Mixed organofluorine-organosilicon chemistry. 13. One-pot synthesis of difluoroaldols from acylsilanes and trifluoromethyltrimethylsilane. Application to the synthesis of a difluoro analogue of egomaketone

Article abstract of DOI:10.1021/jo001549j

Difluoroaldol compounds 3 were synthesized in a one-pot procedure involving an acylsilane 1, trifluoromethyltrimethylsilane (TFMTMS), and an aldehyde. The key intermediate of this reaction is a difluoroenoxysilane 2. Ytterbium trifiate proved to be a very

Full text of DOI:10.1021/jo001549j

J . Org. Chem. 2001, 66, 1941-1946
1941
Mixed Or ga n oflu or in e-Or ga n osilicon Ch em istr y. 13. On e-P ot
Syn th esis of Diflu or oa ld ols fr om Acylsila n es a n d
Tr iflu or om eth yltr im eth ylsila n e. Ap p lica tion to th e Syn th esis of a
Diflu or o An a logu e of Egom a k eton e
Olivier Lefebvre, Thierry Brigaud,* and Charles Portella*
Laboratoire “Re´actions Se´lectives et Applications”, Associe´ au CNRS (UMR 6519), Universite´ de Reims
Champagne-Ardenne, Faculte´ des Sciences, BP 1039, 51687 Reims Cedex 2, France
thierry.brigaud@univ-reims.fr
Received November 1, 2000
Difluoroaldol compounds 3 were synthesized in a one-pot procedure involving an acylsilane 1,
trifluoromethyltrimethylsilane (TFMTMS), and an aldehyde. The key intermediate of this reaction
is a difluoroenoxysilane 2. Ytterbium triflate proved to be a very efficient catalyst for promoting
the aldol type reaction under very mild conditions. The potential of this reaction for the convergent
synthesis of difluorinated compounds was illustrated by the synthesis of difluoroegomaketone 7d
through dehydration of the corresponding aldol compound 3d .
In tr od u ction
the synthesis of functionalized R,R-difluorocarbonyl com-
pounds has proven to be very productive. Besides difluo-
roenolate chemistry,6 successful aldol-type reactions have
been reported from difluoroenol ethers,7 difluoroketene
silyl acetals,8 and difluoroenoxysilanes. The latter were
prepared from chlorodifluoromethyl ketones,9 trifluoro-
acetylsilane,10 and trifluoromethyl ketones.11 These pro-
cedures produce metal wastes or use solvents incompat-
ible with Lewis acids, so the difluoroenoxysilane has to
be isolated before performing the aldol reaction. More-
over, these procedures need the preliminary synthesis
of a fluorinated substrate. We report here a highly
convergent one-pot procedure for the synthesis of R,R-
difluoro-â-hydroxy ketones starting from an acylsilane,
trifluoromethyltrimethylsilane (TFMTMS), and an alde-
hyde. The key intermediate of this reaction is a difluo-
roenoxysilane whose reactivity in Michael additions,12
glycosylations,13 allylations and benzylations,14,15 and
aldol reactions with benzaldehyde14 and acylsilanes16 has
The introduction of a difluoromethylene unit into an
organic molecule presents a significant importance in
bioorganic and medicinal chemistry.1 More precisely, due
to their strong electron-withdrawing effect, fluorine
atoms activate the hydration of an adjacent carbonyl
group when they are introduced in the R position. This
hydrate acts as a transition state mimic for ester and
amide bond cleavage. Therefore, numerous bioactive
compounds containing the difluoromethylene ketone unit
are inhibitors of HIV-1 protease,2 elastase,3 renin,4 and
human heart chymase.5
The aldol reaction is a powerful synthetic tool for the
creation of carbon-carbon bonds, and its application to
* To
whom
correspondence
should
be
addressed.
thierry.brigaud@univ-reims.fr or charles.portella@univ-reims.fr.
(1) (a) Biomedical Frontiers of Fluorine Chemistry; Ojima, I., Mc-
Carthy, J . R., Welch, J . T., Eds.; American Chemical Society: Wash-
ington, DC, 1996. (b) Fluorine in Bioorganic Chemistry; Welch, J . T.,
Eswarakrishnan, S., Eds.; J ohn Wiley and Sons: New York, 1991. (c)
Tozer, M. J .; Herpin, T. Tetrahedron 1996, 52, 8619-8683. (d) Resnati,
G. Tetrahedron 1993, 49, 9385-9445. (e) Bravo, P.; Resnati, G.
Tetrahedron Asymm. 1990, 1, 661-692. (f) Welch, J . T. Tetrahedron
1987, 43, 3123-3197.
(2) (a) Schirlin, D.; Baltzer, S.; Van Dorsselaer, V.; Weber, F.; Weill,
C.; Altenburger, J . M.; Neises, B.; Flynn, G.; Remy, J . M.; Tarnus, C.
Bioorg. Med. Chem. Lett. 1993, 3, 253-258. (b) Schirlin, D.; Van
Dorsselaer, V.; Tarnus, C.; Taylor, D. L.; Tyms, A. S.; Baltzer, S.;
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Y.; Fukaya, C.; Nakajima, M.; Fukuyama, H.; Imada, T.; Nakamura,
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10.1021/jo001549j CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/22/2001

1942 J . Org. Chem., Vol. 66, No. 6, 2001
Lefebvre et al.
Sch em e 1
MS under tetrabutylammonium difluorotriphenylstannate
(DFTPS) initiation. The aldehyde and a Lewis acid were
then added to the solution. The reaction was first carried
out with a stoichiometric amount of conventional Lewis
acids (TiCl4 or BF3‚OEt2) added at low-temperature,
giving the expected aldol compounds in a good yield
despite the one-pot process (Scheme 1, Table 1). The
reaction was applied to aromatic, aliphatic, and ethylenic
aldehydes. It is worth noting that TiCl4 was not suitable
to use in aldol reactions with unsaturated aldehydes
(Table 1, entry 6). In this case, the major product was
the chlorinated compound 3f probably resulting from a
SN′ reaction of the intermediate titanium oxide. We can
assume that the chlorination took place in situ and did
not occur during hydrolysis because aldol 3e did not give
3f when treated under hydrolysis conditions. Further-
more, it is known that SN′ chlorination of this kind of
allylic alcohol in the non-fluorinated series required
stronger acidic conditions (12 N hydrochloric acid)18 than
that used in our workup procedure. This side reaction
could easily be avoided by using BF3‚OEt2 as the Lewis
acid to give the unique compound 3e (Table 1, entry 7).
The use of lanthanide salts such as Yb(OTf)3 as catalyst
is one of the major improvements of the last few years
in aldol type reactions.19 Our one-pot reaction proceeded
smoothly at room temperature with only 10% Yb(OTf)3
to give 3e in 78% yield (Table 1, entry 8). With this mild
catalyst, both free hydroxy- and trimethylsilyl-protected
aldol 3g and 3h were obtained (Table 2, entry 1). In a
standard procedure, removal of the trimethylsilyl pro-
tecting group was achieved by workup with fluoride ions.
Difluoroaldol compounds were then obtained in good yield
in a very convergent way starting from aromatic or
aliphatic acylsilanes and aldehydes (Scheme 2, Table 2).
The reaction with R,â-unsaturated aldehydes selectively
gave the aldol compounds 3e-j (Table 2, entries 4, 5, 6,
8). No Michael adducts were obtained as we observed
with enones.12 It should be noticed that the aliphatic aldol
3k (Table 2, entry 6) was the only one to be isolated as
the hydrate.
Ta ble 1. On e-P ot Ald ol Rea ction w ith Va r iou s Lew is
Acid s
a
b
Isolated yield. Overall yield based on the starting acylsilane.
Con str u ction of th e r,r-Diflu or o-â,γ-u n sa tu r a ted
Keton e Un it. Syn th esis of Diflu or oegom a k eton e. In
the course of our studies on gem-difluoroterpene ana-
logues synthesis, we recently demonstrated the useful-
ness of difluoroenoxysilanes to build, in a one-pot reac-
tion, the difluorohomoallylic and difluorohomobenzylic
units of difluorodehydro-ar-curcumene and difluoro-ar-
turmerone, respectively.15 We now present an application
of the one-pot aldol reaction to the synthesis of a difluoro
analogue of egomaketone.20 Such a compound, possessing
a difluoroallylic moiety, could be reached by a formal â,γ-
dehydration of the corresponding difluoroaldol 3d (Scheme
3). This transformation proved to be problematic, and
appropriate conditions had to be found. The aldol 3c was
used as a model to determine suitable conditions for this
reaction. Due to the electron-withdrawing effect of fluo-
rine, the acid-catalyzed dehydration of difluoroaldol 3c
already been reported by our group. This strategy,
applied to the aldol reaction, has allowed a short syn-
thesis of a fluorinated analogue of the furan monoterpe-
noid egomaketone.
Resu lts a n d Discu ssion
Lew is Acid -Ca ta lyzed On e-p ot Ald ol Rea ction s.
The chain reaction of TFMTMS with an acylsilane under
fluoride activation giving a difluoroenoxysilane can be
achieved with the same efficiency in ether, THF, or
dichloromethane14 which is the standard solvent for
Mukaiyama type aldol reactions.17 Therefore, the difluo-
roenoxysilanes 2 were quantitatively generated in dichlo-
romethane from the reaction of acylsilane 1 and TFMT-
(13) (a) Brigaud, T.; Lefebvre, O.; Plantier-Royon, R.; Portella, C.
Tetrahedron Lett. 1996, 37, 6115-6116. (b) Berber, H.; Brigaud, T.;
Lefebvre, O.; Plantier-Royon, R.; Portella, C. Chem. Eur. J ., in press.
(14) Brigaud, T.; Doussot, P.; Portella, C. J . Chem. Soc., Chem.
Commun. 1994, 2117-2118.
(18) Marvell, E. N.; Nelson, J . W. J . Org. Chem. 1980, 45, 5217-
5218.
(19) (a) Kobayashi, S.; Hachiya, I.; Takahori, T. Synthesis 1993,
371-373. (b) Lanthanides: Chemistry and Use in Organic Synthesis;
Kobayashi, S., Ed.; Springer-Verlag: Berlin Heidelberg, 1999.
(20) (a) Koyanagi, J .; Yamamoto, K.; Nakayama, K.; Tanaka, A. J .
Nat. Prod. 1995, 58, 1955-1957. (b) Ueda, T.; Fujita, Y. Chem. Ind.
1962, 1618-1619. (c) Tokuda, M.; Satoh, S.; Suginome, H. J . Org.
Chem. 1989, 54, 5608-5613. (d) Gosselin, P.; Masson, S.; Thuillier, A.
J . Org. Chem. 1979, 44, 2807-2809.
(15) Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1999, 55,
7233-7242.
(16) Saleur, D.; Brigaud, T.; Bouillon, J .-P.; Portella, C. Synlett 1999,
432-434.
(17) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1011-1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J . Am. Chem.
Soc. 1974, 96, 7503-7509.

One-Pot Synthesis of Difluoroaldols
J . Org. Chem., Vol. 66, No. 6, 2001 1943
Sch em e 2
Sch em e 4
the kinetic product 5. We anticipated that this side
reaction could be avoided by performing the elimination
reaction on the tosylate derivative. Indeed, â-elimination
took place in the presence of DBU, but only 33% of the
tosylate (NMR monitoring) was transformed after 8 h at
reflux in toluene. The difluoroaldol 3c was successfully
dehydrated via its triflate derivative 6c which underwent
a mild â-elimination at room temperature in toluene
using DBU as a base according to a reported procedure
(Scheme 5).21 One should notice, that because of the
presence of fluorine atoms in R-position of the triflate,
6c happened to be very stable, and it could be obtained
in a very good yield after purification by silica gel
chromatography. The conversion of 3c into 7c was
effective even without isolation of the intermediate
triflate, but replacement of dichloromethane by toluene
was essential for the elimination step. Finally, the furan-
derived aldol 3d was subjected to this reaction sequence.
Its preparation proved to be more efficient with BF3‚OEt2
than with Yb(OTf)3 as the Lewis acid. It was converted
in fair yield into the triflate 6d whose â-elimination
occurred in a good yield to give the difluoroegomaketone
7d (Scheme 5).
Ta ble 2. On e-P ot Ald ol Rea ction P r om oted by a
Ca ta lytic Am ou n t of Yb(OTf)3
Con clu sion
Acylsilane + TFMTMS + aldehyde constitute an
effective convergent three-component system for the
synthesis of difluoroaldol via the key intermediate di-
fluoroenoxysilane. The possibility of quantitatively gen-
erating the difluoroenoxysilane in dichloromethane, the
effectiveness of ytterbium triflate used in a catalytic
amount, and the one-pot character of this transformation
are the main attractive features of this chemistry. The
application of the above strategy to the synthesis of
difluoroegomaketone is an illustration of the potential
of this methodology toward the synthesis of elaborate
fluorinated compounds.
a
b
Isolated yield. Overall yield based on the starting acylsilane.
c O-Silylated aldol. This reaction was carried out without fluoride
workup. 75/25 mixture of isomers. e Isolated as the hydrate. f 75/
d
25 mixture of diastereomers.
Sch em e 3
failed because of the destabilization of the intermediate
carbocation. For example, 3c did not undergo dehydration
when treated with H2SO4 or H3PO4 in THF, CH2Cl2, or
DMF even at reflux temperature. Compound 3c was then
converted into the corresponding sulfonic or phosphoric
derivatives in order to attempt a â-elimination under
basic conditions. No elimination reaction occurred when
3c was reacted with thionyl chloride or phosphorus
oxychloride in the presence of triethylamine whereas the
corresponding mesylate 4 led to the sultone 5 under
treatment with potassium tert-butoxide (Scheme 4). The
deprotonation of the methanesulfonyl moiety and sub-
sequent intramolecular addition to the carbonyl group
proved to be more favorable than â-elimination. One can
assume that the difluoromethylene unit stabilizes the
quaternization of the adjacent carbon atom and prevents
a retro-aldol process, thus explaining the formation of
Exp er im en ta l Section 15
Commercially available reagents were used as supplied.
Tetrabutyl-n-ammonium difluorotriphenylstannate (DFTPS)
was prepared according to the reported procedure.22
Wa r n in g. Care should be taken in the manipulation of the
following fluorinated compounds, as they may be biochemically
active. Their toxicological properties are unknown.
Acylsila n es P r ep a r a tion s. The acylsilanes 1a 23 and 1b
were synthesized by the Brook and Corey method.23,24
(21) Morikawa, T.; Nishiwaki, T.; Nakamura, K.; Kobayashi, Y.
Chem Pharm. Bull. 1989, 37, 813-815.
(22) Gingras, M. Tetrahedron Lett. 1991, 32, 7381-7384.
(23) Corey, E. J .; Seebach, D. J . Am. Chem. Soc. 1967, 89, 434-
439.
(24) Brook, A. G.; Duff, J . M.; J ones, P. F.; Davis, A. R. J . Am. Chem.
Soc. 1967, 89, 431-434.

1944 J . Org. Chem., Vol. 66, No. 6, 2001
Lefebvre et al.
Sch em e 5
3
3-F u r oyltr im eth ylsila n e (1b): yellow oil; flash chroma-
ether-CH2Cl2, 1:1); 1H NMR δ 0.96 (d, J HH ) 6.5 Hz, 3H),
1
3
3
tography (petroleum ether-CH2Cl2, 4:1); H NMR δ 0.32 (s,
1.01 (d, J HH ) 6.5 Hz, 3H), 1.50 (ddt, J AB ) 14.1 Hz, J HH )
3
3
3
9H), 6.73 (d, J HH ) 1.9 Hz, 1H), 7.41 (d, J HH ) 1.9 Hz, 1H),
8.07 (s, 1H); 13C NMR δ -2.13, 106.4, 129.2, 143.7, 148.2,
228.5; IR (neat) 1593, 1248, 1153 cm-1; MS m/z 168 (M+• + 1,
79), 167 (100), 125 (96), 107 (81). Anal. Calcd for C8H12O2Si:
C, 57.10, H, 7.19. Found: C, 57.22, H, 7.41.
6.9 Hz, J HH
J AB ) 14.1 Hz, J HH ) 9.7 Hz, J HH ) 4.2 Hz, 1H), 2.46 (m,
)
4J HF ) 2.3 Hz, 1H), 1.44 (m, 1H), 1.66 (ddd,
3 3
3
3
3
1H), 4.33 (ddd, J HF ) 16.0 Hz, J HH ) 9.7 Hz, J HH ) 6.9 Hz,
3
3
1H), 7.51 (tm, J HH ) 7.6 Hz, 2H), 7.66 (tm, J HH ) 7.2 Hz,
1H), 8.11 (d, J HH ) 8.4 Hz, 2H); 19F NMR δ -108.5 (d, J AB
)
3
3
Ald ol Rea ction . Gen er a l P r oced u r e
293.7 Hz, 1F), -117.5 (dd, J AB ) 293.7 Hz, J FH ) 16.0 Hz,
2
In Situ P r ep a r a tion of th e Diflu or oen oxysila n e (2). To
a solution of acylsilane 1 (1.5 mmol) and TFMTMS (0.30 mL,
2.0 mmol) in dry CH2Cl2 (5 mL) at 0 °C under argon and
protected from light was added a catalytic amount of n-
tetrabutylammonium difluorotriphenylstannate (54 mg, 0.08
mmol). After 5 min of stirring at 0 °C, the reaction mixture
was stirred for 25 min at room temperature. The formation of
the difluoroenoxysilane was monitored by GC, and it was used
in the next step in a one-pot procedure.
TiCl4 Activa tion of th e Ald eh yd e. To the solution of
difluoroenoxysilane were added the aldehyde (1.8-2.2 mmol,
1.2-1.5 equiv) and TiCl4 (1.8-2.2 mmol, 1.2-1.5 equiv) at -78
°C (see Table 1). After being stirred 24 h at room temperature,
the reaction was quenched by addition of a saturated NaHCO3
solution (10 mL). After extraction with CH2Cl2 (3 × 15 mL),
the organic layer was washed with brine and dried over
MgSO4, and the solvent was evaporated under reduced pres-
sure. The crude product was purified by silica gel column
chromatography.
1F); 13C NMR δ 21.2, 23.5, 24.1, 37.6, 69.7 (t, J CF ) 25.6 Hz),
116.8 (t, J CF ) 258.9 Hz), 128.9, 130.2, 132.4, 134.4, 190.7 (t,
2J CF ) 30.5 Hz); IR (neat) 3452, 2957, 2926, 1697, 1116 cm-1
.
Anal. Calcd for C13H16O2F2: C, 64.54, H, 6.66. Found: C, 64.37,
H, 6.74.
2,2-Diflu or o-3-h yd r oxy-4-m et h yl-1-p h en ylp en t a n -1-
on e (3c): light yellow oil; flash chromatography (petroleum
3
ether-AcOEt, 9:1); 1H NMR δ 1.07 (d, J HH ) 6.1 Hz, 3H),
3
3
1.01 (d, J HH ) 6.1 Hz, 3H), 2.16 (o, J HH ) 6.1 Hz, 1H), 2.53
3
3
3
(d, J HH ) 6.1 Hz, 1H), 4.07 (dt, J HF ) 19.5 Hz, J HH ) 6.1
Hz, 1H), 7.39-7.68 (m, 3H), 8.10 (d, J HH ) 8.4 Hz, 2H); 19F
3
NMR δ -105.8 (d, J AB ) 289.9 Hz, 1F), -116.0 (dd, J AB ) 289.9
Hz, J HF ) 19.5 Hz, 1F); 13C NMR δ 17.1, 20.2, 28.3, 74.9 (dd,
3
2J CF ) 26.6 Hz, J CF ) 22.6 Hz), 117.6 (dd, J CF ) 258.9 Hz,
2
2
J CF ) 268.8 Hz), 128.6, 130.1, 132.5, 134.4, 190.8 (t, J CF
)
30.5 Hz); IR (neat) 3460, 2957, 1697 cm-1; MS m/z 228 (M+,
10), 208 (M+-HF, 60), 192 (51), 165 (100). Anal. Calcd for
C
12H14O2F2: C, 63.15, H, 6.18. Found: C, 63.55, H, 6.57.
2,2-Diflu or o-1-(3-fu r yl)-3-h yd r oxy-4-m et h ylp en t a n -1-
BF 3‚OEt2 Activa tion of th e Ald eh yd e. To the solution of
difluoroenoxysilane were added the aldehyde (2.2 mmol, 1.5
equiv) and BF3‚OEt2 (1.8 mmol, 1.2 equiv) at -30 °C. After
being stirred 24 h at room temperature, the reaction was
quenched by addition of a saturated NaHCO3 solution (10 mL).
After extraction with CH2Cl2 (3 × 15 mL), the organic layer
was washed with brine and dried over MgSO4, and the solvent
was evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography.
on e (3d ): light yellow oil; flash chromatography (petroleum
3
ether-AcOEt, 9:1); 1H NMR δ 1.06 (d, J HH ) 5.9 Hz, 6H),
3
3
1.63 (m, 1H), 2.12 (m, 1H), 3.99 (ddd, J HF ) 19.5 Hz, J HH
)
3
6.9 Hz, J HF ) 4.9 Hz, 1H), 6.88 (s, 1H), 7.47 (s, 1H), 8.26 (s,
1H); 19F NMR δ -108.8 (dd, J AB ) 274.7 Hz, J HF ) 4.9 Hz,
3
1F), -119.3 (dd, J AB ) 274.7 Hz, 3J HF ) 19.5 Hz, 1F); 13C NMR
2
δ 17.0, 19.9, 28.3, 77.8 (t, J CF ) 23.6 Hz), 109.2, 117.4 (dd,
3
J CF ) 259.9 Hz, J CF ) 256.0 Hz), 122.6, 143.9, 150.6 (dd, J CF
3
2
) 11.8 Hz, J CF ) 5.9 Hz), 186.2 (t, J CF ) 33.5 Hz); IR (neat)
3460, 2966, 2936, 1691 cm-1. Anal. Calcd for C10H12O3F2: C,
55.05, H, 5.54. Found: C, 55.22, H, 5.86.
Yb(OTf)3 Activa tion of th e Ald eh yd e. To the solution of
difluoroenoxysilane were added the aldehyde (1.8 mmol, 1.2
equiv) and Yb(OTf)3 (0.15 mmol, 0.1 equiv) at room temper-
ature. The reaction mixture was stirred 24 h at room temper-
ature, and Bu4NF‚3H2O (1 equiv) or an aqueous solution of
KF (6 mmol, 4 equiv, in 2 mL) was added. The mixture was
then stirred for 3 h (Bu4NF‚3H2O) or 48 h (KF), and a
saturated NaHCO3 solution (10 mL) was added. After extrac-
tion with CH2Cl2 (3 × 15 mL), the organic layer was washed
with brine and dried over MgSO4, and the solvent was
evaporated under reduced pressure. The crude product was
purified by column chromatography over silica gel.
2,2-Diflu or o-3-h yd r oxy-5-m et h yl-1-p h en ylh ex-4-en -1-
on e (3e): light yellow oil; flash chromatography (petroleum
ether-CH2Cl2, 1:1); 1H NMR δ 1.73 (s, 3H), 2.00 (s, 3H), 2.50
(m, 1H), 4.97 (dddd, 3J HF ) 15.1 Hz, 3J HF ) 7.9 Hz, 3J HH ) 8.6
3
3
Hz, J HH ) 6.2 Hz, 1H), 5.36 (dm, J HH ) 8.6 Hz, 1H), 7.49
3
3
(tm, J HH ) 7.6 Hz, 2H), 7.64 (tm, J HH ) 7.6 Hz, 1H), 8.09
(dm, J HH ) 7.6 Hz, 2H); 19F NMR δ -108.5 (dd, J AB ) 286.1
3
3
3
Hz, J HF ) 7.9 Hz, 1F), -115.3 (dd, J AB ) 286.1 Hz, J HF
)
15.1 Hz, 1F); 13C NMR δ 18.5, 25.9, 68.8 (t, J CF ) 26.6 Hz),
2
116.7 (dd, J CF ) 256.0 Hz, J CF ) 261.9 Hz), 118.2, 128.6, 130.1,
2,2-Diflu or o-3-h ydr oxy-1,3-diph en ylpr opan -1-on e (3a):11d
yellow oil; flash chromatography (petroleum ether-CH2Cl2,
1:1); 1H NMR δ 3.10 (d, 3J HH ) 5.0 Hz, 1H, OH), 5.34 (dt, 3J HF
132.7, 134.3, 141.7, 190.5 (t, J CF ) 29.5 Hz); IR (neat) 3427,
2
1697, 1450 cm-1; MS m/z 241 (M+, 10), 205 (50), 156 (42);
HRMS calcd for C13H15O2F2 240.0961, found 240.0927.
5-Ch lor o-2,2-d iflu or o-5-m e t h yl-1-p h e n ylh e x-3-e n -1-
on e (3f): colorless oil; flash chromatography (petroleum ether-
CH2Cl2, 4:1); 1H NMR δ 1.73 (s, 6H), 6.09 (dt, 3J HH ) 16.0 Hz,
) 18.6 Hz, 3J HF ) 3J HH ) 5.0 Hz, 1H), 7.34-8.04 (m, 10H); 19
F
NMR δ -106.0 (d, J AB ) 292.0 Hz, 1F), -116.8 (dd, J AB ) 292.0
3
2
Hz, J FH ) 18.6 Hz, 1F); 13C NMR δ 73.4 (dd, J CF ) 27.6 Hz,
2J CF ) 21.7 Hz), 116.0 (dd, J CF ) 263.8 Hz, J CF ) 258.0 Hz),
134.9, 134.5, 132.6, 130.2, 129.0, 128.6, 128.3, 128.1, 191.0 (t,
2J CF ) 29.5 Hz); IR (neat) 3474, 3036, 1693 cm-1. Anal. Calcd
for C15H12O2F2: C, 68.70, H, 4.61. Found: C, 68.35, H, 6.63.
2,2-Diflu or o-3-h yd r oxy-5-m e t h yl-1-p h e n ylh e xa n -1-
on e (3b): light yellow oil; flash chromatography (petroleum
3J HF ) 11.1 Hz, 1H), 6.48 (dt, J HH ) 16.0 Hz, J HF ) 2.5 Hz,
3
4
3
3
1H), 7.51 (tm, J HH ) 7.4 Hz, 2H), 7.65 (tm, J HH ) 7.4 Hz,
1H), 8.08 (d, J HH ) 7.4 Hz, 2H); 19F NMR δ -98.5 (d, J HF
)
3
3
11.1 Hz, 2F); 13C NMR δ 31.6, 65.7, 115.6 (t, J CF ) 250.0 Hz),
2
120.0 (t, J CF ) 24.6 Hz), 128.7, 130.1, 131.9, 134.3, 143.8 (t,
3J CF ) 8.9 Hz), 188.6 (t, J CF ) 31.5 Hz); IR (neat) 1705, 1259
2

One-Pot Synthesis of Difluoroaldols
J . Org. Chem., Vol. 66, No. 6, 2001 1945
cm-1. Anal. Calcd for C13H13OF2Cl: C, 60.36, H, 5.06. Found:
C, 60.58, H, 4.95.
3935, 2918, 1471, 1142 cm-1; MS m/z 250 (18), 229 (58), 157
(93), 129 (100).
(1R)-4-(6,6-Dim eth ylbicyclo[3.1.1]h ep t-2-en -2-yl)-3,3-d i-
flu or o-4-h yd r oxybu ta n -2-on e (3l) (75:25 mixture of dia-
stereomers): colorless oil; flash chromatography (petroleum
ether-ethyl acetate, 92:8); 1H NMR δ 0.85 (s, 3H), 1.34 (s, 3H),
3,3-Diflu or o-4-h yd r oxy-4-(2-n a p h th yl)bu ta n -2-on e (3g):
white solid; flash chromatography (petroleum ether-AcOEt,
1
4
9:1); mp 108 °C; H NMR δ 2.29 (t, J HF ) 1.1 Hz, 3H), 2.65
3
3
(m, 1H), 5.31 (dd, J HF ) 15.9 Hz, J HF ) 7.5 Hz, 1H), 7.47-
4
7.58 (m, 3H), 7.81-7.92 (m, 4H); 19F NMR δ -113.0 (dd, J AB
1.97-2.49 (m, 7H), 2.33 (d, J HF ) 3.4 Hz, 3H minor isomer),
2.38 (d, 4J HF ) 2.3 Hz, 3H major isomer), 4.49 (dd, 3J HF ) 18.3
3
) 270.3 Hz, J HF ) 7.5 Hz, 1F), -122.2 (dd, J AB ) 270.3 Hz,
3
Hz, J HF ) 7.6 Hz 1H), 5.70 (m, 1H); 19F NMR (major isomer)
3J HF ) 15.9 Hz, 1F); 13C NMR δ 25.7, 73.2 (dd, 2J CF ) 28.5 Hz,
2J CF ) 24.6 Hz), 114.6 (dd, J CF ) 261.8 Hz, J CF ) 255.9 Hz),
124.9, 126.4, 126.7, 127.5, 127.7, 128.2, 132.1, 132.9, 133.6,
200.1 (dd, 2J CF ) 32.5 Hz, 2J CF ) 27.5 Hz); IR (KBr) 3462, 1736,
1601, 1111 cm-1; MS m/z 250 (M+, 24), 157 (90), 129 (100).
Anal. Calcd for C14H12O2F2: C, 67.20, H, 4.83. Found: C, 67.04,
H, 4.83.
3
δ -112.3 (dd, J FF ) 270.8 Hz, J HF ) 7.6 Hz, 1F), -122.8 (dd,
3
J FF ) 270.8 Hz, J HF ) 18.3 Hz, 1F); (minor isomer) δ -110.9
3
(d, J FF ) 267.0 Hz, 1F), -123.8 (dd, J FF ) 267.0, J HF ) 15.3
Hz, 1F); 13C NMR (major isomer) δ 21.1, 25.5, 26.0, 31.5, 31.7,
2
2
40.6, 42.6, 73.1 (dd, J C-F ) 27.6 Hz, J C-F ) 23.6 Hz), 115.3
(dd, J C-F ) 261.8 Hz, J C-F ) 253.9 Hz), 124.6, 142.3, 200.1
2
2
(dd, J CF ) 27.3 Hz, J CF ) 33.5 Hz); (minor isomer) δ 21.3,
3,3-Diflu or o-4-(2-n a p h th yl)-4-tr im eth ylsilyloxybu ta n -
2
25.8, 26.1, 31.5, 31.7, 40.3, 42.6, 73.4 (dd, J C-F ) 29.5 Hz,
2-on e (3h ): white solid; flash chromatography (petroleum
2J C-F ) 26.6 Hz), 115.3 (dd, J C-F ) 261.8 Hz, J C-F ) 253.9
Hz), 124.7, 142.5, 200.1 (dd, 2J C-F ) 33.6 Hz, 2J C-F ) 27.1 Hz);
IR (neat) 3449, 2922, 1743 cm-1; MS m/z 244 (M+, 8), 227 (25),
121 (23); 107 (100); HRMS calcd for C13H18O2F2 244.1275,
found 244.1294.
1
ether-AcOEt, 95:5); mp 69 °C; H NMR δ 0.07 (s, 9H), 2.37
4
3
3
(d, J HF ) 2.7 Hz, 3H), 5.25 (dd, J HF ) 17.9 Hz, J HF ) 6.5
Hz, 1H), 7.50-7.59 (m, 3H), 7.85-7.88 (m, 4H); 19F NMR δ
3
-111.2 (dd, J AB ) 255.5 Hz, J HF ) 6.5 Hz, 1F), -124.7 (dd,
J AB ) 255.5 Hz, J HF ) 17.9 Hz, 1F); 13C NMR δ -0.2, 26.6,
3
Deh yd r a tion of Ald ol Com p ou n d s
2
2
74.2 (dd, J CF ) 31.5 Hz, J CF ) 23.6 Hz), 115.2 (dd, J CF
)
2,2-Diflu or o-3-m eth a n esu lfon yloxy-4-m eth yl-1-p h en yl-
p en ta n -1-on e (4). Triethylamine (0.55 mL, 3.6 mmol, 6 equiv)
and methanesulfonyl chloride (0.15 mL, 2.0 mmol, 3 equiv)
were added to a solution of 3c (0.15 g, 0.6 mmol) in CH2Cl2 (3
mL) at 0°. The mixture was stirred overnight, and water (10
mL) was added. After extraction with CH2Cl2 (3 × 15 mL),
the organic layer was washed with brine and dried over
MgSO4, and the solvent was evaporated under reduced pres-
261.1 Hz, J CF ) 253.1 Hz), 125.3, 126.3, 126.5, 127.7, 127.8,
2
127.9, 128.2, 132.8, 133.2, 133.6, 200.9 (dd, J CF ) 33.2 Hz,
2J CF ) 24.0 Hz); IR (KBr) 2959, 1738, 1253 cm-1; MS m/z 322
(M+, 20), 250 (15), 229 (100); HRMS calcd for C17H2O2F2Si
322.1200, found 322.1188.
2,2-Diflu or o-3-h yd r oxy-1-p h en ylp en t-4-en -1-on e (3i):
colorless oil; flash chromatography (petroleum ether-CH2Cl2,
3
3
1:1); 1H NMR δ 2.75 (m, 1H), 4.78 (dt, J HF ) 15.6 Hz, J HF
)
1
sure, giving 4 (0.150 g, 74%) as a red liquid. H NMR δ 1.09
3J HH ) 5.7 Hz, 1H), 5.45 (dd, J HH ) 10.6 Hz, J HH ) 1.4 Hz,
3
4
3
(d, J HH ) 6.1 Hz, 6H), 2.19-2.27 (m, 1H), 3.08 (s, 3H), 5.23
3
3
1H), 5.52 (d, J HH ) 17.2 Hz, 1H), 6.03 (ddd, J HH ) 17.2 Hz,
(ddd, 3J HF ) 14.9 Hz, 3J HF ) 10.9 Hz, 3J HH ) 4.0 Hz, 1H), 7.51-
3J HH ) 10.6 Hz, J HH ) 5.7 Hz, 1H), 7.50 (t, J HH ) 7.9 Hz,
3
3
3
7.72 (m, 3H), 8.10 (d, J HH ) 8.2 Hz, 2H); 19F NMR δ -103.4
3
3
2H), 7.65 (t, J HH ) 7.9 Hz, 1H), 8.11 (d, J HH ) 7.9 Hz, 2H);
3
(dd, J AB ) 288.0 Hz, J HF ) 10.9 Hz, 1F), -110.4 (dd, J AB
)
19F NMR δ -107.1 (dd, J AB ) 293.7 Hz, J HF ) 5.7 Hz, 1F),
3
288.0 Hz, J HH ) 14.9 Hz, 1F); 13C NMR δ 16.8, 20.1, 28.4,
3
-115.6 (dd, J AB ) 293.7 Hz, J HF ) 15.6 Hz, 1F); 13C NMR δ
3
38.9, 82.5 (dd, 2J CF ) 23.6 Hz, J CF ) 19.7 Hz), 116.2 (t, J CF
)
2
2
2
72.5 (dd, J CF ) 27.6 Hz, J CF ) 25.6 Hz), 115.8 (dd, J CF
)
3
259.8 Hz), 129.0, 130.0 (t, J CF ) 3.9 Hz), 131.8, 134.9, 188.3
3
261.8 Hz, J CF ) 257.9 Hz), 120.4, 128.7, 130.2 (t, J CF ) 3.9
(t, J CF ) 31.5 Hz); MS m/z 201 (M+-105, 65), 105 (100).
2
2
Hz), 131.2, 134.6, 190.3 (t, J CF ) 29.5 Hz); IR (neat) 3439,
3,3-Diflu or o-2-h yd r oxy-2-p h en yl-4-isop r op ylbu ta n -1,4-
su lton e (5). To a solution of mesylate 4 (0.15 g, 0.5 mmol) in
THF (3 mL) was added t-BuOK (0.07 g, 0.6 mmol, 1.2 equiv)
at room temperature. The mixture was stirred 24 h, and water
(5 mL) was added. After extraction with Et2O (3 × 15 mL),
the organic layer was washed with brine and dried over
MgSO4, and the solvent was evaporated under reduced pres-
sure. Purification by flash chromatography (petroleum ether-
1699, 1599 cm-1; MS m/z 213 (M+, 5), 156 (43), 105 (100).
2,2-Diflu or o-3-h yd r oxy-5,9-d im eth yl-1-p h en yld eca -4,8-
d ien -1-on e (3j) (75:25 isomers mixture): light yellow oil; flash
chromatography (petroleum ether-ethyl acetate, 93:7); 1H
4
NMR (major isomer) δ 1.59 (s, 3H), 1.66 (s, 3H), 1.71 (d, J HH
3
) 1.1 Hz, 3H), 2.07 (m, 4H), 2.40 (d, J HH ) 5.7 Hz, 1H), 5.00
3
(m, 1H), 5.05 (m, 1H), 5.34 (d, J HH ) 9.1 Hz, 1H), 7.49 (tm,
3J HH ) 7.6 Hz, 2H), 7.64 (tm, 3J HH ) 7.6 Hz, 1H), 8.10 (d, 3J HH
) 7.6 Hz, 2H); (minor isomer) δ 1.60 (s, 3H), 1.68 (s, 3H), 1.80
1
CH2Cl2, 3:2) gave 5 (0.085 g, 60%) as a solid; mp 197 °C; H
NMR δ 1.14 (m, 6H), 1.56 (s, 1H) 2.39 (m, 1H), 3.46 (d, J AB
)
4
3
3
(d, J HH ) 1.1 Hz, 3H), 2.09 (m, 4H), 2.33 (d, J HH ) 5.2 Hz,
14.5 Hz, 1H), 4.14 (dm, J AB ) 14.5 Hz, 1H), 4.92 (dd, J HF
)
3
3
1H), 5.00 (m, 1H), 5.05 (m, 1H), 5.40 (d, J HH ) 8.7 Hz, 1H),
23.0 Hz, J HH ) 4.8 Hz, 1H), 7.43 (massif, 3H), 7.63 (massif,
2H); 19F NMR δ -128.1 (d, J AB ) 265.1 Hz, 1F), 123.6 (dd, J AB
3
3
7.49 (tm, J HH ) 7.6 Hz, 2H), 7.64 (tm, J HH ) 7.6 Hz, 1H),
8.10 (d, 3J HH ) 7.6 Hz, 2H); 19F NMR (major isomer) δ -108.8
3
4
) 265.1 Hz, J FH ) 23.0 Hz, 1F)); 13C NMR δ 17.4 (d, J CF
)
3
4
4
2
(ddd, J AB ) 286.1 Hz, J HF ) 22.9 Hz, J HF ) 7.6 Hz, 1F),
-115.0 (dd, J AB ) 286.1 Hz, 3J HF ) 15.2 Hz, 1F); (minor isomer)
δ -107.4 (dm, J AB ) 286.1 Hz, 1F), -116.1 (dd, J AB ) 286.1
Hz, 3J HF ) 17.2 Hz, 1F); 13C NMR (major isomer) δ 17.0, 17.6,
25.5, 26.0, 39.6, 68.7 (t, 2J CF ) 25.6 Hz), 116.8 (dd, J CF ) 259.9
Hz, J CF ) 256.0 Hz), 117.9, 123.4, 128.6, 130.0, 131.9, 132.6,
3.9 Hz), 19.8 (d, J CF ) 3.9 Hz), 27.3, 54.2, 74.0 (t, J CF ) 27.6
Hz), 83.0 (dd, J CF ) 35.4 Hz, J CF ) 24.6 Hz), 116.2 (t, J CF
2
2
)
258.8 Hz), 126.5, 128.5, 129.3, 135.2; IR (KBr) 3462, 2922,
1441, 1340 cm-1; MS m/z 201 (M+ - 105, 72), 105 (100). Anal.
Calcd for C13H16O4F2S: C, 50.97, H, 5.26. Found: C, 51.24,
H, 5.03.
2
134.3, 145.0, 191.0 (t, J CF ) 31.5 Hz); (minor isomer) δ 17.0,
2,2-Diflu or o-3-tr iflu or om eth a n esu lfon yloxy-4-m eth yl-
1-p h en ylp en ta n -1-on e (6c). To a solution of aldol 3c (0.255
g, 1.1 mmol) in CH2Cl2 (5 mL) at 0 °C under argon were added
2,6-di-tert-butylpyridine (0.33 mL, 1.3 equiv) and triflic anhy-
dride (0.21 mL, 1.1 equiv). The mixture was stirred overnight
at room temperature. After addition of a saturated NH4Cl
solution (10 mL), the solution was extracted with CH2Cl2 (3 ×
15 mL). The organic layer was washed with brine and dried
over MgSO4, and the solvent was evaporated under reduced
pressure. Purification by flash chromatography (petroleum
ether-CH2Cl2, 4:1) gave 6c (0.335 g, 83%). Oil. 1H NMR δ 1.13
17.6, 25.6, 26.3, 40.5, 68.6 (t, 2J CF ) 25.4 Hz), 116.6 (dd, J CF
)
265.8 Hz, J CF ) 261.9 Hz), 118.4, 123.4, 128.6, 130.0, 132.4,
2
132.9, 134.3, 145.4, 190.5 (t, J CF ) 29.5 Hz); IR (neat) 3418,
2966, 2916, 1699 cm-1; MS m/z 308 (M+, 25), 291 (99), 105
(100); HRMS calcd for C18H22O2F2 308.1585, found 308.1570.
3,3-Diflu or o-d od eca n e-2,2,4-tr iol (3k ): white solid; flash
chromatography (petroleum ether-AcOEt, 9:1); mp 42 °C; 1H
3
NMR δ 0.87 (t, J HH ) 6.5 Hz, 3H), 1.14-1.45 (m, 12 H), 1.52
3
3
(s, 1H), 2.42 (m, 5H), 3.99 (ddd, J HF ) 22.9 Hz, J HH ) 8.4
Hz, J HH ) 4.2 Hz, 1H), 5.15 (m, 2H); 19F NMR δ -129.2 (d,
3
3
3
J AB ) 249.8 Hz, 1F), -131.4 (dd, J AB ) 249.8, 3J HH ) 22.9 Hz,
(d, J HH ) 6.9 Hz, 3H), 1.17 (d, J HH ) 7.2 Hz, 3H), 2.35 (m,
3 3 3
1F); 13C NMR δ 14.1, 22.6, 24.1, 25.1, 29.3, 29.4, 29.5, 31.8,
1H), 5.49 (ddd, J HF ) 17.5 Hz, J HH ) 6.9 Hz, J HF ) 3.4 Hz,
2
2
2
3
3
33.7, 73.8 (dd, J CF ) 29.5 Hz, J CF ) 23.6 Hz), 95.2 (dd, J CF
) 33.5 Hz, 2J CF ) 25.6 Hz), 113.9 (t, J CF ) 253.9 Hz); IR (KBr)
1H), 7.52 (m, 2H), 7.70 (t, J HH ) 7.5 Hz, 1H); 8.16 (d, J HH )
2
7.5 Hz, 2H); 19F NMR δ -74.1 (s, 3F), -100.4 (d, J FF ) 298

1946 J . Org. Chem., Vol. 66, No. 6, 2001
Lefebvre et al.
2
3
2
Hz, 1F), -112.6 (dd, J FF ) 298 Hz, J HF ) 17.5 Hz, 1F); 13C
δ 19.3, 26.6, 115.9 (t, J CF ) 249.0 Hz), 117.7 (t, J CF ) 26.0
2
2
3
NMR δ 16.4, 20.1, 28.6, 87.5 (dd, J CF ) 23.6 Hz, J CF ) 19.7
Hz), 114.8 (t, J CF ) 290.0 Hz), 118.5 (q, J CF ) 318.0 Hz), 129.0,
130.1, 131.3, 135.9, 187.4 (t, J CF ) 30.5 Hz).
Hz), 128.2, 130.0, 132.0, 134.0, 147.2 (t, J CF ) 7.7 Hz), 188.8
(t, J CF ) 31.5 Hz); IR (neat), 2922, 1705, 1441 cm-1. Anal.
2
2
Calcd for C12H12OF2: C, 68.56, H, 5.75. Found: C, 68.67, H,
6.03.
2,2-Diflu or o-3-tr iflu or om eth a n esu lfon yloxy-1-(3-fu r a -
n yl)-4-m eth ylp en ta n -1-on e (6d ). Following the same pro-
cedure than for the aldol 3c, 3d (0.526 g, 2.4 mmol) gave 6d
(0.409 g, 49%) as a colorless oil after purification by flash
chromatography (petroleum ether-CH2Cl2, 9:1). 1H NMR δ
2,2-Diflu or o-1-(3-fu r an yl)-4-m eth ylpen t-3-en -1-on e (7d).
Following the same procedure than for the triflate 6c, 6d
(0.368 g, 1.0 mmol) gave 7d (0.166 g, 79%) as a colorless solid
after purification by flash chromatography (petroleum ether-
3
3
0.99 (d, J HH ) 5.7 Hz, 3H), 1.00 (d, J HH ) 6.9 Hz, 3H), 2.19
1
CH2Cl2, 4:1). mp 42 °C; H NMR δ 1.75 (s, 3H), 1.76 (s, 3H),
3
3
3
(m, 1H), 5.22 (ddd, J HF ) 16.4 Hz, J HF ) 7.6 Hz, J HH ) 3.8
3
5.43 (tm, J HF ) 15.2 Hz, 1H), 6.76 (s, 1H), 7.38 (s, 1H), 8.08
Hz, 1H), 6.80 (s, 1H), 7.43 (s, 1H), 8.22 (s, 1H); 19F NMR δ
(s, 1H); 19F NMR δ -96.4 (d, 3J FH ) 15.2 Hz); 13C NMR δ 19.3,
3
-74.4 (s, 3F), -104.1 (dd, J FF ) 282.0 Hz, J HF ) 7.6 Hz, 1F),
2
26.5, 109.4, 115.7 (t, J CF ) 248.7 Hz), 116.2 (t, J CF ) 27.5
-115.7 (dd, J FF ) 282.0 Hz, J HF ) 16.4 Hz, 1F); 13C NMR δ
3
Hz), 122.0, 143.9, 147.7 (t, 3J CF ) 7.9 Hz), 149.8, 184.2 (t, 2J CF
) 35.5 Hz); IR (KBr) 3148, 2986, 2936, 1693 cm-1; MS m/z
200 (M+, 50), 181 (10), 149 (15), 105 (100). Anal. Calcd for
16.4, 19.7, 28.4, 87.4 (dd, 2J CF ) 23.6 Hz, 2J CF ) 20.7 Hz), 109.0,
114.5 (dd, J CF ) 263.0 Hz, J CF ) 259.0 Hz), 118.5 (q, J CF
)
320 Hz), 144.4, 150.6, 182.6 (t, 2J CF ) 29.5 Hz); IR (neat) 3148,
2986, 1693, 1215 cm-1; MS (CI+) m/z 368 (M + 18, 45), 200
(100), 183 (84), 165 (71).
C
10H10O2F2: C, 60.00, H, 5.04. Found: C, 60.14, H, 5.15.
Ack n ow led gm en t. The authors thank the “Minis-
2,2-Diflu or o-4-m eth yl-1-p h en ylp en t-3-en -1-on e (7c). To
a solution of triflate 6c (0.335 g, 0.9 mmol) in toluene (3 mL)
was added DBU (0.34 mL, 2.3 mmol, 2.5 equiv) under argon.
The mixture was stirred 4 h at room temperature. After
addition of a saturated NH4Cl solution (50 mL), the solution
was extracted with CH2Cl2 (3 × 50 mL). The organic layer was
washed with brine and dried over MgSO4, and the solvent was
evaporated under reduced pressure. Purification by flash
chromatography (petroleum ether-CH2Cl2, 9:1) gave 7c (0.140
g, 72%) as a colorless liquid. 1H NMR δ 1.83 (m, 6H), 5.66 (tm,
te`re de l’Education Nationale, de la Recherche et de la
Technologie” for a Ph.D. fellowship to O. L., and Bayer
A. G. (Dr A. Marhold) for a gift of trifluoromethyltri-
methylsilane. They also express their thanks to Benoit
Didier and Se´bastien Leclerc for their assistance, to H.
Bailla and S. Lanthony for their technical assistance
in the analytical aspects, and to Dr. K. Ple´ for English
correction.
3J HF ) 13.3 Hz, 1H), 7.49 (m, 2H), 7.59 (m, 1H), 8.05 (d, J HH
3
) 7.6 Hz, 2H); 19F NMR δ -93.1 (d, 3J HF ) 13.3 Hz); 13C NMR
J O001549J