Synthesis and reactions of the first fluorine-containing 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Article abstract of DOI:10.1055/s-0028-1083440

The first fluorine-containing 1,3-bis(silyl enol ethers), 2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-butadienes, have been prepared. Their reaction with electrophiles allows a convenient synthesis of various open-chain and cyclic organofluorine compounds which are not readily available by other methods.

Full text of DOI:10.1055/s-0028-1083440

LETTER
2629
Synthesis and Reactions of the First Fluorine-Containing 1,3-Bis(trimethyl-
silyloxy)-1,3-butadienes
S
ynthesis and Reaction
u
s
of Fluorine
h
-Containing
a
1,3-Bis(tri
m
m
-butadienes ad Adeel,a Stefanie Reim,a Verena Wolf,a Mirza A. Yawer,a Ibrar Hussain,a Alexander Villinger,a
Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
E-mail: peter.langer@uni-rostock.de
Received 6 May 2008
O
TMSO
O
O
Abstract: The first fluorine-containing 1,3-bis(silyl enol ethers),
2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-butadienes, have been pre-
pared. Their reaction with electrophiles allows a convenient synthe-
sis of various open-chain and cyclic organofluorine compounds
which are not readily available by other methods.
i
OEt
OEt
F
F
2a 81%
1a
Key words: arenes, organofluorine compounds, regioselectivity,
silyl enol ethers
OTMS
OEt
ii
TMSO
F
Organofluorine compounds play an important role in drug
discovery.1 They exhibit unique stereoelectronic proper-
ties: on the one hand the fluorine atom is fairly small, on
the other hand its high electronegativity often results in a
great improvement of drug-receptor interactions. The car-
bon–fluorine bond is chemically and biologically stable
which avoids undesired metabolic transformations. In ad-
dition, the high lipophilicity of organofluorine com-
pounds improves their in vivo transport. They also show a
very good solubility in fluorophilic solvents. Therefore,
organofluorine compounds are used as ligands2 for cata-
lytic reactions in fluorous biphasic systems and supercrit-
ical carbon dioxide.3 The unique electronic properties of
fluorinated arenes are widely used for applications in or-
ganocatalysis.4 Last but not least, fluorinated arenes and
heteroarenes are versatile building blocks in transition-
metal-catalyzed cross-coupling reactions.5
3a 94%
Scheme 1 Synthesis of diene 3a. Reagents and conditions:
(i) TMSCl, Et3N, benzene, 20 °C, 48 h; (ii) 1. LDA, THF, –78 °C,
1 h; 2. TMSCl, –78 °C → 20 °C, 14 h.
O
O
OTMS
Ph
TMSO
i
Ph
F
F
3b 83%
1b
Scheme 2 Synthesis of dienes 3b. Reagents and conditions:
(i) TMSOTf, Et3N, Et2O, 0 °C → 20 °C, 4 h.
1,3-Bis(trimethylsilyloxy)-1,3-butadienes (e.g., Chan’s
diene)8,9 represent important synthetic building blocks
which have been used in formal [3+2], [3+3], [4+2] and
[4+3] cyclizations and other transformations.10 Herein, we
report the synthesis and reactions of 2-fluoro-1,3-bis(sily-
loxy)-1,3-butadienes which represent, to the best of our
knowledge, the first fluorine-containing 1,3-bis(silyl enol
ethers).11 Their reactions with electrophiles provide a con-
venient and regioselective approach to a variety of orga-
nofluorine compounds which are not readily available by
other methods.
The direct fluorination of arenes, heteroarenes and several
open-chained molecules often suffers from several draw-
backs, such as low chemo- and regioselectivity or multi-
ple fluorination. An alternative strategy for the
regioselective synthesis of organofluorine compounds re-
lies on the use of appropriate fluorine-containing building
blocks in condensation and cyclization reactions. For ex-
ample, aryl fluorides have been prepared by [4+2]-
cycloaddition reactions of 2-fluoro-1-methoxy-3-trimeth-
ylsilyloxybuta-1,3-diene, 2-fluoro-3-methoxybuta-1,3-di-
ene and related dienes with alkenes or alkynes.6 Portella et
al. reported the synthesis of fluorophenols by annulation
reactions of 2,2-difluoro-1,5-diketones which were pre-
pared from trifluoromethyltrimethylsilane, acylsilanes
and enones.7
The silylation of commercially available ethyl 2-fluoro-
acetoacetate (1a) afforded silyl enol ether 2a. The latter
was transformed, by deprotonation (LDA) at –78 °C and
subsequent addition of trimethylchlorosilane, into novel
1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-butadi-
ene (3a) (Scheme 1). The fluorine substituent proved to be
compatible with the reaction conditions. 2-Fluoro-1-phe-
nyl-1,3-bis(silyloxy)-1,3-butadiene (3b) was prepared by
reaction of an Et2O solution of 1b with two equivalents of
trimethylsilyl-trifluoromethanesulfonate (TMSOTf) and
triethylamine (Scheme 2). Dienes 3a and 3b can be stored
at –20 °C under an inert atmosphere for several weeks.
SYNLETT 2008, No. 17, pp 2629–2632
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083440; Art ID: D14608ST
© Georg Thieme Verlag Stuttgart · New York

2630
M. Adeel et al.
LETTER
OTMS
TMSO
OTMS
OEt
TMSO
OEt
i
O
O
O
O
OEt
F
F
i
Ph
OEt
3a
3a
F
F
Cl
O
O
O
+
+
Cl
7 48%
4 31%
Ph
Cl
Scheme 6 Synthesis of 2-alkylidenetetrahydrofuran 7. Reagents
and conditions: (i) TiCl4 (2.0 equiv), CH2Cl2, –78 °C → 20 °C.
Scheme 3 Synthesis of 4. Reagents and conditions: (i) CH2Cl2,
–78 °C → 20 °C; (ii) NaHCO3, H2O.
O
O
O
O
OMe
O
O
OTMS
OEt
TMSO
O
O
i
3a
MeO
OEt
OEt
MeO
Cl
i
F
F
Cl
F
5 89%
3a
8 72%
Scheme 4 Synthesis of 5. Reagents and conditions: (i) TMSOTf
(0.2 equiv), CH2Cl2, –78 °C → 20 °C; (ii) NaHCO3, H2O.
ii
O
OEt
MeO
TMSO
OTMS
R
F
O
O
O
O
9 81%
F
HO
i
F
3a,b
Scheme 7 Synthesis of 9. Reagents and conditions: (i) TMSOTf
(0.5 equiv), CH2Cl2, –78 °C → 20 °C; (ii) DBU (2.0 equiv), THF,
20 °C.
O
Cl
O
R
+
Cl
6a (R = OEt) 35%
6b (R = Ph) 51%
TMSO
OTMS
OEt
Scheme 5 Synthesis of butenolides 6a,b. Reagents and conditions:
(i) TMSOTf (0.3 equiv), CH2Cl2, –78 °C → 20 °C, 14 h.
O
O
ii
CN
F
O
O
i
3a
OEt
The reaction of 3a with benzoyl chloride, following our
recently reported protocol,12 afforded ethyl 2-fluoro-5-
phenyl-3,5-dioxopentanoate (4; Scheme 3). The best
yields were obtained when the reactions were carried out
in the absence of Lewis acid. It is noteworthy that prod-
ucts such as 4 are not available by direct fluorination of
3,5-dioxoalkanoates, due to the formation of a mixture of
regioisomers.
O
F
11
CN
+
O
O
O
10
O
N
OEt
F
The TMSOTf-catalyzed condensation of 3a with methyl
malonyl chloride afforded dimethyl 2-fluoro-3,5-dioxo-
pimelate (5; Scheme 4). The synthesis of 5 is again not
possible by fluorination of dimethyl 3,5-dioxopimelate,
due to the formation of regioisomers.
12 56% (based on 10)
Scheme 8 Synthesis of 1-azaxanthone 12. Reagents and conditions:
(i) 1. 3-cyanochromone, TMSOTf, 1 h, 20 °C; 2. 3a, CH2Cl2, 0 °C →
20 °C, 12 h; 3. HCl (10%); (ii) 1. Et3N, EtOH, 20 °C, 12 h; 2. HCl
(1 M).
The TMSOTf-catalyzed cyclization13 of 1,3-bis(silyl enol
ethers) 3a,b with oxalyl chloride afforded the novel fluor- ated cyclization15 of 8 afforded the Z-configured 4-meth-
inated g-alkylidenebutenolides 6a,b (Scheme 5). The oxy-2-alkylidenetetrahydrofuran 9.16
exocyclic double bond was formed with excellent Z-dias-
The TMSOTf-mediated reaction of 3a with 3-cyano-
tereoselectivity.
chromone (10) gave condensation product 11. The latter
The TiCl4-mediated cyclization of 3a with epichlorohy- was formed by regioselective attack of the terminal car-
drin, following our recently reported protocol,14 afforded bon atom of the diene onto C-2 of the cyanochromone and
the
halogenated
2-alkylidenetetrahydrofuran
7
subsequent hydrolysis upon aqueous workup. Treatment
(Scheme 6). The exocyclic double bond was again formed of an ethanol solution of crude 11 with triethylamine af-
with excellent Z diastereoselectivity.
forded the novel fluorinated 1-azaxanthone 12
(Scheme 8). This type of product is again not available by
direct fluorination. The transformation of 11 into 12 can
be explained by a domino ‘retro-Michael/nitrile-addition/
heterocyclization’ reaction.17
The TMSOTf-catalyzed condensation of 3a with 1-chlo-
ro-2,2-dimethoxyethane gave the 2-fluoro-6-chloro-5-
methoxy-3-oxohexanoate 8 (Scheme 7). The DBU-medi-
Synlett 2008, No. 17, 2629–2632 © Thieme Stuttgart · New York

LETTER
Synthesis and Reactions of Fluorine-Containing 1,3-Bis(trimethylsilyloxy)-1,3-butadienes
2631
Acknowledgment
TMSO
OTMS
OEt
Financial support by the State of Pakistan (HEC scholarship for I.H.
and M.A.Y.) and by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
HO
F
CO2Me
CO2Me
F
i
3a
+
H
CO2Me
H
OH
References and Notes
13 64%
MeO2C
(1) (a) Fluorine in Bioorganic Chemistry; Filler, R.; Kobayasi,
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(b) Filler, R. Fluorine-Containing Drugs in Organofluorine
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(d) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
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MacConnell, J.; White, R.; Dezeny, G. J. Antibiot. 1994, 47,
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Colson, K. L.; Matson, J. A.; Rose, W. C.; Doyle, T. W.;
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Scheme 9 Synthesis of homophthalate 13. Reagents and condi-
tions: (i) 1. neat, 20–80 °C; 2. NEt3(HF)3, EtOH.
Figure 1 Crystal structure of 13
TMSO
OTMS
OEt
OH
N
F
i
F
Ph
S
OEt
3a
O
O
Ph
CN
S
+
14 59%
O
O
Scheme 10 Synthesis of pyridine 14. Reagents and conditions:
(i) 1. neat, –78 °C, then 45 °C, 48 h; 2. NH4Cl, H2O.
The [4+2]-cycloaddition18 of 1,3-bis(trimethylsiloxy)-
1,3-butadiene 3a with dimethyl allene-1,3-dicarboxylate
afforded the novel fluorinated 2,4-dihydroxyhomophtha-
late 13 in good yield and with very good regioselectivity
(Scheme 9). Product 13 is not available by direct fluorina-
tion of the corresponding homophthalate because of the
formation of a regioisomeric mixture. The structure of 13
was independently confirmed by X-ray crystal structure
analysis (Figure 1).19
(2) (a) Schmidbaur, H.; Kumberger, O. Chem. Ber. 1993, 126,
3. (b) Dinger, M. B.; Henderson, W. J. Organomet. Chem.
1998, 560, 233. (c) Liedtke, J.; Loss, S.; Widauer, C.;
Grützmacher, H. Tetrahedron 2000, 56, 143.
(3) See, for example: (a) Schneider, S.; Tzschucke, C. C.;
Bannwarth, W. Multiphase Homogeneous Catalysis;
Cornils, B.; Herrmann, W. A.; Horvath, I. T.; Leitner, W.;
Mecking, S.; Olivier-Booubigou, H.; Vogt, D., Eds.; Wiley-
VCH: Weinheim, 2005, Chap. 4, 346. (b) Clarke, D.; Ali,
M. A.; Clifford, A. A.; Parratt, A.; Rose, P.; Schwinn, D.;
Bannwarth, W.; Rayner, C. M. Curr. Top. Med. Chem. 2004,
7, 729.
The hetero-Diels–Alder reaction20 of 1,3-bis(silyloxy)-
1,3-butadiene 3a with phenylsulfonylcyanide afforded the
fluorinated
4-hydroxy-2-(arylsulfonyl)pyridine
14
(Scheme 10).21 This type of product is again not available
by direct fluorination.
(4) Reviews: (a) Wittkopp, A.; Schreiner, P. R. In The
Chemistry of Dienes and Polyenes, Vol. 2; Rappoport, Z.,
Ed.; John Wiley & Sons: New York, 2000. (b) See also:
Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
In conclusion, we have reported a building block strategy
for the synthesis of novel organofluorine compounds
based on reactions of 2-fluoro-1,3-bis(trimethylsilyloxy)-
1,3-butadienes, the first fluorinated 1,3-bis(silyl enol
ethers). The products are not available by direct fluorina-
tion reactions.
(c) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9,
407. (d) Kleiner, C. M.; Schreiner, P. R. Chem. Commun.
2006, 4315. (e) Kotke, M.; Schreiner, P. R. Synthesis 2007,
779. (f) Review: Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701.
(5) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
Synlett 2008, No. 17, 2629–2632 © Thieme Stuttgart · New York

2632
M. Adeel et al.
LETTER
(6) (a) Shi, G.-Q.; Cottens, S.; Shiba, S. A.; Schlosser, M. A.
Tetrahedron 1992, 48, 10569. (b) Shi, G.-Q.; Schlosser, M.
Tetrahedron 1993, 49, 1445. (c) Patrick, T. B.; Rogers, J.;
Gorrell, K. Org. Lett. 2002, 4, 3155.
(7) Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998,
54, 5939.
(19) CCDC 684861 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(20) Emmrich, T.; Reinke, H.; Langer, P. Synthesis 2006, 2551.
(21) Synthesis of 2-Ethoxy-3-fluoro-6-(phenylsulfonyl)pyr-
idin-4-ol (14): To phenylsulfonyl cyanide was dropwise
added 3a at –78 °C. The neat reaction mixture was
(8) For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
(9) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem.
subsequently stirred at 45 °C for 48 h. To the mixture was
added a sat. aq solution of NH4Cl (20 mL) and the organic
and the aqueous layer were separated. The latter was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by
Commun. 1979, 578.
(10) For a review of [3+3]-cyclizations, see: Feist, H.; Langer, P.
Synthesis 2007, 327.
(11) For [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-dienes with
2-fluoro-3-silyloxy-2-en-1-ones, see: Hussain, I.; Yawer,
M. A.; Lau, M.; Pundt, T.; Fischer, C.; Reinke, H.; Görls, H.;
Langer, P. Eur. J. Org. Chem. 2008, 503.
(12) Rahn, T.; Nguyen, V. T. H.; Dang, T. H. T.; Ahmed, Z.;
Lalk, M.; Fischer, C.; Spannenberg, A.; Langer, P. J. Org.
Chem. 2007, 72, 1957.
(13) Langer, P.; Stoll, M.; Schneider, S. Chem. Eur. J. 2000, 6,
3204.
(14) Langer, P.; Armbrust, H.; Eckardt, T.; Magull, J. Chem. Eur.
J. 2002, 8, 1443.
(15) (a) Bellur, E.; Görls, H.; Langer, P. Eur. J. Org. Chem. 2005,
2074. (b) See also: Langer, P.; Krummel, T. Chem. Eur. J.
2001, 7, 1720.
(16) The synthesis of a difluoro(furan-2-yl)acetate by a different
approach has been recently reported: (a) Eto, H.; Kanwko,
Y.; Sakamoto, T. Chem. Pharm. Bull. 2000, 48, 982.
(b) Murakami, S.; Kim, S.; Ishii, H.; Fuchigami, T. Synlett
2004, 815.
chromatography (silica gel, heptanes–EtOAc) to give 14.
Starting with phenylsulfonyl cyanide (0.167 g, 1.0 mmol)
and 3a (0.589 g, 2.0 mmol), 14 was isolated as a red solid
(0.179 g, 59%). 1H NMR (250 MHz, CDCl3): d = 1.22 (t,
3J = 7.1 Hz, 3 H, OCH2CH3), 4.26 (q, 3J = 7.0 Hz, 2 H,
OCH2CH3), 7.19 (br s, 1 H, OHheter), 7.43 (m, 1 H, CHheter),
7.46–7.50 (m, 2 H, CHPh), 7.53–7.56 (m, 1 H, CHPh), 7.95
(dd, 3J = 8.4 Hz, 4J = 1.5 Hz, 2 H, CHPh). 13C NMR (75 MHz,
CDCl3): d = 14.1 (OCH2CH3), 63.6 (OCH2CH3), 107.8
(CHheter), 128.9 (2 × CHPh), 129.0 (2 × CHPh), 133.8 (CHPh),
136.8 (d, 1J = 252.4 Hz, CFheter), 138.4 (CPh), 149.4 (d, 4J =
6.7 Hz, Cheter), 151.3 (d, 2J = 10.2 Hz, COHheter), 153.8 (d,
2J = 9.9 Hz, Cheter). 19F NMR (235 MHz, CDCl3): d =
–162.05 (CFheter). IR (neat): 3354 (w), 1576 (m), 1440 (m),
1353 (m), 1317 (m), 1149 (s), 1076 (m), 1022 (m), 740 (s),
724 (s), 682 (s), 585 (s) cm–1. HRMS (ESI, positive): m/z
[M + H]+ calcd for C13H13FNO4S: 298.05438; found:
298.05413. HRMS (ESI, positive): m/z [M + Na]+ calcd for
C13H12FNO4SNa: 320.03652; found: 320.03633. All
products gave satisfactory spectroscopic data and correct
elemental analyses and/or high resolution mass data.
(17) (a) Langer, P.; Appel, B. Tetrahedron Lett. 2003, 44, 5133.
(b) Rashid, M. A.; Rasool, N.; Appel, B.; Adeel, M.;
Karapetyan, V.; Mkrtchyan, S.; Reinke, H.; Fischer, C.;
Langer, P. Tetrahedron 2008, 64, 5416.
(18) Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 41, 4545.
Synlett 2008, No. 17, 2629–2632 © Thieme Stuttgart · New York

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