Nucleophilic trifluoromethylation of carbonyl compounds and disulfides with trifluoromethane and silicon-containing bases

Article abstract of DOI:10.1021/jo000150s

Provided that DMF (or another N,N-dialkylformamide) is present in the reaction medium, at least in a catalytic amount, fluoroform trifluoromethylates efficiently carbonyl compounds, even enolizable ones, when opposed to (TMS)₂N- M⁺, generated in situ from N(TMS)₃ and M⁺ F^- or RO^- Na⁺. When F^- is used in a catalytic amount, silylated α-(trifluoromethyl)carbinols are obtained: In this case, the four-component system HCF₃/N(TMS)₃/catalytic F^-/catalytic DMF behaves like the Ruppert's reagent, especially as far as nonenolizable carbonyl compounds are concerned (CF₃SiMe₃ remains more efficient for enolizable carbonyl compounds). This process involves an adduct between DMF and ^-CF₃ which is the true trifluoromethylating agent. In the same way, fluoroform efficiently trifluoromethylates disulfides and diselenides when deprotonated with a strong base selected from t-BuOK or N(SiMe₃)₃/Me₄NF (or TBAT). t-BuOK is more adapted to the trifluoromethylation of awl disulfides whereas N(SiMe₃)₃/F^- is Well suited to that of aliphatic disulfides.

Full text of DOI:10.1021/jo000150s

8848
J . Org. Chem. 2000, 65, 8848-8856
Nu cleop h ilic Tr iflu or om eth yla tion of Ca r bon yl Com p ou n d s a n d
Disu lfid es w ith Tr iflu or om eth a n e a n d Silicon -Con ta in in g Ba ses
Sylvie Large,† Nicolas Roques,‡ and Bernard R. Langlois*,†
Universite´ Claude Bernard-Lyon I, Laboratoire de Synthe`se, Electrosynthe`se et Re´activite´ des
Compose´s Organiques Fluore´s (UMR CNRS 5622), Baˆtiment 303, 43 Bd du 11 Novembre 1918,
69622 Villeurbanne Cedex, France, and Rhodia Co., Centre de Recherche de Lyon,
85 Av. des Fre`res Perret, B.P. 62, 69192 Saint-Fons Cedex, France
Bernard.Langlois@univ-lyon1.fr
Received February 2, 2000 (Revised Manuscript Received October 23, 2000)
Provided that DMF (or another N,N-dialkylformamide) is present in the reaction medium, at least
in a catalytic amount, fluoroform trifluoromethylates efficiently carbonyl compounds, even enolizable
ones, when opposed to (TMS)2N- M+, generated in situ from N(TMS)3 and M+ F- or RO- Na+.
When F- is used in a catalytic amount, silylated R-(trifluoromethyl)carbinols are obtained: in this
case, the four-component system HCF3/N(TMS)3/catalytic F-/catalytic DMF behaves like the
Ruppert’s reagent, especially as far as nonenolizable carbonyl compounds are concerned (CF3SiMe3
remains more efficient for enolizable carbonyl compounds). This process involves an adduct between
-
DMF and CF3 which is the true trifluoromethylating agent. In the same way, fluoroform efficiently
trifluoromethylates disulfides and diselenides when deprotonated with a strong base selected from
t-BuOK or N(SiMe3)3/Me4NF (or TBAT). t-BuOK is more adapted to the trifluoromethylation of
aryl disulfides whereas N(SiMe3)3/F- is well suited to that of aliphatic disulfides.
In tr od u ction
is strongly destabilized by electrostatic repulsions be-
tween the anionic charge and the p-electron pairs of the
fluorine atoms (+ IΠ effect). It collapses into fluoride
anion and difluorocarbene which, in contrast, is stabilized
by an overlap between the vacant orbital of the carbon
and the p-orbitals of the fluorine atoms. Thus, equiva-
lents of -CF3 have been designed in which stabilization
is brought by dispersion of the anionic charge either into
the vacant orbitals of a transition metal (especially CuI)
or in a fragile σ bond (typically C-Si). The first approach
is essentially devoted to the nucleophilic substitution of
aryl halides since strong solvation often lowers the
reactivity of trifluoromethylcopper(I) species which need
a thermal activation to react.9-12 (Trifluoromethyl)tri-
Because of the very peculiar properties of the fluorine
atom, the importance of fluorinated products in life
sciences is steadily expanding at a high rate. At present,
up to 30-40% of agrochemicals and 20-30% of pharma-
ceuticals contain at least one fluorine atom.1 Among
fluorinated compounds, trifluoromethylated ones consti-
tute an important class because of the stereoelectronic
properties of the CF3 moiety and the important bio-
availability brought by this group.2 For a long time, bio-
active trifluoromethylated compounds have been pre-
pared from trifluoromethylated “building blocks” through
iterative modifications but, during the past decade, new
opportunities appeared with the discovery of reagents
and techniques allowing the direct introduction of a CF3
group on an organic substrate.3
(4) (a) Tordeux, M.; Langlois, B.; Wakselman, C. J . Chem. Soc.,
Perkin Trans. 1 1990, 2293. (b) Clavel, J . L.; Langlois, B.; Wakselman,
C.; Tordeux, M. Phosphorus, Sulfur Silicon 1991, 59, 129. (c) Waksel-
man, C.; Tordeux, M.; Clavel, J . L.; Langlois, B. J . Chem. Soc., Chem.
Commun. 1991, 993. (d) Clavel, J . L.; Langlois, B.; Nantermet, R.;
Tordeux, M.; Wakselman, C. J . Chem. Soc., Perkin Trans. 1 1992, 3371.
(5) (a) Clavel, J . L.; Langlois, B.; Laurent, E.; Roidot, N. Phosphorus,
Sulfur Silicon 1991, 59, 169. (b) Langlois, B.; Monte`gre, D.; Roidot,
N. J . Fluorine Chem. 1994, 68, 63.
(6) Billard, T.; Roques, N.; Langlois, B. J . Org. Chem. 1999, 64, 3813.
(7) Langlois, B.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32,
7525.
(8) (a) Langlois, B.; Laurent, E.; Roidot, E. Tetrahedron Lett. 1992,
33, 1291. (b) Langlois, B. R.; Billard, T.; Gue´rin, S.; Large S.; Roidot-
Pe´rol, N. Phosphorus, Sulfur Silicon 1999, 153-154, 323.
(9) a) Burton, D. J .; Yang, Z. Y. Tetrahedron 1992, 48, 189 and
references cited herein. (b) Mawson, S. D.; Weavers, R. T. Tetrahedron
Lett. 1993, 34, 3139. (c) Clark, J . H.; McClinton, M. A. J . Fluorine
Chem. 1992, 59, 257.
Direct electrophilic trifluoromethylation has been
scarcely studied and few reagents has been developed for
this use. Radical trifluoromethylation has been more
•
extensively studied since the electrophilic CF3 radical
can be produced in a variety of ways from CF3Br,4 sodium
trifluoromethanesulfinate5,7,8 or thioesters of trifluoro-
acetic or triflic acids.6 Nucleophilic trifluoromethylation
is more complex since the “naked” trifluoromethyl anion
† Universite´ Claude Bernard-Lyon I.
‡ Rhodia Co., Centre de Recherche de Lyon.
(1) (a) Organofluorine Chemistry; Principles and Commercial Ap-
plications; Banks, R. E., Smart, B. E., Tatlow, J . C., Eds.; Plenum
Press: New York, 1994. (b) Organo-fluorine Compounds in Medicinal
and Biomedical Applications; Filler, R., Kobayashi, Y., Yagupolskii,
L. N., Eds.; Elsevier: Amsterdam, 1993. (c) Biomedical Frontiers of
Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; ACS
Editions: Washington, DC, 1996. (d) Inventory of Industrial Fluoro-
Biochemicals; Becker, A., Ed.; Eyrolles: Paris, 1996.
(10) a) Matsui, K.; Tobita, E.; Ando M.; Kondo, K. Chem. Lett. 1981,
1719.
(11) (a) McNeil, J . G., J r.; Burton, D. J . J . Fluorine Chem. 1991,
55, 225. (b) Su, D. B.; Duan, J . X.; Chen, Q. Y. Tetrahedron Lett. 1991,
52, 7689. (c) Duan, J . X.; Su, D. B.; Chen, Q. Y. J . Fluorine Chem.
1993, 61, 279. (d) Chen, Q. Y.; Duan, J . X. Tetrahedron Lett. 1993, 34,
4241. (e) Duan, J . X.; Chen, Q. Y. J . Chem. Soc., Perkin Trans. 1 1994,
725.
(2) Smart, B. E. In Organofluorine Chemistry; Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J . C.,
Eds.; Plenum Press: New York, 1994; Chapter 3, p 57.
(12) Langlois, B.; Roques, N. International Patent No. WO 94/01383
1994.
(3) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
10.1021/jo000150s CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/07/2000

Nucleophilic Trifluoromethylation of Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 26, 2000 8849
Sch em e 1. Evid en ce for th e Occu r r en ce of 1
methylsilane (Ruppert’s reagent) is presently the most
popular tool to carry out the second methodology.13 When
activated by a fluoride anion in the form of an anionic
pentacoordinated silicon species, it transfers, under mild
conditions, a -CF3 moiety to carbonyl compounds,13
esters14 and disulfides15 or thiocyanates16 to provide,
respectively, R-(trifluoromethyl)carbinols, trifluoromethyl
ketones and trifluoromethyl sulfides. Nevertheless, this
technique suffers from the fact that CF3SiMe3 is presently
prepared from ecotoxic CF3Br. Surprisingly, the use of
trifluoromethane (fluoroform) as a source of -CF3 has
been reported only recently. The large availability of this
cheap and environmentally benign reagent led us to
consider its use for synthetic purposes.
The first results concerning trifluoromethylation with
fluoroform has been reported by Shono et al.: they
treated, at -50 °C, a solution of benzaldehyde in DMF
with an excess of HCF3, in the presence of an electro-
generated base resulting from 2-pyrrolidinone (1.5 equiv),
and obtained 2-(trifluoromethyl)benzyl alcohol in good
yields.17 They claimed that such an electrogenerated base
was far more efficient than, for example, potassium tert-
butoxide. However, aryl trifluoromethyl carbinols have
been also obtained very recently, in moderate to fair
yields, from fluoroform, aromatic aldehydes and potas-
sium dimsylate,18 phenyl anion (generated by cathodic
reduction of iodobenzene),19 or t-BuOK. The latter base
delivered good yields, even at -10 °C, providing that it
was used in a stoichiometric amount to avoid side-
reactions.20 In all these cases, again, DMF was used as
solvent.
Ta ble 1. Desilyla tion of N(TMS)3 by Me4NF a t Room
Tem p er a tu r e in DMF a n d THF
(Me3Si)3N + Me4N+ F- solvent8
rt
H2
Me3SiF + (Me3Si)2N-Me4N+
(
O8 (Me3Si)2NH)
a
N(TMS)3/HN(TMS)2
(mol/mol)
solvent
DMF
time (min)
10
30
60
30
60
90:10
70:30
0:100
100:0
98:2
THF
300
80:20
a
From GC analysis of the ratio N(TMS)3/HN(TMS)2 after
hydrolysis with water.
Nevertheless, as pointed out by Normant et al.,18 this
result cannot be explained by the only formation of CF3K
or CF3NBu4 which are unstable, even at -45 °C.21 As the
reaction failed in THF, they postulated that -CF3 was
trapped by DMF as soon as formed, to deliver the adduct
1 (Scheme 1) which was able to transfer a -CF3 equiva-
lent to the carbonyl substrate. For these authors, the
occurrence of 1 can be deduced from the formation of
fluoral during hydrolysis of such a putative adduct in the
absence of benzaldehyde.18 Soon after, Russel and Roques20
reported more direct proofs from 19F NMR and trapping
experiments: when carefully treated with acetic acid, 1
delivered its conjugated acid and, in the presence of
t-BuMe2SiCl, its silyl ether was formed and isolated. The
latter compound was quite identical to that resulting
from the action of CF3SiMe3 on DMF (Scheme 1).
Such experiments underlined the crucial role of DMF
during trifluoromethylation with fluoroform and strong
bases since its adduct 1 acts as a -CF3 reservoir.
However, though the system HCF3/t-BuOK/DMF was
very efficient to trifluoromethylate benzaldehyde, it
completely failed, in our hands, with acetophenone: in
this case, enolate formation prevailed over trifluorometh-
ylation. Thus, we tried to deprotonate HCF3 with a base
designed to be generated in situ in low concentrations
and slowly enough to decrease enolization.
Resu lts a n d Discu ssion
For this purpose, we used a 1:1 mixture of tris-
(trimethylsilyl)amine and anhydrous tetramethylammo-
nium fluoride since we determined that, in DMF, this
system generates very slowly tetramethylammonium bis-
(trimethylsilyl)amide at room temperature (Table 1).
With such a three-component system [HCF3 (excess),
N(TMS)3 (1.5 equiv), Me4NF (1.5 equiv)], enolizable
ketones were successfully trifluoromethylated in DMF at
-10 °C, though in a modest yield except when enolization
was disfavored by steric factors as, for example, in 2,6-
dimethylcyclohexanone (Scheme 2).
(13) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(14) (a) Wiedemann, J .; Heiner, T.; Mloston, G.; Prakash, G. K. S.;
Olah, G. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 820. (b) Singh, R.
P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J . M. J . Org. Chem. 1999, 64,
2873.
(15) (a) Billard, T.; Langlois, B. Tetrahedron Lett. 1996, 37, 6865.
(b) Billard, T.; Large, S.; Langlois, B. R. Phosphorus, Sulfur Silicon
1998, 136, 137, 138, 521.
(16) (a) Billard, T.; Large, S.; Langlois, B. Tetrahedron Lett. 1997,
38, 65. (b) Bouchu, M. N.; Large, S.; Steng, M.; Langlois, B.; Praly, J .
P. Carbohydr. Res. 1998, 314, 37.
The same three-component reagent was also satisfac-
torily used to trifluoromethylate benzophenone (2). 1,1-
Diphenyl-2,2,2-trifluoroethanol (3) was obtained in yields
comparable to those resulting from HCF3 and NaH,
t-BuOK, or KN(TMS)2 (Table 2). Moreover, as anhydrous
Me4NF is not readily available nor easy to handle because
of its hygroscopic character, it was advantageously
replaced by sodium alcoholates. Table 2 clearly shows
that, under these conditions, alcoholates acted as de-
silylating agents rather than bases since, in the absence
(17) Shono, T.; Ishifune, M.; Okada, T.; Kashimura, S. J . Org. Chem.
1991, 56, 2.
(18) (a) Folle´as, B.; Marek, I.; Normant, J . F.; Saint-J almes, L.
Tetrahedron Lett. 1998, 39, 2973. (b) Folle´as, B.; Marek, I.; Normant,
J . F.; Saint-J almes, L. Tetrahedron 2000, 56, 275.
(19) Barhdadi, R.; Troupel, M.; Pe´richon, J . J Chem. Soc., Chem.
Commun. 1998, 1251.
(20) Russel, J .; Roques, N. Tetrahedron 1998, 54, 13771.
(21) (a) Emeleus, H. J .; Haszeldine, R. N. J . Chem. Soc. 1949, 2948
and 2953. (b) Haszeldine, R. N. J . Chem. Soc. 1954, 1273. (c) McBee,
E. T.; Battershell, R. D.; Braendlin, H. P. J . Org. Chem. 1963, 28, 1131.
(d) Pierce, O. R.; McBee, E. T.; J udd, G. F. J . Am. Chem. Soc. 1954,
76, 474.

8850 J . Org. Chem., Vol. 65, No. 26, 2000
Large et al.
Sch em e 2. Tr iflu or om eth yla tion of En oliza ble
Sch em e 3. Mech a n ism of Tr iflu or om eth yla tion
Keton es w ith HCF 3/N(TMS)3/F -/DMF
w ith HCF 3/N(TMS)3/Ca t. F -/Ca t. DMF
Ta ble 2. Tr iflu or om eth yla tion of Ben zop h en on e w ith
HCF 3/B-/DMF
entry
base (equiv)
yield of 3a (%)
pert’s reagent (CF3SiMe3/catalytic F-), as far as noneno-
lizable carbonyl compounds are concerned, in the sense
that it allows the addition of the elements of CF3-SiMe3
on a CdO double bond under mild conditions. The
Ruppert’s reagent remains, however, far more efficient
than ours for the trifluoromethylation of enolizable
ketones. The fact that DMEU, DMPU and N-formylmor-
pholine plaid the same role as DMF probably indicates
that they also add -CF3 to give “-CF3 reservoirs”.
Trifluoromethylation with HCF3, N(TMS)3, and cata-
lytic amounts of Me4NF and DMF could be rationalized
as indicated in Scheme 3. The first key-step (in which
DMF is recovered) is the transfer of -CF3 from 1 to the
carbonyl function. The second one is the silylation of the
resulting R-(trifluoromethyl)alcoholate by N(TMS)3 which
enables the regeneration of bis-(trimethylsilyl)amide.
The most intriguing point arising from Table 3 is the
relative variation of compounds 3 and 4 between crude
and isolated yields. It might result from a “silicon dance”
between 4 and DMF, through an equilibrium which could
be shifted toward 4 when DMF was extracted by water
from the organic phase during the workup (Scheme 4).
Trifluoromethylation with HCF3/N(TMS)3 (1.5 equiv)/
F- (0.2 equiv) has been also successfully applied to
chalcone 8a , (dibenzylidene)acetone 8b, 4,4′-difluoroben-
zophenone 8c, and fluorenone 8d (Table 4). The relative
variation between crude and isolated yields of 9a -c and
10a -c can be explained as above.
1
2
3
4
5
6
7
8
9
10
11
12
13
NaH (1.1)b
85
100
79
49
0
29
23
20
72
25
80
96
81
t-BuOK (1.1)b
(TMS)2NK (1.1)b
(TMS)2NNa (1.1)b
CF3CH2ONa (1.5)c
MeONa (1.5)c
EtONa (1.5)c
i-PrONa (1.5)c
(TMS)3N (1.5)/Me4NF (1.5)
(TMS)3N (1.5)/CF3CH2ONa (1.5)c
(TMS)3N (1.5)/MeONa (1.5)c
(TMS)3N (1.5)/EtONa (1.5)c
(TMS)3N (1.5)/i-PrONa (1.5)c
a
b
From 19F NMR analysis with an internal standard. Com-
mercial reagent. c Preformed in situ from NaH + ROH.
of N(TMS)3, they did not deprotonate efficiently fluoro-
form. In this procedure, even sodium trifluoroethylate,
which is a very weak base, delivered 3 in a significant
yield (entry 10). The best yields were obtained with
EtONa (entry 12), which is more nucleophilic than
MeONa (entry 11) and less hindered than i-PrONa (entry
13). Comparison of entries 4 and 11-13 also indicates
that commercial (TMS)2NNa was less efficient than the
same salt generated in situ from (TMS)3N/RONa. An
explanation could be that fluoroform was directly depro-
tonated by ([Me3Si(OR)N(TMS)2]- Na+), resulting from
addition of RONa on N(TMS)3.
In further experiments, we also obtained 3 in good
yields when Me4NF, or other anhydrous fluorides such
as CsF or tetrabutylammonium difluorotriphenylsilicate
(TBAT), was used in a catalytic amount only. Under these
conditions, 3 was mainly isolated in the form of its
silylated ether 4, indicating that N(TMS)3 acted as an
efficient silylating agent. Analogous results were ob-
tained in N,N-dimethylethyleneurea (DMEU) or N,N-
dimethylpropyleneurea (DMPU) instead of DMF. More-
over, in contrast with Normant’s results, trifluorometh-
ylation of benzophenone with fluoroform, N(TMS)3 and
catalytic amounts of fluorides was also successfully
carried out in THF, provided that DMF (or another N,N-
dialkylformamide, such as N-formylmorpholine) was
present in small amounts (Table 3). Again, 4 was the
main product of the reaction. Thus, the multicomponent
system HCF3 (excess)/N(TMS)3 (1.5 equiv)/Me4NF (0.2
equiv)/DMF (0.3 equiv) behaves, in THF, like the Rup-
As shown from conjugated ketones 8a or 8b, nucleo-
philic trifluoromethylation with HCF3 exclusively re-
sulted in a 1,2-addition (CF3SiMe3 is known to behave
in the same way). Nevertheless, an exclusive 1,4-trifluo-
romethylation occurred from trans-1-benzoyl-2-(dimeth-
ylamino)ethylene 8e (prepared from acetophenone and
dimethylketal of DMF).22 The resulting N,N-dimethyl-
1-trifluoromethyl-2-benzoylethylamine 11 was trans-
formed into trans-1-benzoyl-2-(trifluoromethyl)ethylene
12 by acidic treatment23 (Scheme 5).
(22) Abdulla, R. F.; Fuhr, K. H. J . Org. Chem. 1978, 43, 4248.
(23) (a) 12 has been already prepared by H. G. Viehe et al. in four
steps from acetophenone and CF3CH2NMe2, through 11 which was not
isolated: Ates, C.; J anousek, Z.; Viehe, H. G. Tetrahedron Lett. 1993,
34, 5711. (b) 12 was also described by C. Wakselman et al.: Molines,
H.; Wakselman, C. J . Fluorine Chem. 1980, 16, 97.

Nucleophilic Trifluoromethylation of Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 26, 2000 8851
Ta ble 3. Tr iflu or om eth yla tion of Ben zop h en on e w ith HCF 3 a n d Ca ta lytic Am ou n ts of F lu or id e
yield of 3a
yield of 4a
3 + 4a
(%)
F-
solvent
(%)
(%)
anhyd Me4NF
anhyd Me4NF
anhyd Me4NF
anhyd Me4NF
DMF
28 (33)
41
51
57 (47)
34
16
85 (80)
75
67
DMEU
DMPU
THF
0
0
0
anhyd Me4NF
CsF
THF + DMF (0.3 equiv)
52 (7)
37
20
91 (36)
60 (46)
38 (60)
62
69
3 (55)
40 (47)
90 (67)
99
89
94 (91)
100 (93)
DMF
Bu4N+ [Ph3SiF2]- (TBAT)
Bu4N+ [Ph3SiF2]- (TBAT)
Bu4N+ [Ph3SiF2]- (TBAT)
DMF
THF + DMF (0.3 equiv)
THF + N-formylmorpholine (0.3 equiv)
a
From 19NMR with internal standard; in parentheses: isolated yield.
Sch em e 4. “Silicon Da n ce” betw een 4 a n d DMF
Ta ble 4. Tr iflu or om eth yla tion of Non en oliza ble Keton es w ith HCF 3/N(TMS)3 (1.5 Equ iv)/F - (0.2 Equ iv)
substrate
9a
(%)
10a
(%)
9 + 10
no.
R1
R2
solvent
DMF
DMF
DMF
DMF
THF + DMF
(0.3 equiv)
F-
(%)
8a
8b
8c
8d
Ph-CHdCH
Ph-CHdCH
4-F-C6H4
Ph
Me4NF
Me4NF
CsF
CsF
Me4NF
0 (26)
40 (0)
43 (0)
0
68 (42)
22 (45)
44 (64)
72 (57)
83 (75)
68 (68)
62 (45)
87 (64)
72 (57)
83 (75)
Ph-CHdCH
4-F-C6H4
0
a
From 19NMR with internal standard; in parentheses: isolated yield.
Sch em e 5. Con ju ga ted Tr iflu or om eth yla tion of
3-Acylen a m in es
Under the same conditions, 4-methoxy-4-methyl-2,5-
cyclohexadien-1-one (8h ) and its 2-tert-butyl analogue (8i)
delivered the expected trifluoromethylated adducts as a
mixture of two diastereomers in which the cis-isomer
(9h -i cis, 10h -i cis) was always predominant over the
trans-isomer (9h -i tr a n s, 10h -i tr a n s).25 Diastereose-
lectivity was dramatically dependent on steric hindrance:
it ranged from 12 to 19% for 8h to 69% for 8i (Table 5).
The major formation of the cis isomer from 8h -i should
(24) (a) McKillop, A.; McLaren, L.; Taylor, R. J . K. J . Chem. Soc.,
Perkin Trans. 1 1994, 2047. (b) Pelter, A.; Elgendy, S. Tetrahedron
Lett. 1988, 29, 677.
4-Substituted 4-methoxy-2,5-cyclohexadien-1-ones (eas-
ily prepared from 4-substituted phenols with I(III) in the
presence of methanol)24 were also submitted to nucleo-
philic trifluoromethylation with HCF3/N(TMS)3/F-. 4,4-
dimethoxy-2,5-cyclohexadien-1-one 8f delivered excellent
crude yields but the isolated product was dependent on
the aqueous workup (Scheme 6).
(25) The relative configurations of compounds 9i cis-tr a n s, 10h
cis-tr a n s and 10i cis-tr a n s have been deduced from 13C NMR
spectra which exhibited through-space 13C-19F coupling constants (from
1.0 to 1.9 Hz) between CF3 and either CH3 (cis series) or OCH3 (trans
series). The configuration of 10i cis has been also confirmed by an
NOE experiment. The configurations of 9h cis and 9h tr a n s have been
attributed by comparison with compounds resulting from desilylation
of 10h cis and 10h tr a n s, respectively.

8852 J . Org. Chem., Vol. 65, No. 26, 2000
Ta ble 5. Tr iflu or om eth yla tion of 4-Meth oxy-4-m eth yl-2,5-cycloh exa d ien -1-on e
Large et al.
substrate 8
base
yield 9-10 cisc (%)
yield 9-10 tr a n sc (%)
cis + transc (%)
de (%)
8h
8h
8i
N(TMS)3/Me4NFa
t-BuOKb
10h cis 38 (21)
9h cis 42 (42)
10i cis 44 (26)
9i cis 50 (47)
10h tr a n s 26 (22)
9h tr a n s 33 (33)
10i tr a n s 8 (7)
9i tr a n s 9 (9)
10h 64 (43)
9h 75 (75)
10i 52 (33)
9i 59 (56)
19
12
69
69
N(TMS)3/CsFa
t-BuOKb
8i
a
b
N(TMS)3 (1.5 equiv)/F- (0.2 equiv). t-BuOK (1.1 equiv). c From 19NMR with internal standard; in parentheses: isolated yield.
Ta ble 6. Tr iflu or om eth yla tion of 13a w ith HCF 3 a n d
Sch em e 6. Tr iflu or om eth yla tion of
4,4-Dim eth oxy-2,5-cycloh exa d ien -1-on e
N(TMS)3/F - in DMF a t -10 °C
1) DMF/-15 °C
2) HCF3 (excess)
(n-C8H17S)2
8 n-C8H17SCF3
3) M+F-(1.5 equiv)
13a
14a
4) N(TMS)3 (1.5 equiv)
M+ F-
yield of 14a (%)
n-Bu4N+ [Ph3SiF2]-
anhydr Me4NF
60 (50)
73 (65)
a
From 19F NMR with internal standard; in parentheses:
isolated yield.
(crude: 51%, isolated: 45%), provided that LiN(TMS)2 was
buffered with hexamethyldisilazane (0.2 equiv) to avoid
competitive deprotonation of the substrate. When using
t-BuOK in place of LiN(TMS)2, 14a was obtained in
almost the same crude yield (54%). However, the side
formation of octyl difluoromethyl sulfide 15a and N,N-
bis(trimethylsilyl)octanesulfenamide could not be avoided.
Thus, we turned again to N(TMS)3/Me4NF and N(TMS)3/
TBAT systems to minimize the steady-state concentra-
tion of base. As expected, 14a was formed in yields up to
73% (Table 6) and no trace of 15a was detected with such
systems, even used in excess.
Nevertheless, the trifluoromethylation of disulfides
with HCF3/N(TMS)3/Me4NF contrasted with that of car-
bonyl compounds. First, it required a stoichiometic
amount of Me4NF because the resulting thiolates were
unable to react with N(TMS)3, as we verified under the
reaction conditions. Second, whereas the trifluorometh-
ylation of carbonyl compounds could not be carried out
in the absence of DMF, that of dioctyl disulfide was
successfully carried out, at -10 °C, either in DMF (crude
yield 14a ) 73%) or in pure THF (crude yield 14a ) 66%).
Since desilylation of N(TMS)3 by F- in far slower in THF
than in DMF (Table 1), this means that, in THF, -CF3
was generated in such a low concentration that it was
trapped very rapidly by the disulfide before collapsing.
Apparently, the soft nucleophile -CF3 interacted better
with the soft electrophile RSSR than with the harder
carbonyl moiety and was more efficiently trapped by the
former. Thus, different mechanisms can be proposed in
DMF and in THF (Scheme 7).
be consistent with the occurrence of two six-membered
transition states during the -CF3 transfer; the cis-isomer
could result from the one in which electrostatic repulsions
(between p-electrons of O and F) were minimized. This
interpretation is in accordance with a very recent paper
concerning nucleophilic additions to 4,4-disubstituted-2,5-
cyclohexadienones.26
The trifluoromethylation of other carbonyl compounds
with HCF3/N(TMS)3/Me4NF/DMF was also investigated:
under the usual conditions, esters were unreactive and
benzaldehyde was transformed into its N-trimethylsilyl
imine. For the trifluoromethylation of such substrates,
Ruppert’s reagent remains the most adapted tool.
Because trifluoromethyl sulfides can be prepared by
nucleophilic trifluoromethylation of disulfides or thiocy-
anates, as we demonstrated with CF3SiMe3,15,16 we were
also interested in studying the ability of fluoroform to
trifluoromethylate such substrates, all the more so since
Roques and Russell reported very briefly some prelimi-
nary results from diphenyl disulfide.20 Thus, we exam-
ined the ability of fluoroform to trifluoromethylate a
panel of disulfides and diselenides, under the same
conditions as carbonyl compounds. Preliminary experi-
ments, carried out from dioctyl disulfide 13a , HCF3, and
commercial LiN(TMS)2 (1.1 equiv) in DMF at -15 °C,
gave octyl trifluoromethyl sulfide 14a in a fair yield
Other disulfides 13b-f, as well as diphenyl diselenide
16f, were also trifluoromethylated with fluoroform under
the different conditions studied with 13a . The results are
summarized in Table 7.
(26) Wipf, P.; J ung, J . K. Chem. Rev. 1999, 99, 1469.

Nucleophilic Trifluoromethylation of Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 26, 2000 8853
Sch em e 7. P ossible Mech a n ism s for th e
Tr iflu or om eth yla tion of Disu lfid es w ith
HCF 3/N(TMS)3/Me4NF
t-BuOK by using mixtures of N(TMS)3 and fluorides or
alcoholates which generate amides slowly enough to
allow the trifluoromethylation of enolizable ketones.
Moreover, the system HCF3/N(TMS)3/catalytic F-/catalytic
DMF constitutes an environmentally benign alternative
to CF3SiMe3 for the preparation of R-trifluoromethyl silyl
ethers, especially from nonenolizable ketones. Neverthe-
less, in contrast to CF3SiMe3, it is not yet adapted to the
trifluoromethylation of aldehydes and esters. Our work
confirms that, under these conditions, trifluoromethyla-
tion occurs through the formation of an adduct between
-CF3 and DMF, which acts as the true trifluorometh-
ylating agent. Concerning the trifluoromethylation of
disulfides with fluoroform, we also demonstrated that the
binary system N(SiMe3)3/Me4NF is especially adapted to
the treatment of aliphatic disulfides, whereas t-BuOK is
more suited to that of aryl disulfides. In the former case,
the reaction can be carried out in pure THF.
Ta ble 7. Tr iflu or om eth yla tion of Differ en t Disu lfid es
a n d Diselen id es w ith HCF 3
Exp er im en ta l Section
Prior to use, DMF was distilled over calcium hydride and
THF over sodium/benzophenone. Both were stored over 3 Å
molecular sieves under N2. CsF was ground and dried at 250
°C for 24 h. Other reagents were used as received. TLC
analyses were carried out on Kieselgel 60F 254 deposited on
aluminum plates, detection being done by UV (254 nm),
phosphomolybdic acid (10% in ethanol), or ninhydrine (1% in
ethanol). Flash chromatographies were performed on silica gel
Geduran SI 60. Uncorrected melting points were determined
in capillary tubes. Unless stated otherwise, NMR spectra were
recorded in CDCl3. 1H NMR were recorded at 200 MHz or 300
MHz and 13C NMR spectra at 50 or 75 MHz. The substitution
pattern of the different carbons were determined by a “DEPT
135” sequence. 19F NMR spectra were recorded at 188 MHz.
Chemical shifts (δ) are given in ppm vs TMS (1H, 13C) or CFCl3
(19F) used as internal references. Coupling constants are given
in hertz. Crude yields were determined by 19F NMR vs PhOCF3
used as standard. GC was carried out on an apparatus fitted
with a semi-capillar column (length: 15 m, Φ: 0.53 mm, film
thickness (DB1): 1 µm) and a catharometric detector. Mass
spectrometry, coupled with gas chromatography, was carrried
out under electron impact at 70 eV. Elemental analyses were
carried out by the “Service Central d’Analyses du CNRS”.
(E)-3-(N,N-d im et h yla m in o)-1-p h en yl-2-p r op en -1-on e
(8e). Prepared according to ref 22. Dimethylketal of DMF (4.3
mL, 30 mmol) was added to a solution of acetophenone (1.20
g, 10 mmol) in DMF (10 mL) and the mixture was brought to
reflux for 15 h. After hydrolysis with water (10 mL), the
aqueous phase was extracted with diethyl ether. The combined
organic phases were washed with brine then water and dried
over Na2SO4. After filtration and concentration at room
temperature in vacuo, chromatography on silica gel (petroleum
ether (PE)/acetone 50:50) yielded 8e (1.09 g, 62%) as a yellow
RYYR
+
HCF3 basic system I, II, or III8 RYCF3
(excess)
I: LiN(TMS)2 (1.1 equiv)/HN(TMS)2 (0.2 equiv)
II: N(TMS)3 (1.5 equiv)/Me4NF (1.5 equiv)
III: t-BuOK (1.1 equiv)
DMF/-15 °C/5.5 h
(Y ) S, Se)
RSSR or RSeSeR
RSCF3 or RSeCF3
base
yielda (%)
(C8H17S)2
13a
C8H17SCF3
I
51
73 (65)
14a
II
III
I
54 (34)
(c-C6H11S)2
13b
c-C6H11SCF3
2b
14b
II
III
I
54 (50)
45
0
23
0
0
(t-BuS)2
13c
t-BuSCF3
14c
II
III
II
III
II
(PhCH2S)2
13d
PhCH2SCF3
14d
CF3SCH2CH2CO2Et
0
0
(EtO2CCH2CH2S)2
13e
PhSSPh
13f
14e
PhSCF3
14f
I
II
4c
6d
III
II
82 (75)
61 (47)
77
PhSeSePh
16f
PhSeCF3
17f
III
a
From 19F NMR with internal standard; in parentheses:
isolated yield. c-C6H11SCF2H (15b): 1%. c PhSCF2H (15f): 23%;
b
d
PhSN(TMS)2: (46%). PhSCF2H (15f): 0%; PhSN(TMS)2: detected.
As shown from Table 7, N(TMS)3/Me4NF was more
efficient than t-BuOK with aliphatic disulfides, except
with substrates which were too sensitive to proton
abstraction (13d ) or â-elimination (13e). Though the yield
was sensitive to steric hindrance, this reagent was even
able to deliver tert-butyl trifluoromethyl sulfide 14c from
tert-butyl disulfide, in contrast to other trifluorometh-
ylation processes.6,15a On the contrary, t-BuOK was far
more adapted to aromatic disulfides. Concerning diphenyl
diselenide, which is less electrophilic but more polarizable
than 13f, both techniques were almost equivalent.
1
solid: mp 90-92 °C; H NMR (200 MHz) δ 7.90 (d, J ) 8.0,
2H), 7.77 (d, J ) 12.3, 1H), 7.34-7.44 (M, 3H), 5.69 (d, J )
12.3, 1H), 3.04 (broad s, 3H), 2.87 (broad s, 3H); 13C NMR (50
MHz) δ 188.50, 154.23, 140.55, 130.84, 128.11, 127.45, 92.12,
44.88, 37.22; MS m/z 175 (M•+), 158, 143, 131, 105, 98, 91, 77,
70, 55, 42, 28, 15.
4-Meth oxy-4-m eth yl-2,5-cycloh exa d ien -1-on e (8h ). Pre-
pared according to ref 24. Bis(trifluoroacetoxy)iodo-benzene
(5.00 g, 11 mmol) was added, at -10 °C, to a solution of p-cresol
(1.10 g, 10 mmol) in methanol (32 mL). The mixture was
stirred at 0 °C for 1 h then hydrolyzed with water (32 mL).
The aqueous phase was extracted with CH2Cl2. The combined
organic phases were washed with water and then dried over
Na2SO4. After filtration and concentration at room tempera-
ture in vacuo, chromatography on silica gel (PE/ethyl ether
(EE) 40:60) yielded 8h (0.840 g, 61%) as a pale yellow solid:
mp 57-59 °C; 1H NMR (200 MHz) δ 6.80 (d, J ) 9.8, 2H),
6.32 (d, J ) 9.8, 2H), 3.21 (s, 3H), 1.44 (s, 3H); 13C NMR (50
Con clu sion
The work reported here enlarges the limited previous
reports on trifluoromethylation of carbonyl compounds
with fluoroform. We demonstrated that this reaction can
be carried out with milder bases than KN(TMS)2 or

8854 J . Org. Chem., Vol. 65, No. 26, 2000
Large et al.
MHz) δ 184.98, 151.72, 130.32, 72.53, 53.09, 26.13; MS m/z
138 (M•+), 123, 110, 107, 95, 79, 77, 67.
stage, 19F NMR analysis was performed on a small sample, in
the presence of PhOCF3 as internal standard. Hydrolysis and
workup were carried out as above. 3 was obtained in a 85%
yield (Table 2).
2-ter t-Bu tyl-4-m eth oxy-4-m eth yl-2,5-cycloh exa d ien -1-
on e (8i). This compound was prepared in the same way as
8h , from PhI(OCOCF3)2 (5.00 g, 11 mmol) and 2-tert-butyl-4-
methylphenol (1.65 g, 10 mmol). The latter was completely
converted within 1.5 h at 0 °C. 8i (1.34 g, 69%) was obtained
Tr iflu or om eth yla tion of Ben zop h en on e w ith HCF 3/
N(TMS)3/Sod iu m Alcoh ola tes (CF 3CH2ONa , MeONa , Et-
ONa , i-P r ONa ). Gen er a l P r oced u r e. NaH (72 mg, used as
a 50% suspension in oil) was added to a solution of the alcohol
(1.5 mmol) in anhydrous DMF (1 mL). The mixture was
warmed to 60 °C then cooled to -10 °C. N(SiMe3)3 (350 mg,
1.5 mmol), dissolved in anhydrous THF (1 mL), then ben-
zophenone (180 mg, 1 mmol), dissolved in anhydrous DMF (1
mL), were successively dropped at -10 °C. HCF3 (200-600
mg, 1.4-8.6 mmol) was bubbled at the same temperature. The
resulting mixture was stirred at -10 °C for 1 h, warmed to
room temperature and stirred for 5 h. At this stage, 19F NMR
analysis was performed on a small sample, in the presence of
PhOCF3 as internal standard. Hydrolysis and workup were
carried out as above. 3 was obtained in yields indicated in
Table 2.
Tr iflu or om eth yla tion of Keton es w ith HCF 3/N(TMS)3/
St oich iom et r ic M+F - (MF ) Me4N+F -, Cs+F -, Bu 4N+
[P h 3SiF 2]-). Gen er a l P r oced u r e. HCF3 (200-600 mg, 1.4-
8.6 mmol) was bubbled at -10 °C into a mixture of the ketone
(1 mmol), DMF (2 mL), and anhydrous fluoride (1.5 mmol)
[Me4NF (140 mg), CsF (230 mg), TBAT (810 mg)]. Then, a
solution of N(TMS)3 (352 mg, 1.5 mmol) in anhydrous THF
(1.5 mL) was dropped at -10 °C. The resulting mixture was
stirred at -10 °C for 1 h, warmed to room temperature and
stirred for 5 h. At this stage, 19F NMR analysis was performed
on a small sample, in the presence of PhOCF3 as internal
standard. Hydrolysis and workup were carried out as above.
The R-(trifluoromethyl)carbinol was obtained in yields indi-
cated in Schemes 3 and 7 as well as in Table 2.
Tr iflu or om eth yla tion of Keton es w ith HCF 3/N(TMS)3/
Ca ta lytic M+F - (MF ) Me4N+F -, Cs+F -, Bu 4N+[P h 3SiF 2]-).
Gen er a l P r oced u r e. The same procedure was carried out
until hydrolysis, except that 0.24 mmol of fluoride was used
[Me4NF (22 mg), CsF (30 mg), TBAT (108 mg)] and DMF can
be replaced by the solvents (2 mL) indicated in Tables 3 and
4. Hydrolysis can be performed either with pure water (to
obtain the R-(trifluoromethyl)carbinol along with its silyl ether)
or with water after previous treatment with TMSCl (130 µL)
(to obtain the silyl ether only) or with 1 N aqueous HCl (to
obtain the R-(trifluoromethyl)carbinol only). In all cases, the
aqueous phase was extracted with Et2O, and the combined
organic phases were washed with brine then water and finally
dried over Na2SO4. After filtration and concentration at room
temperature in vacuo, chromatography on silica gel delivered
the R-(trifluoromethyl)carbinol and/or its silyl ether in yields
indicated in Tables 3-5.
1,1-Dip h en yl-2,2,2-tr iflu or oeth a n ol (3). Oil. Purification
by chromatography with PE/acetone (20:1) as eluent. Spectral
features were in accordance with those reported in the
literature:28 1H NMR (200 MHz) δ 7.46-7.50 (M, 4H), 7.31-
7.34 (M, 6H), 3.09 (broad s, 1H); 13C NMR (50 MHz) δ 139.54,
128.74, 128.36, 127.55 (q, J ) 1.6), 125.46 (q, J ) 286), 79.57
(q, J ) 28.7); 19F NMR δ -74.70 (s); MS m/z 252 (M•+), 189,
105, 77. Anal. Calcd for C14H11F3O: C, 66.67; H, 4.39. Found:
C, 66.68; H, 4.55.
1
as a pale yellow solid: mp 57-58 °C; H NMR (200 MHz) δ
6.64 (d, J ) 3.0, 1H), 6.51 (dd, J ) 9.9 and 3.0, 1H), 6.21 (d,
J ) 9.9, 1H), 3.15 (s, 3H), 1.40 (s, 3H), 1.24 (s, 9H); 13C NMR
(50 MHz) δ 185.38, 149.07, 147.94, 144.86, 132.15, 72.86, 52.76,
34.66, 29.25, 26.72; MS m/z 194 (M•+), 179, 163, 151, 138, 123,
121, 105, 91, 77.
Di-n -octyl Disu lfid e 13a . n-Octanethiol (20.0 g, 0.14 mol)
was dropped in a solution of NaOH (5.6 g, 0.14 mol) in water
(32 mL). Then, iodine (17.8 g, 0.07 mol) was added by portions
within 15 min. The mixture was stirred for 7 h at room
temperature then 13a was extracted with toluene. After
washing the organic phase with saturated aqueous Na2S2O3
and drying it over MgSO4, the solvent was evaporated in vacuo
at room temperature. 13a was obtained as a pure colorless
liquid (19.3 g, 95%): 1H NMR δ 0.88 (t, J ) 6.8, 6H), 1.27 (m,
20H), 1.66 (quint, J ) 7.1, 4H), 2.66 (t, J ) 7.1, 4H); 13C NMR
δ 14.10, 22.66, 28.56, 29.20, 29.22, 29.25, 31.83, 39.23; MS m/z
290 (M•+), 178, 145, 71, 57, 43.
Tr iflu or om eth yla tion of Ben zop h en on e w ith HCF 3/
(Me3Si)2NK. Fluoroform (200 to 600 mg, 1.4 to 8.6 mmol) was
bubbled into a solution of benzophenone (1 mmol) in anhydrous
DMF (2 mL), maintained at -10 °C. Then, HN(TMS)2 (45 µL,
0.2 mmol)27 and KN(TMS)2 (1.1 mL of a 1M solution in THF,
1.1 mmol) were successively added at -10 °C. The resulting
mixture was stirred at -10 °C for 1 h, warmed to room
temperature and stirred at this temperature for 5 h. At this
stage, 19F NMR analysis was performed on a small sample, in
the presence of PhOCF3 as internal standard. Then, the crude
mixture was hydrolyzed with 1 N aqueous HCl until neutral.
The aqueous phase was extracted with Et2O. The combined
organic phases were washed with brine then water and dried
over Na2SO4. After filtration and concentration at room
temperature in vacuo, chromatography on silica gel delivered
the expected R-(trifluoromethyl)carbinol in a 79% yield.
Tr iflu or om eth yla tion of Keton es w ith HCF 3/t-Bu OK.
Gen er a l P r oced u r e. The same procedure was used to tri-
fluoromethylate 2, 8h and 8i, except that KN(TMS)2 and HN-
(TMS)2 were replaced by t-BuOK (1.1 mL of a 1 M solution in
THF, 1.1 mmol). Yields are indicated in Tables 2 and 5.
Tr iflu or om eth yla tion of Ben zop h en on e w ith HCF 3
a n d Sod iu m Alcoh ola tes (MeONa , EtONa , i-P r ONa ).
Gen er a l P r oced u r e. NaH (72 mg, used as a 50% suspension
in oil) was added to a solution of the alcohol (1.5 mmol) in
anhydrous DMF (1 mL). The mixture was warmed to 60 °C
then cooled to -10 °C. Benzophenone (180 mg, 1 mmol),
dissolved in DMF (1 mL), was added at -10 °C then HCF3
(200 to 600 mg, 1.4 to 8.6 mmol) was bubbled at this
temperature. The resulting mixture was stirred at -10 °C for
1 h, warmed to room temperature and stirred at this temper-
ature for 5 h. At this stage, 19F NMR analysis was performed
on a small sample, in the presence of PhOCF3 as internal
standard. Then, the crude mixture was hydrolyzed with 1 N
aqueous HCl until neutral. The aqueous phase was extracted
with Et2O. The combined organic phases were washed with
brine then water and dried over Na2SO4. After filtration and
concentration at room temperature in vacuo, chromatography
on silica gel delivered 3 in yields indicated in Table 2.
Tr iflu or om eth yla tion of Ben zop h en on e w ith HCF 3/
Na H. NaH (53 mg, 1.1 mmol, used as a 50% suspension in
oil) was added at -10 °C to a solution of benzophenone (1
mmol) in anhydrous DMF (2 mL). Then, HCF3 (200-600 mg,
1.4-8.6 mmol) was bubbled at this temperature. The resulting
mixture was stirred at -10 °C for 1 h, warmed to room
temperature, and stirred at this temperature for 5 h. At this
1,1-Dip h en yl-1-t r im et h ylsilyloxy-2,2,2-t r iflu or oet h -
a n e (4). Oil. Purification by chromatography with PE/acetone
(7:1) as eluent. Spectral features were in accordance with those
reported in the literature:28 1H NMR (300 MHz) δ 7.45-7.46
(M, 4H), 7.34-7.37 (M, 6H), -0.002 (s, 9H); 13C NMR (75 MHz)
δ 140.98, 128.32, 128.23 (q, J ) 1.5), 127.88, 125.24 (q, J )
287), 82.03 (q, J ) 28.3), 1.32; 19F NMR δ -73.10 (s); MS m/z
324 (M•+), 255, 239, 213, 185, 165, 105, 77, 73. Anal. Calcd for
C
17H19F3OSi: C, 62.94; H, 6.32; F, 17.57. Found: C, 63.05; H,
5.84; F, 17.72.
(E)-1-Tr iflu or om eth yl-1,3-d ip h en yl-2-p r op en -1-ol (9a ).
Oil. Purification by chromatography with PE/EE (90:10) as
(27) HN(TMS)2 was added as a buffer to ensure the reproducibilty
of the results whatever the origin of KN(TMS)2.
(28) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J . Org. Chem.
1991, 56, 984.

Nucleophilic Trifluoromethylation of Carbonyl Compounds
J . Org. Chem., Vol. 65, No. 26, 2000 8855
eluent: 1H NMR (200 MHz) δ 7.64 (d, J ) 9.5, 2H), 7.22-7.43
(m, 8H), 6.88 (d, J ) 16.0, 1H), 6.71 (d, J ) 16.0, 1H), 2.79
(broad s, 1H); 13C NMR (50 MHz) δ 137.57, 135.68, 133.71,
128.97, 128.90, 128.80, 128.54, 127.08, 126.98 (q, J ) 1.2),
126.64, 125.20 (q, J ) 286), 80.35 (q, J ) 28.5); 19F NMR δ
-78.97 (s); MS m/z 278 (M•+), 209, 191, 131, 105, 103, 77. Anal.
Calcd for C16H13F3O: C, 69.06; H, 4.71. Found: C, 69.42; H,
4.98.
(Z)-1-Tr iflu or om eth yl-1-tr im eth ylsilyloxy-4-m eth oxy-
4-m eth yl-2,5-cycloh exa d ien e (10h cis). Oil. Purification by
chromatography with PE/EE (80:20) as eluent: 1H NMR (200
MHz) δ 6.07 (d, J ) 10.5, 2H), 5.98 (d, J ) 10.5, 2H), 3.10 (s,
3H), 1.31 (s, 3H), 0.19 (s, 9H); 13C NMR (50 MHz) δ 137.57,
127.16 (q, J ) 5.6), 124.38 (q, J ) 285), 71.28 (q, J ) 30.9),
71.21, 52.95, 27.50, (q, J ) 1.0), 2.04; 19F NMR δ -81.78 (s);
MS m/z 280 (M•+), 265, 249, 233, 211, 195, 173, 157, 91, 77,
73.
(E)-1-Tr iflu or om eth yl-1-tr im eth ylsilyloxy-4-m eth oxy-
4-m eth yl-2,5-cycloh exa d ien e (10h tr a n s). Oil. Purification
by chromatography with PE/EE (80:20) as eluent: 1H NMR
(200 MHz) δ 6.07 (d, J ) 10.5, 2H), 5.98 (d, J ) 10.5, 2H),
3.20 (s, 3H), 1.37 (s, 3H), 0.16 (s, 9H); 13C NMR (50 MHz) δ
137.54, 127.80, 124.45 (q, J ) 285), 70.64, 70.56 (q, J ) 30.4),
52.07 (q, J ) 1.2), 26.70, 1.94; 19F NMR δ -81.11 (s); MS m/z
280 (M•+), 265, 249, 233, 211, 195, 173, 157, 91, 77, 73.
(Z)-1-Tr iflu or om eth yl-1-h yd r oxy-4-m eth oxy-4-m eth yl-
2,5-cycloh exa d ien e (9h cis). White solid. Purification by
chromatography with PE/EE (60:40) as eluent: mp 58-59 °C;
1H NMR (200 MHz) δ 6.06 (d, J ) 10.5, 2H), 5.99 (d, J ) 10.5,
2H), 3.07 (s, 3H), 3.01 (broad s, 1H), 1.33 (s, 3H); 13C NMR
(50 MHz) δ 138.35, 125.86 (q, J ) 1.0), 124.50 (q, J ) 285),
70.99, 68.16 (q, J ) 30.5), 52.22, 27.49; 19F NMR δ -80.63 (s);
MS m/z 208 (M•+), 193, 177, 173, 157, 139, 124, 109, 108, 91,
77, 69. Anal. Calcd for C9H11F3O2: C, 51.92; H, 5.33; F, 27.38.
Found: C, 52.27; H, 5.53; F, 26.40.
(E)-1-Tr iflu or om eth yl-1-tr im eth ylsilyloxy-1,3-diph en yl-
2-p r op en e (10a ). Oil. Purification by chromatography with
PE/acetone (14:1) as eluent: 1H NMR (300 MHz) δ 7.63 (d,
J ) 9.5, 2H), 7.40-7.43 (M, 8H), 6.73 (d, J ) 16.3, 1H), 6.59
(d, J ) 16.3, 1H), 0.18 (s, 9H); 13C NMR (75 MHz) δ 138.03,
135.74, 135.30, 128.87, 128.69, 128.61, 127.99, 126.93 (q, J )
1.1), 126.89, 125.37 (q, J ) 331), 79.98 (q, J ) 28.8), 2.07; 19
F
NMR δ -77.95 (s); MS m/z 350 (M•+), 281, 260, 239, 191, 183,
161, 133, 131, 105, 103, 77, 73. Anal. Calcd for C19H21F3OSi:
C, 65.12; H, 6.04; F, 16.26. Found: C, 65.37; H, 6.09; F, 16.19.
(E,E)-3-Tr iflu or om eth yl-3-tr im eth ylsilyloxy-1,5-diph en -
yl-1,4-p en ta d ien e (10b). Oil. Purification by chromatography
with PE/acetone (7:1) as eluent: 1H NMR (200 MHz) δ 7.37-
7.56 (m, 10H), 6.97 (d, J ) 16.0, 2H), 6.51 (d, J ) 16.0, 2H),
0.29 (s, 9H); 13C NMR (50 MHz) δ 135.93, 135.19, 128.93,
128.69, 127.09, 125.32, 124.99 (q, J ) 286), 78.57 (q, J ) 29.0),
2.36; 19F NMR δ -80.41 (s); MS m/z 376 (M•+), 361, 307, 286,
217, 205, 131, 103, 91, 77, 73.
1-Tr im et h ylsilyloxy-1,1-b is(4-flu or op h en yl)-2,2,2-t r i-
flu or oeth a n e (10c). Oil. Purification by chromatography with
PE/acetone (90:10) as eluent: 1H NMR (200 MHz) δ 7.41 (dd,
(E)-1-Tr iflu or om eth yl-1-h yd r oxy-4-m eth oxy-4-m eth yl-
2,5-cycloh exa d ien e (9h tr a n s). White solid. Purification by
chromatography with PE/EE (60:40) as eluent: mp 57-58 °C;
1H NMR (200 MHz) δ 6.02 (d, J ) 10.6, 2H), 5.95 (d, J ) 10.6,
2H), 3.40 (broad s, 1H), 3.11 (s, 3H), 1.29 (s, 3H); 13C NMR
(50 MHz) δ 137.64, 125.39, 124.44 (q, J ) 285), 71.22, 68.72
(q, J ) 30.7), 52.28, 27.24; 19F NMR δ -81.29 (s); MS m/z 208
(M•+), 193, 177, 173, 157, 139, 124, 109, 108, 91, 77, 69. Anal.
Calcd for C9H11F3O2: C, 51.92; H, 5.33; F, 27.38. Found: C,
51.30; H, 5.33; F, 26.42.
J ) 8.5, 5.3, 4H), 7.05 (dd, J ) 8.5, 5.3, 4H), -0.04 (s, 9H); 13
C
NMR (50 MHz) δ 162.73 (d, J ) 249), 136.73 (d, J ) 3.4),
130.15 (dq, J ) 8.2, 1.7), 125.06 (q, J ) 287), 114.95 (d, J )
21.5), 81.40 (q, J ) 28.8), 1.30; 19F NMR δ -73.45 (s, 3F),
-113.83 (s, 2F); MS m/z 360 (M•+), 291, 249, 221, 201, 73.
9-Tr iflu or om eth yl-9-(tr im eth ylsilyloxy)flu or en e (10d ).
White solid. Purification by chromatography with PE/acetone
(90:10) as eluent: 1H NMR (200 MHz) δ 7.73 (d, J ) 7.6, 2H),
7.69 (d, J ) 7.6, 2H), 7.50 (t, J ) 7.6, 2H), 7.37 (t, J ) 7.6,
2H), -0.20 (s, 9H); 13C NMR (50 MHz) δ 141.91, 141.16, 130.64,
128.13, 126.26 (q, J ) 1.5), 125.23 (q, J ) 284), 120.31, 83.10
(q, J ) 32.9), 1.20; 19F NMR δ -80.26 (s); MS m/z 322 (M•+),
253, 233, 211, 183, 77, 73.
(Z)-1-Tr iflu or om eth yl-1-tr im eth ylsilyloxy-2-ter t-bu tyl-
4-m eth oxy-4-m eth yl-2,5-cycloh exa d ien e (10i cis). Oil. Pu-
rification by chromatography with PE/EE (90:10) as eluent:
1H NMR (200 MHz) δ 5.94-6.02 (M, 3H), 3.12 (s, 3H), 1.26-
1.32 (M, 12H), 0.22 (s, 9H); NOE 1H-{1H} irradiation of the
Si(CH3)3 signal (0.22 ppm) increased the intensity (+3.5%) of
the CH3O signal (3.12 ppm); 13C NMR (50 MHz) δ 145.04,
135.97 (q, J ) 1.1), 134.72 (q, J ) 1.1), 129.31 (q, J ) 2.0),
124.56 (q, J ) 288), 75.39 (q, J ) 30.5), 71.84, 52.23, 36.73,
32.77 (q, J ) 1.9), 26.72 (q, J ) 1.1), 2.15; 19F NMR δ -75.66
(s); MS m/z 321 (M•+ - CH3), 279, 245, 211, 77, 73, 57.
(E)-1-Tr iflu or om eth yl-1-tr im eth ylsilyloxy-2-ter t-bu tyl-
4-m eth oxy-4-m eth yl-2,5-cycloh exa d ien e (10i tr a n s). Oil.
Purification by chromatography with PE/EE (90:10) as elu-
ent: 1H NMR (200 MHz) δ 5.79-6.87 (m, 3H), 2.90 (s, 3H),
1.11-1.17 (m, 12H), 0.00 (s, 9H); 13C NMR (50 MHz) δ 146.48,
135.11 (q, J ) 1.1), 134.92 (q, J ) 1.1), 130.58 (q, J ) 1.9),
124.73 (q, J ) 288), 75.39 (q, J ) 30.5), 71.46, 52.00 (q, J )
1.9), 36.65, 32.77 (q, J ) 1.9), 29.70, 1.91; 19F NMR δ -73.51
(s); MS m/z 321 (M•+ - CH3), 279, 245, 211, 77, 73, 57.
(Z)-1-Tr iflu or om et h yl-1-h yd r oxy-2-ter t-b u t yl-4-m et h -
oxy-4-m eth yl-2,5-cycloh exa d ien e (9i cis). Oil. Purification
by chromatography with PE/acetone (90:10) as eluent: 1H
NMR (300 MHz) δ 5.80-5.95 (m, 3H), 3.36 (broad s, 1H), 3.04
(s, 3H), 1.27 (s, 9H), 1.24 (s, 3H); 13C NMR (75 MHz) δ 144.00,
135.54 (q, J ) 1.1), 134.85 (q, J ) 1.1), 129.59 (q, J ) 2.1),
124.65 (q, J ) 287), 73.71 (q, J ) 30.3), 72.45, 51.60, 32.36 (q,
J ) 1.7), 32.35, 26.22 (q, J ) 1.1); 19F NMR δ -75.22 (s).
(E)-1-Tr iflu or om eth yl-1-h yd r oxy-2-ter t-bu tyl-4-m eth -
oxy-4-m eth yl-2,5-cycloh exa d ien e (9i tr a n s). Oil. Purifica-
tion by chromatography with PE/acetone (90:10) as eluent: 1H
NMR (300 MHz) δ 5.85-5.97 (m, 3H), 3.24 (broad s, 1H), 3.01
(s, 3H), 1.27 (s, 9H), 1.24 (s, 3H); 13C NMR (75 MHz) δ 145.63,
135.10, 134.41, 130.28 (q, J ) 3.2), 124.80 (q, J ) 287), 72.54
(q, J ) 30.1), 71.97, 51.98 (q, J ) 1.7), 32.36 (q, J ) 1.7), 32.35,
28.23; 19F NMR δ -72.53 (s).
4,4,4-Tr iflu or o-3-N,N-d im et h yla m in o-1-p h en yl-1-b u -
ta n on e (11). Chromatography on silica gel did not allow us
to isolate this compound: 19F NMR δ -69.97 (d, J ) 6.7); MS
m/z 245 (M•+), 176, 142, 126, 105, 77, 42.
(E)-4,4,4-Tr iflu or o-1-p h en yl-2-bu ten -1-on e (12). Oil. Pu-
rification by chromatography with PE/EE (70:30) as eluent:
1H NMR (200 MHz) δ 7.99 (d, J ) 7.0, 2H), 7.50-7.71 (M, 4H),
6.80 (dq, J ) 14.5, 6.5, 1H); 19F NMR δ -65.67 (d, J ) 6.5);
MS m/z 200 (M•+), 105, 77, 51.
1-Tr iflu or om eth yl-1-h yd r oxy-4,4-d im eth oxy-2,5-cyclo-
h exa d ien e (9f). Oil. Purification by chromatography with PE/
EE (50:50) as eluent: 1H NMR (200 MHz) δ 6.06-6.19 (m,
4H), 3.99 (broad s, 1H), 3.28 (s, 3H), 3.24 (s, 3H); 13C NMR
(50 MHz) δ 131.74, 128.21, 124.11 (q, J ) 285), 92.87, 68.53
(q, J ) 30.9), 50.16, 49.87; 19F NMR δ -80.78 (s).
4-Tr iflu or om eth yl-4-h yd r oxy-2,5-cycloh exa d ien -1-on e
(9g). Oil. Purification by chromatography with PE/EE (50:50)
as eluent. Spectral features were in accordance with those
reported in the literature:29 1H NMR (200 MHz) δ 6.87 (d, J )
10.3, 2H), 6.43 (d, J ) 10.3, 2H), 3.25 (broad s, 1H); 13C NMR
(50 MHz) δ 184.50, 141.80, 131.74, 123.54 (q, J ) 286), 69.49
(q, J ) 31.0); 19F NMR δ -79.67 (s).
4-Tr iflu or om eth yl-4-tr im eth ylsilyloxy-2,5-cycloh exa -
d ien -1-on e (10g). White solid. Purification by chromatogra-
phy with PE/EE (90:10) as eluent. Spectral features were in
accordance with those reported in the literature:29 1H NMR
(200 MHz) δ 6.84 (d, J ) 10.0, 2H), 6.40 (d, J ) 10.0, 2H),
0.14 (s, 9H); 13C NMR (50 MHz) δ 183.92, 142.73, 132.05,
123.30 (q, J ) 287), 71.52, 1.74; 19F NMR δ -80.16 (s); MS
m/z 235 (M•+), 185, 181, 139, 111, 83, 77, 73.
1-Meth yl-1-p h en yl-2,2,2-tr iflu or oeth a n ol. Oil. Purifica-
tion by chromatography with PE/EE (70:30) as eluent. Spectral
(29) Stahly, G. P.; Bell, D. R. J . Org. Chem. 1989, 54, 2873.

8856 J . Org. Chem., Vol. 65, No. 26, 2000
Large et al.
features were in accordance with those reported in the
literature:28 1H NMR (200 MHz) δ 7.38-7.57 (m, 5H), 2.62
(broad s, 1H), 1.79 (s, 3H); 13C NMR (50 MHz) δ 138.44, 128.59,
128.32, 126.01 (q, J ) 1.0), 125.0 (q, J ) 280), 74.60 (q, J )
30.0), 23.91; 19F NMR δ -81.45 (s); MS m/z 190 (M•+), 121,
105, 77, 51, 43.
1-Tr iflu or om eth yl-2,6-d im eth ylcycloh exa n ol. Oil. Pu-
rification by chromatography with PE/acetone (90:10) as
eluent: 1H NMR (200 MHz) δ 1.97-2.17 (m, 2H), 1.26-1.49
(m, 6H), 1.06 (m, 3H), 0.95 (m, 3H); 13C NMR (50 MHz) δ
126.62 (q, J ) 289), 76.96 (q, J ) 25.0), 34.29 (q, J ) 1.1),
30.34 (q, J ) 1.1), 30.13 (q, J ) 1.1), 28.29 (q, J ) 1.1), 19.66,
15.75 (q, J ) 1.9), 14.64 (q, J ) 1.9); 19F NMR δ -74.25 (s);
MS m/z 196 (M•+), 178, 163, 127, 109, 97, 83, 71, 70, 69, 57,
56, 55, 43, 42, 41, 39, 29, 27.
Tr iflu or om eth yla tion of Disu lfid es a n d Diselen id es
w ith HCF 3 a n d Ba ses. Gen er a l P r oced u r es. With LiN-
(TMS)2 a s Ba se. HCF3 (200-600 mg, 1.4-8.6 mmol) was
bubbled at -15 °C in a solution of disulfide or diselenide (1
mmol) in DMF (2 mL). Then, hexamethyldisilazane (45 µL,
0.2 mmol) and a 1 M solution of LiN(TMS)2 in THF (1.1 mL,
1.1 mmol) were successively dropped at the same temperature.
After addition, the reaction mixture was stirred at -15 °C for
5.5 h and then warmed to room temperature and kept at this
temperature under stirring for 12 h. After reaction, the crude
mixture was analyzed by 19F NMR with an internal standard
(PhOCF3).
With N(TMS)3/Me4NF a s Ba se. HCF3 (200-600 mg, 1.4-
8.6 mmol) was bubbled at 0 °C in a mixture of disulfide or
diselenide (1 mmol), anhydrous Me4NF (140 mg, 1.5 mmol),
and anhydrous solvent (DMF or THF, 2 mL). Then, a solution
of N(TMS)3 (352 mg, 1.5 mmol) in THF (1.5 mL) was added at
0 °C. After addition, the reaction mixture was stirred at 0 °C
for 5.5 h and then warmed to room temperature and kept at
this temperature under stirring for 12 h. After reaction, the
crude mixture was analyzed by 19F NMR with an internal
standard (PhOCF3).
With t-Bu OK a s Ba se. HCF3 (200-600 mg, 1.4-8.6 mmol)
was bubbled at -15 °C in a solution of disulfide or diselenide
(1 mmol) in DMF (2 mL). Then, a 1 M solution of t-BuOK in
THF (1.1 mL, 1.1 mmol) was dropped at the same temperature.
After addition, the reaction mixture was stirred at -15 °C for
5.5 h then warmed to room temperature and kept at this
temperature under stirring for 12 h. After reaction, the crude
mixture was analyzed by 19F NMR with an internal standard
(PhOCF3).
Com m on Wor k u p of Th ese P r oced u r es. Water (2 mL)
and 1 N aqueous HCl (0.5 mL) were added to the reaction
mixture. After separation, the aqueous phase was extracted
with diethyl ether. The combined organic phases were washed
with brine and then water, dried over Na2SO4, and evaporated
in vacuo at room temperature to deliver a crude oil which was
purified by column chromatography with petroleum ether as
eluent.
Compounds 14a ,b,f and 17f exhibited spectral features in
accordance with the well documented literature,6,16a,20,30 as well
as 15f,31 and will not be detailed again.
Ack n ow led gm en t. S.L. thanks the Rhodia Co. for
a PhD grant, and the SERCOF team is grateful to the
same company for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and 19F NMR spectra of compounds 3, 4, 8e,h ,i, 9a ,f-i, 10a -
d ,g-i, 11, 12, 13a , 1-methyl-1-phenyl-2,2,2-trifluoroethanol,
and 1-trifluoromethyl-2,6-dimethylcyclohexanol. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O000150S
(30) Chen, Q. Y.; Duan, J . X. J . Chem. Soc., Chem. Commun. 1993,
918.
(31) (a) De Cat, A. Bull. Soc. Chim. Belges 1965, 74, 270. (b)
Langlois, B. R. J . Fluorine Chem. 1988, 41, 247.