Aldol reactions of acylsilanes and difluoroenoxysilanes. Application to the synthesis of 2-fluoro-1,3-diketones

Article abstract of DOI:10.1055/s-1999-2632

We describe the synthesis of new gem-difluoro-C-silylated aldols from acylsilanes and trifluoromethyltrimethylsilane via an aldol reaction. Their defluorosilylation gives aliphatic and alicyclic 2-fluoro-1,3-diketones. The overall reaction sequence can be

Full text of DOI:10.1055/s-1999-2632

432
LETTER
Aldol Reactions of Acylsilanes and Difluoroenoxysilanes. Application to
the Synthesis of 2-Fluoro-1,3-diketones1
Damien Saleur, Thierry Brigaud, Jean-Philippe Bouillon, Charles Portella*
Laboratoire “Réactions Sélectives et Applications”, Associé au CNRS (UMR 6519), Université de Reims, Faculté des Sciences, B.P. 1039,
51687 Reims Cedex 2, France
Fax 33 3 26 05 31 66, E-mail: charles.portella@univ-reims.fr
Received 1 December 1998
Abstract: We describe the synthesis of new gem-difluoro-C-silylat-
ed aldols from acylsilanes and trifluoromethyltrimethylsilane via an
aldol reaction. Their defluorosilylation gives aliphatic and alicyclic
2-fluoro-1,3-diketones. The overall reaction sequence can be con-
sidered as a new complementary method giving access to a wide va-
riety of such fluorinated 1,3-diketones.
Key words: acylsilane, difluoroenoxysilane, aldol reaction, 1,3-
diketone
The trifluoromethyltrimethylsilane (TFMTMS)-acylsi-
lane system is a convenient source of difluoroenoxysi-
lanes.2,3 These enoxysilanes may be trapped in situ with
various types of electrophilic substrates to give gem-di-
fluoro compounds. In our preliminary account2a we men-
tioned the trapping of an enoxysilane with benzaldehyde
in a Mukaiyama aldol reaction. This paper is devoted to
the aldol reaction of difluoro-enoxysilanes with acylsi-
lanes and the transformation of the corresponding C-sil-
ylated aldols into 2-fluoro-1,3-diketones. Extension of
these reactions to 1,5-bis-acylsilanes and then to cyclic 2-
fluoro-1,3-diketones is also reported.
Scheme 1
The general one-pot methodology depicted in Scheme 1
was applied.4 In a first experiment, two equivalents of
benzoylsilane were reacted in dichloromethane with
TFMTMS and a catalytic amount of tetrabutyl-ammoni-
um difluorotriphenylstannate (DFTPS) as the initiator.2
To the difluoroenoxysilane generated in situ was added
boron trifluoride etherate in order to activate the benzoyl-
silane in excess and to induce the aldol reaction. The ex-
pected aldol 1 was isolated in 57 % yield (Scheme 1,
Table 1: entry 1).
The same one-pot methodology4 was successfully applied
to one equivalent of acylsilane with, in the second step,
addition of a second different acylsilane. Among several
Lewis acids tested, good results were obtained with boron
trifluoride (excess) or bismuth trichloride (catalytic
amount) (Table 1). It is important to notice that the yields
refer to the overal one-pot process and are determined
from the starting acylsilane. As pointed out previously,2a
the choice of DFTPS as fluoride initiator is crucial to
avoid self-condensation of the difluoroenoxysilane,
which was observed with TBAF and can sometimes occur
as a minor side reaction with DFTPS especially after a
long storage of the reagent.
In order to evaluate the effectiveness of the aldol step, we
carried out the reaction on the isolated 1-tert-butyldimeth-
ylsilyloxy-1-phenyldifluoroethene 4,2a whose preparation
was optimized (88% yield). This difluoroenoxysilane was
then treated with benzoyl- or acetyl-trimethysilane under
bismuth trichloride activation, leading to the correspond-
ing C-silyl aldols 1 and 3 in 59% and 69% yields, respec-
tively (Scheme 2). Hence the one-pot process is a valuable
methodology for the syntheses of such aldols.
It was interesting to extend these reactions to 1,5-bis-acyl-
silanes.6 Our aim was to build a difluoroenoxysilane from
one acylsilane function and to induce an intramolecular
aldol reaction in a second step. The first experiment was
carried out with the bis-acylsilane 5.6 Application of a
one-pot methodology allowed the isolation of the expect-
ed cyclic aldol 6 in 33 % yield (Scheme 3). The latter was
Synlett 1999, No. 4, 432–434 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Aldol Reactions of Acylsilanes and Difluoroenoxysilanes
433
Scheme 2
Scheme 3
Scheme 4
separated from several other products among which was
identified the 2,6-bis-trimethylsilyl-4H-pyrane coming
from the cyclodehydration of the starting bis-acylsilane.6 lane should be a thermodynamically favorable transfor-
Obviously some other by-products came from double ad- mation owing to the formation of both a silicon-fluorine
dition in the first step.
bond and a 1,3-diketone system. Such an elimination
might be induced either by an initial deprotonation of the
hydroxyl group followed by silicon migration and fluo-
ride b-elimination, or by an initial nucleophilic attack on
silicon. The aldols 1 and 2 were treated with tetrabutylam-
monium fluoride (TBAF) in a THF/H2O mixture to yield
the corresponding 2-fluoro-1,3-diketones9 1410 and 1510
(Scheme 5, Table 2). The cyclic aldols 10 and 13 were
also converted into 2-fluoro-3-hydroxy-cyclohexen-2-
ones 1611 and 17 in 68% and 80% yields. The acyclic 2-
fluoro-1,3-diketones 14 and 15 exist mainly as the keto
tautomers, while the cyclic derivatives 16 and 17 are al-
most completely enolic. This phenomenon has already
been observed and discussed in the literature.10 Whether
fluoride acts as a base or a nucleophile in this reaction re-
main undetermined. We did not observe any O-silylated
compound derived from a Brook rearrangement of a pos-
sible aldolate intermediate, which do not exclude its oc-
currence owing to the expected easy b-elimination of
fluoride.
A two-step procedure would make the intramolecular al-
dol reaction more effective (Scheme 4). The tert-butylated
bis-acylsilane 76 was treated under fluoride initiation with
1.3 equivalents of TFMTMS to give the expected mono
difluoroenoxysilane 8 as the major product (52%) and the
bis difluoroenoxysilane 9 (22%) which were separated by
silica gel chromatography. Bismuth trichloride was added
to a dichloromethane solution of compound 8 and the
mixture was stirred overnight at room temperature. After
the usual work-up,4 the C-silyl cycloaldol 107 was isolated
in 60 % yield. The same compound was obtained in 35%
yield using the one-pot procedure (Scheme 4). We felt that
the modification of one of the two carbonyl groups should
allow a higher selectivity for monoaddition in the first
step. The 2-methyl-1,5-bis-acylsilane 116 was submitted
to the same one-pot or two-step procedure (Scheme 4).
The addition of the trifluoromethyl group proved to be
completely regioselective on the less hindered carbonyl
group, leading to a single difluoroenoxysilane 12 (76%)
besides the unreacted starting material 11 (11%). The bis-
muth trichloride activation gave the cycloaldol 13 in 81%
yield (mixture of diastereomers 58/42).
The structure of the minor diastereomer of 13 was deter-
mined by X-ray diffraction analysis8 and presented the
TBDMS and the methyl groups in a cis relationship. Ow-
ing to the higher selectivity of the first step, the one-pot
procedure allowed to directly synthesize the compound 13
in fairly good yield (52%) (Scheme 4).
These inter- or intramolecular aldol reactions constitute
an original route towards gem-difluoro functionalized
compounds including vicinal silicon and fluorine. We
then anticipated that an elimination of fluoro-trialkylsi-
Scheme 5
Synlett 1999, No. 4, 432–434 ISSN 0936-5214 © Thieme Stuttgart · New York

434
D. Saleur et al.
LETTER
(5) Spectral data for aldol 3: IR (film, cm-1): 3488, 1680. 19F-
NMR (CDCl3/CFCl3, 235.4 MHz, J / Hz) d -101.4 (d, 2JFF 288,
1F), -103.5 (d, 2JFF 288, 1F). 1H-NMR (CDCl3, 250 MHz, J /
Hz) d 0.20 (s, 9H, SiMe3), 1.43 (m, 3H, CH3), 2.63 (s, 1H,
OH), 7.45 (t, 2H, 3JHH 7.3, aromatic), 7.61 (t, 1H, 3JHH 7.3, aro-
matic), 8.11 (d, 2H, 3JHH 7.3, aromatic). 13C-NMR (CDCl3,
62.9 MHz, J / Hz) d -2.8 (s, SiMe3), 19.4 (dd, 3JCF 7.5, 3JCF 3.8,
CH3), 69.7 (t, 2JCF 31.6, C4), 120.3 (t, 1JCF 257.6, CF2), 128.5,
130.3, 133.5, 134.2, 192.0 (t, 2JCF 33.4, CO).
(6) Saleur, D.; Bouillon, J. -P.; Portella, C. Tetrahedron Lett.
1999, in press.
Some 2-fluoro-1,3-diketones have already been reported.
In general, they have been prepared by electrophilic fluo-
rination of diketones or silyl enol ethers, using molecular
fluorine10-12 or electrophilic fluorine donor reagents.13
(7) Spectral data for aldol 10: IR (KBr, cm-1): 3470, 1751. 19F-
NMR (CDCl3/CFCl3, 235.4 MHz, J / Hz) d -106.7 (d, 2JFF 252,
1F), -123.2 (d, 2JFF 252, 1F). 1H-NMR (CDCl3, 250 MHz, J /
Hz) d 0.15 (s, 6H, SiMe2), 1.01 (s, 9H, SitBu), 1.67 (s, 1H,
OH), 1.8-2.4 (m, 4H, CH2CH2CH2CO), 2.7 (m, 2H,
CH2CH2CH2CO). 13C-NMR (CDCl3, 62.9 MHz, J / Hz) d -6.6
(s, SiMe), -6.5 (s, SiMe), 18.1 (s, C4), 20.6 (s, CH2), 27.3 (s,
tBu), 31.0 (d, 3JCF 6.9, CH2), 38.6 (s, CH2), 75.2 (t, 2JCF 33.5,
C4), 117.1 (t, 1JCF 256.0, CF2), 199.5 (t, 2JCF 27.6, CO).
(8) Selected data for X-ray diffraction analysis of the minor dia-
stereomer of 13: C13H24F2O2Si, M = 278.41, monoclinic, spa-
ce group P21/c, a = 12.132(4) Å, b = 9.182(3) Å, c = 14.022(4)
Å, b = 99.76(3)°, V = 1539.4(8) Å3, Z = 4. Atomic coordina-
tes, bond lengths and bond angles were deposited at the Cam-
bridge Crystallographic Data Centre.
In conclusion, the synthesis of a new class of gem-difluo-
ro-C-silylated aldols, in both aliphatic and alicyclic series,
is described. They can be defluoro-silylated under fluo-
ride treatment. The overall reaction sequence can be con-
sidered as a complementary method giving access to a
variety of 2-fluoro-1,3-diketones, a type of compounds so
far prepared by demanding procedures and expensive re-
agents.
Acknowledgement
(9) Typical procedure for the preparation of 2-fluoro-1,3-diket-
ones 14 - 17: To a solution of aldol (2.0 mmol) in THF (25
mL) was added tetrabutylammonium fluoride (TBAF) (631
mg, 2.0 mmol). After stirring at room temperature until total
conversion, the reaction was quenched by addition of HCl
(1M, 10 mL) for the aliphatic diketones 14 and 15 or by addi-
tion of a saturated HCl/THF solution (50 ml) for the alicyclic
diketones 16 and 17. After extraction with ether (4 x 15 mL)
and drying over MgSO4 (for 14 and 15), the solvent was eva-
porated under reduced pressure. The crude product was puri-
fied by column chromatography on silicagel (eluent: AcOEt/
petroleum ether).
(10) Purrington, S. T.; Bumgardner, C. L.; Lazaridis, N. V.; Singh,
P. J. Org. Chem. 1987, 52, 4307.
(11) Chambers, R. D.; Hutchinson, J.; Batsanov, A. S.; Lehmann,
C. W.; Naumov, D. Y. J. Chem. Soc., Perkin Trans. 1 1996,
2271.
The authors thank Dr. B. Tinant and J. -P. Declercq for X-ray dif-
fraction analysis and Bayer A.G. for a generous gift of CF3SiMe3.
References and Notes
(1) Part 9 of "Mixed Organofluorine-Organosilicon Chemistry".
(2) a) Brigaud, T.; Doussot, P.; Portella, C. J. Chem. Soc., Chem.
Commun. 1994, 2117. b) Brigaud, T.; Lefebvre, O.; Plantier-
Royon, R.; Portella, C. Tetrahedron Lett. 1996, 37, 6115. c)
Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998, 54,
5939.
(3) Other preparations of difluoroenoxysilanes: a) Yamana, M.;
Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24, 507. b) Jin,
F.; Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 33, 1221.
c) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc.,
Perkin Trans. 1 1998, 1215. d) Uneyama, K.; Maeda, K.;
Kato, T.; Katagiri, T. Tetrahedron Lett. 1998, 39, 3741.
(4) Typical one-pot procedure for the synthesis of aldol 3: To a
solution of benzoyltrimethylsilane (1.50 mmol) and trifluoro-
methyltrimethylsilane (0.30 mL, 1.89 mmol) in CH2Cl2 (5
mL) under argon, at 0°C, was added a catalytic amount of te-
trabutyl-ammonium difluorotriphenylstannate (DFTPS, 54
mg, 0.075 mmol). After 5 min at 0°C, the reaction mixture was
stirred for 30 min at room temperature. The formation of the
difluoroenoxysilane was monitored by GC. Acetyltrimethyl-
silane (0.26 mL, 1.80 mmol) and BiCl3 (142 mg, 0.45 mmol)
were then added and the reaction mixture was stirred until to-
tal conversion (GC). The reaction was quenched by addition
of a saturated NaHCO3 solution (10 mL). The aqueous layer
was extracted with CH2Cl2 (4 x 15 mL). The organic layer was
dried over MgSO4 and the solvent was evaporated under redu-
ced pressure. The crude product was purified by silica gel
column chromatography (eluent: ether/petroleum ether).
(12) Chambers, R. D.; Greenhall, M. P.; Hutchinson, J. Tetrahe-
dron 1996, 52, 1
(13) XeF2: a) Zajc, B.; Zupan, M. J. Chem. Soc., Chem. Commun.
1980, 759. b) Zajc, B.; Zupan, M. J. Org. Chem. 1982, 47,
573. c) Stavber, S.; Sket, B.; Zajc, B.; Zupan, M. Tetrahedron
1989, 45, 6003. C19XeF6: d) Yemul, S. S.; Kagan, H. B.; Set-
ton, R. Tetrahedron Lett. 1980, 21, 277. N-Fluoro sulfonimi-
des: e) Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991,
56, 4925. f) Xu, Z. -Q.; DesMarteau, D. D.; Gotoh, Y. J.
Chem. Soc., Chem. Commun. 1991, 179. F-TEDA-BF4:
g) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. J. Chem.
Soc., Chem. Commun. 1994, 343.
Synlett 1999, No. 4, 432–434 ISSN 0936-5214 © Thieme Stuttgart · New York