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

Article abstract of DOI:10.1016/j.tetlet.2010.05.082

The first fluoroalkylated 1,3-bis(silyloxy)-1,3-butadienes have been prepared. Their reaction with oxalyl chloride provides a convenient approach to fluoroalkylated γ-alkylidenebutenolides.

Full text of DOI:10.1016/j.tetlet.2010.05.082

Tetrahedron Letters 51 (2010) 5106–5108
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and reactions of the first fluoroalkylated
1,3-bis(trimethylsilyloxy)-1,3-butadienes
Stefan Büttner a, Franziska Bendrath a, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The first fluoroalkylated 1,3-bis(silyloxy)-1,3-butadienes have been prepared. Their reaction with oxalyl
Received 21 March 2010
Revised 15 May 2010
Accepted 19 May 2010
Available online 8 June 2010
chloride provides a convenient approach to fluoroalkylated
c
-alkylidenebutenolides.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
1,3-Dicarbonyl dianions
Organofluorine compounds
Regioselectivity
Silyl enol ethers
Organofluorine compounds play an important role in medicinal
and agricultural chemistry, due to their stereoelectronic properties,
solubility, bioavailability, and metabolic stability.1 Prominent clin-
ically used fluorinated molecules include, for example, 5-fluoro-
uracil (an antineoplastic agent),2 ciprofloxacin and flurithromycin
(antibiotics), fluoxetine (prozac, an antidepressant), faslodex (an
antitumor drug), and efavirenz (an antiviral drug).3,4 Several per-
fluoroalkyl-substituted molecules show amphiphilic properties
and represent promising liquid crystals.5 Fluoroalkylated com-
pounds are also used as ligands6 in catalytic reactions, as organo-
catalysts,7 and as substrates in palladium catalyzed reactions.8
Direct fluorination reactions of arenes and heteroarenes often
suffer from low chemo- and regioselectivity or multiple fluorina-
tion. An alternative approach to fluorinated molecules relies on
the application of a building block strategy. For example, aryl fluo-
rides have been prepared by [4+2] cycloaddition reactions of fluo-
rinated dienes.9 The synthesis of fluorophenols by annulation
reactions of 2,2-difluoro-1,5-diketones has been developed by Por-
tella and co-workers.10 In recent years, we have studied11,12 the
synthesis of fluorinated arenes based on cyclocondensation reac-
tions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes.13 Herein, we
report the synthesis and reactions of what are, to the best of our
knowledge, the first fluoroalkylated 1,3-bis(trimethylsilyloxy)-
1,3-butadienes. In this context we also report chain elongation
reactions of fluoroalkylated 1,3-diketones by reaction of their dia-
nions with alkyl halides. The cyclization of the new dienes with
oxalyl chloride provides a convenient approach to fluoroalkylated
c
-alkylidenebutenolides. While butenolides are of considerable
pharmacological relevance,14,15 the fluoroalkylated derivatives re-
ported herein have not been prepared so far. It can be anticipated
that they are not readily available by other methods.
The silylation of commercially available 1,1,1-trifluoro-pen-
tane-2,4-dione (1a) with trimethylsilyl-trifluoromethanesulfonate
(Me3SiOTf), using the conditions reported by Simchen and co-
workers for the silylation of acetylacetone,16,17 afforded the novel
diene 2a in high yield (Scheme 1). The reaction of the dianion of
1a, generated by means of LDA (2.3 equiv), with various alkyl
O
O
O
O
ii
R
I
R
CF3
CF3
i
1a
1b-g
ii
Me3SiO OSiMe3
Me3SiO OSiMe3
R
CF3
CF3
2a (94%)
2b-g
Scheme 1. Synthesis of diketones 1b–g and dienes 2a–g: (i) (1) LDA (2.3 equiv),
THF, 0 °C, 1 h; (2) R–I, 78 °C?20 °C, 16 h; (ii) NEt3 (3.0 equiv), TMSOTf (3.0 equiv),
Et2O, 20 °C, 72 h.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.082

S. Büttner et al. / Tetrahedron Letters 51 (2010) 5106–5108
5107
Table 1
Table 2
Synthesis of diketones 1b–g and dienes 2b–g
Synthesis of diketones 1h–l and dienes 2h–l
1,2
R
% (1)a
% (2)a
3
4
1,2
RF
R
% (2)a
b
c
d
e
f
nBu
nHex
nOct
nDec
nDodec
CH2Ph
33
42
59
41
55
40
98
96
75
95
94
91
a
b
b
c
b
a
b
b
b
h
i
j
k
l
C2F5
C3F7
C3F7
C6F13
C7F15
Et
H
Et
Et
Et
80
97
80
77
73
d
g
a
Yields of isolated products.
a
Yields of isolated products.
Me3SiO OSiMe3
RF
iodides afforded the novel trifluoromethylated 1,3-diketones
1b–g.18,19 Diketones 1b–g were transformed into the dienes 2b–g
in high yields17 (Table 1).
The reaction of the dianion of 1a with alkyl halides has, to the
best of our knowledge, not been previously reported.20,21 Rösch-
enthaler and co-workers reported the condensation of 1a with es-
ters by application of a sequential deprotonation protocol (use of
LiH).22 However, the application of these conditions to the synthe-
sis of 1b–g proved to be unsuccessful.
RF
O
O
R
RF
R
R
2a-l
i
O
O
O
OH
Cl
+
OH
Cl
O
O
O
5b-h,j-l
5a,i
R = H
R = Alkyl
Scheme 3. Synthesis of butenolides 5a–l: (i) TMSOTf (0.5 equiv), CH2Cl2, ꢀ78 °C?
20 °C, 16 h.
Perfluoroalkylated molecules are of relevance as building blocks
for the synthesis of liquid crystals and of ligands in fluorinated sol-
vent systems.5–7 The perfluoroalkylated 1,3-diketones 1h–l were
prepared, following a modified known procedure,20 by Claisen
reaction of the fluorinated esters 3a–d with acetone (4a, R = H)
or butan-2-one (4b, R = Et) in 48–80% yield (Scheme 2, Table 2).
The synthesis of derivatives 1h–k has been previously re-
ported.20,23 Diketones 1h–l were transformed into the novel dienes
2h–l in 73–97% yield.17 1,3-Diketones 1a–l exist exclusively in
their enol tautomeric form. Dienes 2a–l exist as inseparable mix-
tures of E/Z isomers.
Table 3
Synthesis of butenolides 5a–l
5
RF
R
% (5)a
a
b
c
d
e
f
g
h
i
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C3F7
C3F7
C6F13
C7F15
H
54
67
60
35
42
20
52
53
68
50
40
54
nBu
nHex
nOct
nDec
nDodec
CH2Ph
Et
H
Et
Et
Et
The reaction of dienes 2a–l with oxalyl chloride in the presence
of Me3SiOTf (0.5 equiv) afforded the novel fluoroalkylated c-alky-
lidenebutenolides 5a–l (Scheme 3, Table 3).24–26 In contrast, the
reaction of the monoanions or dianions of 1,3-diketones 1a–l with
oxalyl derivatives (oxalyl chloride or diethyl oxalate) failed. During
the optimization, it proved to be important to use 2.0 equiv of the
diene. Butenolides 5a and 5i, containing a hydrogen atom located
at carbon atom C-4 of the butenolide, were isolated as E-configured
isomers. The other derivatives, containing an alkyl group located at
carbon atom C-4, were isolated as Z-configured isomers, due to the
steric effect of the alkyl group. The configuration of the products
was established based on NOESY experiments. All products were
isolated in moderate to good yields (except for 5f). No systematic
trend of the yields could be observed.
j
k
l
a
Yields of isolated products.
oroalkylated dienes in other cyclocondensation and cycloaddition
reactions.
Acknowledgment
In conclusion, we have reported the synthesis of the first
fluoroalkylated 1,3-bis(silyloxy)-1,3-butadienes and their applica-
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
tion to the synthesis of fluoroalkylated
c-alkylidenebutenolides.
Our current studies are directed toward the application of perflu-
References and notes
1. (a)Fluorine in Bioorganic Chemistry; Filler, R., Kobayasi, Y., Yagupolskii, L. M.,
Eds.; Elsevier: Amsterdam, 1993; (b) Filler, R. Fluorine Containing Drugs in
Organofluorine Chemicals and their Industrial Application; Pergamon: New York,
1979. Chapter 6; (c) Hudlicky, M. Chemistry of Organic Compounds; Ellis
Horwood: Chichester, 1992; (d) Kirsch, P. Modern Fluoroorganic Chemistry;
VCH: Weinheim, 2004; (e) Chambers, R. D. Fluorine in Organic Chemistry;
Blackwell Publishing CRC Press, 2004; (f) Bégué, J.-P.; Bonnet-Delpon, D.
Bioorganic and Medicinal Chemistry of Fluorine; Wiley-VCH: Heidelberg, 2008;
(g) Tressaud, A.; Haufe, G. Fluorine and Health; Elsevier: Amsterdam, 2008.
2. Heidelberger, C.; Chaudhuri, K. N.; Danneberg, P.; Mooren, D.; Griesbach, L.;
Duschinsky, R.; Schnitzer, J. R. Nature 1957, 179, 663.
O
EtO
3a-d
RF
O
O
i
R
O
RF
+
ref. 20
R
1h-l (48-80%)
4a,b
ii
3. Wong, T. D.; Bymaster, P. F.; Engleman, A. E. Life Sci. 1995, 57, 411.
4. Roman, L. D.; Walline, C. C.; Rodriguez, J. G.; Barker, L. Eur. J. Pharmacol. 2003,
479, 53.
5. (a) Stegemeyer, H.; Steinkopff, K. Liquid Crystals; Springer: New York, 1994; (b)
Miethchen, R.; Hein, M. Carbohydr. Res. 2000, 327, 169; (c) Hein, M.; Miethchen,
R.; Schwäbisch, D.; Schick, C. Liq. Cryst. 2000, 27, 163; (d) Schwäbisch, D.; Wille,
S.; Hein, M.; Miethchen, R. Liq. Cryst. 2004, 31, 1143; (e) Nicoletti, M.; Bremer,
M.; Kirsch, P.; O’Hagan, D. Chem. Commun. 2007, 5075; (f) Kirsch, P.; Hahn, A.;
Me3SiO OSiMe3
R
RF
2h-l
Scheme 2. Synthesis of diketones 1h–l and dienes 2h–l: (i) Na, MeOH, 0?20 °C,
16 h; (ii) NEt3 (3.0 equiv), TMSOTf (3.0 equiv), Et2O, 20 °C, 72 h.

5108
S. Büttner et al. / Tetrahedron Letters 51 (2010) 5106–5108
Fröhlich, R.; Haufe, G. Eur. J. Org. Chem. 2006, 4819. and references cited
therein.
diisopropylamine (2.3 equiv) at 0 °C and the mixture was stirred for 30 min
followed by dropwise addition of 1a (1.0 equiv) and subsequent stirring for 1 h
at 0 °C. The mixture was cooled to ꢀ78 °C and the iodoalkane (1.0 equiv) was
added. The temperature of the reaction mixture was allowed to rise to 20 °C
during 14 h and, subsequently, hydrochloric acid (10%, 40 mL) was added. The
organic layer was separated and extracted with diethylether (3 ꢁ 40 mL). The
combined organic layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column chromatography
(silica gel, n-heptane/EtOAc = 20:1) or by distillation.
6. (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; See for example: (a)
Schneider, S.; Tzschucke, C. C.; Bannwarth, W. In Multiphase Homogeneous
Catalysis; Cornils, B., Herrmann, W. A., Horvath, I. T., Leitner, W., Mecking, S.,
Olivier-Bourbigou, H., Vogt, D., Eds.; Wiley VCH, 2005; p 346. Chapter 4; (b)
Clarke, D.; Ali, M. A.; Clifford, A. A.; Parratt, A.; Rose, P.; Schwinn, D.;
Bannwarth, W.; Rayner, C. M. Top. Med. Chem. 2004, 7, 729.
7. Reviews: (a) Wittkopp, A.; Schreiner, P. R.. In The Chemistry of Dienes and
Polyenes; John Wiley & Sons Ltd, 2000; Vol. 2; (b) Schreiner, P. R. Chem. Soc. Rev.
2003, 32, 289; See also: (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; Review: Tsogoeva, S. B. Eur. J. Org.
Chem. 2007, 1701.
19. 1,1,1-Trifluoro-6-phenyl-2,4-hexanedione (2g): Starting with 1a (1.541 g,
10 mmol), benzyl bromide (1.710 g, 10 mmol), n-butyllithium (9.2 mL of a
2.5 M solution in hexanes), and diisopropylamine (3.2 mL, 23 mmol) in THF
(30 mL), 2g was isolated as a colorless liquid (0.966 g, 40%) by distillation;
bp = 113–115 °C/1.1 Torr; 1H NMR (250 MHz, DMSO-d6): d = 2.73–2.82 (m, 2H,
CH2), 2.99 (t, 3J = 7.6 Hz, 2H, CH2), 5.90 (s, 1H, CH), 7.15–7.38 (m, 5H, ArH); 19
F
NMR (235 MHz, DMSO-d6): d = ꢀ76.6 (CF3); 13C NMR (75 MHz, DMSO-d6):
d = 31.2 (CH2), 40.2 (CH2), 96.1 (q, 3J = 2.0 Hz, CH), 117.0 (q, 1J = 282.3 Hz, CF3),
126.6 (CH), 128.2 (CH), 128.7 (CH), 139.6 (C), 174.9 (q, 2J = 36.5 Hz, COCF3),
8. Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
9. (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.
196.4 (CO); IR (ATR, cmꢀ1):
m = 3109 (w), 3088 (w), 3065 (w), 3030 (w), 2932
(w), 2866 (w), 1593 (m), 1497 (w), 1454 (m), 1275 (m), 1196 (s), 1146 (s), 1105
(s), 1077 (m), 1030 (w); MS (EI, 70 eV): m/z (%) = 244 (M+, 16), 175 (28), 139
10. Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998, 54, 5939.
11. Review: Langer, P. Synlett 2009, 2205.
(12), 105 (20), 91 (100); HRMS (EI, 70 eV): calcd for
244.07057, found 244.06985.
C
12H11F3O2 (M+):
12. For [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-dienes with 2-fluoro-3-silyloxy-
2-en-1-ones, see: (a) Hussain, I.; Yawer, M. A.; Lau, M.; Pundt, T.; Fischer, C.;
Reinke, H.; Görls, H.; Langer, P. Eur. J. Org. Chem. 2008, 503; For [3+3]
cyclizations of 1,3-bis(silyloxy)-1,3-dienes with trifluoromethyl-substituted 3-
ethoxy-2-en-1-ones, see: (b) Mamat, C.; Pundt, T.; Dang, T. H. T.; Klassen, R.;
Reinke, H.; Köckerling, M.; Langer, P. Eur. J. Org. Chem. 2008, 492; For reactions
of 2-fluoro-1-alkoxy-1,3-bis(silyloxy)-1,3-butadienes, see: (c) Adeel, M.; Reim,
S.; Wolf, V.; Yawer, M. A.; Hussain, I.; Villinger, A.; Langer, P. Synlett 2008,
2629; For the synthesis of 3-(perfluoroalkyl)phenols by [3+3]
cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 3-silyloxy-1-
(perfluoroalkyl)prop-2-en-1-ones, see: (d) Büttner, S.; Lubbe, M.; Reinke, H.;
Fischer, C.; Langer, P. Tetrahedron 2008, 64, 7968.
13. For a review of 1,3-bis(silyl enol ethers) in general, see: Langer, P. Synthesis
2002, 441.
14. Reviews: (a) Rao, Y. S. Chem. Rev. 1976, 76, 625; (b) Pattenden, G. Prog. Chem.
Nat. Prod. 1979, 35, 133; (c) Gill, M.; Steglich, W. Prog. Chem. Org. Nat. Prod.
1987, 51, 1; (d) Knight, D. W. Contemp. Org. Synth. 1994, 1, 287; (e) Negishi, E.-
20. The synthesis of 1d by a different approach has been reported: Hemmilä, I.
Anal. Chem. 1985, 57, 1676.
21. For an isolated example of the reaction of the dianion of 1a with an aldehyde,
see: Tius, M. A.; Hu, H.; Kawakami, J. K.; Busch-Petersen, J. J. Org. Chem. 1998,
63, 5971.
22. (a) Chizhov, D. L.; Pashkevich, K. I.; Röschenthaler, G.-V. J. Fluorine Chem. 2003,
123, 267; (b) Sevenard, D. V.; Kazakova, O.; Chizhov, D. L.; Röschenthaler, G.-V.
J. Fluorine Chem. 2006, 127, 983.
23. (a) Moore, R. A.; Levine, R. J. Org. Chem. 1964, 29, 1439; (b) Park, J. D.; Brown, H.
A.; Lacher, J. R. J. Am. Chem. Soc. 1953, 75, 4753; (c) Nikolaev, V. A.; Kantin, G. P.;
Utkin, P. Y. Russ. J. Org. Chem. 1994, 1354; (d) Krokhalev, V. M.; Saloutin, V. I.;
Pashkevich, K. I. Bull. Acad. Sci. USSR Div. Chem. Sci. 1987, 36, 1962.
24. Langer, P.; Stoll, M.; Schneider, S. Chem. Eur. J. 2000, 6, 3204.
25. General procedure for the synthesis of butenolides 5a–l: To a CH2Cl2 solution
(10 mL) of oxalyl chloride (1.0 mmol) and 2a–l (2.0 mmol) was added TMSOTf
(0.5 mmol) at ꢀ78 °C under argon atmosphere. The temperature of the reaction
mixture was allowed to rise to 20 °C during 14 h, and, subsequently,
a
i.; Kotora, M. Tetrahedron 1997, 53, 6707; For reviews of syntheses of
alkylidenebutenolides, see: (f) Brückner, R. Chem. Commun. 2002, 141; (g)
Brückner, R. Curr. Org. Chem. 2001, 5, 679.
c
-
saturated aqueous solution of ammonium chloride (50 mL) was added. The
organic layer was separated and extracted with diethylether (3 ꢁ 50 mL). The
combined organic layers were dried (Na2SO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by washing with CH2Cl2 or by
crystallization.
15. For a review of the synthesis of butenolides by cyclization reactions of silyl
enol ethers with oxalyl chloride, see: Langer, P. Synlett 2006, 3369.
16. Krägeloh, K.; Simchen, G. Synthesis 1981, 30.
26. (Z)-4-(n-Butyl)-3-hydroxy-5-(3,3,3-trifluoro-2-oxopropylidene)furan-2(5H)-
one (5b): Starting with oxalyl chloride (0.296 g, 2.33 mmol), 2b (1.702 g,
4.8 mmol), and TMSOTf (0.22 mL, 1.2 mmol), 5b was obtained as a yellowish
solid (0.415 g, 67%); mp = 185–187 °C; 1H NMR (300 MHz, DMSO-d6): d = 0.87
(t, 3J = 7.1 Hz, 3H, CH3), 1.23–1.44 (m, 4H, CH2), 2.70 (t, 3J = 7.4 Hz, 2H, CCH2),
7.08 (s, 1H, CH); 19F NMR (282 MHz, DMSO-d6): d = ꢀ70.3 (CF3); 13C NMR
(75 MHz, DMSO-d6): d = 13.7 (CH3), 22.3 (CH2), 23.3 (CH2), 30.2 (CH2), 113.5 (q,
3J = 2.4 Hz, CH), 118.3 (q, 1J = 273.9 Hz, CF3), 133.2 (C), 150.0 (C), 150.4 (q,
~
17. General procedure for the synthesis of 1,3-bis(silyloxy)-1,3-butadienes 2a–l: To a
stirred diethyl ether solution (2 mL per 1.0 mmol of 1) of 1a–l (1.0 equiv) were
added triethylamine (3.0 equiv) and TMSOTf (3.0 equiv) at 0 °C under an argon
atmosphere. The solution was stirred for 30 min at 0 °C. The temperature of the
reaction mixture was allowed to rise to 20 °C and the stirring was continued
for 3 days. A liquid salt layer separated at the bottom of the flask. The upper
layer (ether solution containing the product) was transferred to a dry flask by
syringe under argon atmosphere. Diethyl ether (1.5 mL per 1.0 mmol of 1) was
added to the liquid salt layer, the mixture was stirred for 2 min and the layers
were allowed to separate by standing for 2 h. The combined ether solutions
were concentrated in vacuo to give the pure dienes 2a–l. Due to their unstable
nature, the products had to be immediately used after their preparation.
18. General procedure for the synthesis of diketones 1b–g: To a solution of n-
butyllithium (2.3 equiv) in THF (3 mL per 1.0 mmol of 1a) was added
2J = 39.2 Hz, COCF3), 161.3 (COH), 177.8 (CO); IR (ATR, cmꢀ1):
m ¼ 3078 (w),
2959 (m), 2934 (w), 2875 (w), 2747 (w), 2437 (w), 1881 (w), 1721 (m), 1657
(m), 1585 (m), 1468 (w), 1423 (m), 1360 (m), 1328 (w), 1273 (m), 1236 (s),
1229 (s), 1215 (s), 1173 (s), 1154 (s), 1103 (m), 1070 (m), 1029 (m); MS (EI,
70 eV): m/z (%) = 264 (M+, 68), 247 (26), 235 (20), 219 (100); HRMS (ESI, TOF/
MS): calcd for C11H12F3O4 ([M+H]+): 265.06822, found 265.06809.