic Mn*. The unsaturated amides 5 derived from
morpholine were readily transformed into the corresponding ke-
tones by reaction with organolithium compounds. Generalization
of the reported synthesis is currently under investigation within
our laboratory.
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.
5 (a) E. Bellur and P. Langer, Eur. J. Org. Chem., 2005, 22, 4815–4828;
(b) A. Sorg, F. Blank and R. Bru¨ckner, Synlett, 2005, 8, 1286–1290;
(c) V. J. Majo, J. Prabhakaran, N. R. Simpson, R. L. Van Heertum,
J. J. Mann and J. S. D. Kumar, Bioorg. Med. Chem. Lett., 2005, 15,
4268–4271.
6 Examples of the most important methods to prepare a,b-unsaturated
haloesters are available from the literature in ref. 7.
7 D. K. Barma, A. Kundu, H. Zhang, C. Mioskowski and J. R. Falck,
J. Am. Chem. Soc., 2003, 125, 3218–3219.
8 J. R. Falck, A. Bandyopadhyay, D. K. Barma, D.-S. Shin, A. Kundu
and R. V. Krishna Kishore, Tetrahedron Lett., 2004, 45, 3039–3042.
9 Other methods to prepare a-chloro-a,b-unsaturated amides with high
selectivity have been reported: (a) C. Lambert, B. Caillaux and H. G.
Viehe, Tetrahedron, 1985, 41, 3331–3338; (b) Synthesis of a-bromo-a,b-
unsaturated amides (no data of setereoselectivity was reported) was
also described: N. H. Cromwell and F. Pelletier, J. Org. Chem., 1950,
15, 877–883.
10 Aldrich Catalogue (2007–2008): CrCl2 (99.99%): 25g—£ 585.00.
11 J. R. Falck, R. Bejot, D. K. Barma, A. Bandyopadhyay, S. Joseph and
C. Mioskowski, J. Org. Chem., 2006, 71, 8178–8182.
12 Electrochemical redox potential: Mn+2/Mn(0) −1.03V, Handbook of
Chemistry and Physics, CRC Press, Boca Raton, FL, 62nd edn, 1982.
13 To see a revision about the synthetic applications of organomanganese
compounds see: K. Oshima, J. Organomet. Chem., 1999, 575, 1–20.
14 G. Cahiez, A. Mart´ın and T. Delacroix, Tetrahedron Lett., 1999, 40,
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15 J. M. Concello´n, H. Rodr´ıguez-Solla, P. D´ıaz and R. Llavona, J. Org.
Notes and references
Chem., 2007, 72, 4396–4400.
16 J. M. Concello´n, H. Rodr´ıguez-Solla and P. D´ıaz, J. Org. Chem., 2007,
72, 7974–7979.
‡ Preparation of Rieke Manganese (Mn*): A mixture of lithium (26 mmol)
and 2-phenylpyridine (4 mmol) in THF (20 mL) under a nitrogen
atmosphere was stirred for 1 h. 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. General
procedure for the synthesis of a,b-unsaturated compounds 3 or 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. 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 sequentially 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.
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(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.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 451–453 | 453
©