Palladium-Catalyzed Stereoconvergent Formylation of (E/Z)-β-Bromo- β-fluorostyrenes: Straightforward Access to (Z)-α-Fluorocinnamic Aldehydes and (Z)-β-Fluorocinnamic Alcohols

Article abstract of DOI:10.1021/jo200798h

We report here the stereoconvergent formylation of (E/Z)-β-bromo- β-fluorostyrene mixtures with carbon monoxide and sodium formate catalyzed by palladium. Optimization of reaction conditions leads to the corresponding pure (Z)-α-fluorocinnamaldehydes in g

Full text of DOI:10.1021/jo200798h

ARTICLE
pubs.acs.org/joc
Palladium-Catalyzed Stereoconvergent Formylation of
(E/Z)-β-Bromo-β-fluorostyrenes: Straightforward Access to
(Z)-R-Fluorocinnamic Aldehydes and (Z)-β-Fluorocinnamic Alcohols
Rajae Zemmouri,† Mohammed Kajjout,† Yves Castanet,§ Said Eddarir,†,‡ and Christian Rolando*,†
†USR CNRS 3290, Miniaturisation pour la Synthꢀese, l’Analyse et la Protꢁeomique
§UMR CNRS 8181, Unitꢁe deCatalyse etde Chimie duSolide, Universitꢁe de Lille 1, Sciences et Technologies, 59655 Villeneuve d’Ascq, France
‡Facultꢁe des Sciences et Techniques Guꢁeliz, Universitꢁe de Cadi Ayyad, BP 549 Marrakech, Morocco
S Supporting Information
b
ABSTRACT: We report here the stereoconvergent formylation of
(E/Z)-β-bromo-β-fluorostyrene mixtures with carbon monoxide and
sodium formate catalyzed by palladium. Optimization of reaction condi-
tions leads to the corresponding pure (Z)-R-fluorocinnamaldehydes in
good yields. The reaction was extended to styrenes bearing electro-
attracting or electro-donating groups. The obtained R-fluoroaldehydes
were smoothly reduced to the corresponding (Z)-β-fluorocinnamic
alcohol by NaBH4. The reaction could be performed on functionalized
substrates as demonstrated by the access to the glucoside of β-
fluoroconiferyl alcohol, (Z)-β-fluoroconiferin, a strong inhibitor of
lignin polymerization.
’ INTRODUCTION
nonfluorinated conjugated acids, reduction by NaBH4 also may
yield the alcohol. The corresponding 2-fluoropropenal is ob-
tained by mild oxidation of the corresponding alcohol, using for
example the tetrapropylammonium perruthenate/N-methyl-
morpholine-N-oxide (TPAP/NMO) system or DessꢀMartin
reagent. There are few syntheses leading directly to the alde-
hyde, and they use even harsher conditions, which are not
compatible with functionalized molecules.10 We were con-
fronted with this problem during the synthesis the O-glucoside
of fluoroconiferyl alcohol, (Z)-β-fluoroconiferin, a strong in-
hibitor of lignin polymerization.11 The final step involves the
reduction of the fully protected glucoside ester by NaBH4
(7.4 equiv), in the presence of LiCl (10 equiv) in glyme
(80 °C, 18 h), and leads to a time-consuming purification due
to the deprotection of the pentaacetate glucose moiety. As a
result, we are particularly interested in applying the same
strategy we developed for the synthesis of the natural compound
coniferin, which is based on the mild reduction of the corre-
sponding aldehyde by NaBH4.12
In the past few years, there has been an increased interest in
fluoroorganic compounds in the pharmaceutical and agrochem-
ical industries.1,2 Indeed, the introduction of only one fluorine
atom in a strategic position often leads to analogues of natural
compounds with the same MichaelisꢀMenten affinity constant
but with very different reaction rates or completely different
reaction pathways.3 Among this class of monofluorinated mol-
ecules, 2-fluoropropenal and 2-fluoropropenol derivatives have
attracted much attention. 2-Fluoropropenals are key intermedi-
ates for the synthesis of more complex structures.4 (Z)-R-
Fluorocinnamic aldehydes themselves have been transformed
in a conjugated chain by reaction with a WittigꢀHorner reagent
during the synthesis of retinoid X receptor agonists or RXR-
selective modulators. They have also been used as precursors to
obtain chiral 2-fluoro-3-phenylpropionic acid or transformed
into an imine, which leads to chiral fluorinated allyl amines by
addition of Grignard reagents.5 The 2-fluoropropenol motif is
also the key structure of several biologically active compounds6
and is used as a building block.7 Introduction of a fluorine atom in
the cinnamic alcohol part of the Factor Xa inhibitor leads to the
most active compound, which furthermore responds negatively
to the Ames test, unlike the nonfluorinated analogue.8 (Z)-R-
Fluorocinnamic aldehydes and (Z)-β-fluorocinnamic alcohols
themselves are found in several patents either as intermediate or
final products.9 In most syntheses, 2-fluoropropenol is obtained
by the reduction of the corresponding ester synthesized
by WittigꢀHorner condensation of triethylfluorophosponace-
tate with a strong reducing reagent such as DIBAL-H. Unlike
Our group and others have proposed an efficient methodology
for the stereoselective access to fluoroolefins starting from R-
bromo-R-fluoroolefins by palladium-catalyzed coupling reac-
tions.13 These olefins could be easily obtained via a Zn(Cu)-
or Et2Zn-promoted WittigꢀBurton reaction of CBr3F and PPh3
with aldehydes, which gave an E/Z R-bromo-R-fluorolefins
mixture in good yields.14 Recently, Burton et al. have described
Received: April 22, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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Scheme 1. Reaction of β-Bromo-β-fluorostyrene 1 with CO
and HCOONa Catalyzed by PdCl2(PPh3)2
Table 2. Formylation of Substituted β-Bromo-β-fluorostyr-
enes 1 with Sodium Formate (1 equiv) under 40 bar Pressure
of CO in DMFa
isolated yield
1
R, meta R0, para R00, meta 1 (E/Z)c
2/3
(%) 2
1a
1b
1c
1d
1e
1f
H
H
H
26/74
90/10
74/26
87/13
85/15
90/10
91/9
78
74
81
76
85
84
61
61
60
H
Cl
H
H
F
H
H
NO2
H
H
MeO
Br
MeO
H
95/5
MeO
GluOb
GluOb
GluOb
73/27
90/10
67/33
67/33
67/33
1g
1h
1i
MeO
H
H
H
Table 1. Effects of Several Parameters on the Formylation of
β-Bromo-β-fluorostyrene 1aa
MeO
MeO
a Substrate 1 (1.83 mmol), PPh3 (0.18 mmol), powdered HCOONa
(1.83 mmol), PdCl2(PPh3)2 (0.091 mmol), DMF (13 mL), and CO (40
atm) at 80 °C for 18 h. b GluO = 2,3,4,6-tetra-O-acetyl-β-D-glucopyra-
nosyl. c From 19F NMR and checked by GCꢀMS.
isolated
yield (%)
entry solvent HCOONa (equiv) T (°C) P(CO) t (h) 2a, Z 3a, E
a
b
c
d
e
f
ACN
THF
1.0
1.0
1.0
1.0
0.5
5.0
1.0
1.0
100
100
100
100
100
100
80
1
1
48
48
48
48
48
48
18
18
0
0
30
30
20
51
21
0
Scheme 2. Reduction of (Z)-R-Fluorocinnaldehydes 2 by
Sodium Borohydride
DMSO
DMF
DMF
DMF
DMF
DMF
1
0
1
20
6
1
1
0
g
h
10
40
31
78
41
20
80
a 1a E/Z mixture (26/74), (1.83 mmol), PPh3 (0.18 mmol), powdered
HCOONa (1 equiv: 1.83 mmol), PdCl2(PPh3)2 (0.091 mmol), solvent
(13 mL), CO (P bar)) at T °C for t h.
reduction is much more difficult than carbonꢀchlorine bond
reduction, as observed during the reaction of 1-chloro-1-fluoro-
ethylene in the presence of Et3SiH using (PPh3)3RhCl as catalyst
at 35 °C.21 So, as expected for a palladium-catalyzed reaction, no
fluorine atom loss was observed even in our strongly reducing
conditions due to the presence of carbon monoxide and sodium
formate. The reduction of the double bond, which has been
previously described on R-fluoroconjugated aldehydes using Pd/
C as catalyst, was also not detected.22
In order to optimize the reaction, several parameters were
examined: (i) nature of the solvent, (ii) number of sodium
formate equivalents, (iii) temperature, (iv) CO pressure, and (v)
reaction time.
The trend observed is very similar to the behavior of
bromobenzene.20 The reaction in apolar solvents such as aceto-
nitrile and THF gave only reduction product 3a (Table 1, entries
a, b). However, formylation of β-bromo-β-fluorostyrene appears
to be more sensitive as no product is observed in DMSO
(Table 1, entry c), unlike bromobenzene, which gave a fair yield.
The reaction yield and the product repartition also depend on
the amount of sodium formate used. Formation of the reduction
byproduct 3a was favored when only 0.5 equiv of HCOONa was
added to the mixture, leading to a 2/3 ratio of 0.3 (Table 1, entry
e). The 2/3 ratio increased to 0.4 when 1 equiv of HCOONa was
used (Table 1, entry d). However, no reaction was observed
when an excess of sodium formate was used (Table 1, entry f),
unlike the result observed for bromobenzene. The data shown in
Table 1 (entries d and e) suggest that (Z)-β-bromo-β-fluoro-
styrene 1a, Z reacts preferentially to give the reduced (E)-β-
fluorostyrene 3a, E, whereas (E)-β-bromo-β-fluorostyrene 1a, E
leads to (Z)-R-fluorocinnamaldehyde 2a, Z.
the convergent carbonylation reactions of 1,2-difluoro-1-iodo-
olefins or 1-bromo-1-fluoroolefins with carbon monoxide in the
presence of an alcohol or amine, catalyzed by palladium, leading
to (E)- and (Z)-R-fluoro-R,β-unsaturated esters and amides.15
Starting from these interesting results, we decided to investi-
gate the formylation of R-bromo-R-fluoroolefins by CO in the
presence of a reducing reagent and catalyzed by palladium. The
palladium-catalyzed formylation of aryl or vinyl halides16 is less
documented than their carbonylation.17 Whereas the carbonyla-
tion of nonfluorinated gemdihalides has previously been de-
scribed by one of the authors,18 their formylation has not been
documented. Nevertheless, several mild conditions have been
described for the formylation of aryl or vinyl halides.19 Among
those, we chose to use as hydrogen source for the formylation
sodium formate, a very weak reducing agent that is easily handled
and does not introduce any toxic reagents which could be
deleterious for biological tests.20
’ RESULTS AND DISCUSSION
Formylation Optimization. We were delighted to find that
under Okano’s standard conditions (HCOONa, 1 equiv; CO
pressure 1 bar; DMF, 100 °C for 18 h)20 an E/Z mixture (26/74)
of β-bromo-β-fluorostyrene itself 1a gave the expected (Z)-R-
fluorocinnamicaldehyde in pure Z configuration (Scheme 1).
However, the reaction mixture also contained the expected
reduction product, R-fluorolefin byproduct 3a, but in pure
E configuration (Table 1, entry d). Carbonꢀfluorine bond
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ARTICLE
As expected, the use of high CO pressures resulted in an
increase of the aldehyde yield but also in a sharp increase of the
reaction rate, allowing a decrease in temperature from 100 to
80 °C and in reaction time from 48 to 18 h (Table 1, entries g, h).
In these optimized conditions, no (E)-R-fluorocinnamicalde-
hyde 2a, E was detected and the percentage of (Z)-R-fluorocin-
namaldehyde 2a, Z (74%) was higher than the percentage of (E)-
β-bromo-β-fluorostyrene 1a, E (26%). This result suggests that
(E)-R-fluorocinnamaldehyde 2a, E obtained from (Z)-β-bromo-
β-fluorostyrene 1a is isomerized in the reaction conditions. The
same isomerization was previously observed during the palla-
dium-catalyzed formylation of (Z)-β-bromostyrene by CO/H2,
which yielded (E)-cinnamaldehyde.16d The fact that we obtain
(E)-R-fluorocinnamaldehyde 2a instead of the reduced product
(E)-β-fluorostyrene 3a at higher CO pressure can be explained
by an easier insertion of CO on the π-allylpalladium intermedi-
ate, which is less stable in the case of the (Z)-β-bromo-β-
fluorostyrene 1a isomer. In summary, high CO pressure favors
orienting the reaction toward the formation of R-fluorocinna-
maldehyde 2a and so decreases the formation of the reduced (E)-
β-fluorostyrene 3a. This is shown by the 2a/3a ratio, which
increases from 0.4 to nearly 4 when CO pressure is increased
from 1 to 40 bar (Table 1, entries d and h). As (E)-R-fluorocinna-
maldehyde 2a isomerizes in the reaction medium, the combination
of a 80 °C temperature and high CO pressures (40 bar) allowed us
to isolate pure (Z)-R-fluorocinnamaldehyde 2a in 78% yield.
The most frequently described mechanism for the formylation
of aryl bromide in presence of formate involves (i) the oxidative
addition of the substrate to the Pd(0) catalyst, (ii) the insertion of
CO, (iii) the exchange of the bromide by the formate anion, (iv)
the expulsion of carbon dioxide leading to a palladium hydride
species, and (v) the transfer of the hydride leading to the
aldehyde.20 This mechanism implies that the hydrogen on the
aldehyde comes from the formate anion. However, recently
Zawisza et al. have shown that in the palladium-catalyzed
reduction of aryl halides using dimethylformamide as solvent
DMF is the hydride source.23a In order to check the origin of the
hydrogen in the aldehyde group, the reaction was performed in
DMF-d7 under the optimized reaction on substrate 1d. The mass
spectrum obtained by GCꢀMS analysis using electron ionization
at 70 eV shows no incorporation of deuterium in the aldehyde
2d. This result is highly in favor of a mechanism identical to the
one described previously for the formylation of aryl bromide in
which the hydrogen on the aldehyde comes from the formate
anion. Dimethylformamide was also described as a source of CO
in Pd-catalyzed reaction under microwave irradiation.23b The
strong dependency of the formylation reaction yield on CO
pressure precludes this mechanism.
Table 3. Reduction of Substituted (Z)-R-Fluorocinnalde-
hydes 2 by NaBH4
4
R, meta
R0, para
R00, meta
isolated yield (%) 4
These conditions were applied to the formylation of a wide
variety of β-bromo-β-fluorostyrenes (Table 2) bearing either
simple electron-donating groups (substrate 1h), weakly or
strongly electron-attractive groups (substrates 1b, c and 1d, e
respectively), mixed groups (substrates 1f, g, i), and functional-
ized groups (substrates 1g, h, i). In each case, (Z)-R-fluorocin-
naldehydes were exclusively isolated and the observed
formylation yields ranged from good to excellent. The compar-
ison of E/Z ratio from the starting material 1 to the 2/3 ratio
demonstrates that the reaction is steroconvergent.
4a
4b
4c
4d
4e
4f
H
H
H
86
84
87
90
93
83
80
78
74
H
Cl
H
H
F
H
H
NO2
H
H
MeO
Br
MeO
H
MeO
GluOa
GluOa
GluOa
4g
4h
4i
MeO
H
H
H
MeO
MeO
Reduction of (Z)-R-Fluoro Conjugated Aldehydes to
(Z)-β-Fluoro Conjugated Alcohols. The reduction of
a GluO = 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl.
Scheme 3. Synthesis of (Z)-β-Fluoroconiferin
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ARTICLE
(Z)-R-fluorocinnaldehydes by sodium borohydride in cold metha-
nol (ꢀ10 °C), not previously described to the best of our
knowledge, afforded the corresponding (Z)-β-fluorocinna-
myl alcohols 4 in good yield (74ꢀ93%) without saturation
of the double bond (Scheme 2 and Table 3) as observed for
other (Z)-R-substituted R,β-conjugated aldehydes bearing a
chlorine, a bromine, an iodine, or an alkoxy group.24
Synthesis of (Z)-β-Fluoroconiferin and Analogues. This
methodology gave us a new and straightforward access to (Z)-β-
fluoroconiferin (Scheme 3). Vanilin was first O-glucosylated by
reaction with 1-bromo-2,3,4,6-tetraacetyl-β-D-glucopyranoside
in biphasic conditions, using tris-2-(2-methoxy-ethoxy-ethyl)-
amine (TDA) as the phase transfer agent.25 The corresponding
R-bromo-R-fluoroolefin 1g was obtained via a Zn(Cu)-pro-
moted WittigꢀBurton-type reaction with CBr3F and PPh3 in
THF.13e
Formylation of 1g was achieved with CO, sodium formate, and
Pd under the optimized conditions previously mentioned to give
the corresponding pure (Z)-R-fluoroaldehyde 2g (Table 2, entry
1g). Reduction of aldehyde 2g into alcohol 4g was accomplished
by sodium borohydride in THF. Finally, (Z)-β-fluoroconiferin
5g was obtained by deprotection of acetyl groups by sodium
methanoate in quantitative yields.11,12 The two others fluori-
nated analogues of lignin precursors 5h (R = R00 = H) and 5i (Z)-
β-fluorosyringin (R = R00= OMe) were obtained in a similar way.
condenser. Then freshly prepared Zn(Cu) (1.5 equiv 2 mmol) was added.
The solution was refluxed for 7 h. After cooling, the organic phase was
diluted in diethyl ether, then washed with water, and dried over MgSO4.
The residue obtained after evaporation of the solvent was purified by flash
column chromatography using a mixture of ethyl acetate/dichloromethane
as eluent to obtain the desired β-bromo-β-fluoroolefins as an E/Z
mixture (50/50).
2,3,4,6-Tetra-O-acetyl-1-[4-((2Z)-2-fluoro-2-bromoethenyl)-
2-methoxyphenyl]-β-D-glucopyranoside (1g). Mp 79ꢀ80 °C;
19F NMR (CDCl3) δ ꢀ69.22 (d, E, 3JHF = 32.5 Hz, 1 F), ꢀ65.99 (d, Z,
3JHF = 14.9 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 2.02 (s, 6 H), 2.06 (s, 3
H), 2.15 (s, 3 H), 3.72ꢀ3.78 (m, 1 H), 3.79 (s, Z, 1.5 H), 3.81 (s, E, 1.5
H), 4.11 (dd, 2JHH = 12.3 Hz, 3JHH = 2.5 Hz, 1 H), 4.22 (dd, 2JHH = 12.3
Hz, 3JHH = 5.1 Hz, 1 H), 4.90ꢀ5.17 (m, 2 H),5.25ꢀ5.30 (m, 2 H), 5.90
(d, E, 3JHF = 32.2 Hz, 0.5 H), 6.59 (d, Z, 3JHF = 14.9 Hz, 0.5 H), 6.86 (d,
Z, 3JHH = 8.4 Hz, 0.5 H), 6.87 (d, E, 3JHH = 8.4 Hz, 0.5 H), 6.95 (dd, Z,
3JHH = 8.4 Hz, 4JHH = 1.9 Hz, 0.5 H), 6.96 (dd, E, 3JHH = 8.4 Hz, 4JHH
=
1.9 Hz, 0.5 H), 7.05 (d, Z, 4JHH = 1.9 Hz, 0.5 H), 7.06 (d, E, 4JHH = 1.9
Hz, 0.5 H) ppm. Elemental analysis: theoretical for C23H26BrFO11
(C4H8O2) C, 48.73, H, 5.15, O, 31.26; observed C, 48.40, H, 5.04,
O, 31.52.
2,3,4,6-Tetra-O-acetyl-1-[4-((2Z)-2-fluoro-2-bromoethenyl)-
phenyl]-β-D-glucopyranoside (1h). Mp 72ꢀ73 °C; 19F NMR
(CDCl3) δ ꢀ69.79 (d, E, 3JHF = 32.8 Hz, 1 F) ppm, ꢀ66.47 (d, Z, 3JHF
=
15.0 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 2.03 (s, 3 H), 2.04 (s, 3 H), 2.05
(s, 3 H), 2.06 (s, 3 H), 3.82ꢀ3.89 (m, 1 H), 4.13 (dd, 2JHH = 12.3 Hz,
2
3
3JHH = 2.5 Hz, 1 H), 4.22 (dd, JHH = 12.3 Hz, JHH = 5.1 Hz, 1 H),
5.06ꢀ5.19 (m, 2 H), 5.25ꢀ5.35 (m, 2 H), 5.91 (d, E, 3JHF = 32.4 Hz, 0.5
H), 6.59 (d, Z, 3JHF = 14.5 Hz, 0.5 H), 6.94 (d, Z, 3JHH = 8.6 Hz, 1 H),
6.96 (d, E, 3JHH = 8.7 Hz, 1 H), 7.32 (d, Z, 3JHH = 8.9 Hz, 1 H), 7.40 (d, E,
3JHH = 8.8 Hz, 1 H) ppm. Elemental analysis: theoretical for
C22H24BrFO10 (C4H8O2) C, 49.14, H, 5.08, O, 30.21; observed C,
49.87, H, 4.91; O, 30.62.
’ CONCLUSION
We report on a new and efficient synthesis of (Z)-R-fluoro-
aldehydes that involves formylation of R-bromo-R-fluoroolefins
Z/E mixture with carbon monoxide and sodium formate and is
catalyzed by palladium. Optimization of the reaction parameters
allowed us to drive the formylation toward the formation of pure
(Z)-R-fluoroaldehydes in good yields.
This method can be extended to functionalized substrates
such as R-bromo-R-fluorostyrene p-O-glucoside derivative 1g,
which leads to pure (Z)-β-fluoroconiferin 5g after reduction and
deprotection. By using this straightforward synthesis, several
hundred milligrams of (Z)-β-fluoroconiferin 5g and analogues
5h and 5i were obtained and will be used to further understand
the inhibition of lignin biosynthesis in plantlets growing in an
artificial medium.11,26 Experiments are in progress and results
will be published in a forthcoming paper.
2,3,4,6-Tetra-O-acetyl-1-[4-((2Z)-2-fluoro-2-bromoethenyl)-
2,6-dimethoxyphenyl]-β-D-glucopyranoside (1i). Mp 83ꢀ84 °C;
NMR 19F (CDCl3, 300 MHz) δ ꢀ68.52 (d, E, 3JHF = 32.3 Hz, 1 F), - 65.52
(d, Z, 3JHF = 15.1 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 1.99 (s, 3 H), 2.01 (s,
3 H), 2.02 (s, 3 H), 2.04 (s, 3 H), 3.64ꢀ3.72 (m, 1 H), 3.79 (s, Z, 3 H), 3.81
(s, E, 3 H), 4.13 (dd, 2JHH = 12.3 Hz, 3JHH = 2.5 Hz, 1 H), 4.22 (dd, 2JHH
=
12.3 Hz, 3JHH = 5.1 Hz, 1 H), 5.03ꢀ5.31 (m, 4 H), 5.88 (d, E, 3JHF = 32.2
Hz, 0.5 H), 6.57 (d, Z, 3JHF = 14.5 Hz, 0.5 H), 6.59 (s, Z, 1 H), 6.69 (s, E, 1
H) ppm. Elemental analysis: theoretical for C24H28BrFO12 C, 47.46, H,
4.65, O, 31.61; observed C, 47.51, H, 4.92, O, 32.23.
General Procedure for the Preparation of (Z)-R-Fluoro-
cinnamic aldehydes. A 50 mL stainless steel autoclave equipped
with a magnetic stirrer bar was charged with β-bromo-β-fluoroolefins
(0.5 mmol), PdCl2(PPh3)2 (5%), PPh3 (10%), HCOONa (0.5
mmol), and 5 mL of DMF under nitrogen. The autoclave was
pressurized to 40 bar with CO, and the mixture was agitated and
warmed at 80 °C for 18 h. After cooling to room temperature, the
reactor was vented, the crude solution was filtered, then the resulting
precipitate was washed with dichloromethane, and the solvents were
evaporated. The resulting residue was diluted in dichloromethane
and washed with water (3 ꢁ 50 mL). The organic layer was dried over
MgSO4, and the solvent was evaporated. The product was isolated
by flash column chromatography using a mixture of ethyl acetate/
petroleum ether as eluent.
’ EXPERIMENTAL SECTION
All commercially available products were used as received. Tetrahy-
drofuran (THF) was distilled over sodium benzophenone ketyl under
argon before use. Dimethylformamide (DMF) was distilled under
reduced pressure before use. For flash chromatography, silica- gel 60
(230ꢀ400 mesh ASTM) was used. The melting points were not
1
corrected. NMR spectra were recorded at 300 MHz for H and 13C,
using CDCl3 or CD3OD as solvents and TMS as internal standard;
chemical shifts and J values are given in ppm and Hz, respectively.
Deuterated solvents were 99.9% or better. GCꢀMS were recorded on an
ion trap mass spectrometer fitted with a 60 m ꢁ 0.32 mm apolar column
using electron ionization (EI) at 70 eV. Fast atom bombardment (FAB)
mass spectra were measured on a high resolution double focusing
magnetic sector mass spectrometer.
General Procedure for the Preparation of β-Bromo-β-fluoro-
styrenes. Glucosyloxy-benzaldehydes (1 mmol), fluorotribromethane
(1.5 equiv, 2 mmol), triphenylphosphine (1 equiv, 1 mmol), and 5 mL of
freshly distilled THF were added under argon to a flask fitted with a reflux
(2Z)-2-Fluoro-3-phenyl-2-propenal (2a). 19F NMR (CDCl3)
3
3
1
δ ꢀ126.54 (dd, JHF = 33.2 Hz, JHF = 17.2 Hz) ppm; H NMR
(CDCl3) δ 6.61 (d, 3JHF = 33.1 Hz, 1 H), 7.33 (m, 1 H), 7.47 (d, 3JHH
=
8.4 Hz, 2 H), 7.73 (d, 3JHH = 8.4 Hz, 2 H), 9.37 (d, 3JHF = 17.2 Hz, 1 H)
ppm; 13C NMR (CDCl3) δ 121.14 (d, 2JCF = 4.2 Hz), 128.45, 129.02,
130.28, 131.25, 155.24 (d, 1JCF = 264.8 Hz), 183.15 (d, 2JCF = 26.4 Hz)
ppm. MS (EI) m/z (relative intensity): 150 (M+, 42), 149 (100),
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121 (16), 101 (21), 96 (19), 75 (18). HRMS (m/z): observed 151.0554,
calcd for C9H8OF 151.0553 [M + H]+.
148.07, 150.61, 154.44, 169.22, 169.39, 170.25, 170.53, 183.72 ppm. HRMS
(NH3) (m/z): observed 544.1833, calcd for C24H31O12NF 544.1825.
(2Z)-2-Fluoro-3-[4-(2,3,4,6-tetra-O-acetyl)-β-D-glucopyra-
nosyloxy-phenyl]-2-propenal (2h). Mp 114ꢀ115 °C; 19F NMR
(CDCl3, 300 MHz) δ ꢀ130.63 (dd, 3JHF = 34.2 Hz, 3JHF = 17.4 Hz, 1 F)
ppm; 1H (CDCl3) δ 2.02 (s, 6 H), 2.04 (s, 3 H), 2.08 (s, 3 H), 3.86ꢀ3.91
(2Z)-2-Fluoro-3-(4-chlorophenyl)-2-propenal (2b). 19F
NMR (CDCl3) δ ꢀ128.04 (dd, 3JHF = 33.7 Hz, 3JHF = 16.9 Hz) ppm.
1H NMR (CDCl3) δ 6.57 (d, 3JHF = 33.7Hz, 1 H), 7.41 (d, 3JHH = 8.6 Hz,
2 H), 7.64 (d, 3JHH = 8.6 Hz, 2 H), 9.35 (d, 3JHF = 16.7 Hz, 1 H) ppm; 13
C
(m, 1 H), 4.1 (dd, 2JHH = 14.3 Hz, 3JHH = 7.09 Hz, 1 H), 4.27 (dd, 2JHH
=
NMR (CDCl3) δ 125.15 (d, 2JCF = 3.8 Hz), 129.05 (d, 4JCF = 4.2 Hz),
129.42, 131.76, 136.18, 155.24 (d, 1JCF = 271.72), 183.15 (d, 2JCF = 25.75
Hz) ppm. MS (EI) m/z (relative intensity): 186 (M+ + 2, 7), 184 (M+,
21), 183 (15), 150 (10), 149(100), 121(14), 120 (18), 112 (7), 101 (25),
99 (9), 75 (14), 74 (11). HRMS (m/z): observed 185.0160, calcd for
C9H7OClF 185.0164 [M + H]+.
12.3 Hz, 3JHH = 4.9 Hz, 1 H), 5.13ꢀ5.20 (m, 2 H), 5.27ꢀ5.31 (m, 2 H),
3
3
6.56 (d, JHF = 34.2 Hz, 1 H), 7.02 (d, JHH = 8.4 Hz, 2 H), 7.66 (d,
3JHH = 8.4 Hz, 2 H), 9.30 (d, JHF = 17.4 Hz, 1 H) ppm; NMR 13C
3
(CDCl3) δ 20.61, 61.81, 68.13, 71.03, 72.28, 72.52, 98.29, 117.01,
125.82, 126.10, 132.54, 154.41, 158.41, 169.18, 169.42, 170.22, 170.41,
183.74 ppm. HRMS (NH3) (m/z): observed 514.1722, calcd for
C23H29O11NF 514.1719.
(2Z)-2-Fluoro-3-[4-(2,3,4,6-tetra-O-acetyl)-β-D-glucopyra-
nosyloxy-3,5-dimethoxyphenyl]-2-propenal (2i). Mp 125ꢀ
(2Z)-2-Fluoro-3-(4-fluorophenyl)-2-propenal (2c). 19F
NMR (CDCl3) δ ꢀ129.86 (dd, 3JHF = 33.9 Hz, 3JHF = 16.9 Hz, 1 F),
107.53 (m, 1 F) ppm; 1H NMR (CDCl3) δ 6.57 (d, 3JHF = 34.0 Hz, 1 H),
7.14 (dd, 3JHF = 8.7 Hz, 3JHH = 8.7 Hz, 2 H), 7.72 (dd, 3JHH = 8.7 Hz, 4JHF
= 5.4 Hz, 2 H), 9.34 (d, 3JHF = 16.9 Hz, 1 H) ppm. 13C NMR (CDCl3) δ
116.37 (d, 2JCF = 21.9 Hz), 125.41 (d, 2JCF = 3.6 Hz), 126.9, 132.80 (dd,
3
3
127 °C; 19F NMR (CDCl3) δ ꢀ129.49 (dd, JHF = 33.6 Hz, JHF
=
17.1 Hz, 1 F); 1H NMR (CDCl3) δ 2.02 (s, 6 H), 2.04 (s, 3 H), 2.07 (s, 3
3JCF = 8.4 Hz, 4JCF = 8.4), 154.41(d, 1JCF = 267.5 Hz), 163.95 (d, 1JCF
=
H), 3.40ꢀ3.69 (m, 1 H), 3.85 (s, 6 H), 4.12 (dd, 2JHH = 12.3 Hz, 3JHH
=
250.0), 183.76 (d, 2JCF = 25.7 Hz) ppm. MS (EI) m/z (relative intensity):
168 (M+, 48), 167 (100), 149 (7), 140 (9), 139 (19), 120 (18), 119 (27),
114 (11), 99 (22), 96 (20), 75 (7), 74 (10). HRMS (m/z): observed
169.0456, calcd for C9H7OF2 169.0459 [M + H]+.
7.3 Hz, 1 H), 4.27 (dd, 2JHH = 12.3 Hz, 3JHH = 4.9 Hz, 1 H), 4.98ꢀ5.17
(m, 2 H), 5.26ꢀ5.30 (m, 2 H), 6.52 (d, 3JHF = 33.6 Hz, 1 H), 6.93 (s, 2
H), 9.32 (d, 3JHF = 17.0 Hz, 1 H); 13C NMR (CDCl3) δ 20.60, 56.41,
62.20, 68.45, 71.23, 72.02, 72.88, 100.81, 108.10, 126.43, 127.09, 136.58,
153.22, 154.61, 169.23, 169.44, 170.26, 170.51, 183.70 ppm. HRMS
(NH3) (m/z): observed 574.1927, calcd for C25H33O13NF 574.1930.
General Procedure for the Preparation of (Z)-β-Fluorocin-
namic Alcohols. NaBH4 (1.3 mmol) was added to a solution of R-
fluoroaldehydes (1 mmol) in a mixture of MeOH/THF (50:50) at
ꢀ10 °C. The solution was stirred at room temperature for 2 h, and then
20 mL of HCl (1%) was added to reach pH = 4. After solvent
evaporation, the residue was extracted with CH2Cl2 (2 ꢁ 50 mL).
The organic layer was dried over MgSO4, and the solvent was evapo-
rated. The product was isolated by flash column chromatography using a
mixture of ethyl acetate/petroleum ether as eluent.
(2Z)-2-Fluoro-3-(4-nitrophenyl)-2-propenal (2d). 19F NMR
3
3
(CDCl3) δ ꢀ124.04 (dd, JHF = 33.1 Hz, JHF = 15.7 Hz) ppm;
1H NMR (CDCl3) δ 6.68 (d, 3JHF = 33.1 Hz, 1 H), 7.86 (d, 3JHH = 8.8
Hz, 2 H), 8.27 (d, 3JHH = 8.8, 2 H), 9.44 (d, 3JHF = 15.7 Hz, 1 H) ppm;
13C NMR (CDCl3) δ 122.54 (d, 2JCF = 3.5 Hz), 124.17, 131.25, 136.53
(d, 3JCF = 4.2), 148.45, 155,70 (d, 1JCF = 277.1 Hz), 183,61 (d, 2JCF
=
27.5 Hz) ppm. MS (EI) m/z (relative intensity): 195 (M+, 27), 179 (18),
178 (100) 165 (12), 149 (20), 148 (70), 120 (12), 109 (14), 101 (48),
95 (7), 83 (13), 75 (53), 74 (19). HRMS (m/z): observed 196.0400,
calcd for C9H7O3NF: 196.0404 [M + H]+.
(2Z)-2-Fluoro-3-(3,5-dimethoxyphenyl)-2-propenal (2e).
3
3
19F NMR (CDCl3) δ ꢀ127.94 (dd, JHF = 33.6 Hz, JHF = 16.9 Hz)
(2Z)-2-Fluoro-3-phenyl-2-propen-1-ol (4a). 19F NMR
ppm; 1H NMR (CDCl3) δ 3.81 (s, 6 H), 6.55 (s, 1 H), 6.58 (d, 3JHF
=
(CDCl3) δ ꢀ110.86 (dt, JHF = 38.9 Hz, JHF = 14.8 Hz) ppm;
3
3
33.6 Hz, 1 H), 6.85 (s, 2 H), 9.33 (d, 3JHF = 17.0 Hz, 1 H); 13C NMR
1H NMR (CDCl3) δ 4.46 (d, 3JHF = 14.8 Hz, 2 H), 5.56 (d, 3JHF
=
1
(CDCl3) δ 55.47, 103.34, 108.53, 126.87, 132.15, 154.09 (d, JCF
=
38.9 Hz, 1 H), 7.26 (m, 1 H), 7.32 (d, 3JHH = 8.4 Hz, 2 H), 7.52 (d,
2
2
271.4 Hz), 160.86, 183.98 (d, JCF = 25.4 Hz) ppm. MS (EI) m/z
(relative intensity): 210 (M+, 100), 182 (80), 153 (58), 152 (15), 123
(10), 122 (22), 121 (10), 109 (20), 107 (12), 105 (40), 103 (20), 96
(20). HRMS (m/z): observed 211.0764, calcd for C11H12O3F 211.0765
[M + H]+.
3JHH = 8.4 Hz, 2 H) ppm; 13C NMR (CDCl3) δ 61.22 (d, JCF
=
28.8 Hz) 102.26 (d, 2JCF = 6.7 Hz), 128.17, 128.92, 130.18, 131.97,
157.93 (d, 1JCF = 265.9 Hz) ppm. MS (EI) m/z (relative intensity):
152 (M+, 76), 133 (39), 131 (100), 106 (43), 91 (45), 78 (48), 77 (34),
51 (16). HRMS (m/z): observed 153.0710, calcd for C9H10OF 153.0710
[M + H]+.
(2Z)-2-Fluoro-3-(3-bromo-4-methoxyphenyl)-2-propenal
(2f). 19F NMR (CDCl3) δ ꢀ130.23 (dd, 3JHF = 34.2 Hz, 3JHF = 17.2 Hz)
ppm.1H NMR (CDCl3) δ 3.94 (s, 3 H), 6.51 (d, 3JHF = 34.1 Hz, 1 H),
6.95 (d, 3JHH = 9.0 Hz, 1 H), 7.66 (d, 3JHH = 9.0 Hz, 1 H), 7.90 (s, 1 H),
9.29 (d, 3JHF = 17.2 Hz, 1 H) ppm; 13C NMR (CDCl3) δ 56.41, 111.95,
112.34, 124.61, 125.29, 131.48 (d, 4JCF = 8.4 Hz), 135.48 (d, 4JCF = 8.1
Hz), 154.30 (d, 1JCF = 269.1 Hz), 157.77, 183.53 (d, 2JCF = 24.9 Hz)
ppm. MS (EI) m/z (relative intensity): 260 (M+ + 1, 68), 259 (M+, 18),
258 (M+ - 1, 70), 229 (30), 227(30), 215 (10), 188 (12), 179 (100), 164
(13), 136 (41), 1107 (41), 81 (12), 75 (10). HRMS (m/z): observed
258.9760, calcd for C10H9O2BrF 258.9764 [M + H]+.
(2Z)-2-Fluoro-3-(4-chlorophenyl)-2-propen-1-ol (4b). 19F
NMR (CDCl3) δ ꢀ112.76 (dt, 3JHF = 38.3 Hz, 3JHF = 13.7 Hz) ppm;
1H NMR (CDCl3) δ 4.27 (d, 3JHF = 13.7 Hz, 2 H) 6.57 (d, 3JHF = 38.5
Hz, 1 H), 7.27 (d, 3JHH = 8.6 Hz, 2 H), 7.41 (d, 3JHH = 8.6 Hz, 2 H) ppm;
13C NMR (CDCl3) δ 61.47 (d, 2JCF = 32.9 Hz), 106.38 (d, 2JCF = 6.5
Hz), 128.69, 129.86, 131.17, 133.11, 158.58 (d, 1JCF = 267.4 Hz) ppm.
MS (EI) m/z (relative intensity): 188 (M+ + 2, 23), 186 (M+, 59), 167
(28), 149 (47), 131 (100), 125 (59), 111 (45), 103 (33), 97 (24), 81
(24), 57 (40). HRMS (m/z): observed 187.0317, calcd for C9H9OClF
187.0320 [M + H]+.
(2Z)-2-Fluoro-3-(4-fluororophenyl)-2-propen-1-ol (4c). 19F
NMR (CDCl3) δ ꢀ114.81 (dt, 3JHF = 37.9 Hz, 3JHF = 14.3 Hz, 1 F),
113.97 (m, 1 F) ppm; 1H NMR (CDCl3) δ 4.28 (d, 3JHF = 14.5 Hz, 2 H),
5.75 (d, 3JHF = 37.9 Hz, 1 H), 7.02 (dd, 3JHF = 8.7 Hz, 3JHH = 8.7 Hz, 2
(2Z)-2-Fluoro-3-[4-(2,3,4,6-tetra-O-acetyl)-β-D-glucopyra-
nosyloxy-3-methoxyphenyl]-2-propenal (2g). Mp 123ꢀ
3
3
125 °C; 19F NMR (CDCl3) δ ꢀ130.17 (dd, JHF = 33.9 Hz, JHF
=
17.1 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 2.02 (s, 6 H), 2.05 (s, 6 H),
3.76ꢀ3,82 (m, 1 H), 3.83 (s, 3 H), 4.15 (dd, 2JHH = 14.3 Hz, 3JHH = 7.1
Hz, 1 H), 4.25 (dd, 2JHH = 12.3 Hz, 3JHH = 4.9 Hz, 1 H), 5.01ꢀ5.17 (m,
3
4
H), 7.48 (dd, JHH = 8.7 Hz, JHF = 5.4 Hz, 2 H) ppm; 13C NMR
(CDCl3) δ 61.83 (d, 2JCF = 32.6 Hz), 106.53 (d, 2JCF = 6.8 Hz), 115.62
(d, 2JCF = 21.5 Hz), 128.79, 130.37 (dd, 3JCF = 8.4 Hz, 4JCF = 8.4 Hz),
157.54 (d, 1JCF = 263.8 Hz), 162.36 (d, 1JCF = 247.5 Hz) ppm. MS (EI)
m/z (relative intensity): 170 (M+, 91), 151 (38), 149 (100), 133 (53),
122 (29), 121 (39), 109 (79), 101 (41), 99 (16), 96 (38), 75 (26), 74
2 H), 5.24ꢀ5.33 (m, 2 H), 6.55 (d, 3JHF = 34.0 Hz, 1 H), 7.12 (d, 3JHH
=
=
8 Hz, 1 H), 7.20 (d, 3JHH = 7.8 Hz, 1 H), 7.29 (s, 1 H), 9.30 (d, 3JHF
17.2 Hz, 1 H) ppm; 13C NMR (CDCl3) δ 20.61, 56.12, 61.84, 68.29,
71.04, 72.14, 72.41, 100.02, 114.25, 119.14, 124.43, 126.32, 126.91,
7695
dx.doi.org/10.1021/jo200798h |J. Org. Chem. 2011, 76, 7691–7698

The Journal of Organic Chemistry
ARTICLE
(14). HRMS (m/z): observed 171.0615, calcd for C9H9OF2 171.0616
[M + H]+.
(d, 3JHF = 38.1 Hz, 1 H), 6.72 (s, 2 H) ppm; 13C NMR (CDCl3) δ 20.71,
56.30, 61.71, 62.23, 68.54, 71.30, 71.91, 73.14, 101.17, 106.28, 107.10,
128.51, 132.11, 152.80, 158.22, 169.34, 169.41, 170.38, 170.63 ppm. HRMS
(NH3) (m/z): observed 576.2090, calcd for C25H35O13NF 576.2086.
General Procedure for the Deprotection of (Z)-β-Fluoro-
cinnamic Alcohols. The (Z)-β-fluorocinnamic alcohol (0.5 mmol)
was dissolved in 40 mL of a mixture of MeOH/THF (50:50). A sodium
methylate solution prepared from 10 mg of sodium metal in methanol
(10 mL) was added. When the deprotection was completed, the solution
was neutralized by adding 2.0 g of an ion-exchange resin (H+ form). The
agitation was maintained during 30 min, and then the resin was filtered.
The methanol was eliminated by vacuum evaporation, at room tem-
perature. The product was isolated by chromatography on 5 mL C18
cartridge (LC-SPE) using a mixture of MeOH/H2O.
(2Z)-2-Fluoro-3-(4-nitrophenyl)-2-propen-1-ol (4d). 19F
NMR (CDCl3) δ ꢀ107.53 (dt, 3JHF = 37.9 Hz, 3JHF = 11.2 Hz) ppm;
3
3
1H NMR (CDCl3) δ 4.32 (d, JHF = 11.2 Hz, 2 H), 5.91 (d, JHF
=
37.9 Hz, 1 H), 7.63 (d, 3JHH = 8.8 Hz, 2 H), 8.19 (d, 3JHH = 8.8 Hz)
ppm; 13C NMR (CDCl3) δ 61.25 (d, 2JCF = 33.9 Hz), 105.21 (d, 2JCF
= 5.5 Hz), 123.82, 129.22, 139.39 (d, 3JCF = 4.2 Hz), 146.53, 161.24
(d, 1JCF = 272.7 Hz) ppm. MS (EI) m/z (relative intensity): 197 (M+,
54), 161 (10), 160 (100) 149 (21), 133 (25), 131 (17), 130 (50), 109
(18), 103 (25), 102 (15), 91 (18), 77 (23), 75 (14). HRMS (m/z):
observed 198.0560, calcd for C9H9O3NF 198.0561 [M + H]+.
(2Z)-2-Fluoro-3-(3,5-dimethoxyphenyl)-2-propen-1-ol
(4e). 19F NMR (CDCl3) δ ꢀ112.21 (dt, 3JHF = 38.4 Hz, 3JHF = 14.0 Hz)
ppm; 1H NMR (CDCl3) δ 3.78 (s, 6 H), 4.26 (d, 3JHF = 14.0 Hz, 2 H),
5.71 (d, 3JHF = 38.4 Hz, 1 H), 6.38 (s), 6.67 (s) ppm; 13C NMR (CDCl3)
1-[4-((2Z)-2-Fluoro-3-hydroxyprop-1-enyl)-2-methoxy-
phenyl]-β-D-glucopyranoside, (Z)-β-Fluoroconiferin (5g).
3
Mp 140ꢀ141 °C; 19F NMR (CD3OD) δ ꢀ113.11 (dt, JHF = 38.9
2
2
δ 55.32, 61.81 (d, JCF = 32.8 Hz), 99.97, 106.80 (d, JCF = 7.4 Hz),
107.41 (d, 4JCF = 6.0 Hz), 134.40, 158.71 (d, 1JCF = 267.6 Hz), 160.28
ppm. MS (EI) m/z (relative intensity): 212 (M+, 100), 184 (15), 183
(70), 153 (12), 135 (14), 121 (11), 109 (15), 105 (11), 91 (10), 77 (10),
57 (9). HRMS (m/z): observed 213.0919, calcd for C11H14O3F
213.0921 [M + H]+.
Hz, 3JHF = 15.4 Hz, 1 F) ppm; 1H NMR (CD3OD) δ 3.34ꢀ3.48 (m,
4 H), 3.63 (m, 1 H), 3.69 (m, 1 H), 3.85 (s, 3 H), 4.17 (d, 3JHF = 15.4
Hz, 2 H), 4.88 (d, 3JHH = 7 Hz, 1 H), 5.79 (d, 3JHF = 38.9 Hz, 1 H),
7.05 (d, 3JHH = 8.3 Hz, 1 H), 7.12 (d, 3JHH = 8.1 Hz, 1 H), 7.19 (s, 1 H)
ppm; 13C NMR (CD3OD) δ 56.71, 61.80, 62.43, 71.31, 74.92, 77.78,
78.06, 102.61, 107.65, 113.90, 117.71, 123.11, 129.60, 147.21,
150.54, 159.80, ppm. HRMS (NH3) (m/z): observed 378.1557, calcd
for C16H25O8NF 378.1559.
(2Z)-2-Fluoro-3-(3-bromo-4-methoxyphenyl)-2-propen-1-ol
(4f). 19F NMR (CDCl3) δ ꢀ114.62 (dt, 3JHF = 38.4 Hz, 3JHF = 14.5 Hz)
ppm; 1H NMR (CDCl3) δ 3.89 (s, 3 H), 4.26 (d, 3JHF = 14.5 Hz, 2 H),
5.67 (d, 3JHF = 38.6 Hz, 1 H), 6.84 (d, 3JHH = 8.5 Hz, 1 H), 7.42 (d, 3JHH
= 8.5 Hz, 1 H), 7.72 (s, 1 H) ppm; 13C NMR (CDCl3) δ 56.23, 61.80 (d,
1-[4-((2Z)-2-Fluoro-3-hydroxyprop-1-enyl)-phenyl]-β-D-
glucopyranoside (5h). Mp 127ꢀ129 °C; 19F NMR (CD3OD)
3
3
1
2
2JCF = 32.5 Hz), 105.94 (d, JCF = 6.7 Hz), 111.69, 114.54, 126.72,
δ ꢀ112.53 (dt, JHF = 39.2 Hz, JHF = 15.2 Hz, 1 F) ppm; H NMR
(CD3OD) δ 3.32ꢀ3.48 (m, 4 H), 3.71 (m, 1 H), 3.89 (m, 1 H), 4.16 (d,
3JHF = 15.2 Hz, 2 H), 4.80 (d, 3JHH = 7.0 Hz, 1 H), 5.79 (d, 3JHF = 39.2
Hz, 1 H), 7.05 (d, 3JHH = 8.2 Hz, 2 H), 7.44 (d, 3JHH = 8.3 Hz, 2 H) ppm;
13C NMR (CD3OD) δ 61.81, 62.40, 71.41, 71.91, 74.80, 77.92, 102.13,
107.44, 117.69, 128.76, 130.91, 158.22, 159.54 ppm. HRMS (NH3)
(m/z): observed 348.1462, calcd for C15H23O7NF 348.1453.
1-[4-((2Z)-2-Fluoro-3-hydroxyprop-1-enyl)-2,6-dimeth-
oxyphenyl]-β-D-glucopyranoside, (Z)-β-Fluorosyringin (5i).
Mp 137ꢀ138 °C; 19F NMR (CDCl3) δ ꢀ110.94 (dt, 3JHF = 38.7 Hz,
3JHF = 14.5 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 3.16ꢀ3.48 (m, 4 H),
3.59 (m, 1 H), 3.69 (m, 1 H), 3.84 (s, 6 H), 4.17 (d, 3JHF = 14.5 Hz, 2 H),
4.25 (d, 3JHH = 7.0 Hz, 1 H), 5.81 (d, 3JHF = 38.7 Hz, 1 H), 6.87 (s, 2 H)
ppm; 13C NMR (CDCl3) δ 57.12, 61.70, 62.43, 71.31, 75.73, 77.78,
78.29, 105.28, 107.60, 107.92, 131.21, 135.62, 154.15, 160.53 ppm.
HRMS (NH3) (m/z): observed 408.1670, calcd for C17H27O9NF
408.1664.
128.87 (d, 4JCF = 7.4 Hz), 132.01 (d, 4JCF = 7.8 Hz), 155.13, 157.73 (d,
1JCF = 265.8 Hz) ppm. MS (EI) m/z (relative intensity): 262 (M+ + 1,
80), 261 (M+, 14), 260 (M+ - 1, 91), 253 (31), 231 (20), 219 (14), 181
(100), 166 (100), 152 (65), 136 (24), 109 (26), 55 (23). HRMS (m/z):
observed 260.9920, calcd for C10H11O2BrF 260.9921 [M + H]+.
2,3,4,6-Tetra-O-acetyl-1-[4-((2Z)-2-fluoro-3-hydroxyprop-
1-enyl)-2-methoxyphenyl]-β-D-glucopyranoside (4g). Mp
3
133ꢀ134 °C; 19F NMR (CDCl3) δ ꢀ114.17 (dt, JHF = 38.5 Hz,
3JHF = 14.3 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 2.00 (s, 6 H), 2.04 (s, 6
H), 3.67ꢀ3.75 (m, 1 H), 3.77 (s, 3 H), 4.11 (dd, 2JHH = 14.3 Hz, 3JHH
=
7.1 Hz, 1 H), 4.20 (dd, 2JHH = 12.3 Hz, 3JHH = 4.9 Hz, 1 H), 4.22 (d, 3JHF
= 14.3 Hz, 2 H), 5.09ꢀ5.15 (m, 2 H), 5.24ꢀ5.26 (m, 2 H), 5.68 (d, 3JHF
= 38.5 Hz, 1 H), 6.93 (d, 3JHH = 7.8 Hz, 1 H), 7.02 (d, 3JHH = 8.0 Hz,
1 H), 7.08 (s, 1 H) ppm; 13C NMR (CDCl3) δ 20.61, 55.91, 61.52,
61.93, 68.38, 71.20, 71.92, 72.66, 100.61, 106.60, 112.92, 113.02, 121.53,
128.61, 145.35, 150.34, 158.10, 169.20, 169.44, 170.31, 170.72 ppm.
HRMS (NH3) (m/z): observed 546.1987, calcd for C24H33O12NF
546.1981.
’ ASSOCIATED CONTENT
2,3,4,6-Tetra-O-acetyl-1-[4-((2Z)-2-fluoro-3-hydroxyprop-
1-enyl)-phenyl]-β-D-glucopyranoside (4h). Mp 120ꢀ122 °C;
NMR 19F (CDCl3) δ ꢀ114.79 (dt, 3JHF = 38.9 Hz, 3JHF = 14.3 Hz, 1 F);
1H NMR (CDCl3) δ 2.03 (s, 6 H), 2.05 (s, 6 H), 3.80ꢀ3.89 (m, 1 H),
4.10 (dd, 2JHH = 14.3 Hz, 3JHH = 7.09 Hz, 1 H), 4.20 (dd, 2JHH = 12.3 Hz,
3JHH = 4.9 Hz, 1 H), 4.23 (d, 3JHF = 14.3 Hz, 2 H), 5.05ꢀ5.17 (m, 2 H),
5.24ꢀ5.27 (m, 2 H), 5.71 (d, 3JHF = 38.9 Hz, 1 H), 6.92 (d, 3JHH = 8.1
Hz, 2 H), 7.41 (3JHH = 8.1 Hz, 2 H) ppm; 13C NMR (CDCl3) δ 20.62,
61.60, 61.93, 68.32, 71.14, 72.03, 72.69, 98.88, 106.44, 116.90, 128.61,
129.93, 155.92, 157.79, 169.29, 169.43, 170.31, 170.63. HRMS (NH3)
(m/z): observed 516.1871, calcd for C23H31O11NF 516.1876.
2,3,4,6-Tetra-O-acetyl-1-[4-((Z)-2-fluoro-3-hydroxyprop-
1-enyl)-2,6-dimethoxyphenyl]-β-D-glucopyranoside (4i). Mp
Supporting Information. 1H, 13C, and 19F spectra for the
S
b
model compounds and for the coniferin series. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: christian.rolando@univ-lille1.fr.
’ ACKNOWLEDGMENT
The NMR and mass spectrometry facilities used in this study
were funded by the European Community (FEDER), the Rꢁegion
Nord-Pas de Calais (France), the CNRS, and the Universitꢁe de
Lille 1, Sciences et Technologies. S.E. thanks the Universitꢁe Cadi
Ayyad, Facultꢁe des Sciences et Techniques Guꢁeliz, Marrakech,
Morocco for a sabbatical leave and the Rꢁegion Nord-Pas de Calais
129ꢀ130 °C; 19F NMR (CDCl3) δ ꢀ113.67 (dt, 3JHF = 38.1 Hz, 3JHF
=
13.9 Hz, 1 F) ppm; 1H NMR (CDCl3) δ 2.01 (s, 6 H), 2.07 (s, 6 H),
3.59ꢀ3.73 (m, 1 H), 3.81 (s, 6 H), 4.12 (dd, 2JHH = 12.3 Hz, 3JHH
=
7.3 Hz, 1 H), 4.21 (dd, 2JHH= 12.3 Hz, 3JHH = 4.9 Hz, 1 H), 4.26 (d,
3JHF = 13.9 Hz, 2 H), 5.05ꢀ5.10 (m, 2 H), 5.19ꢀ5.32 (m, 2 H), 5.69
7696
dx.doi.org/10.1021/jo200798h |J. Org. Chem. 2011, 76, 7691–7698

The Journal of Organic Chemistry
ARTICLE
(France) for a position as an invited professor. The authors thank
Dr Jo€el Lyskawa for his participation in the writing of the manu-
script and Dr. Maria van Agthoven for her help with editing this
manuscript.
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