Ohmic Heating and Ionic Liquids in Combination for the Indium-Promoted Synthesis of 1-Halo Alkenyl Compounds: Applications to Pd-Catalysed Cross-Coupling Reactions

Article abstract of DOI:10.1002/ejoc.201501162

We have explored the combination of ohmic heating (ΩH) with ionic liquids for indium-promoted reactions and report herein the indium-promoted dehalogenation of gem-dibromo alkenes and the indium-mediated reductive elimination of chlorohydrins for the synthesis of 1-halo alkenyl derivatives. Heck, Stille, Suzuki, Kumada and Sonogashira couplings of the resulting 1-halo-1-alkenes with appropriate reagents were carried out to give alkenes, dienes and enynes. We report herein the combination of ohmic heating (ΩH) with ionic liquids for the indium-promoted dehalogenation of gem-dibromo alkenes and the indium-mediated reductive elimination of chlorohydrins. The 1-halo alkenyl derivatives synthesized were then submitted to a series of cross-coupling reactions to give conjugated alkenes, dienes and enynes.

Full text of DOI:10.1002/ejoc.201501162

DOI: 10.1002/ejoc.201501162
Full Paper
Indium Chemistry
Ohmic Heating and Ionic Liquids in Combination for the
Indium-Promoted Synthesis of 1-Halo Alkenyl Compounds:
Applications to Pd-Catalysed Cross-Coupling Reactions
Raquel G. Soengas,*[a] Vera L. M. Silva,*[a] Joana Pinto,[a] Humberto Rodríguez-Solla,[b] and
Artur M. S. Silva*[a]
Abstract: We have explored the combination of ohmic heating of chlorohydrins for the synthesis of 1-halo alkenyl derivatives.
(ΩH) with ionic liquids for indium-promoted reactions and re- Heck, Stille, Suzuki, Kumada and Sonogashira couplings of the
port herein the indium-promoted dehalogenation of gem-di- resulting 1-halo-1-alkenes with appropriate reagents were car-
bromo alkenes and the indium-mediated reductive elimination ried out to give alkenes, dienes and enynes.
Introduction
It was recently reported that ionic liquids improve the per-
formance of several indium-promoted processes, probably
through the formation of stable indium(III) complexes with the
carbene intermediates. As a result of its low toxicity, environ-
mental benefits and favourable effects on chemical transforma-
tions, indium metal has recently attracted considerable atten-
tion.[4] It has been used extensively in carbon–carbon bond for-
mation[5] and reductive dehalogenation reactions,[6] and re-
cently our group[7] and others[8] have reported the use of in-
dium in reductive elimination reactions.
Considering the above information, it is reasonable to think
that the combination of ohmic heating with ionic liquids for
indium-promoted reactions may provide great opportunities for
green chemistry. Therefore we applied this idea to the synthesis
of 1-halo alkenyl derivatives, of great interest as substrates in
palladium-catalysed cross-coupling reactions. In this paper we
describe the details of the indium-mediated reduction of 1,1-
dibromo-1-alkenes and the reductive elimination of 2,4-di-
chloro-3-alken-1-ols in ionic liquid media under ohmic heating
conditions. The reactions, including their mechanisms, scope,
and limitations, and also the usefulness of the resulting 1-halo-
1-alkenes for the preparation of conjugated polyenes and ene-
diynes by Pd-catalysed cross-coupling reactions are also dis-
cussed.
Ohmic heating is an energy-efficient heating process in which
an a.c. electric current of tunable high frequency passes
through a conductive reaction medium (which behaves as an
electrical heater) with the primary purpose of heating it. Heat
is generated directly within the reaction medium by internal
energy transformation (from electric to thermal) so it is not
transmitted to the medium by means of temperature gradients
or hot surfaces.[1,2] The thermal energy transfer occurs mostly
between the electrode plates cross-section region (electrodes
are in contact with the medium) and the surroundings. Thus,
heating is less dependent on the heat transfer to the medium,
which results in a high heating rate allowing fast, volumetric
and uniform heating and increased dynamics of charged spe-
cies in solution leading to shorter reaction times and increased
yields.[1,2] Ohmic heating is a convenient alternative to classical
heating and microwave (MW) irradiation, as demonstrated re-
cently by Silva and co-workers.[2] On the other hand, ionic
liquids (ILs) are excellent solvents to use in ohmic heating be-
cause they are naturally conductive and they are becoming in-
creasingly popular as solvents in organic synthesis for several
reasons;[3] they are practically non-volatile and non-flammable,
avoiding the risks associated with volatile organic compounds,
and they can be recycled easily without any significant loss of
activity.
[a] Department of Chemistry & QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
Results and Discussion
E-mail: rsoengas@ua.pt
verasilva@ua.pt
artur.silva@ua.pt
Indium-Mediated Reduction of gem-Dibromo Alkenes
https://sites.google.com/site/artursilvaua/
[b] Departamento de Química Orgánica e Inorgánica, Facultad de Química,
Universidad de Oviedo,
Vinyl bromides are extremely useful tools in organic chemistry
and their use as coupling partners in a wide range of transition-
metal-mediated cross-coupling reactions has sparked a great
deal of interest in their stereoselective synthesis.[9]
Julián Clavería 8, 33006 Oviedo, Spain
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501162.
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The reduction of gem-dibromides, readily available from the substrate.[12] The treatment of 1a with indium in both [bmim]I
simple reaction of an aldehyde with carbon tetrabromide and (bmim = 1-butyl-3-methylimidazolium) and [bmim]Br at 95 °C
triphenylphosphine, presents a practical alternative to the syn-
thesis of vinyl bromides. Few examples of the hydrogenolysis of
1,1-dibromo-1-alkenes have been reported in the literature.[10]
However, because these methods have some drawbacks
(i.e., very low temperatures, highly toxic reagents, limited sub-
strate scope), a simpler, more efficient and environmentally
friendly method for the synthesis of 1-halo-1-alkenes is still de-
sirable.
afforded bromovinyl 2a in moderate yields and diastereoselect-
ivity after 12 h along with some recovered starting material
(Table 1, entries 3 and 4). The reaction needed 36 h to reach
completion (Table 1, entry 5). When other ILs with different
counter ions and cations were used, for example, [bmim]PF6,
[bim]BF4 (bim = 1-butylimidazolium), [mim]BF4 (mim = 3-meth-
ylimidazolium) and TBAP (tetrabutylammonium perchlorate),
the reaction did not proceed (Table 1, entries 8–11).
In our preliminary studies, the reduction of galactose-de-
rived dibromo alkene 1a was assessed under various conditions
and the results are reported in Table 1. Thus, the treatment of
1a (1 mmol) with indium metal (1.1 mmol) in either a mixture
of ethanol and water or ethanol and an aqueous saturated am-
monium chloride solution under reflux led to complete recov-
ery of the dihalo precursor in both cases (Table 1, entries 1
and 2). These unsatisfactory results were somehow expected,
because indium has proven effective in the reduction of aro-
matic-substituted gem-dibromo alkenes, but failed to effectively
reduce their alkyl-substituted counterparts.[10e]
The most appropriate reaction medium is [bmim]Br, because
in this IL the product was obtained in good yield and could
easily be separated from the water-soluble IL by adding water
and extracting with diethyl ether. The ionic liquid can be recov-
ered by evaporation of the aqueous layer followed by filtration
and used in subsequent experiments without affecting the yield
or selectivity (Table 1, entries 6 and 7).
In an attempt to improve the methodology by reducing the
reaction time, the reduction of 1a was performed following the
same procedure but by changing the mode of heating of the
reaction mixture from classical heating (oil bath) to ohmic heat-
ing. With this modification, bromovinyl 2a was obtained after
3 h in high yield (84 %) and with good (E/Z) selectivity (90:10;
Table 1, entries 13 and 14). Microwave irradiation was not as
effective as ohmic heating, affording bromovinyl 2a in lower
yield (46 %) and diastereoselectivity (61:39 E/Z; Table 1, en-
try 15). It is interesting to note that in the absence of ohmic
heating, no significant amounts of the desired 2a were de-
tected (Table 1, entry 12).
Table 1. Reduction of gem-dibromo alkene 1a.
Entry
Solvent
T [°C]
t [h]
Yield [%][a]
E/Z[b]
A plausible mechanism for the reductive dehalogenation of
dibromo alkenes by In0 in [bmim]Br would include the forma-
tion of an intermediate radical by single-electron transfer (SET)
from In0 to the dibromo alkene followed by hydrogen atom
abstraction from [bmim]Br to generate a carbene intermediate,
which forms a stable complex with InBr3.[13] The excellent se-
lectivity can be explained by the higher thermodynamic stabil-
ity of the intermediate conducting to the (E)-alkene.
1
2
3
4
5
6
EtOH/H2O
EtOH/aq. NH4Cl
[bmim]I
100
100
95
95
95
12
12
12
12
36
36
n.r.
n.r.
48
45
82
80
–
–
91:9
92:8
90:10
90:10
[bmim]Br
[bmim]Br
[bmim]Br
(second run)
[bmim]Br
(third run)
[bmim]PF6
[bmim]BF4
[bmim]BF4
TBAP/H2O
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
95
7
95
36
78
90:10
To study the scope of this novel reduction methodology, a
series of dibromo alkenes were submitted to the indium-medi-
ated reduction protocol under classical and ohmic heating con-
ditions. As depicted in Table 2, a wide range of structurally var-
ied gem-dibromides underwent reduction by this procedure to
provide the corresponding (E)-vinyl bromides predominantly in
high yields. Several functional groups such as OMe, OBn, Cl, Br,
CN and CO2Me remained unaffected under the present reaction
conditions. In general, the crude reaction products were ob-
tained in high purity after aqueous work up; it is noteworthy
that no column chromatographic purification was necessary to
obtain compounds 2 with high purity.
8
9
95
95
95
95
95
36
36
36
36
1
1
3
3
n.r.
n.r.
n.r.
n.r.
n.r.
46
–
–
–
–
–
10
11
12
13
14
15
95[c]
95[c]
95[d]
91:9
90:10
61:39
84
46
[a] Isolated yield; n.r.: no reaction. [b] Determined by 1H NMR spectroscopy
of the crude reaction mixtures. [c] Ohmic heating. [d] Microwave irradia-
tion.
This method offers significant improvements over existing
procedures owing to the absence of undesired side-reactions,
including over-reduction, the mild conditions required, the
wide range of functionalities tolerated, the good results ob-
tained with alkyl-substituted gem-dibromides, the good yields
To overcome this limitation, we decided to test the use of
ionic liquids (ILs) as the reaction medium. In addition to having
well-known properties as green solvents, ILs have also been
shown to enhance the rate of many transformations.[11] Thus,
we expected that ILs would accelerate single-electron transfer and stereoselectivities and the environmentally friendly reac-
(SET) from indium in the powder form to the dibromo alkenyl tion conditions.
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Table 2. Synthesis of vinyl bromides 2.
[a] Temperature 95 °C. [b] Determined by 1H NMR spectroscopy of the crude reaction mixtures. [c] Isolated yield.
Indium-Promoted Reductive Elimination of
Chlorohydrins
The acetates 3 used as starting materials could be easily pre-
pared from aldehydes by the indium-promoted addition of 3-
bromo-1,3-dichloropropene[15] followed by acetylation of the
crude alcohols. Under these conditions a collection of 2,4-di-
chlorohomoallyl acetates 3a–j featuring different substituents
and patterns afforded the desired (1E)-4-chloro-1-substituted-
1,3-dienes 4a–j in good yields and with excellent stereoselectiv-
ities (Table 3). Again, ohmic heating was much more efficient
than classical heating, leading to an impressive decrease in the
reaction time (from 12 to 1 h). The observed (E) configuration
of the newly formed double bond, obtained through the β-
elimination process, can be explained according to a chelation-
control model.[7]
We decided to investigate the indium-promoted reductive β-
elimination of 2,4-dichloro-3-alken-1-yl acetates for the prepara-
tion of 1-chlorodienes, interesting intermediates that undergo
a variety of synthetically useful transformations to give unsatu-
rated compounds (e.g., enynes, 1,3-diynes, chloropolyenes, ene-
diynes and polyenes).[14]
Taking into account our previous experience of dehalogena-
tion reactions, initial studies were focused on the β-elimination
reactions of 2,4-dichlorohomoallyl acetates using indium in
[bmim]Br under both classical and ohmic heating.
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Table 3. Synthesis of (1E)-4-chloro-1,3-dienes 4.
[a] Temperature 95 °C. [b] Determined by 1H NMR spectroscopy of the crude reaction mixtures. [c] Isolated yield.
Pd-Catalysed Cross-Coupling Reactions
First, galactose-derived bromovinyl compound 2a was se-
lected for a Suzuki cross-coupling reaction and subjected to
the standard protocol with phenylboronic acid using 5 mol-%
Pd(OAc)2 in the presence of 0.2 equiv. of PPh3 and potassium
carbonate as base to afford compound 5a (Table 4, entry 1).
This procedure proved to be successful and hence a Sonoga-
shira reaction with ethynylbenzene was assayed, which pro-
vided compound 5b in excellent yield (Table 4, entry 2). A Kum-
ada cross-coupling reaction of chlorodiene 4h with phenylmag-
nesium bromide gave diene 5c (Table 4, entry 3). Lyxose-de-
rived bromovinyl compound 2m was submitted to a Stille cou-
pling reaction to give diene 5d (Table 4, entry 4). Mannose-
derived vinyl bromide 2n was subjected to a Suzuki cross-cou-
pling reaction with phenylboronic acid to afford 5e (Table 4,
entry 5). Xylose-derived bromovinyl compound 2o and chloro-
diene 4i also underwent smooth palladium-catalysed transfor-
mations, as demonstrated by the synthesis of Heck and Kumada
coupling products 5f and 5g, respectively (Table 4, entries 6
and 7).
The presence of the halo alkenyl moiety makes sugar halovinyls
ideal precursors for palladium-catalysed coupling reactions,
which can be exploited for the introduction of new substituents
and the elongation of the sugar chain. Accordingly, these deriv-
atives have been used as intermediates in the preparation of
natural products,[16] C-glycosides,[17] polyols[18] and nucleo-
sides.[19] However, probably as a result of the limited access to
these intermediates, this topic has not been extensively investi-
gated.
Taking into account these considerations, we decided to in-
vestigate the introduction of new substituents into the alkenyl
sugar chain through the palladium-catalysed cross-coupling re-
actions (Sonogashira, Suzuki, Stille, Kumada, and Heck) of the
obtained sugar-derived halovinyl substrates, which yielded
highly substituted sugar derivatives of considerable interest for
further synthetic elaborations. The results of the cross-coupling
reactions between bromovinyls 2 and chlorodienes 4 as precur-
sors are summarized in Table 4.
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Table 4. Pd-catalysed cross-coupling reactions of sugar-derived bromovinyls 2 and (1E)-4-chloro-1,3-dienes 4.
[a] Reagents and conditions: A: Phenylboronic acid (1.2 equiv.), Pd(OAc)2 (5 mol-%), PPh3 (0.2 equiv.), K2CO3 (1.5 equiv.), DMF, 70 °C, 12 h. B: Ethynylbenzene
(1.2 equiv.), Pd(OAc)2 (5 mol-%), PPh3 (0.2 equiv.), CuI (5 mol-%), iPr2NH, DMF, room temp., 10 h. C: PhMgBr, (2 equiv.), [Pd(PPh3)4] (5 mol-%), Et3N (3 equiv.),
THF, room temp., 1 h. D: Tributyl(vinyl)stannane (1.1 equiv.), Pd(OAc)2 (10 mol-%), PPh3 (0.2 equiv.), DMF, 60 °C, 10 h. E: Methyl acrylate (1.5 equiv.), Pd(OAc)2
(5 mol-%), LiCl (3 equiv.), Et3N (1 equiv.), DMF, 70 °C, 12 h. [b] Isolated yield.
Thus, we have developed a novel, efficient and general
methodology for the reduction of aryl- and alkyl-substituted
gem-dibromides to the corresponding vinyl bromides through
the use of ohmic heating. To the best of our knowledge, this
is the first report of the indium-promoted reduction of gem-
dibromides to vinyl bromides that is effective for alkyl-substi-
tuted gem-dibromides, and certainly it broadens the scope of
these indium-mediated reductions.
Without any optimization the yields for these coupling reac-
tions were good, which demonstrates that the scope of the
chain-elongation of carbohydrate derivatives by the dibromo
alkene reduction/cross-coupling reaction sequence is broad
and will allow the modification of carbohydrates into libraries
of highly diverse compounds.
Conclusions
We have also described a general method for the synthesis
of highly functionalized (1E)-4-chloro-1-substituted-1,3-dienes
from 2,4-dichlorohomoallyl acetates, derived from the indium-
promoted allylation of aldehydes with 3-bromo-1,3-dichloro-
We have demonstrated that the combination of ohmic heating
with ionic liquids for indium-promoted reactions is of consider-
able synthetic interest and provides convenient alternatives to
the existing methodologies for the synthesis of halo alkenyl propene and subsequent acetylation. This process was carried
compounds.
out by reductive β-elimination promoted by indium and,
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Methyl 2,3,4-Tri-O-benzyl-7-bromo-6,7-dideoxy-α-D-manno-
in contrast to previously reported procedures, by using ionic
liquid media and ohmic heating there is no need of any addi-
tive.
Finally, we prepared a series of sugar-derived alkenes, dienes
and enynes of considerable interest for further synthetic elabo-
rations by palladium-catalysed cross-coupling reactions of the
obtained sugar halo alkenyl substrates.
hept-6-enepyranoside (2n): Pale-yellow oil. Rf = 0.24 (hexane/
EtOAc, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.35–7.25 (m, 30 H), 6.50–
6.31 (m, 4 H), 4.88–4.58 (m, 14 H), 3.99 (dd, J = 9.5, 6.4 Hz, 1 H),
3.99–3.72 (m, 7 H), 3.38 (s, 3 H), 3.28 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 138.6, 138.4, 138.3, 138.2, 138.1, 134.8, 132.6, 120.5,
128.4, 128.3, 128.2, 128.1, 120.8, 127.9, 127.8, 127.7, 127.6, 112.7,
112.5, 110.7, 110.3, 112.9, 109.4, 99.3, 75.3 (CH2), 75.1, 74.8, 74.7,
72.9, 72.6, 72.4, 72.1, 63.3, 55.2, 54.9 ppm. MS (ESI+-TOF): m/z (%) =
In view of the results presented herein, we are sure that the
synergy arising from the combined use of indium, ionic liquids 563 (12, 81Br) [M + Na]+, 561 (14, 79Br) [M + Na]+, 487 (100). HRMS
(ESI+): calcd. for C29H3179BrNaO5 [M + Na]+ 561.1247; found
and ohmic heating will certainly go a long way to meet the
increasing demand for environmentally benign chemical proc-
561.1238.
esses.
3-O-Benzyl-6-bromo-5,6-dideoxy-1,2-O-isopropylidene-α-D-
xylo-hex-5-enefuranose (2o): Yellow oil. Rf = 0.31 (hexane/EtOAc,
1
9:1). H NMR (300 MHz, CDCl3): δ = 7.36–7.26 (m, 10 H), 6.51–6.31
(m, 4 H), 5.98 (d, J = 3.8 Hz, 1 H), 5.94 (d, J = 3.4 Hz, 1 H), 4.69–4.50
(m, 8 H), 4.10 (d, J = 3.2 Hz, 1 H), 3.87 (d, J = 3.1 Hz, 1 H), 1.53 (s, 3
H), 1.48 (s, 3 H), 1.33 (s, 3 H), 1.31 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 137.3, 137.1, 131.7, 130.6, 128.5, 128.0, 127.9, 127.7,
127.6, 111.9, 111.8, 110.3, 110.3, 104.9, 104.8, 82.8, 82.7, 82.5, 80.3,
78.9, 72.3, 72.2, 26.9, 26.8, 26.4, 26.2 ppm. MS (ESI+-TOF): m/z (%) =
374 (74, 81Br) [M + NH4]+, 372 (75, 79Br) [M + NH4]+, 314 (34), 274
(12). HRMS (ESI+): calcd. for C16H2379BrNO4 [M + NH4]+ 372.0805;
found 372.0795.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a 300 MHz
NMR spectrometer [300.13 MHz (1H), 75.47 MHz (13C)] with TMS as
internal reference and with CDCl3 as solvent. Chemical shifts (δ) are
quoted in ppm relative to TMS; coupling constants (J) are quoted
in Hz. ESI-MS and ESI-HRMS (70 eV) were carried out with an elec-
trospray ionization mass spectrometer with a micro-TOF analyser.
For experiments carried out under ohmic heating, the 10 mL reactor
was filled with the reaction mixture, closed and the mixture was
heated to 95 °C. For 4 mL of reaction mixture, the length of the
electrodes immersed in the reaction medium was 9 mm and the
distance between the electrodes was 10 mm. An average magnetic
stirring speed of 740 rpm was used in all the experiments carried
out in the ohmic heating reactor. The temperature was measured
with a type J glass-sheathed thermocouple inside the reactor. For
experiments carried out under conventional heating (oil bath), an
average magnetic stirring speed of 740 rpm was used. Microwave-
assisted reactions were carried out in a circular single-mode cavity
instrument (300 W max magnetron power output). The temperature
was measured by using an IR sensor. An average stirring speed (ca.
900–1000 rpm) was used in the experiments.
3-(2-Bromovinyl)-4H-chromen-4-one (2p): White solid; m.p. 107–
109 °C (CH2Cl2/hexane). Rf = 0.30 (hexane/EtOAc, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 8.27 (dd, J = 1.5, 8.0 Hz, 1 H), 7.92 (s, 1 H),
7.74 (d, J = 13.6 Hz, 1 H), 7.69–7.66 (m, 1 H), 7.48–7.41 (m, 2 H),
6.82 (d, J = 13.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.9,
156.0, 154.9, 133.9, 126.2, 125.5, 123.8, 123.0, 119.8, 118.3,
108.5 ppm. MS (ESI+-TOF): m/z (%) = 252 (5, 81Br) [M + H]+, 250 (5,
79Br) [M + H]+, 291 (100). HRMS (ESI+): calcd. for C11H879BrO2 [M +
H]+ 250.9702; found 250.9695.
General Procedure for the Preparation of 1-Chloro-1,3-dienes
4: A mixture of the corresponding 2,4-dichlorohomoallyl acetate 3
(0.50 mmol) and indium metal (0.60 mmol) in [bmim]Br (2.00 g) was
stirred under ohmic heating at 95 °C for the time specified in
Table 3. The reaction mixture was then partitioned between Et2O
(10 mL) and H2O (10 mL). The aqueous layer was extracted with
Et2O (2 × 10 mL) and the combined extracts were dried with Na2SO4
and evaporated under reduced pressure to afford products 4. The
physical data of the known 1-chloro-1,3-dienes 4a–g are compara-
ble to those in the literature.[14] The physical data of the new 1-
chloro-1,3-dienes 4h–j are given below.
General Procedure for the Preparation of 1-Bromo Alk-1-enes
2:
A mixture of the corresponding gem-dibromo alkene 1
(0.50 mmol) and indium metal (0.60 mmol) in [bmim]Br (2.00 g) was
stirred under ohmic heating at 95 °C for the time specified in
Table 2. The reaction mixture was then partitioned between Et2O
(10 mL) and H2O (10 mL). The aqueous layer was extracted with
Et2O (2 × 10 mL) and the combined extracts were dried with Na2SO4
and evaporated under reduced pressure to afford the products 2.
The physical data of the known 1-bromo alk-1-enes 2a–l are compa-
rable to those in the literature.[10] The physical data of the new 1-
bromo alk-1-enes 2m–p are given below.
9-Chloro-1,2:3,4-di-O-isopropylidene-6,7,8,9-tetradeoxy-β-D-
galacto-non-6(E),8-dieno-1,5-pyranose (4h): Pale-yellow oil. Rf =
0.34 (hexane/EtOAc, 9:1). 1H NMR (300 MHz, CDCl3): δ = 6.77–6.68
(m, 1 H, 8-HZ), 6.66–6.63 (m, 1 H, 8-HE), 6.34 (dd, J = 11.6, 7.9 Hz, 1
H, 7-HE), 6.34 (dd, J = 10.4, 7.2 Hz, 1 H, 7-HZ), 6.21 (d, J = 12.9 Hz, 1
H, 9-HE), 6.02 (d, J = 7.1 Hz, 1 H, 9-HZ), 5.93 (dd, J = 15.9, 6.7 Hz, 1
H, 6-HZ), 5.84–5.75 (m, 1 H, 6-HE), 5.60–5.57 (m, 2 H, 1-HE, 1-HZ),
4.65–4.60 (m, 2 H), 4.39–4.30 (m, 4 H), 4.25–4.19 (m, 2 H), 1.56 (s, 3
H), 1.55 (s, 3 H), 1.47 (s, 3 H), 1.46 (s, 3 H), 1.35 (s, 6 H), 1.35 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3): major isomer: δ = 132.1, 129.2,
126.0, 119.0, 109.4, 108.5, 96.4, 73.74, 70.28, 70.3, 68.6, 26.2, 25.9,
24.9, 24.3 ppm. MS (ESI+-TOF): m/z (%) = 319 (35, 37Cl) [M + H]+,
317 (100, 35Cl) [M + H]+. HRMS (ESI+): calcd. for C15H2235ClO5 [M +
H]+ 317.1150; found 317.1150.
6-Bromo-1-O-tert-butyldimethylsilyl-5,6-dideoxy-2,3-O-iso-
propylidene-α-D-lyxo-hex-5-enefuranose (2m): Pale-yellow oil.
1
Rf = 0.38 (hexane/EtOAc, 9:1). H NMR (300 MHz, CDCl3): δ = 6.37–
6.19 (m, 4 H), 5.21 (s, 1 H), 5.17 (s, 1 H), 4.86–4.82 (m, 1 H), 4.73–
4.65 (m, 1 H), 4.59–4.56 (m, 1 H), 4.46–4.40 (m, 2 H), 4.36–4.32 (m,
1 H), 1.47 (s, 3 H), 1.33 (s, 3 H), 1.18 (s, 3 H), 1.08 (s, 3 H), 0.77 (s, 9
H), 0.75 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H), –0.01 (s, 3 H), –0.04 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 132.0, 130.2, 112.7, 112.5,
110.7, 110.3, 101.3, 101.2, 87.1, 81.0, 80.6, 80.3, 79.9, 77.8, 26.1, 26.0,
25.6, 25.6, 24.9, 24.8, 17.9, 15.3, –4.5, –5.4 ppm. MS (ESI+-TOF): m/z 3-O-Benzyl-8-chloro-1,2-O-isopropylidene-5,6,7,8-tetradeoxy-
(%) = 380 (4, 81Br) [M]+, 378 (4, 79Br) [M]+, 317 (100). HRMS (ESI+):
calcd. for C15H2979BrNO7Si [M]+ 380.8415; found 380.8400.
α-D-xylo-oct-5(E),7-dieno-1,4-furanose (4i): Pale-yellow oil. Rf =
0.32 (hexane/EtOAc, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.34–7.28
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(m, 10 H), 6.83–6.74 (m, 1 H), 6.51–6.46 (m, 1 H), 6.39–6.32 (m, 3 H),
6.07–5.96 (m, 4 H), 5.82 (dd, J = 15.3, 7.1 Hz, 1 H), 4.73 (dd, J = 7.4,
2.6 Hz, 1 H), 4.67–4.63 (m, 5 H), 4.55–4.49 (m, 2 H), 3.90–3.86 (m, 2
H), 1.51 (s, 3 H), 1.49 (s, 3 H), 1.33 (s, 3 H), 1.32 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): major isomer: δ = 137.4, 130.4, 129.0, 128.5,
127.9, 127.6, 127.3, 119.5, 111.7, 104.9, 83.6, 82.7, 80.9, 72.2, 26.8,
26.2 ppm. MS (ESI+-TOF): m/z (%) = 339 (35, 37Cl) [M + H]+, 337
(100, 35Cl) [M + H]+. HRMS (ESI+): calcd. for C18H2235ClO4 [M + H]+
337.1201; found 317.1239.
The resulting residue was purified by column chromatography (sil-
ica gel, hexane/EtOAc).
(6E)-1,2:3,4-Di-O-isopropylidene-9-C-phenyl-6,7,8,9-tetrade-
oxy-β-D-galacto-nona-6-en-8-ynopyranose (5b): Yellow oil.
1
[α]D22 = +4.6 (c = 0.6, CHCl3). Rf = 0.31 (hexane/EtOAc, 8:1). H NMR
(300 MHz, CDCl3): δ = 7.42–7.39 (m, 2 H), 7.33–7.26 (m, 3 H), 6.11
(dd, J = 11.0, 8.0 Hz, 1 H, 8-H), 5.90 (dd, J = 11.0, 1.0 Hz, 1 H, 7-H),
5.58 (d, J = 5.0 Hz, 1 H, 1-H), 5.01 (dd, J = 8.0, 2.0 Hz, 1 H, 5-H), 4.67
(dd, J = 7.9, 2.5 Hz, 1 H, 3-H), 4.39–4.44 (m, 2 H, 2-H, 4-H), 1.57 (s, 3
H), 1.50 (s, 3 H), 1.35 (s, 3 H), 1.34 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 138.7, 131.4, 128.4, 128.3, 122.9, 111.4, 109.3, 108.9, 96.4,
95.1, 85.2, 73.2, 70.8, 70.3, 67.0, 26.1, 25.9, 25.0, 24.3 ppm. MS (ESI+-
TOF): m/z (%) = 357 (4) [M + Na]+, 241 (100). HRMS (ESI+): calcd. for
C21H25O5 [M + H]+ 357.1696; found 357.1707.
3-[(1E)-4-Chlorobuta-1,3-dien-1-yl]-6-methyl-4H-chromen-4-
one (4j): Yellow oil. Rf = 0.38 (hexane/EtOAc, 9:1). 1H NMR (300 MHz,
CDCl3): δ = 8.08–7.96 (m, 4 H), 7.79–7.33 (m, 6 H), 6.66–6.31 (m, 5
H), 6.09 (d, J = 7.1 Hz, 1 H), 2.46 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): major isomer: δ = 176.5, 159.3, 153.7, 135.4, 134.9, 134.4,
128.3, 125.5, 123.8, 123.7, 121.7, 117.8, 21.0 ppm. MS (ESI+-TOF): m/z
(%) = 249 (35, 37Cl) [M + H]+, 248 (15), 247 (100, 35Cl) [M + H]+. HRMS
(ESI+): calcd. for C14H1237ClO2 [M + H]+ 249.0491; found 249.0487.
General Procedure for the Kumada Reaction (Method C): A reac-
tion flask containing the corresponding chlorodiene 4 (1 equiv.) and
[Pd(PPh3)4] (5 mol-%) was degassed and filled with argon. DMF
(5 mL/mmol) and Et3N (3 equiv.) were added followed by phenyl-
magnesium bromide (2 equiv.). After stirring at room temp. for 1 h,
the mixture was quenched with an aqueous saturated solution of
NH4Cl (8 mL/mmol) and extracted with Et2O (5 mL/mmol). The com-
bined organic extracts were washed with H2O (5 mL/mmol) and
brine (5 mL/mmol), dried (Na2SO4) and concentrated to dryness.
The resulting residue was purified by column chromatography (sil-
ica gel, hexane/EtOAc).
General Procedure for the Suzuki Reaction (Method A): A reac-
tion flask containing the corresponding bromo alkene 2 (1 equiv.),
Ph3P (0.2 equiv.), Pd(OAc)2 (5 mol-%), K2CO3 (1.5 equiv.) and phenyl-
boronic acid (1.2 equiv.) was degassed and filled with argon. DMF
(5 mL/mmol) was added and the resulting mixture was stirred at
70 °C. After 12 h, the reaction mixture was diluted with H2O (8 mL/
mmol) and extracted with Et2O (5 mL/mmol). The combined or-
ganic extracts were washed with H2O (5 mL/mmol) and brine (5 mL/
mmol), dried (Na2SO4) and concentrated to dryness. The resulting
residue was purified by column chromatography (silica gel, hexane/
EtOAc).
(6E,8E)-1,2:3,4-Di-O-isopropylidene-9-C-phenyl-6,7,8,9-tetra-
deoxy-β-D-galacto-nona-6,8-dieno-1,5-pyranose (5c): Yellow oil.
1
Rf = 0.38 (hexane/EtOAc, 9:1). H NMR (300 MHz, CDCl3): δ = 7.34–
7.26 (m, 10 H), 6.92–6.79 (m, 2 H), 6.59–6.26 (m, 4 H), 5.98–5.90 (m,
2 H), 5.61–5.56 (m, 2 H), 4.63–4.60 (m, 2 H), 4.36–4.30 (m, 4 H), 4.24–
4.21 (m, 2 H), 1.56 (s, 3 H), 1.52 (s, 3 H), 1.49 (s, 3 H), 1.46 (s, 3 H),
1.38 (s, 3 H), 1.36 (s, 3 H), 1.35 (s, 3 H), 1.33 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): major isomer: δ = 137.4, 131.2, 130.5, 129.6, 129.0,
128.2, 127.0, 115.3, 109.3, 108.5, 96.4, 73.5, 70.9, 70.4, 68.7, 26.1,
26.0, 24.9, 24.3 ppm. MS (ESI+-TOF): m/z (%) = 359 (100) [M + H]+,
358 (12) [M]+. HRMS (ESI+): calcd. for C21H27O5 [M + H]+ 359.1853;
found 359.1853.
(6E)-6,7-Dideoxy-1,2:3,4-di-O-isopropylidene-7-C-phenyl-β-D-
galacto-hept-6-enopyranose (5a): [α]D22 = +32.1 (c = 2.1, CHCl3).
1
Rf = 0.31 (hexane/EtOAc, 8:1). H NMR (300 MHz, CDCl3): δ = 7.43–
7.40 (m, 2 H), 7.32–7.22 (m, 3 H), 6.68 (d, J = 15.8 Hz, 1 H, 7-H), 6.31
(dd, J = 15.8, 6.7 Hz, 1 H, 6-H), 5.62 (d, J = 5.0 Hz, 1 H, 1-H), 4.65
(dd, J = 7.8, 2.3 Hz, 1 H, 3-H), 4.35 (dd, J = 5.0, 2.3 Hz, 1 H, 2-H),
4.46–4.44 (m, 1 H, 5-H), 4.28 (dd, J = 7.8, 2.0 Hz, 1 H, 4-H), 1.57 (s,
3 H), 1.50 (s, 3 H), 1.35 (s, 3 H), 1.34 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.1, 129.0, 128.7, 128.5, 128.2, 127.8, 111.4, 109.1, 96.2,
73.1, 70.9, 70.2, 69.4, 26.1, 26.0, 25.0, 24.5 ppm. MS (ESI+-TOF): m/z
(%) = 355 (23) [M + Na]+, 333 (41) [M + H]+. HRMS (ESI+): calcd. for
C19H24NaO5 [M + Na]+ 355.1516; found 355.1519.
(5E,7E)-3-O-Benzyl-1,2-O-isopropylidene-8-phenyl-5,6,7,8-
tetradeoxy-α-D-xylo-oct-5,7-dieno-1,4-furanose (5g): Yellow oil.
1
Rf = 0.38 (hexane/EtOAc, 9:1). H NMR (300 MHz, CDCl3): δ = 7.37–
7.26 (m, 20 H), 6.83–6.74 (m, 1 H), 6.66–6.46 (m, 1 H), 6.39–6.21 (m,
2 H), 6.07–5.94 (m, 5 H), 5.90–5.76 (m, 1 H), 4.74–4.50 (m, 8 H), 3.90
(d, J = 3.2 Hz, 1 H), 3.86 (d, J = 3.1 Hz, 1 H), 1.51 (s, 3 H), 1.49 (s, 3
H), 1.33 (s, 3 H), 1.32 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): major
isomer: δ = 137.4, 130.4, 129.0, 128.5, 127.9, 127.6, 127.3, 119.5,
111.7, 104.9, 83.6, 82.9, 80.9, 72.2, 26.8, 26.2 ppm. MS (ESI+-TOF):
m/z (%) = 379 (25) [M + H]+, 123 (100). HRMS (ESI+): calcd. for
C24H27O4 [M + H]+ 379.1904; found 379.1938.
Methyl (6E)-2,3,4-Tri-O-benzyl-7-C-phenyl-6,7-dideoxy-α-D-
manno-hept-6-enepyranoside (5e): Pale-yellow oil. [α]D22 = +2.4
(c = 0.4, CHCl3). Rf = 0.26 (hexane/EtOAc, 9:1). 1H NMR (300 MHz,
CDCl3): δ = 7.30–7.20 (m, 20 H), 6.75 (d, J = 15.9 Hz, 1 H, 7-H), 6.33
(dd, J = 15.9, 7.0 Hz, 1 H, 6-H), 4.84–4.59 (m, 7 H, 3 OCH2Ph, 2-H),
4.19 (dd, J = 9.0, 7.0 Hz, 1 H, 5-H), 3.94–3.79 (m, 3 H, 2-H, 3-H, 4-H),
3.32 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.7, 138.3,
133.8, 133.1, 128.6, 128.4, 128.3, 128.0, 127.7, 127.6, 127.5, 126.8,
126.6, 99.4, 80.0, 78.9, 75.4, 74.9, 73.0, 72.9, 72.6, 54.9 ppm. MS
(ESI+-TOF): m/z (%) = 559 (100) [M + Na]+. HRMS (ESI+): calcd. for
C35H36NaO5 [M + Na]+ 559.2455; found 559.2423;
General Procedure for the Stille Reaction (Method D): A reaction
flask containing the corresponding bromo alkene 2 (1 equiv.) in
DMF (5 mL/mmol) was degassed and filled with argon. Ph3P
(0.2 equiv.) and Pd(OAc)2 (5 mol-%) were added, followed by tri-
butyl(vinyl)stannane (1.1 equiv.). After stirring at 60 °C for 10 h, the
reaction mixture was diluted with H2O (8 mL/mmol) and extracted
with EtOAc (5 mL/mmol). The combined organic extracts were
washed with H2O (5 mL/mmol) and brine (5 mL/mmol), dried
(Na2SO4) and concentrated to dryness.
General Procedure for the Sonogashira Reaction (Method B): A
reaction flask containing the corresponding bromo alkene 2
(1 equiv.), Ph3P (0.2 equiv.), Pd(OAc)2 (5 mol-%) and CuI (5 mol-%)
was degassed and filled with argon. DMF (5 mL/mmol) and iPr2NH
(2.5 mL/mmol) were added followed by ethynylbenzene (1.2 equiv.).
After stirring at room temp. for 10 h, the mixture was diluted with
H2O (8 mL/mmol) and extracted with Et2O (5 mL/mmol). The com- (5E)-1-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-5,6,7,8-
bined organic extracts were washed with H2O (5 mL/mmol) and
brine (5 mL/mmol), dried (Na2SO4) and concentrated to dryness.
tetradeoxy-α-D-lyxo-oct-5,7-dieno-1,4-furanose (5d): Colourless
oil. [α]D22 = –27.5 (c = 1.2, CHCl3). Rf = 0.27 (hexane/EtOAc, 9:1). 1H
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2010, 21, 436–441; c) P. Richardson (Ed.), Thermal Technologies in Food
Processing, CRC Press, Boca Raton, FL, 2001, p. 241; d) B. K. Sastry, Advan-
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A. M. G. Silva, L. M. N. B. F. Santos, A. M. S. Silva, J. Org. Chem. 2015, 80,
6649–6659; c) M. F. do C. Cardoso, A. T. P. C. Gomes, V. L. M. Silva, A. M. S.
Silva, M. G. P. M. S. Neves, F. de C. da Silva, V. F. Ferreira, J. A. S. Cavaleiro,
RSC Adv. 2015, 5, 66192–66199.
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2084; b) P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 2000, 39, 3772–
3789; Angew. Chem. 2000, 112, 3926; c) R. Sheldon, Chem. Commun.
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see: c) M. B. Isaac, T.-H. Chan, J. Chem. Soc., Chem. Commun. 1995, 1003–
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NMR (300 MHz, CDCl3): δ = 6.33–6.20 (m, 2 H), 5.73 (dd, J = 4.8,
8.9 Hz, 1 H), 5.21 (s, 1 H), 5.14 (dd, J = 1.3, 9.8 Hz, 1 H), 5.03 (dd,
J = 1.3, 5.9 Hz, 1 H), 4.59 (dd, J = 2.2, 3.5 Hz, 1 H), 4.45 (d, J = 3.5 Hz,
1 H), 4.41 (dd, J = 2.2, 4.8 Hz, 1 H), 1.37 (s, 3 H), 1.20 (s, 3 H), 0.78
(s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 163.4, 134.8, 127.4, 118.2, 112.4, 101.3, 87.3, 81.7, 80.5, 26.1,
25.6, 24.9, 17.9, –4.5, –5.4 ppm. MS (ESI+-TOF): m/z (%) = 521 (100)
[M + H]+. HRMS (ESI+): calcd. for C28H45O7Si [2M – OTBS – H]+
521.2929; found 521.2925.
[2]
[3]
General Procedure for the Heck Reaction (Method E): A reaction
flask containing the corresponding bromo alkene 2 (1 equiv.) in
DMF (5 mL/mmol) was degassed and filled with argon. LiCl
(3 equiv.) and Et3N (1 equiv.) were added, followed by Pd(OAc)2
(5 mol-%) and methyl acrylate (1.5 equiv.). After stirring at 70 °C for
12 h, the reaction mixture was diluted with H2O (8 mL/mmol) and
extracted with EtOAc (5 mL/mmol). The combined organic extracts
were washed with H2O (5 mL/mmol) and brine (5 mL/mmol), dried
(Na2SO4) and concentrated to dryness. The resulting residue was
purified by column chromatography (silica gel, hexane/EtOAc).
Methyl (5E,7E)-3-O-Benzyl-1,2-O-isopropylidene-5,6,7,8-tetra-
deoxy-α-D-xylo-nona-5,7-dienofuranuronate (5f): Yellow oil.
1
[α]D21 = –2.6 (c = 0.4, CHCl3). Rf = 0.21 (hexane/EtOAc, 7:1). H NMR
(300 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H), 6.50 (dd, J = 15.4, 11.1 Hz,
1 H), 6.17 (dd, J = 15.4, 6.4 Hz, 1 H), 5.99 (d, J = 3.7 Hz, 1 H), 5.91
(d, J = 15.2 Hz, 1 H), 4.75–4.71 (m, 1 H), 4.66–4.62 (m, 3 H), 4.50 (d,
J = 12.2 Hz, 1 H), 3.92 (d, J = 3.1 Hz, 1 H), 3.76 (s, 3 H, OCH3), 1.50
(s, 3 H, CH3), 1.33 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.4, 143.7, 137.2, 135.8, 130.8, 128.5, 128.0, 127.7, 121.7, 111.8,
104.9, 83.2, 82.8, 80.3, 72.2, 51.6, 26.8, 26.2 ppm. MS (ESI+-TOF): m/z
(%) = 361 (100) [M + H]+. HRMS (ESI+): calcd. for C20H25O6 [M + H]+
361.1646; found 361.1645.
[4]
[5]
Acknowledgments
[6]
Thanks are due to the University of Aveiro and Fundação para
a Ciência e Tecnologia / Ministério da Educação e Ciência (FCT/
MEC) for financial support to the QOPNA research project (FCT
UID/QUI/00062/2013) through national funds and where appli-
cable co-financed by Fundo Europeu de Desenvolvimento Re-
gional (FEDER) within the PT2020 Partnership Agreement and
also to the Portuguese NMR Network and the Spanish Minis-
terio de Economía y Competitividad (MEC) (CTQ2010-14959).
We further wish to thank Aveiro Institute of Materials (CICECO)
for specific funding toward the purchase of the single-crystal
X-ray diffractometer. R. G. S. and V. L. M. S. thank the projects
Harvesting the Energy of the Sun for a Sustainable Future (MI-
PI-6-ARH/2014) and New Strategies Applied to Neuropathologi-
cal Disorders (CENTRO-07-ST24-FEDER-002034), respectively, co-
funded by Quadro de Referência Estratégica Nacional (QREN),
Mais Centro-Programa Operacional Regional do Centro, the Eu-
ropean Union (EU) and FEDER, for their Assistant Research posi-
tions, and J. P. thanks the Fundação para a Ciência e Tecnologia
(FCT) for her Ph. D. grant (SFRH/BD/77807/2011).
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Z. Rappoport (Ed.), The Chemistry of Dienes and Polyenes, Wiley, New
York, 1997.
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Keywords: Ohmic heating · Ionic liquids · Dehalogenation ·
Elimination · Cross-coupling · Palladium · Indium
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Published Online: November 13, 2015
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