Electrosynthesis of halogenated δ-lactones

Article abstract of DOI:10.1002/ejoc.201100316

The cathodic reduction of 2, 2-disubstituted-3-oxopropyl trichloroacetates in dichloromethane/tetraethylammonium chloride yields 3, 3-dichloro-4-hydroxy-5, 5-disubstitutedtetrahydro-2H-pyran-2-ones or alternatively, depending on the workup, 3-chloro-4-hyd

Full text of DOI:10.1002/ejoc.201100316

FULL PAPER
DOI: 10.1002/ejoc.201100316
Electrosynthesis of Halogenated δ-Lactones
Gloria Quintanilla,*[a] Iván Pérez,[a] Lenka Záková,[a] Christina Uth,[a] and
Fructuoso Barba[a]
Keywords: Reduction / Electrochemistry / Lactones / Halogens
The cathodic reduction of 2,2-disubstituted-3-oxopropyl tri-
chloroacetates in dichloromethane/tetraethylammonium
chloride yields 3,3-dichloro-4-hydroxy-5,5-disubstituted-
tetrahydro-2H-pyran-2-ones or alternatively, depending on
the workup, 3-chloro-4-hydroxy-5,5-disubstituted-5,6-dihy-
dro-2H-pyran-2-ones. The charge consumption is 2 Faradays
per mol. The aldol trichloroacetates, required for the re-
duction, are obtained in a one-step synthesis based on com-
mercially available compounds.
pared with the aromatic precedent,[1–4] but at the same time
provides a wide range of potential possibilities, because of
the different substituents that can be attached to the C2
atom in the alkyl fragment (α-position with respect to the
aldehyde group). By this straightforward method, a family
of new α,α-dichloro-β-hydroxy-δ-lactones or, depending on
the workup, α-chloro-β-hydroxy-α-β-unsaturated-δ-lactones
substituted in the γ-position have been obtained in good
yields.
Both types of halogenated lactones have high interest as
versatile templates in synthesis, as the chlorine atoms are
able to undergo substitution with different nucleophiles.
There are no previous references in the literature for the
synthesis of nonaromatic α,α-dichloro-β-hydroxy-δ-lact-
ones. α-Chloro-β-hydroxy-α-β-unsaturated-δ-lactones sub-
stituted in the γ-position have also not been reported in the
literature. However, there are two references of δ-substi-
Introduction
The cathodic reduction of the carbon–halogen bond of-
fers a large variety of possible reactions that are not always
easily achieved by conventional methods. In earlier publica-
tions of our research group we described easy methodology
to prepare heterocycles such as 3-chloro-4-alkyl(or aryl)-
coumarins[1,2] or 1-alkyl-4-alkyl(or aryl)-3-chloroquinolin-
ones[3] in good yield by electrochemical reduction of tri-
chloroacetyl esters of o-hydroxyphenones or o-(N-alkyl)-
aminophenones, respectively. After the first electron trans-
fer, the electrogenerated radical–anion undergoes C–Cl
cleavage to give a chlorine radical and an organic anion
that is responsible for intramolecular addition to the car-
bonyl group. The aromatic skeleton of these starting materi-
als provides a rigid structure in which the negative carbon
atom and the carbonyl group are in a suitable position for
the cyclization. The reduction takes place at –0.5 V and the
consumption of the charge is 1 e– persubstratemolecule.[2]
The final products are obtained after a second electron
transfer of two electrons per molecule and the subsequent
loss of chloride and hydroxide anions. Our group has also
reported the cathodic reduction of trichloroacetyl esters of
salicylaldehydes. In this case, the electrogenerated organic
anion follows two different routes leading to alternatively
3-chlorocoumarins and styrenes.[4]
tuted-α-chloro-β-hydroxy-α-β-unsaturated-δ-lactones.
H.
Li[5] in La Jolla synthesized, through a very complex five-
step synthesis, a family of this kind as precursors of potent
RNA polymerase inhibitors, with biological activity against
the hepatitis C virus (HCV). The last step of the synthesis
is in fact the substitution of the chlorine atom for various
thiophenols under basic conditions, which leads to the final
antiviral molecules. Also, Shank[6] obtained 3-chloro-4-hy-
droxy-1-oxaspiro[5.5]undec-3-en-2-one by chlorination of
4-hydroxy-1-oxaspiro[5.5]undec-3-en-2-one.
In the present work, we describe the cathodic reduction
of the carbon–chlorine bond in a series of aliphatic aldol
trichloroacetates 2. Formed carbanion i leads to a six-mem-
bered ring by nucleophilic attack on the aldehyde group
(Scheme 2). The non-existence of a rigid structure in the
molecule makes the process in principle more difficult com-
Results and Discussion
A series of new aldol trichloroacetates 2 (Scheme 1) re-
quired for the electrochemical reduction were obtained by
a very convenient modification of the patent by Merger[7]
et al. (Scheme 2, see the Experimental Section).
[a] Departamento de Química Orgánica, Universidad de Alcalá,
28871 Alcalá de Henares, Madrid, Spain
E-mail: gloria.quintanilla@uah.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100316.
Eur. J. Org. Chem. 2011, 4681–4686
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Quintanilla, I. Pérez, L. Záková, C. Uth, F. Barba
FULL PAPER
cathodic compartment. Electrogenerated anion i is highly
stabilized by the electron-withdrawing effect of two halogen
atoms and by the resonance effect of the carbonyl group.
Anion i attacks nucleophilically the carbonyl group, leading
to cyclic anion ii (Scheme 2). In order to compare exactly
the effect of the workup in the results of the reaction, the
electrolysis mixture was split into two identical portions.
The first half was immediately worked up as described in
the Experimental Section, yielding exclusively lactones 3 by
protonation of anion ii. The other half was stored for at
least 18 h at 3 °C. The alkaline conditions of the reaction
mixture allowed dehydrohalogenation of intermediate
anion ii, leading to lactones 4. The results are shown in
Table 1.
Scheme 1. Synthesis of aldol trichloroacetates 2.
The spectroscopic and analytical properties of com-
pounds 3a–e are consistent with the proposed structure.
1
The coupling in the H NMR spectrum is remarkable. The
two diastereotopic protons of the methylene group, C6 (δ-
position) present two doublets with J = 11 Hz, more shield-
ed than the original ester (δ =3.87 ppm and 4.15 ppm in
3d). The proton placed in the C4 position (CH-OH,
3.6 ppm in 3d) presents a clear W coupling with one of the
protons of the methylene (4J = 1.7 Hz), which means that
the C4 proton is in an equatorial position. The ethyl groups
in lactone 3d are also nonequivalent, especially the two
methylene groups, because they are more affected by the
asymmetry caused by the stereochemistry of the formed
ring (Figure 1). The two hydrogen atoms of one of the
methylene groups are nonequivalent, presenting even a ge-
minal coupling, whereas in the other methylene group the
two hydrogen atoms are equivalent appearing as a quadru-
plet. The nonequivalency is also observable in the 13C
Scheme 2. Electrosynthesis of lactones 3 and 4.
Compounds 2a–e were characterized by their spectro- NMR spectra.
scopic properties. It is interesting to observe the different
The synthesis of lactones 3b and 3e yielded exclusively
pattern of the signals for the methylene group (C1 in the one geometrical isomer. The existence of the W coupling
alkyl rest) in the 1H NMR spectrum: a singlet when substit- implies that the OH group occupies the axial position. The
uent R1 an R2 are identical (esters 2a, 2d) or two doublets isomer with the bulkiest substituent at C5 in the equatorial
with Jgem = 11 Hz, corresponding to the two diastereotopic position should be more stable, because of the minimization
protons due to the vicinity of the asymmetric carbon atom of gauche interactions in the molecule. Therefore, we pro-
in esters 2b and 2c.
pose for the obtained compounds the cis configuration be-
Cyclic voltammograms of aldol trichloracetates 2, car- tween the OH group and the bulkiest substituent (Ph in 3b
ried out using dry dichloromethane/tetraethylammonium and Bu in 3e, Figure 2). This proposal is supported by fur-
chloride as solvent supporting electrolyte (SSE), display ther evidence obtained by 1D NOESY spectroscopic experi-
irreversible reduction peaks at a potential between –0.75 ments.
and –0.9 V.
The reduction of aldol trichloroacetate 2c under the
The cathodic reduction of aldol trichloracetates 2a–e was same conditions produced geometrical isomers 3c (Pr and
performed at a controlled potential under the same SSE OH in cis configuration, more stable) and 3cЈ (Pr and OH
conditions as those mentioned in the above paragraph, in a in trans configuration, less stable) in a 3:1 ratio, both pres-
separated cell under an argon atmosphere. A mercury pool enting W coupling explained above (see Table 1).
1
was used as the cathode and platinum as the anode. To
Crystalline monochlorolactones 4a and 4d present in H
ensure the complete reduction of the starting materials, a NMR spectroscopy a more unshielded singlet in the meth-
slightly more negative potential than that shown in the cy- ylene region, 4.27 ppm, because now the quasiflat ring
clic voltammograms was applied (see the Supporting Infor- makes the two protons enantiotopic, as in the correspond-
mation).
ing esters. Remarkably, the methylene hydrogen atoms of
Unlike the aromatic precedent,[4] the reaction is a two- the ethyl groups in 4d are diastereotopic (Figure 3). The
electron process and produces a chloride anion, instead of OH signal appears at 5.88 ppm, and it is exchangeable with
a radical chlorine. This fact is evidenced by the evolution deuterium oxide. Compounds 4b and 4c also present two
of chlorine gas in the anodic compartment but not in the doublets in the region 4.2–4.5 ppm corresponding to the
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Electrosynthesis of Halogenated δ-Lactones
Table 1. Left side lactones 3a–e, structure and yields. Right side lactones 4a–e, structure and yields.
Figure 3. 3D model of 4d.
Figure 1. 3D model of 3d.
In the mass spectra the classical isotopic peak of only
one chlorine atom could be found.
Conclusions
A family of new trichloroacetyl ester of aliphatic aldols
has been obtained with good yields in a one-pot synthesis
starting from commercial available starting materials. The
potential-controlled reduction of the obtained aldol tri-
chloroacetates at a mercury cathode in dichloromethane/
Figure 2. 3D model of 3b.
two diastereotopic protons of the methylene group, due to tetraethylammonium chloride supplies an easy, clean, and
the asymmetry of C5. Lactone 4e, despite of the asymmetry economical method to obtain two series of new lactones:
at C5, presents the methylene group as a singlet, as it occurs When the reaction workup is carried out immediately after
in the corresponding ester. In the 13C NMR spectrum, the the electrochemical process, α,α-dichloro-β-hydroxy-γ-di-
most significant signals appear at δ = 138 ppm (C-OH) and substituted-δ-lactones with yields between 70 and 90% and
at δ = 128 ppm (C-Cl), both more unshielded than those in geometrical selectivity are obtained. If the workup is per-
lactones 3 because of the sp2 hybridization.
formed after at least 18 h at 3 °C, a molecule of hydrogen
Eur. J. Org. Chem. 2011, 4681–4686
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G. Quintanilla, I. Pérez, L. Záková, C. Uth, F. Barba
FULL PAPER
Jgem = 10.9 Hz, 1 H, 1a-H), 4.57 (d, Jgem = 10.9 Hz, 1 H, 1b-H),
1.65 (s, 3 H, CH3) ppm. 13C NMR (300 MHz, CDCl3): δ = 199.0
(CHO) 161.5 (COO), 135.5 (C-Ar), 129.3, 128.5 and 127.2 (CH-
Ar), 74.2 (CCl3), 71.4 (CH2), 54.1 (Cquat), 16.8 (CH3Ј) ppm. IR
chloride is removed and α,β-unsaturated α-chloro-β-hy-
droxy-γ-disubstituted-δ-lactones are obtained in good
yields and high purity.
(KBr): ν = 3089–3028 (Csp2–H), 2980–2817 (Csp3–H), 2713 (Csp2–
˜
H)1765 (O–C=O), 1725 (H–C=O) cm–1. C12H11Cl3O3 (309.58):
calcd. C 46.56, H 3.58; found C 46.71, H 3.70.
Experimental Section
2-Methyl-2-propyl-3-oxopropyl Trichloroacetate (2c): Yield: 11.74 g,
71%, light yellow oil. B.p. 110 °C (1 mbar). H NMR (300 MHz,
General: IR measurements were performed with a Perkin–Elmer
Model 583 spectrophotometer; liquid samples were measured neat
on NaCl plates; solid samples as KBr pellets. 1H NMR (300 MHz)
and 13C NMR (75 MHz and 125 MHz) spectra were recorded with
Varian Unity 300 and Unity Plus 500 apparati with deuteriochloro-
form as internal standard; the chemical shifts are given in ppm.
Elemental Analyses were performed with a Perkin–Elmer Model
240-B analyzer. Cyclic voltammetry was conducted with a Volta-
Lab PGZ100 using a 0.1 m solution of CH2Cl2/Et4NCl as SSE. A
hanging mercury drop electrode was used as the working electrode.
A platinum plate and an Ag/AgCl/saturated (3 m KCl) electrode
were used as the counter and reference electrodes, respectively. The
electrolyses were carried out using an Amel potentiostat Model 552
with an electronic integrator Amel Model 721 in a concentric cell
with two compartments separated by a low porosity (D4) glass frit
diaphragm, equipped with a magnetic stirrer (temperature main-
tained at 15°). A mercury pool was used as the cathode, a platinum
plate (2.25 cm2) as the anode, and an Ag/AgCl saturated (3 m KCl)
electrode as the reference.
1
CDCl3): δ = 9.51 (s, 1 H, CHO), 4.44 (d, Jgem = 11.2 Hz, 1 H, 1a-
H), 4.37 (d, Jgem = 11.2 Hz, 1 H, 1b-H), 1.52–1.59 (m, 2 H, 1Ј-H),
1.23–1.36 (m, 2 H, 2Ј-H), 1.17 (s, 3 H, CH3), 0.92 (t, Jvic = 7.1 Hz,
3 H, 3Ј-H) ppm. 13C NMR (300 MHz, CDCl3): δ = 202.7 (CHO),
161.6 (COO), 70.6 (CH2), 66.0 (CCl3), 49.7 (Cquat), 35.0 (CH2ЈЈ),
16.9 (CH ЈЈ), 16.8 (CH Ј), 14.5 (CH ЈЈ) ppm. IR (KBr): ν = 2963–
˜
2
3
3
2875 (Csp3–H), 2708 (Csp2–H), 1770 (O–C=O), 1730 (H–C=O)
cm–1. C9H13Cl3O3 (275.56): calcd. C 39.23, H 4.76; found C 39.41,
H 4,81.
2,2-Diethyl-3-oxopropyl Trichloroacetate (2d): Yield: 11.04 g,
66.78%, colorless oil. B.p. 120 °C (1 mbar). 1H NMR (300 MHz,
CDCl3): δ = 9.47 (s, 1 H, CHO), 4.44 (s, 2 H, 1-H), 1.74 (q, Jvic
=
7.6 Hz, 4 H, 1Ј-H), 0.93 (t, Jvic = 7.6 Hz, 6 H, 2Ј-H) ppm. 13C
NMR (300 MHz, CDCl3): δ = 203.4 (CHO), 161.7 (COO), 89.2
(CCl3), 67.7 (CH2), 53.2 (Cquat), 23.2 (CH2Ј), 7.8 (CH3Ј) ppm. IR
(KBr): ν = 2971–2881 (Csp3–H), 2710 (Csp2–H), 1769 (O–C=O),
˜
1729 (H–C=O) cm–1. C9H13Cl3O3 (275.56): calcd. C 39.23, H 4.76;
found C 39.21, H 4.70.
General Procedure for the Synthesis of Aldol Trichloroacetates:
Merger[7] treated the corresponding aldehyde 1 with paraformalde-
hyde and trichloroacetic acid in a one-pot acid-catalyzed aldoliza-
tion and esterification. The huge excess amount (30ϫ) of tri-
chloroacetic acid used, which had to be removed by distillation,
made the method very inconvenient. Therefore, we improved the
procedure by reducing the amount of trichloroacetic acid to 3ϫ
the amount of aldehyde and removing the excess amount of acid
with a 5% aqueous solution of sodium hydrogencarbonate.
2-Butyl-2-ethyl-3-oxopropyl Trichloroacetate (2e): Yield: 4.21 g,
23.09%, light yellow oil. B.p. 100 °C (1 mbar). 1H NMR (300 MHz,
CDCl3): δ = 9.47 (s, 1 H, CHO), 4.44 (s, 2 H, 1-H), 1.52–1.72 (m,
4 H), 1.18–1.32 (m, 4 H), 0.89 (m, 6 H) ppm. 13C NMR (300 MHz,
CDCl3): δ = 203.4 (CHO), 161.6 (COO), 67.9 (CH2), 63.0 (CCl3),
52.9 (Cquat), 30.2 (CH2Ј), 25.5 (CH2Ј), 23.6 (CH2Ј), 23.2 (CH2ЈЈ),
13.8 (CH Ј), 7.9 (CH ЈЈ) ppm. IR (KBr): ν = 2939–2873 (Csp3–H),
˜
3
3
2709 (Csp2–H), 1765 (O–C=O), 1721 (H–C=O) cm–1. C11H17Cl3O3
(303.61): calcd. C 43.52, H 5.64; found C 43.62, H 5.60.
In a one-necked, round-bottomed flask fitted with a magnetic stir-
ring bar and a refluxing cooler was dissolved the corresponding
aldehyde (0.06 mol), paraformaldehyde (1.85 g, 0.06 mol), and
trichloracetic acid (30 g, 0.18 mol) in toluene (20 mL). The color-
less mixture was stirred for 4 h at 130 °C, during which the color
changed to dark brown. After the solution was cooled, toluene was
distilled (15 mbar, 50 °C) off. The solid residue was treated with
5% aqueous solution of NaHCO3 and extracted with diethyl ether
to remove the excess amount of trichloracetic acid. The organic
phase was dried with MgSO4 and filtered. Ether was removed, and
the mixture was distilled under reduced pressure. The pure aldol
trichloroacetates were obtained at their corresponding boiling
points.
General Procedure for the Electroreduction of the Trichloroacetyl
Esters of Aldols 2a-e: Reference electrode: saturated calomel elec-
trode (SCE); anode: platinum plate; analyte: tetraethylammonium
chloride (3 mmol) in dry dichloromethane (20 mL); cathode: mer-
cury pool; catholyte: tetraethylammonium chloride (7 mmol) in dry
dichloromethane (40 mL), and corresponding aldol trichloro-
acetate 2a–e (4 mmol). The electrochemical reductions were carried
out in a concentric cell with two compartments separated by a low
porosity (D4) glass frit diaphragm, equipped with a magnetic stir-
rer (refrigeration at 15°). The cell top was fitted with O-ring sealed
ports for the working electrode, reference electrode, and argon con-
nection (bubbling through the solution for 20 min before the reac-
tion started and then sweeping smoothly during the whole process).
The potential applied in the electrolyses was always more negative
than the potential observed in CV (see below) to ensure the com-
plete reduction of the aldol trichloroacetate. In order to prevent
the evaporation of the solvent due to the extremely exothermic re-
action, the aldol trichloroacetate was added gradually in four por-
tions. Evolution of chlorine was observed only in the anodic com-
partment, which supports the formation of chloride anion as pro-
posed in the mechanism. Once two electrons per molecule were
consumed (current intensity = 200 mA, time = 64 min), the current
decreased until values near zero. As described in the theoretical
part, one half of the crude solution was evaporated under vacuum,
and the residue was extracted with water/ether to remove the elec-
2,2-Dimethyl-3-oxopropyl Trichloroacetate (2a):[6] Merger described
only the synthesis of this compound, but its physical and spectro-
scopic properties are not described in the literature. Yield: 9.43 g,
63.5%, colorless oil. B.p. 85 °C (1 mbar). 1H NMR (300 MHz,
CDCl3): δ = 9.53 (s, 1 H, CHO), 4.37 (s, 2 H, 1-H), 1.19 (s, 6 H,
CH3) ppm. 13C NMR (300 MHz, CDCl3): δ = 202.2 (CHO), 162.0
(COO), 74.2 (CCl3), 71.9 (CH2), 46.5 (Cquat), 18.9 (CH3Ј) ppm. IR
(KBr): ν = 2973–2815 (Csp3–H), 2710 (Csp2–H), 1769 (O–C=O),
˜
1733 (H–C=O) cm–1. C7H9Cl3O3 (247.51): calcd. C 33.97, H 3.67;
found C 33.84, H 3.72.
2-Methyl-2-phenyl-3-oxopropyl Trichloroacetate (2b): Yield: 9.20 g,
49.53%, yellow oil. B.p. 140 °C (0.1 mbar). 1H NMR (300 MHz,
CDCl3): δ = 9.59 (s, 1 H, CHO), 7.20–7.43 (m, 5 H, Ar), 4.78 (d, trolyte. The ethereal extracts were dried with anhydrous magnesium
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Electrosynthesis of Halogenated δ-Lactones
sulfate and concentrated under reduced pressure. In this way, α,α-
dichloro-β-hydroxy-δ-lactones 3a–e were obtained. The second half
of the crude solution was kept in the fridge at 3 °C for at least
18 h. Afterwards, the workup was carried out by following the same
procedure, yielding α-chloro-β-hydroxy-α,β-unsaturated-δ-lactones
4a–e.
CDCl3): δ = cis-isomer 3c: 4.05 (d, Jgem = 11.2 Hz, 1 H, 6ax-H),
4
4
3.84 (dd, Jgem = 11.2 Hz, J = 1.7 Hz, 1 H, 6eq-H), 3.55 (d, J =
1.7 Hz, 1 H, 4-H), 1.5 (t, Jvic = 5.6 Hz, 2 H, CH2ЈЈ), 1.48–1.27 (m,
2 H, CH2ЈЈ), 1.09 (s, 3 H, CH3Ј), 0.93 (t, Jvic = 7.6 Hz, 3 H, CH2ЈЈ)
ppm; trans-isomer 3cЈ: 4.17 (d, Jgem = 11.2 Hz, 1 H, 6ax-H), 3.74
(dd, Jgem = 11.2 Hz, 4J = 1.7 Hz, 1 H, 6eq-H), 3.58 (d, 4J = 1.7 Hz,
1 H, 4-H), 1.54 (t, Jvic = 5.6 Hz, 2 H, CH2ЈЈ), 1.48–1.27 (m, 2 H,
CH2ЈЈ), 1.18 (s, 3 H, CH3Ј), 0.87 (t, Jvic = 7.6 Hz, 3 H, CH3ЈЈ) ppm.
13C NMR (300 MHz, CDCl3): δ = cis-isomer 3c: 162.4 (C-2), 72.1
(C-6), 68.2 (C-3), 67.2 (C-4), 37.5 (C-5), 36.4 (CH2ЈЈ), 18.9 (CH3Ј),
16.9 (CH2ЈЈ), 14.60 (CH3ЈЈ) ppm; trans-isomer 3cЈ: 162.4 (C-2), 73.8
(C-6), 68.2 (C-3), 67.2 (C-4), 35.9 (CH2ЈЈ), 35.0 (C-5), 18.4 (CH3Ј),
Cathodic Reduction of 2a: CV measurements showed a reduction
peak at –0.8 V. A constant cathodic potential at –1 V was applied
until the current decreased to values near zero.
3,3-Dichloro-4-hydroxy-5,5-dimethyltetrahydro-2H-pyran-2-one
(3a): Yield: 0.21 g, 65%, yellow oil obtained from the first half of
the solution, and identified by its spectroscopic data. 1H NMR
(300 MHz, CDCl3): δ = 4.12 (d, Jgem = 11.2 Hz, 1 H, 6ax-H), 3.72
(dd, Jgem = 11.2 Hz, 4J = 1.7 Hz, 1 H, 6eq-H), 3.53 (d, 4J = 1.7 Hz,
1 H, 4-H), 1.21 (s, 3 H, CH3), 1.13 (s, 3 H, CH3) ppm. 13C NMR
(300 MHz, CDCl3): δ = 162.3 (C-2), 74.0 (C-6), 70.5 (C-3), 68.1
16.6 (CH ЈЈ), 14.5 (CH ЈЈ) ppm. IR (KBr): ν = 3464 (OH), 2962–
˜
2
3
2874 (Csp3), 1761 (O–C=O) cm–1. C9H14Cl2O3 (241.11): calcd. C
44.83, H 5.85; found C 44.75, H 5.81.
3-Chloro-4-hydroxy-5-methyl-5-propyl-5,6-dihydro-2H-pyran-2-one
(4c): Yield: 0.25 g, 82%, yellow-green oil obtained from the second
half of the solution and identified by its spectroscopic data. 1H
NMR (300 MHz, CDCl3): δ = 4.28 (d, 1 H, Jgem = 11.2 Hz, H-6a),
4.10 (d, 1 H, Jgem = 11.2 Hz, H-6b), 1.33 (t, 2 H, Jvic = 6.6 Hz,
CH2ЈЈ), 1.30–1.27 (m, 2 H, H-2ЈЈ), 1.17 (s, 3 H, CH3Ј), 0.91 (t, 3
H, Jvic = 7.3 Hz, CH3ЈЈ). 13C NMR (300 MHz, CDCl3): δ = 162.5
(C-2), 135.8 (C-4), 129.6 (C-3), 74.7 (C-6), 40.1 (C-5), 39.3 (CH2ЈЈ),
(C-4), 32.9 (C-5), 21.2 (CH ), 20.6 (CH ) ppm. IR (KBr): ν = 3505
˜
3
3
(OH), 2973–2879 (Csp3–H), 1765 (O–C=O) cm–1. C7H10Cl2O3
(213.06): calcd. C 39.46, H 4.73; found C 39.43, H 4.81.
3-Chloro-4-hydroxy-5,5-dimethyl-5,6-dihydro-2H-pyran-2-one (4a):
Yield: 0.16 g, 60%, pale yellow crystals, m.p. (hexane) 82–85 °C
obtained from the second half of the solution, and identified by its
spectroscopic data. 1H NMR (300 MHz, CDCl3): δ = 5.88 (s, 1 H,
OH), 4.14 (s, 2 H, 6-H), 1.23 (s, 6 H, CH3) ppm. 13C NMR
(300 MHz, CDCl3): δ = 162.3 (C-2), 135.3 (C-4), 130.0 (C-3), 76.4
21.9 (CH Ј), 17.5 (CH ЈЈ), 14.5 (CH ЈЈ) ppm. IR (KBr): ν = 3401
˜
3
2
3
(OH), 2963–2874 (Csp3 –H), 1724 (conj. O–C=O) cm– 1
.
C9H13Cl1O3 (204.65): calcd. C 52.82, H 6.40; found C 53.01, H
6.45.
(C-6), 37.2 (C-5), 23.2 (CH ) ppm. IR (KBr): ν = 3389 (OH), 2976–
˜
3
2873 (Csp3–H), 1723 (conj. O–C=O) cm–1. C7H9Cl1O3 (176.60):
Cathodic Reduction of 2d: CV measurements showed a reduction
peak at –0.75 V. A constant cathodic potential at –1.2 V was ap-
plied until the current decreased to values near zero.
calcd. C 47.61, H 5.14; found C 47.72, H 5.21.
Cathodic Reduction of 2b: CV measurements showed a reduction
peak at –0.9 V. A constant cathodic potential at –1.2 V was applied
until the current decreased to values near zero.
3,3-Dichloro-5,5-diethyl-4-hydroxytetrahydro-2H-pyran-2-one (3d):
Yield: 0.25 g, 70%, yellow oil obtained from the first half of the
solution and identified by its spectroscopic data. 1H NMR
(300 MHz, CDCl3): δ = 4.11 (d, Jgem = 11.2 Hz, 1 H, 6ax-H), 3.87
(dd, Jgem = 11.2 Hz, 4J = 1.7 Hz, 1 H, 6eq-H), 3.60 (d, 4J = 1.7 Hz,
1 H, 4-H), 1.70–1.50 (m, 2 H, CH2Ј), 1.48 (c, Jvic = 7.6 Hz, 2 H,
CH2ЈЈ), 0.97 (t, Jvic = 7.6 Hz, 3 H, CH3Ј), 0.95 (t, Jvic = 7.6 Hz, 3
H, CH3ЈЈ) ppm. 13C NMR (300 MHz, CDCl3): δ = 162.61 (C-2),
71.18 (C-6), 70.31 (C-3), 66.71 (C-4), 38.56 (C-5), 24.51 (CH2Ј),
3,3-Dichloro-4-hydroxy-5-methyl-5-phenyltetrahydro-2H-pyran-2-
one (3b): Yield: 0.30 g, 73%, yellow oil obtained from the first half
1
of the solution, and identified by its spectroscopic data. H NMR
(300 MHz, CDCl3): δ = 7.41–7.27 (m, 5 H, Ar), 4.37 (Jgem
=
4
10.6 Hz, 1 H, 6ax-H), 4.21 (dd, Jgem = 10.6 Hz, J = 1.3 Hz, 1 H,
4
6eq-H), 3.96 (d, J = 1.3 Hz, 1 H, 4-H), 1.51 (s, 3 H, CH3) ppm.
13C NMR (300 MHz, CDCl3): δ = 161.9 (C-2), 139.0 (C-Ar),
129.45, 128.3 and 125.7 (CH-Ar), 73.7 (C-6), 67.24 (C-3), 65.80 (C-
23.74 (CH ЈЈ), 7.54 (CH Ј), 7.50 (CH ЈЈ) ppm. IR (KBr): ν = 3402
˜
2
3
3
˜
(OH), 2968–2884 (Csp3–H), 1762 (O–C=O) cm–1. C9H14Cl2O3
4), 40.08 (C-5), 21.68 (CH ) ppm. IR (KBr): ν = 3479 (OH), 2976–
3
2873 (Csp3–H), 1760 (O–C=O) cm–1. C12H12Cl2O3 (275.13): calcd.
(241.11): calcd. C 44.83, H 5.85; found C 44.71, H 5.80.
C 52.39, H 4.40; found C 52.33, H 4.50.
3-Chloro-5,5-diethyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one (4d):
Yield: 0.14 g, 45%, white crystals m.p. (hexane) 70–73 °C, obtained
from the second half of the solution and identified by its spectro-
3-Chloro-4-hydroxy-5-methyl-5-phenyl-5,6-dihydro-2H-pyran-2-one
(4b): Yield: 0.20 g, 55%, yellow oil obtained from the second half
of the solution, and identified by its spectroscopic data. H NMR
1
1
scopic data. H NMR (300 MHz, CDCl3): δ = 5.98 (s, 1 H, OH),
(300 MHz, CDCl3): δ = 7.41–7.25 (m, 5 H, Ar), 4.50 (d, Jgem
=
4.27 (s, 2 H, 6-H), 1.68 (qd, Jvic = 7.6 Hz, Jgem = 7.25 Hz, 2 H),
1.57 (cd, Jvic = 7.6 Hz, Jgem = 7.25 Hz, 2 H), 0.91 (t, Jvic = 7.6 Hz,
6 H, CH3) ppm. 13C NMR (300 MHz, CDCl3): δ = 162.3 (C-2),
136.9 (C-4), 127.7 (C-3), 72.9 (C-6), 43.5 (C-5), 28.9 (CH2), 8.5
11.5 Hz, 1 H, 6a-H), 4.31 (d, Jgem = 11.5 Hz, 1 H, 6b-H), 1.66 (s,
3 H, CH3) ppm. 13C NMR (300 MHz, CDCl3): δ = 162.2 (C-2),
139.8 (C-4), 137.2 (C-3), 133.12 (C-Ar), 128.8, 128.0 and 126.5
˜
(CH ) ppm. IR (KBr): ν = 3389 (OH), 2971–2881 (Csp3–H), 1705
(CH-Ar), 77.2 (C-6), 45.1 (C-5), 22.2 (CH ) ppm. IR (KBr): ν =
˜
3
3
3478 (OH), 2970–2863 (Csp3–H), 1728 (conj. O–C=O) cm–1
.
(conj. O–C=O) cm–1. C9H13Cl1O3 (204.65): calcd. C 52.82, H 6.40;
C12H11Cl1O3 (238.67): calcd. C 60.39, H 4.65; found C 60.42, H
4.49.
found C 52.94, H 6.37.
Cathodic Reduction of 2e: CV measurements showed a reduction
peak at –0.8 V. A constant cathodic potential at –1 V was applied
until the current decreased to values near zero.
Cathodic Reduction of 2c: CV measurements showed a reduction
peak at –0.9 V. A constant cathodic potential at –1.2 V was applied
until the current decreased to values near zero.
5-Butyl-3,3-dichloro-5-ethyl-4-hydroxytetrahydro-2H-pyran-2-one
(3e): Yield: 0.27 g, 68%, yellow oil obtained from the first half of
the solution and identified by its spectroscopic data. 1H NMR
(300 MHz, CDCl3): δ = 7.05 (s, 1 H, OH), 4.10 (d, Jgem = 11.2 Hz,
3,3-Dichloro-4-hydroxy-5-methyl-5-propyltetrahydro-2H-pyran-2-
one (3c): Yield: 0.33 g, 90%, (mixture of cis and trans isomers in a
3:1 ratio), orange oil obtained from the first half of the solution,
and identified by its spectroscopic data. 1H NMR (300 MHz,
4
1 H, 6ax-H), 3.86 (dd, Jgem = 11.2, Hz J = 1.65 Hz, 1 H, 6eq-H),
Eur. J. Org. Chem. 2011, 4681–4686
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4685

G. Quintanilla, I. Pérez, L. Záková, C. Uth, F. Barba
FULL PAPER
4
3.60 (d, J = 1.65 Hz, 1 H, 4-H), 1.62–1.43 (m, 4 H, CH2), 1.37–
Acknowledgments
1.30 (m, 4 H, CH2), 0.97–0.88 (m, 6 H, CH3) ppm. 13C NMR
(300 MHz, CDCl3): δ = 162.3 (C-2), 71.5 (C-6), 70.3 (C-3), 66.4
(C-4), 38.4 (C-5), 31.7 (CH2Ј), 30.8 (CH2Ј), 24.9 (CH2ЈЈ), 22.4
This study was financed by the Spanish Ministry of Science
and Education (CTQ2007-62612). The authors are very indebted
to Sebastian Hörner, Belén Batanero, Katarzyna Górecka, and
Martin Drazinsky for their invaluable help.
(CH Ј), 14.0 (CH Ј), 6.8 (CH ЈЈ) ppm. IR (KBr): ν = 3466 (OH),
˜
2
3
3
2962–2874 (Csp3–H), 1764 (O–C=O) cm–1. C11H18Cl2O3 (269.17):
calcd. C 49.08, H 6.74; found C 48.96, H 6.88.
[1] B. Batanero, M. J. Pérez, F. Barba, J. Electroanal. Chem. 1999,
469, 201–205.
5-Butyl-3-chloro-5-ethyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one
(4e): Yield: 0.15 g, 44%, yellow oil obtained from the second half
of the solution and identified by its spectroscopic data. H NMR:
[2] B. Batanero, F. Barba, Electrochem. Commun. 2001, 3, 595–
1
598.
δ = 4.34 (s, 2 H, 6-H), 1.82–1.52 (m, 4 H, CH2), 1.47–1.32 (m, 4
H, CH2), 0.93–0.86 (m, 6 H, CH3) ppm. 13C NMR (300 MHz,
CDCl3): δ = 162.0 (C-2), 136.8 (C-4), 128.0 (C-3), 73.6 (C-6), 46.3
(C-5), 43.2 (CH2Ј), 35.9 (CH2Ј), 29.4 (CH2ЈЈ), 26.1 (CH2Ј), 14.1
[3] B. Batanero, F. Barba, J. Org. Chem. 2003, 68, 3706–3709.
[4] Dolly, B. Batanero, F. Barba, Tetrahedron 2003, 59, 9161–9165.
[5] H. Li, J. Tatlock, A. Linton, J. Gonzalez, A. Borchardt, P. Dra-
govich, T. Jewell, T. Prins, R. Zhou, J. Blazel, H. Parge, R.
Love, M. Hickey, C. Doan, S. Shi, R. Duggal, C. Lewis, S.
Fuhrman, Bioorg. Med. Chem. Lett. 2006, 16, 4834–4838.
[6] K. Shank, R. Blattner, G. Bouillon, Chem. Ber. 1981,
114,1951–1957.
(CH Ј), 8.3 (CH ЈЈ) ppm. IR (KBr): ν = 3466 (OH), 2958–2871
˜
3
3
(Csp3–H), 1720 (conj. O–C=O) cm–1. C11H17Cl1O3 (232.71): calcd.
C 56.78, H 7.36; found C 56.87, H 7.28.
[7] F. Merger, W. Fuchs, T. Dockner, United States Patent Office,
1973, 3,749,749.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of the prepared com-
pounds.
Received: March 5, 2011
Published Online: June 22, 2011
4686
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4681–4686