The first synthesis and reaction of β-ethoxy-α-fluoro-α- (phenylselanyl)ethene: Scandium or lanthanum triflate catalyzed α-fluoroformylalkenylation of aldehydes

Article abstract of DOI:10.1055/s-2005-871961

We describe the first preparation of the hitherto unknown β-ethoxy-α-fluoro-α-(phenylselanyl)ethenes and the successful Lewis acid catalyzed α-fluoroformylalkenylation of non-enolizable aldehyde acetals to provide α,β-unsaturated aldehydes or acetals excl

Full text of DOI:10.1055/s-2005-871961

LETTER
2191
The First Synthesis and Reaction of b-Ethoxy-a-fluoro-a-(phenyl-
selanyl)ethene: Scandium or Lanthanum Triflate Catalyzed
a-Fluoroformylalkenylation of Aldehydes
Scandium or
L
u
a
nthanum
T
m
riflate Catalyzed
a
-F
i
luorof
n
ormylalkeny
o
lation of
A
ld
r
ehydes i Hatanaka, Miyuki Tsuchiya, Mitsuhiro Yoshimatsu*
Department of Chemistry, Faculty of Education, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
Fax +81(58)2932207; E-mail: yoshimae@cc.gifu-u.ac.jp
Received 17 May 2005
PhSe
Abstract: We describe the first preparation of the hitherto unknown
R1
R2
b-ethoxy-a-fluoro-a-(phenylselanyl)ethenes and the successful
Lewis acid catalyzed a-fluoroformylalkenylation of non-enolizable
aldehyde acetals to provide a,b-unsaturated aldehydes or acetals ex-
clusively.
F
OEt
R1
R2
F
O
CHO
Scheme 1 a-Fluoroformylalkenylation using b-ethoxy-a-fluoro-a-
Key words: (phenylselanyl)ethane, scandium triflate, lanthanum
triflate, double bond formation, fluorine, a,b-unsaturated aldehydes
organoselanylalkene
hitherto unknown b-ethoxy-a-fluoro-a-(phenylsela-
nyl)ethene (Scheme 1).
a-Fluoro-a,b-unsaturated carbonyl compounds have re-
cently attracted considerable attention as novel starting
materials for the synthesis of a wide variety of fluorine
containing alkenes or polyenes.1 Although many synthetic
methods have been developed for the preparation of a-flu-
oro-a,b-unsaturated esters and ketones,2 there are very
few methods for the preparation of a-fluoro-a,b-unsatur-
ated aldehydes (fluoroacrolein). Furthermore, they have
the following disadvantages: the usual methods by Hor-
ner–Wadsworth–Emmons reactions involves the succes-
sive transformation of functional groups such as a,b-
unsaturated esters and nitriles to the corresponding alde-
hydes;3 direct synthesis from carbonyl compounds using
1,1,2-trifluorovinyl lithium, which could be generated
by transmetalation of chlorotrifluoroethene with BuLi at
–135 °C, is efficient for the preparation of a,b-unsaturated
acid fluorides, however, they cannot be converted to the
corresponding aldehydes;4 the acid-mediated or solvolytic
ring-opening of alkoxychlorofluorocyclopropanes is the
most popular route,5 however, the chlorofluorocyclopro-
panation of enol ethers requires longer reaction times;6
2,3,3-trifluoro-1-propenyl ammonium iodides7 or
tosylates8 are good precursors for b-amino and b-organo-
sulfanylfluoroacrolein derivatives, however, these are
also multi-step-procedures.9 We previously investigated
the two-step alkenylation using alkenyl lithiums bearing a
b-alkoxy group,10 which gave the expected a,b-unsaturat-
ed aldehydes. In order to explore new synthetic methods
for the synthesis of a-fluoro-a,b-unsaturated aldehydes
using b-alkoxy-a-fluoroethenes, we investigated and re-
port here the preparation and Lewis acid catalyzed direct
a-fluoro-a-formylalkenylation of aldehydes using the
First, we prepared the new b-ethoxy-a-fluoro-a-(phe-
nylselanyl)ethene (4) by our original method as shown in
Scheme 2.11 The a-fluoro-a-(phenylselanyl)acetic acid
ethyl ester (1), which was prepared from ethyl chloroflu-
oroacetate and diphenyl diselenide, was converted to the
hemiacetal 2 by DIBAL-H reduction in toluene at –70 °C.
Successive acetalization by the usual method (triethyl
orthoformate and a catalytic amount of p-toluenesulfonic
acid) afforded a-fluoro-a-(phenylselanyl)acetaldehyde
diethyl acetal (3) in good yield. The deethanolysis of 3
was accomplished by treatment with lithium isopropyl-
cyclohexylamide at –60 to –40 °C in diethyl ether. The
reactions in THF gave rise to a low yield of 4. Next, we
attempted the generation of b-ethoxyalkenyl metals and
their reaction with electrophiles. Although the transmeta-
lation of 4 with BuLi or ethylmagnesium bromide in THF
at –78 °C proceeded and gave the butyl or ethyl phenyl
selenide, the reactions with electrophiles was not success-
ful. This result showed that the b-ethoxy-a-(phenyl-
selanyl)ethene (4) is not a suitable precursor of b-ethoxy-
a-fluoroethenyl metals; therefore, we modified the course
of the reaction to employ a new a-formylalkenylation
using b-ethoxy-a-(phenylselanyl)ethenes, thus avoiding
the alkenyllithium intermediates.
OH
PhSe
CO2Et
i
ii
PhSe
PhSe
OEt
F
1
2
F
OEt
PhSe
n-BuLi or
ii
OEt
OEt
EtMgBr
F
F
3 (91%)
4 (80%)
Scheme 2 Conditions and reagents: i) DIBAL-H (1.2 equiv, tolu-
ene, –70 °C, 30 min; ii) CH(OEt)3 (3.0 equiv), p-TsOH (0.1 equiv),
EtOH, r.t., 12 h; lithium isopropylcyclohexylamide (1.5 equiv), Et2O,
–60 to –40 °C, 10 min.
SYNLETT 2005, No. 14, pp 2191–2194
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-871961; Art ID: U15305ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
7
.2
0
0
5

2192
F. Hatanaka et al.
LETTER
Table 1 Lewis Acid Catalyzed a-Fluoroformylalkenylation of
Benzaldehyde Dimethyl or Diethyl Acetals
In order to explore new areas in the organic chemistry of
the alkenylations using enol ethers, we examined the
Lewis acid catalyzed reactions using b-ethoxy-a-fluoro-
ethene 4. When hafnium triflate was used as a catalyst, the
corresponding a-fluorocinnamaldehydes 5a,b were ob-
tained in low yields (Scheme 3). We optimized both the
reaction conditions and the electrophiles, and found that
the acetals are effective electrophiles for the Lewis acid
catalyzed a-fluoroformylalkenylation. These results are
shown in Table 1.
F
F
conditions
+
Ph
Ph
4
PhCH(OR1)2
CH(OR1)2
CHO
5a
6a
Entry Acetal Conditionsa
R1
Yields (%)b
5a
6a
1
Me
BF3·Et2O, Cl(CH2)2Cl, 83 °C,
56
–
12 h
F
2
3
4
5
Me
Me
Me
Me
SnCl4, Cl(CH2)2Cl, r.t., 12 h
Zn(OTf)2, Cl(CH2)2Cl, r.t.,12 h
Yb(OTf)3, Cl(CH2)2Cl, r.t., 12 h
46
–
–
–
–
–
i
R1
4
+ PhSeSePh
CHO
5a (R1 = Ph) (26%)
5b (R1 = 2,4,6-trimethylphenyl) (20%)
42
52
Scheme 3 Conditions and reagents: R1CHO, Hf(OTf)3 (5 mol%),
Yb(OTf)3, Cl(CH2)2Cl, 83 °C,
10 min
ClCH2CH2Cl, r.t.
6
7
Me
Me
Me
Me
Me
Me
Et
Hf(OTf)4, Cl(CH2)2Cl, r.t., 12 h
Sc(OTf)3, Cl(CH2)2Cl, r.t., 12 h
Sc(OTf)3, MeNO2, r.t., 12 h
Sc(OTf)3, THF, 65 °C, 5 min
Sc(OTf)3, MeCN, r.t., 45min
La(OTf)3, Cl(CH2)2Cl, r.t., 12 h
La(OTf)3, Cl(CH2)2Cl, r.t., 25 h
La(OTf)3, Cl(CH2)2Cl, r.t., 25 h
28
36
39
10
3
–
We examined the reaction of 4 with benzaldehyde di-
methyl acetal in the presence of BF3·Et2O (5 mol%) and
obtained 5a in 56% yield (Table 1, entry 1). Scandium or
lanthanum triflate gave satisfactory results (Table 1, en-
tries 7 and 11). Next, we examined the reactions in other
solvents (Table 1, entries 8–10), however, the yields of
products were almost the same. When the reaction was
quenched by triethylamine, acetal was obtained exclu-
sively (Table 1, entry 13).
–
8
25
52
54
–
9
10
11
12
13
59
48
–
46
85c
Next, we performed the alkenylations with a range of al-
dehydes as shown in Table 2.12 p-Methoxybenzaldehyde
gave satisfactory results; however, p-chlorobenzaldehyde
produced a low yield of 5c or 6c (Table 2, entries 4 and 5).
a-Fluoropenta-2,4-dienal (5f) was obtained in good yield;
however, the enynal 6g was afforded in low yield
(Table 2, entries 9 and 10). We further investigated the
a-fluoroalkenylation of ketone acetals such as 4-phenyl-
cyclohexanone; however, the coupling products were not
observed.
Et
a Lewis acid (5 mol%).
b Diphenyl diselenide was obtained in each case in 72–100% yield.
c The reaction was quenched with Et3N.
F
F
i
Ar
Ar
Nu
7a (Nu = CH2COPh) (77%)
CH(OEt)2
ii
6b
OEt
7b (Nu = allyl) (53%)
a-Fluoro-a,b-unsaturated aldehydes could be converted to
useful 3-fluoropyridines,13 fluoro-2-cyclohexenol, fluoro-
2,5-dihydropyranols, fluoro-3,6-dihydro-1,2-oxadines,14
fluorothiophenes,15 3-fluoro-1,3-butadienes,6 and 3-fluo-
rovinylglycines, which are efficient irreversible inhibitors
of E. coli Alanine Racemase,16 and fluorinated analogues
of insect sex pheromones.6 The new catalytic a-fluoroal-
kenylation of aldehydes is much better in producing prod-
ucts such as aldehydes or acetals than the usual methods.
Some useful transformations of a-fluoro-a,b-unsaturated
aldehyde 5b or acetal 6b were examined (Scheme 4). The
Lewis acid mediated or catalyzed nucleophilic substitu-
tion reactions of 6b with allyltrimethylsilane or 1-phenyl-
1-(trimethylsilyloxy)ethylene occurred regioselectively at
the acetal carbon to give the alkylated products 7a,b, re-
spectively. The phenylsulanyltrimethylsilane gave exclu-
sively the disulfanyl acetal 7c in good yield. The usual
transformations to the fluorobuta-1,3-dienes using Wittig
reagents were mostly satisfactory.
F
Ar
iii
Nu
7c (Nu = SPh) (72%)
Nu
F
F
Ar
8a (R1 = CO2Et) (53%)
Ar
R1
CHO
5b
Scheme 4 Conditions and reagents:i) CH2=C(OTMS)Ph (3 equiv),
TMSOTf (1.5 equiv), CH2Cl2, –78 °C, 10 min or Me3SiCH2CH=CH2
(5 equiv), Sc(OTf)3 (5 mol%), ClCH2CH2Cl, r.t., 1 h; ii) TMSSPh,
ClCH2CH2Cl, r.t., 1 h; iii) R1CH2PPh3Br (1.5 equiv), LDA, THF,
–78 °C.
In summary, we prepared b-ethoxy-a-fluoro-a-(phenylse-
lanyl)ethenes for the first time and successfully utilized
them in the Lewis acid catalyzed a-fluoroalkenylation of
the non-enolizable aldehydes. However, the reactivity and
scope of b-ethoxy-a-fluoro-a-(organoselanyl)ethenes in
organic chemistry has not been fully determined; this is
Synlett 2005, No. 14, 2191–2194 © Thieme Stuttgart · New York

LETTER
Scandium or Lanthanum Triflate Catalyzed a-Fluoroformylalkenylation of Aldehydes
2193
Table 2 Lewis Acid Catalyzed a-Fluoroformylalkenylation of Aldehyde Acetals
F
F
conditions
R1
R1
+
4
CH(OR2)2
R1CH(OR2)2, Cl(CH2)2Cl
CHO
5
6
Entry
Acetal
R1
Conditionsa
Yields (%)b
R2
5
6
1
2
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
Et
La(OTf)3, 83 °C, 15 min
La(OTf)3, 83 °C, 15 min
La(OTf)3, 83 °C, 15 min
La(OTf)3, 83 °C, 10 min
Sc(OTf)3, 83 °C, 10 min
La(OTf)3, 83 °C, 15 min
Sc(OTf)3, 83 °C, 10 mind
La(OTf)3, r.t., 12 h
5b (58)
5b (57)
–
6b (19)
Me
Me
Me
Me
Me
Me
Et
6b (7)
3
6b (85)
4
5c (26)
5c (16)
5d (54)
5e (12)
5f (47)
5f (70)
–
–
5
p-ClC6H4
6c (2)c
6
2,4,6-Me3C6H2
p-HOC6H4
–
7
–
8
(E)-Cinnamyl
(E)-Cinnamyl
Phenylethynyl
–
9
Et
Hf(OTf)4, r.t., 12 hd
–
10
Et
La(OTf)3, 83 °C, 1 min
6g (12)
a Lewis acid (5 mol%).
b Diphenyl diselenide was obtained in each entry in 79–100% yield.
c Acetal 6c was obtained as ethyl methyl acetal.
d Lewis acid (20 mol%).
(4) Sauvetre, R.; Masure, D.; Chuit, C.; Normant, J. F. Synthesis
1978, 128.
(5) Bessiere, Y.; Savary, D. N.-H.; Schlosser, M. Helv. Chim.
Acta 1977, 60, 1739.
currently under investigation and results will be reported
elsewhere.
(6) Camps, F.; Coll, J.; Fabrias, G.; Guerrero, A. Tetrahedron
1984, 40, 2871.
(7) (a) Yamakawa, H.; Yamashita, S.; Ishihara, T. Synlett 1993,
353. (b) Yamakawa, H.; Odani, Y.; Ishihara, T.; Gupton, J.
T. Tetrahedron Lett. 1998, 39, 6943.
Acknowledgment
The support of part of this work by the Endo Seijiro Memorial
Foundation is gratefully acknowledged.
(8) (a) Funabiki, K.; Ohtsuki, T.; Yamanaka, H. Chem. Lett.
1994, 1075. (b) Funabiki, K.; Kurita, T.; Matsui, M.;
Shibata, K. Chem. Lett. 1997, 739. (c) Funabiki, K.;
Ohtake, C.; Muramatsu, H.; Matsui, M.; Shibata, K. Synlett
1996, 444.
(9) (a) Blanco, L.; Rousseau, G. Bull. Soc. Chim. Fr. 1985, 455.
(b) Patrick, T. B.; Hosseini, S.; Bains, S. Tetrahedron Lett.
1990, 31, 179.
(10) (a) Yoshimatsu, M. J. Synth. Org. Chem., Jpn. 2002, 60,
847. (b) Vlattas, I.; Vecchia, L. D.; Lee, A. O. J. Am. Chem.
Soc. 1976, 98, 2008. (c) Yoshimatsu, M.; Oguri, K.; Ikeda,
K.; Gotoh, S. J. Org. Chem. 1998, 63, 4475.
References
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Biomedicinal Aspects of Fluorine Chemistry; Kodansha/
Elsevier: Tokyo/New York, 1993.
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Teranishi, R.; Nagao, Y. Tetrahedron Lett. 2002, 43, 9183.
(b) Suzuki, Y.; Sato, M. Tetrahedron Lett. 2004, 45, 1679.
(c) Sano, S.; Yokoyama, K.; Teranishi, R.; Shiro, M.; Nagao,
Y. Tetrahedron Lett. 2002, 43, 281. (d) Sano, S.; Saito, K.;
Nagao, Y. Tetrahedron Lett. 2003, 44, 3987. (e) Zn-Cu
promoted synthesis using methyl dichlorofluoroacetate:
Ishihara, T.; Kuroboshi, M. Chem. Lett. 1987, 1145.
(f) From trifluorovinyl lithiums: Normant, J. F.; Foulon, J.
P.; Masure, D.; Sauvetre, R.; Villieras, J. Synthesis 1975,
122. (g) Using a-fluoro-a-organosulfinylacetate: Chevrie,
D.; Lequeux, T.; Pommelet, J.-C. Tetrahedron 2002, 58,
4759. (h) Wong, A.; Welch, C. J.; Kuethe, J. T.; Vazquez,
E.; Shaimi, M.; Henderson, D.; Davies, I. W.; Hughes, D. L.
Org. Biomol. Chem. 2004, 168.
(d) Yoshimatsu, M.; Yamaguchi, S.; Matsubara, Y. J. Chem.
Soc., Perkin Trans. 1 2001, 2560. (e) Yoshimatsu, M.;
Sugimoto, T.; Okada, N.; Kinoshita, S. J. Org. Chem. 1999,
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2000, 65, 4456. (g) Yoshimatsu, M.; Timura, Y. J. Org.
Chem. 2002, 67, 5678.
(11) Preparation of b-ethoxy-a-fluoro-a-
(phenylselanyl)ethene(4). To a toluene (80 mL) solution of
ethyl 2-fluoro-2-(phenylselanyl)acetate (1; 4.00 g, 15.3
mmol) was added DIBAL-H (18.4 mL, 1 M toluene solution,
18.4 mmol) at –78 °C under an Ar atmosphere. After the
reaction mixture was stirred for 30 min, 1 M HCl solution
(16 mL) was added to the mixture. The resulting mixture was
(3) (a) Liu, J.; Colmenarres, L. U.; Liu, R. S. H. Tetrahedron
Lett. 1997, 38, 8495. (b) Andres, D. F.; Dietrich, U.;
Laurent, E. G.; Marquet, B. S. Tetrahedron 1997, 53, 647.
Synlett 2005, No. 14, 2191–2194 © Thieme Stuttgart · New York

2194
F. Hatanaka et al.
LETTER
extracted with Et2O. The combined organic layers were
stirred for 10 min and then poured into H2O (200 mL). The
organic layer was separated and the aqueous layer was
extracted with Et2O. The combined organic layer was dried
over MgSO4. The solvent was removed under reduced
pressure. To the residue in EtOH (23 mL) was added ethyl
orthoformate (11.4 g, 76.6 mmol) and p-TsOH (0.26 g, 1.53
mmol). The mixture was stirred for 12 h at 20 °C and poured
into a sat. soln of NaHCO3 (200 mL). Work-up and
purification by column chromatography on silica gel eluting
with EtOAc–hexane (1:50) gave 2-fluoro-2-
(phenylselanyl)acetaldehyde diethyl acetal(3) (14.1 g, 91%)
as a yellow oil. IR: 2978, 2929, 2884, 2362, 2344, 1579,
1478, 1372, 1340, 1301, 1118, 1067, 1023, 999, 891, 741,
691, 470 cm–1; 1H NMR: d = 1.25 (3 H, t, J = 7 Hz, Me), 1.26
(3 H, t, J = 7 Hz, Me), 3.62–3.68 (2 H, m, OCH2), 3.76–3.82
(2 H, m, OCH2), 4.71 (1 H, dd, J = 4, 9 Hz, acetal H), 6.02
(1 H, dd, J = 4, 52 Hz, CHF), 7.24–7.33 (3 H, m, ArH), 7.64–
7.66 (2 H, m, ArH); 19F NMR (referenced to CF3CO2H): d =
–87.05 (dd, J = 9, 53 Hz); MS: m/z = 292 (M+). Anal. Calcd
for C12H17FO2Se: C, 49.49; H, 5.88. Found: C, 49.27; H,
5.79
dried over MgSO4. The solvent was removed under reduced
pressure. The residue was purified by flash chromatography
on silica gel eluting with EtOAc–hexane (1:100) to give 4
(2.02 g, 80%) as a yellow oil. IR: 3444, 2980, 2357, 1658,
1577, 1477, 1439, 1395, 1313, 1194, 1130, 1061, 1000, 902,
737, 689, 535, 515, 466, 441, 425, 406 cm–1; 1H NMR: d =
1.33 (3 H, t, J = 7 Hz, Me), 3.97 (2 H, q, J = 7 Hz, OCH2),
6.24 (1 H, d, J = 19 Hz, olefinic H), 7.24–7.30 (3 H, m,
ArH), 7.48 (2 H, d, J = 8 Hz, ArH); 19F NMR: d = –39.67 (d,
J = 18 Hz); MS: m/z = 246 (weak M+). Compound 4 was too
volatile to measure the elemental analysis.
(12) A typical procedure for the preparation of 2-fluoro-4¢-
methoxycinnamaldehyde dimethyl acetal(6a): Lanthanum
triflate (60 mg, 0.10 mmol) was added to a ClCH2CH2Cl (5.0
mL) solution of 4 (0.50 g, 2.04 mmol) and p-methoxybenz-
aldehyde dimethyl acetal (0.80 g, 4.07 mmol) under an Ar
atmosphere. The reaction mixture was refluxed for 10 min,
cooled, and treated with Et3N (2 drops). Work-up afforded 2-
fluoro-4¢-methoxycinnamaldehyde dimethyl acetal (6a, 0.77
g, 85%).
An ethereal (5.0 mL) solution of 3 (3.0 g, 10.3 mmol)was
added to lithium isopropylcyclohexylamide (prepared from
isopropylcyclohexylamine (2.90 g, 20.6 mmol) and BuLi
(6.0 mL, 15.4 mmol) in Et2O (60 mL)) at –60 °C. The
reaction mixture was warmed to –40 °C and then stirred for
10 min. The mixture was poured into H2O (200 mL). The
organic layer was separated and the aqueous layer was
(13) Ghosh, S.; Schlosser, M. J. Fluorine Chem. 1994, 67, 53.
(14) Shi, G.-q.; Schlosser, M. Tetrahedron 1993, 49, 1445.
(15) Andres, D. F.; Laurent, E. G.; Marquet, B. S. Tetrahedron
Lett. 1997, 38, 1049.
(16) Thornberry, N. A.; Bull, H. G.; Taub, D.; Greenlee, W. J.;
Patchett, A. A.; Cordes, E. H. J. Am. Chem. Soc. 1987, 109,
7543.
Synlett 2005, No. 14, 2191–2194 © Thieme Stuttgart · New York