Stereoselective hydrohalogenation of alkynoic acids and their esters in ionic liquids

Article abstract of DOI:10.3184/030823407X200038

A novel procedure is described for the hydrohalogenation of alkynoic acids and their esters using N-alkylpyridinium ionic liquids. Hydrohalogenating agents were prepared by mixing N-alkylpyridinium halides with an equimolar amount of trifluoroacetic acid.

Full text of DOI:10.3184/030823407X200038

170 RESEARCH PAPER
MARCH, 170–172
JOURNAL OF CHEMICAL RESEARCH 2007
Stereoselective hydrohalogenation of alkynoic acids and their esters in
ionic liquids
José Salazar*, Francys Fernández, Jelem Restrepo and Simón E. López
Departamento de Química, Universidad Simón Bolívar, Valle de Sartenejas, Baruta, Caracas 1080-A, Apartado 89000, Venezuela
A novel procedure is described for the hydrohalogenation of alkynoic acids and their esters using N-alkylpyridinium
ionic liquids. Hydrohalogenating agents were prepared by mixing N-alkylpyridinium halides with an equimolar
amount of trifluoroacetic acid. The corresponding halogenated alkenes were obtained in good yields with high
diastereoselectivity.
Keywords: hydrohalogenation, ionic liquids, alkynoic acids, N-alkylpyridinium
1-Functionalised 3-haloalk-2-enes are important classes
of compounds for organic synthesis. For example,
3-halopropenoic acids and their derivatives have proved
to be valuable intermediates owing to the presence of three
functional groups, i.e., the carbonyl group, the conjugated
carbon–carbon double bond, and the C–X bond.1 Due to
the great attention to transition-metal-catalysed sp2–sp2
or sp–sp2 carbon–carbon bond formation during the last
25 years, this type of compound is of vital importance as they
are in widespread use as starting materials for such reactions.
Palladium-catalysed cross coupling of vinyl bromides or
iodides2 with vinyl or acetylide organometallic reagents3
permits the easy preparation of diene or enyne compounds
which are important synthetic intermediates4 and their
structural features are present in numerous natural products.5
Among the most important preparation procedures for
the synthesis of functionalised 3-haloalk-2-enes is the
hydrohalogenation of alkynes. Several methods have been
published for this reaction. These include: the preparation
of 2-bromoalk-1-enes starting from terminal alkynes by
reaction with a dichloromethane solution of hydrogen
bromide in tetraethylammonium bromide;6 hydrobromination
or hydroiodination of terminal alkynes using hydrogen
bromide or acetyl iodide and alumina;7 employing a BI3-N,
N-diethylaniline complex in acetic acid;8 forming vinyl iodides
from terminal alkynes using a mixture of iodine, triethylsilane
and CuO.HBF4 in dichloromethane at low temperature;9 the
use of sodium iodide and trimethylsilane chloride in water
for the stereoselective preparation of alkenyl iodides;10 the
formation of E/Z mixtures of 3-halopropeanoate esters from
the corresponding 2-propiolates and aqueous mixtures of HI
or HBr;11 stereospecific reaction of 2-propiolate esters or
propynoic acids with lithium halides in acetic acid yielding the
corresponding (Z)-3-halopropenoates or (Z)-3-halopropenoic
acids;12 Z/Emixturesof3-halopropen-2-onesfrom3-propyn-2-
ones and lithium halides in acetic acid at room temperature;12c
3-chloroalkenoic acids, esters and amides from alk-2-ynoic
acids by treatment with thionyl chloride or oxalyl chloride
and dimethylformamide followed by quenching with water,
alcohols or amines.13,14 The above mentioned methodologies,
however, suffer from some disadvantages such as the use of
hazardous hydrogen halides, dangerous chlorinated reagents,
volatile solvents and large work-up procedures; many of those
problems should be avoided by the use of “green” systems,
such as that exemplified by reactions performed in ionic
liquids. A widespread interest in ionic liquids has emerged,15
basically due to their unique properties, such as lack of
measurable vapour pressure and good thermal stability, which
make them a possibly environmentally benign alternative to
volatile solvents. These properties have led to a variety of
successful applications, ranging from industrial16 to green
chemistry.17 Alkylpyridinium salts are well documented ionic
liquids;18 the combination of an alkylpyridinium bromide
with bromine, for example, generates a useful-ionic liquid-
brominating agent.19 The latter is a good example of an ionic
liquid which integrates the function of solvent and reagent.
Trying to combine those useful advantages turned our attention
to the development of a new hydrohalogenating methodology
based on alkylpyridinium ionic liquids. The addition of
trifluoroacetic acid to the corresponding alkylpyridinium
halide generates HX-equivalent hydrohalogenating mixtures
which were efficiently used as new solvent-reagent systems
for the hydrohalogenation of different alkynoic acids and
esters (see Table 1).20 Good yields were obtained and only
the corresponding Z-diastereoisomer was detected in all the
studied cases. As can be seen, the method could be applied
even for the hydrochlorination of an alkynoic ester (2j),
a difficult task to achieve in high yield and stereoselectivity for
most alkynes.21 An in situ generation of the hydrohalogenating
agent in the reaction avoids the preparation and transfer of
hydrogen halide reagents, which are both highly hygroscopic
and gaseous, and make the reaction difficult to handle and
perform stoichiometrically.21a Many hydrohalogenation
procedures still require an aqueous work-up, which generates
environmentally toxic hydrogen halides, a task avoided in
this new non-aqueous work-up methodology. Also, the
procedure permits the easy preparation of deuterium-labelled
compounds (2b, 2f) if deuterated trifluoroacetic acid is
employed.
In conclusion, this report represents a new, stereoselective
and high-yielding methodology for the hydrohalogenation
of alkynoic acids and their esters. The low cost of the
hydrohalogenating mixtures, containing only simple
alkylpyridinium ionic liquids and trifluoroacetic acid, make
this an affordable, attractive and simple procedure for the
hydrohalogenation of other organic compounds, a study
which is ongoing in our research group and will be published
elsewhere.
Experimental
Melting points were determined in a Fischer-Johns micro hot-stage
apparatus and are uncorrected. NMR spectra were obtained on a
JEOL Eclipse Plus spectrometer in deuterated chloroform, operating
at 400 MHz (1H, internal standard TMS). The IR spectra were
recorded as liquid films using an FT-IR Nicolet Magna Spectrometer.
Mass spectra (GC-MS) were recorded using a gas chromatograph
Hewlet Packard 5890 Series I coupled to a mass detector (EI, 60 eV)
Hewlett Packard 5917 A. Microanalyses of synthesised compounds
were performed by Atlantic Microlab Inc. (Norcross, GA, USA);
results fell in the range of ± 0.4% of the required theoretical values.
Silica gel plates ALUGRAM® SIL G/UV254 (Macherey-Nagel
GmbH & Co., Germany) were used for TLC testing. Reagents were
obtained from Aldrich (Milwaukee, MI, USA) or Merck (Darmstadt,
Germany) and used without further purification.
* Correspondent. E-mail: jsalazar@usb.ve
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JOURNAL OF CHEMICAL RESEARCH 2007 171
Table 1 Hydrohalogenation of alkynoic acids (esters) using different ionic liquid hydrohalogenating mixtures
Hydrohalogenating
mixture
X
R
CO2R'
Y
R
CO2R'
1a–k
2a–k
Compound
R
R’
X
Y
Hydrohalogenating
mixture (equiv)
Time/h
Temp/°C
Yield/%
Ref.*
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
Et
Et
Et
Me
Et
Et
Et
Me
H
Br
Br
Br
Br
I
H
D
H
H
H
D
H
H
H
H
H
nBuPy+Br-/CF3CO2H (1)
nBuPy+Br-/CF3CO2D (1)
nBuPy+Br-/CF3CO2H (3)
nBuPy+Br-/CF3CO2H (1)
nBuPy+I-/CF3CO2H (1)
nBuPy+I-/CF3CO2D (1)
nBuPy+I-/CF3CO2H (3)
nBuPy+I-/CF3CO2H (1)
nBuPy+I-/CF3CO2H(1)
nHexPy+Cl-/CF3CO2H (2)
nBuPyr+I-/CF3CO2H(1.5)
4
4
12
4
8
8
12
6
6
70
70
80
60
25
25
80
60
60
60
60
77
61
74
85
68
65
97
82
76
85
80
12a
23
H
Ph
CO2Me
H
H
Ph
24
25
12c
–
12e
26
26
I
I
CO2Me
CO2H
H
I
I
2j
2k
Et
H
Cl
I
12
12
12a
27
CH3
aCompounds were isolated in pure isomeric form after work-up. Their physical and spectroscopical data were identical with those
reported in the references given.
2
(a) E.C. Stracker and G. Zweifel, Tetrahedron Lett., 1991, 32, 3329;
(b) A.O. King, N.J. Okukado and E. J. Negishi, J. Chem. Soc. Chem.
Commun., 1977, 683.
Procedure for the preparation of hydrohalogenating mixtures:
The N-alkylpyridinium salt22 (ionic liquid, 8 mmol) was gently
warmed until it melted and was then mixed thoroughly with
trifluoroacetic or deuterated trifluoroacetic acid (8 mmol).
The mixture was vigarously stirred until one phase was formed and
then cooled to room temperature.
Procedure for the hydrohalogenation of alkynoic acids and
their esters: The alkynoic acid or ester (1 mmol) was mixed with
the hydrohalogenating mixture and stirred at the indicated ratios,
temperatures and times (see Table 1). The reaction mixture was then
cooled to room temperature, extracted with diethyl ether (3 × 10 ml),
the extract passed through a silica-gel-charcoal column and the
solvent evaporated to give the corresponding compound (2a–k).
Spectroscopic and physical data corresponded to reported compounds
(see Table 1).
3
4
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5
6
7
Typical examples
8
9
Ethyl Z-3-bromopropenoate (2a): Colourless oil. Yield: 77%;
IR (cm-1): 1730; 1H NMR: d 6.93 (d, 1H, J = 8.4 Hz, CH), 6.55 (d, 1H,
J = 8.4 Hz, CH), 4.16 (q, 2H, J = 7.0 Hz, CH2), 1.24 (t, 3H, J = 7.0 Hz,
CH3); 13C NMR: d 163.9, 124.5, 122.0, 60.7, 14.1. MS: m/z 150 and
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129.9 (t, 1C, J = 26.4 Hz, CD), 94.9, 60.8, 14.3 Anal. Calcd. for
C5H6DIO2: C 26.45%, H 3.10%; found: C 26.6%, H 3.2%.
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The authors thank Decanato de Investigación
y Desarrollo
14 N. Urdaneta, J. Salazar, J. Herrera and S.E. Lopez, Synth. Commun., 2004,
34, 657.
(Universidad Simón Bolívar, Caracas) for its financial support, as well
as to the Laboratorio de Resonancia Magnética Nuclear (Laboratorio
B, Universidad Simón Bolívar, Caracas) for the spectroscopic
facilities. FF thanks Decanato de Estudios Profesionales (Universidad
Simón Bolívar, Caracas) for an undergraduate research financial
support. JR thanks FONACIT (Caracas, Venezuela) for a doctoral
fellowship.
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Received 12 December 2006; accepted 27 March 2007
16 M. Freemantle, Chem. Eng. News, 2001, 79, 36.
Paper 06/4372
doi: 10.3184/030823407X200038
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