Synthesis of (E)-1-benzyloxy-3-fluoro-1,3-butadiene: A novel fluorinated diene for Diels-Alder reactions

Article abstract of DOI:10.1055/s-0030-1259013

A new approach has been developed for the synthesis of the fluorinated Kitahara-Danishefskys diene analogue, (E)-1-benzyloxy-3-fluoro-1,3-butadiene, via a Pd-catalyzed process. This novel fluorine-containing diene reacts with various dienophiles to provide useful 1-fluorocyclohexene derivatives in good yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259013

LETTER
2843
Synthesis of (E)-1-Benzyloxy-3-fluoro-1,3-butadiene: A Novel Fluorinated
Diene for Diels–Alder Reactions
Synthesis of
(
E
)
s
-1-Benzy
u
y
-1,3-butadie
o
ne shi Hayashi, Yoshinosuke Usuki,* Yosuke Wakamatsu, Hideo Iio
Department of Material Science, Graduate School of Science, Osaka City University, Sugimoto, Sumioshi-ku, Osaka 558-8585, Japan
Fax +81(6)66052522; E-mail: usuki@sci.osaka-cu.ac.jp.
Received 1 September 2010
1) n-BuLi, THF, 0 °C
2) BnOCH2CHO
F
Abstract: A new approach has been developed for the synthesis of
the fluorinated Kitahara–Danishefsky’s diene analogue, (E)-1-ben-
zyloxy-3-fluoro-1,3-butadiene, via a Pd-catalyzed process. This
novel fluorine-containing diene reacts with various dienophiles to
provide useful 1-fluorocyclohexene derivatives in good yields.
EtO2CCHFPO(OEt)2
HO
OBn
3) DIBAL-H, CH2Cl2
0 °C to r.t.
2 (E/Z = 10:1)
76%
F
F
Ac2O, py
88%
Key words: Diels–Alder reaction, fluorine, palladium
AcO
OBn
HO
OBn
3 (E/Z = 10:1)
2 (E/Z = 10:1)
The ability of fluorine to impart unique properties to or-
ganic molecules has been exploited in the design of fluo-
rine-containing bioactive compounds.1,2 Rapid and
efficient procedures for the production of fluorinated
compounds are therefore in high demand. The Diels–Al-
der reaction has been one of the most widely used synthet-
ic tools since O. Diels and K. Alder established the correct
structure of the cycloadduct of p-quinone and cyclopenta-
diene in 1928.3 Various functional groups have been in-
corporated into the dienophile component,4,5 while the
variation in substituents on the diene component has been
fairly limited. Reports of fluorine-substituted 1,3-dienes
and their reactions are still quite rare in synthetic organic
chemistry.6
Pd(PPh3)4(1 mol%)
F
F
Me3SiSiMe3 (3 equiv)
100 °C, 2 h, 42%
OBn
AcO
OBn
3 (E/Z = 10:1)
1
OTMS
OMe
Kitahara–Danishefsky's diene
Scheme 1 Synthesis of (E)-1-benzyloxy-3-fluoro-1,3-butadiene (1)
ene was expected because of b-hydride elimination of the
p-allyl palladium intermediate.11 Significant amounts of
the starting material were recovered even after prolonged
heating. The obtained fluorine-substituted diene 1 is a
1-Alkyloxy-3-fluoro-1,3-butadiene derivatives have not
been reported to date, although they would be useful flu-
orine-containing synthons as analogues of the Kitahara–
Danishefsky’s diene, which is successfully used in normal
and hetero Diels–Alder cycloaddition reactions.7–10 In this
paper, we report our initial findings on the synthesis and
the Diels–Alder reaction of (E)-1-benzyloxy-3-fluoro-
1,3-butadiene (1).
1
clear, unstable liquid. It was characterized by H NMR,
13C NMR, and 19F NMR spectroscopy.
Attention was then directed to the Diels–Alder reaction of
1 with various dienophiles. We first investigated aromatic
solvents in the reaction of 1 with dimethyl fumarate (1.0
equiv) under reflux for 24 hours. The corresponding cy-
cloadducts 4a and 4b were obtained as a mixture of dia-
The synthesis of 1 commences with the Horner–
Wadsworth–Emmons reaction of benzyloxyacetaldehyde
with commercially available ethyl 2-(diethoxyphosphor- Table 1 Solvent Effect on Cyclization of 1 and Dimethyl Fumaratea
yl)-2-fluoroacetate, and the subsequent reduction with
OBn
OBn
OBn
DIBAL-H, to provide 4-benzyloxyl-2-fluoro-but-2-en-1-
ol (2) in 76% yield. Subsequent treatment with acetic an-
hydride in pyridine afforded the corresponding acetate 3
in 88% yield. After several attempts at optimization, we
found that the reaction of 3 in the presence of 1 mol% of
Pd(PPh3)4 and Me3SiSiMe3 (3 equiv) at 100 °C for two
hours produced the desired diene 1 in 42% yield with high
E selectivity (Scheme 1).
CO2Me
CO2Me
CO2Me
MeO2C
+
+
F
CO Me
F
2
CO2Me
F
1
4a
4b
Entry
Solvent
benzene
toluene
xylene
Bath temp (°C)
Yield (%)
drb
1
2
3
110
130
170
62
85
73
50:50
52:48
50:50
The reaction did not proceed at all in the absence of
Me3SiSiMe3, although the formation of the conjugated di-
a A mixture of dimethyl fumarate (0.16 mmol) and 1 (0.16 mmol) in
anhyd solvent (0.6 mL) was heated to reflux in an argon atmosphere
for 24 h. After cooling to r.t., the solvent was removed under reduced
pressure. The crude product was purified by preparative TLC.
b Diastereomer ratio was determined by 19F NMR spectroscopy.
SYNLETT 2010, No. 19, pp 2843–2846
Advanced online publication: 22.10.2010
DOI: 10.1055/s-0030-1259013; Art ID: U07710ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2844
T. Hayashi et al.
LETTER
stereomers in combined yields of 62% (benzene), 85% We then investigated other Diels–Alder reactions of di-
(toluene), and 73% (xylene), respectively (Table 1).
enophiles 5 with 1 under optimized conditions. The re-
sults are summarized in Table 2.
Table 2 Diels–Alder Reaction of 1 with Various Dienophiles 5
Entry
Dienophile 5
Product(s)
Time (h)
Yield (%)
dra
OBn
O
O
F
O
O
O
O
4c
1
0.75
80b
81:19
OBn
O
O
F
O
4d
OBn
CO2Me
CO2Me
F
CO2Me
CO2Me
4e
2
3
4
16
16b
33:67
0:100
7:93
OBn
CO2Me
CO2Me
F
4f
OBn
SO2Ph
SO2Ph
SO2Ph
SO2Ph
4.5
70
F
4g
OBn
SO2Ph
F
4h
SO2Ph
4.5
66
OBn
SO2Ph
F
4i
OBn
CO2Me
CO2Me
CO2Me
CO2Me
F
5
4.5
93b
–
4j
CO2Me
CO2Me
F
10
Synlett 2010, No. 19, 2843–2846 © Thieme Stuttgart · New York

LETTER
Synthesis of (E)-1-Benzyloxy-3-fluoro-1,3-butadiene
2845
Table 2 Diels–Alder Reaction of 1 with Various Dienophiles 5 (continued)
Entry
6
Dienophile 5
Product(s)
Time (h)
1
Yield (%)
90
dra
–
OBn
CO2Et
N
CO2Et
CO2Et
N
N
N
F
CO2Et
4k
OBn
O
CO2n-Bu
F
4l
O
7
4
84
42:58
CO2n-Bu
OBn
O
CO2n-Bu
F
4m
a Diastereomer ratio was determined by 19F NMR spectroscopy.
b Yield was determined by 19F NMR spectroscopy.
The reaction of 1 with maleic anhydride afforded the cor- only if its geometry is pseudoequatorial; the benzyloxy
responding cycloadducts 4c and 4d in 80% combined group is, accordingly, pseudoaxial. This is the expected
yield whereas dimethyl maleate showed rather low reac- result of endo addition, because the benzyloxy functional
tivity (entries 1 and 2). The relative configurations of the group in diene 1 has E configuration.
major products were elucidated by NMR studies. We
1
OBn
compared H NMR data of 4c with those of the corre-
sponding adduct 6 of the Kitahara–Danishefsky’s diene
with maleic anhydride to elucidate the relative configura-
tion of 4c (Figure 1).12
OBn
O
O
1) MeOH, r.t., overnight
2) CH2N2, Et2O
+
O
O
F
F
O
O
4c
4d
3.03
(ddd, J = 2.8, 6.7, 18.3 Hz)
6.4
(81:19)
OBn
5.59
4.51 (dt, J = 6.4, 4.2 Hz)
OBn
OBn
(ddd, J = 2.8, 6.4, 13.4 Hz)H
O
4.2
H
H
CO2Me
CO2Me
13.4
2.8
+
O
H
F
H
H
F
CO2Me
F
CO2Me
O
19F NMR
δ –100.54
δ –96.64
4c
7
8
2.65
(81:19)
(ddd, J = 2.6, 5.1, 17.8 Hz)
6.4
OMe
4.21 (dd, J = 6.4, 4.2 Hz)
O
Scheme 2 Conversion of 4c and 4d into the corresponding dimethyl
esters 7 and 8
5.11
H
H
(dd, J = 2.6, 6.4 Hz)
H
4.2
2.6
O
H
TMSO
H
H
Furthermore to elucidate the relative configuration of 4e
and 4f, we converted 4c and 4d into the corresponding
dimethyl esters 7 and 8, respectively (Scheme 2). The
NMR data of 4f are consistent with those of 8, which in-
dicate that the exo adduct is the major product.
O
6
Figure 1 Comparison of 1H NMR data between 4c and 6
The vinyl hydrogen of 4c was observed at d = 5.59 (ddd).
The relatively large 4JHH (2.8 Hz) coupling value indicates
an ideal relationship for allylic coupling.13 The methine
proton in CHOBn was observed at d = 4.51 (dt). The ob-
served 3JHH coupling with the vinyl proton (6.4 Hz) indi-
The Diels–Alder reaction of dienophiles containing phe-
nylsulfonyl group(s) proceeded with high exo selectivities
(entries 3 and 4) and regioselectivity (entry 4). The eluci-
dation of the relative configuration of 4g was achieved by
comparison of 1H NMR data of 4g with that of the corre-
sponding Diels–Alder adduct 9 reported by De Lucchi
(Figure 2).14
3
cates near co-planarity; the observed JHH coupling with
the angular methine proton (4.2 Hz) indicates a gauche
rather than an anti disposition of these bonds. Both rela-
tionships for the methine proton in CHOBn are satisfied
Synlett 2010, No. 19, 2843–2846 © Thieme Stuttgart · New York

2846
T. Hayashi et al.
LETTER
4.21 (br)
3.94 (dm, J = 11.8 Hz)
11.8
Acknowledgment
H
BnO
H
5.8, 17.1 Hz)
H 2.35 (dt, J =
X
4.68 (br) H
We thank Dr Matsumi Doe (Analytical Division, Osaka City Uni-
versity) for conducting the NMR experiments.
5.4
H
3.37 (dd, J = 11.8, 17.1 Hz)
H
X
F
5.44
(dd, J = 14.4, 5.4 Hz)
4g
References and Notes
X = SO2Ph
4.03 (m)
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2008.
3.78 (m)
H
12.2
MeO
H
H 2.56 (dd, J = 5.8, 17.1 Hz)
X
4.75 (dd, J = 5.8, 2.1 Hz)
5.8
H
H
2.33 (dd, J = 12.2, 17.1 Hz)
H
X
R
5.05 (d, J = 5.8 Hz)
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9
X = SO2Ar, R = OTMS
Figure 2 Comparison of 1H NMR data of 4g and 9
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The vinyl hydrogen of 4g was observed at d = 5.44. The
observed 3JHH coupling with the CHOBn proton (5.4 Hz)
indicates near co-planarity. The methine proton in
CHSO2Ph was observed at d = 3.94. The observed large
3JHH (11.8 Hz) coupling suggests that the methine proton
in CHSO2Ph is pseudoaxial. The phenylsulfonyl group is,
accordingly, pseudoequatorial. The NMR data of 4g are,
thus, consistent with those of 9, which indicates that the
exo adduct is the major product. Similarly, the structures
of 4h and 4i were determined as shown in Figure S1 in
Supporting Information. The NMR data of 4h and 4i are
consistent with those of the analogous adducts of the
Kitahara–Danishefsky’s diene with methyl acrylate.15
Dimethyl acetylenedicarboxylate reacted with 1 to give 4j
in 93% yield, as determined by 19F NMR spectroscopy.
During purification of the preparative TLC, almost 50%
of 4j was converted to dimethyl 4-fluorophthalate (10)16
through an elimination of benzyl alcohol (entry 5).
This method was extended to the hetero Diels–Alder reac-
tion (entries 6 and 7). Diethyl diazodicarboxylate reacted
with 1 to give 4k in 90% yield. The reaction of 1 with bu-
tyl glyoxylate provided the corresponding cycloadducts 4l
and 4m in 84% yield as a 42:58 mixture of diastereomers.
The CHCO2n-Bu proton of 4m was observed at d = 4.68
(b) Motoyama, Y.; Koga, Y.; Nishiyama, H. Tetrahedron
2001, 57, 853.
(10) Paredes, E.; Biolatto, B.; Kneeteman, M.; Mancini, P. M.
Tetrahedron Lett. 2000, 41, 8079.
3
(dd). The observed JHH coupling between the adjacent
methylene protons (4.2 Hz and 11.4 Hz) could be ex-
plained by an axial–equatorial coupling and a diaxial cou-
pling, which suggests that the CHCO2n-Bu proton is axial.
The NMR data of 4l and 4m are consistent with those of
the analogous compounds, cis- and trans-2-methoxy-5,6-
dihydro-a-pyran-6-carboxylic esters.17
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allyl complex, see: (a) Bitar, A. Y.; Frontier, A. J. Org. Lett.
2009, 11, 49. (b) Takenaka, H.; Ukaji, Y.; Inomata, K.
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In summary, we have developed a novel approach for the
synthesis of an analogue of the fluorinated Kitahara–
Danishefsky’s diene via a Pd-catalyzed process. This nov-
el fluorine-containing diene reacted with various dieno-
philes to provide useful 1-fluorocyclohexene derivatives
in good yields. Further works to apply the present protocol
to fluorinated biomimetics are currently underway in our
laboratory.
(15) Quirante, J.; Vila, X.; Bonjoch, J. Synthesis 2001, 1971.
(16) Shi, G.-Q.; Cottens, S.; Shiba, S. A.; Schlosser, M.
Tetrahedron 1992, 48, 10569.
(17) Achmatowicz, O. Jr.; Jurczak, J.; Konowal, A.; Zamojski, A.
Org. Magn. Res. 1970, 2, 55.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 19, 2843–2846 © Thieme Stuttgart · New York