Towards enantioselective nucleophilic trifluoromethylation

Article abstract of DOI:10.1002/chem.200400777

Various trifluoroacetamides and trifluoromethanesulfinamides, derived from chiral silylated amino alcohols, have been synthesized with the goal of achieving enantioselective nucleophilic trifluoromethylation. The best results were obtained with (R)-phenylglycinol derivatives, but the ee values did not exceed 30%.

Full text of DOI:10.1002/chem.200400777

FULL PAPER
Towards Enantioselective Nucleophilic Trifluoromethylation
Solveig Roussel,[a] Thierry Billard,*[a] Bernard R. Langlois,*[a] and Laurent Saint-James[b]
Abstract: Various trifluoroacetamides and trifluoromethanesulfinamides, derived
Keywords:
enantioselectivity
nucleophilic addition
amino alcohols
·
·
from chiral silylated amino alcohols, have been synthesized with the goal of ach-
ieving enantioselective nucleophilic trifluoromethylation. The best results were ob-
tained with (R)-phenylglycinol derivatives, but the ee values did not exceed 30%.
·
fluorination
Introduction
which the CF3 moiety is located at an asymmetric center,
has underlined another important synthetic challenge: asym-
metric trifluoromethylation.
Thanks to the intrinsic properties of fluorine, fluorinated or-
ganic compounds exhibit unique properties.[1] Among them,
trifluoromethyl-substituted molecules constitute a particular
class because of their specific properties, such as the high
lipophilicity associated with this moiety. These compounds
thus find wide application in the pharmaceutical field.[2]
Many reliable methods for the introduction of CF3 moieties
into organic compounds have been reported in the last two
decades,[3] and anionic trifluoromethylation has in recent
years emerged as one of the most powerful strategies. Nu-
merous reagents have been developed to overcome the
great instability of the CF3 anion and to allow nucleophilic
trifluoromethylation.[4,5]
To obtain compounds containing trifluoromethylated
asymmetric carbon moieties, the usual strategy is asymmet-
ric reduction of or nucleophilic addition onto a trifluoroace-
tyl moiety.[8] In contrast, there are very few methods for the
asymmetric nucleophilic addition of CF3. The best enantio-
meric excesses have been obtained from diastereoselective
methods; that is, addition of CF3SiMe3 onto chiral sulfini-
mides.[9] Another strategy involved chiral trifluoromethylat-
ing reagents, achieved by activation of CF3SiMe3 with a
chiral fluoride[10a] or a chiral Lewis base,[10b] both derived
from quinquina alkaloids, but the ee values did not usually
exceed 50%. Better enantiomeric excesses have sometimes
been reached, with cinchonium fluoride and CF3SiMe3, but
only with especially hindered carbonyl substrates.[10c]
We have recently described new efficient reagents for nu-
cleophilic trifluoromethylation.[5] As some of them bear
chiral centers, we focused our interest on their use in asym-
metric reactions.
Recently, the emergence of drugs such as Befloxatone
(antidepressant)[6] (1) and Efavirenz (anti-HIV)[7] (2), in
Results and Discussion
As examples, we have described the trifluoroacetamide 3a
and the trifluoromethanesulfinamide 4a prepared from O-si-
lylated ephedrine (Scheme 1). Both are able, under fluoride
[a] S. Roussel, Dr. T. Billard, Dr. B. R. Langlois
Laboratoire SERCOF (UMR CNRS 5181)
Universitꢀ Claude Bernard—Lyon 1
Bꢁt. Chevreul, 43, Bd du 11 novembre 1918
69622 Villeurbanne (France)
Fax : (+33)472-431-323
E-mail: billard@univ-lyon1.fr
bernard.langlois@univ-lyon1.fr
[b] Dr. L. Saint-James
Rhodia Co., Centre de Recherche de Lyon
85, Av. des Frꢂres Perret—BP 62
69192 Saint-Fons Cedex (France)
Scheme 1. Trifluoromethylation of benzaldehyde with 3a or 4a.
Chem. Eur. J. 2005, 11, 939 – 944
DOI: 10.1002/chem.200400777
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
939

Table 1. Trifluoromethylation of benzaldehyde with 3.
5a: Yield (ee) [%][a]
activation conditions, to trifluoromethylate carbonyl com-
pounds.[5] Such reagents, which were obtained in optically
pure forms (the two diastereomers of 4a arising from the
chirality at the sulfur atom were separated), seemed to be
good candidates for asymmetric trifluoromethylation. How-
ever, their use in the trifluoromethylation of benzaldehyde
did not give any enantiomeric enrichment of the resulting
carbinol.
Entry
3
method A[b]
method B[c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
89 (0)
83 (4)
32 (12)
15[d] (n.d.)[e]
83 (3)
36 (0)
46 (0)
71 (10)
4[d] (n.d.)[e]
86 (5)
82 (0)
72 (0)
53 (0)
83[f] (0)
Faced with these disappointing results, we designed new
trifluoroacetamides 3b–3k, derived from various chiral
86 (1)
9
10
11
no trifluoromethylation
no trifluoromethylation
70 (0)
no trifluoromethylation
no trifluoromethylation
81[f] (1)
3j
3k
[a] Isolated yield: The ee values were determined by chiral HPLC (Chir-
alcel OJ-H column; hexane/iPrOH 19:1). [b] Method A: CsF (10% mol)
in DME (1,2-dimethoxyethane) for 24 h at room temperature
À
[c] Method B: TBAT (Bu4N+Ph3SiF2
; 10 mol%) in THF for 7 h.
[d] Yield after six days. [e] n.d.: not determined. [f] Yield after 24 h.
tramolecular nucleophilic attack of the alcoholate, generated
by desilylation, onto the trifluoroacetamide moiety
(Scheme 2).
amino alcohols, with the goal of achieving stereoselective
trifluoromethylation. The reagents 3b–3k were prepared by
the previously described procedure (global isolated yields
are given in parentheses).[5a]
Scheme 2. Conformer equilibrium of 3j.
These new reagents were tested towards benzaldehyde
under two different sets of conditions to evaluate their po-
tential for stereoselective nucleophilic trifluoromethylation
(Table 1).
With regard to the ephedrine derivatives, it appeared that
increasing the size of the nitrogen substituent reduced the
trifluoromethylation yield (Table 1, entries 1–3). As previ-
ously described,[5a] (R)-phenylglycinol derivative 3i did not
give rise to trifluoromethylation, but only to trifluoroacetyl
group migration from nitrogen to oxygen.
To circumvent this problem, we tried to synthesize an
analogous reagent from a,a-diphenylprolinol, to favor the
right conformer. However, the only product obtained during
this synthesis was the bicyclic compound 6 (Scheme 3). Such
a substrate, which is an isolated and stable form of the tetra-
hedral intermediate postulated for the mechanism of tri-
fluoromethylation,[5a] could be an interesting reagent for our
purpose, since it was obtained enantiomerically pure. Un-
In the case of 3j no reaction occurred, even with heating,
and the starting reagent was recovered. It could be conjec-
tured that the conformation of 3j is not adapted to the in-
Abstract in French: Une grande variꢀtꢀ de trifluoroacꢀtami-
des et de trifluoromꢀthanesulfinamides, dꢀrivꢀs d’aminoal-
cools silylꢀs chiraux, a ꢀtꢀ synthꢀtisꢀe afin de rꢀaliser des tri-
fluoromꢀthylations anioniques ꢀnantiosꢀlectives. Les meil-
leurs rꢀsultats ont ꢀtꢀ obtenus ꢁ partir de dꢀrivꢀs du (R)-phꢀ-
nylglycinol mais les excꢂs ꢀnantiomꢀriques n’excꢂdent pas
30%.
Scheme 3. Formation and reactivity of 6.
940
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Chem. Eur. J. 2005, 11, 939 – 944

Towards Enantioselective Nucleophilic Trifluoromethylation
FULL PAPER
Table 2. Trifluoromethylation of benzaldehyde with 4.
fortunately, no release of CF3 through desilylation of 6 was
observed, no doubt because the formation of the resulting
constrained oxazolidinone 7 is not favorable.
Entry
4 (de) [%]
5a: yield (ee) [%][a]
1
2
3
4
5
6
7
4a (100)
4b (46)
4c (84)
4d (84)
4e (24)
4 f (100)
4g (84)
73 (0)
64 (0)
65 (20)
68 (0)
From a stereoselective point of view, the results from 3a–
3k were rather disappointing, since the ee values of the re-
sulting (trifluoromethyl)carbinol did not exceed 12%
(Table 1, entry 2), the best result being obtained with the N-
benzyl norephedrine derivative 3b. Performing the reaction
at lower temperatures (08C or À788C) clearly dramatically
decreased the reaction kinetics, since only few percents of
carbinol were obtained after several days.
3 (n.d.[b]
23 (1)
)
33 (17)
[a] Isolated yield: The ee values were determined by chiral HPLC (Chir-
alcel OJ-H column; hexane/iPrOH 19:1). [b] n.d.: not determined.
Nevertheless, these results seemed to demonstrate the im-
portance of the nitrogen substituent, which must be larger
than a methyl to produce some excess (Table 1, entry 2) but
not so bulky as to suppress the yield dramatically (Table 1,
entry 3). Furthermore, it seems that a five-membered cyclic
intermediate should be more favorable to stereoselectivity
than a six-membered one (Table 1, entry 11).
To improve these first encouraging results, we then fo-
cused our interest on analogous trifluoromethanesulfina-
mide derivatives. Indeed, such compounds not only each
possess an additional chiral center, because of the chirality
of the sulfur(iv) atom, but this atom bears the CF3 moiety
directly, so we supposed that such reagents should be better
candidates for enantioselective trifluoromethylation.
the corresponding trifluoroacetamides 3i and 3k had not in-
duced any excess. In contrast, the 12% ee achieved with 3b
was not obtained with the corresponding sulfinamide 4d.
These results led to the postulation of a geometry of the re-
active intermediates arising from trifluoromethanesulfina-
mides 4 different from that envisaged from trifluoromethyla-
cetamides 3, presumably because of the geometry of the
sulfur atom.
This hypothesis was also confirmed by the experiments
with the (R)-phenylglycinol derivatives 3i and 4c, since the
former did not release the trifluoromethyl group but under-
went a transfer of the trifluoroacetyl moiety from nitrogen
to oxygen,[5a] whereas the latter gave trifluoromethylation
with 20% ee.
Consequently, various reagents were prepared (4b–4g),
starting from diverse vic-amino alcohols, by a previously de-
scribed procedure (global yields and diastereomeric excesses
after purification are given in parentheses).[5b]
To improve the excess obtained with 4c, the reaction was
carried out under different sets of conditions (Table 3).
Lower temperatures decreased the trifluoromethylation
Table 3. Trifluoromethylation with 4c under various sets of conditions.
Entry
Temperature
Fluoride
[%]
Yield
[%]
ee
[8C]
1
2
3
4
0
À78
RT
0
CsF
CsF
8
49
0
31
0
19
–
30
–
8
yield but did not modify the ee
value (Table 3, entries 1, 2).
The use of a chiral, but hin-
dered, fluoride 8 to initiate the
reaction increased the ee value
slightly but decreased the yield
(Table 3, entries 3, 4).
With regard to enantioselec-
tivity, the disappointing results
obtained with reagents 3 and 4
led us to conclude that the various substituents in such re-
agents had only a moderate influence on the stereoselectivi-
ty of the reaction. The largest effect seemed to be that due
to the nitrogen substituents, though the presence of too
large a one decreased the reaction yield dramatically. This
difficult choice between low yield and ee is not really consis-
tent with the design of a useful and powerful stereoselective
reagent for trifluoromethylation.
Generally these compounds were synthesized with low de
values, but enriched fractions of one diastereomer were ob-
tained after tedious chromatographic separation and then
treated with benzaldehyde as above. Since the two fluorides
(CsF, TBAT) had given almost the same results in the previ-
ous experiments, only CsF was used as activator here
(Table 2).
As far as ephedrine derivatives are concerned, the pres-
ence of a chiral center bearing the CF3 moiety did not seem
to have a great influence from a stereoselective point of
view. However, the best ee values did not arise from the
same type of reagents as with trifluoroacetamides, the best
enantioselectivity being obtained with 4c and 4g, whereas
Chem. Eur. J. 2005, 11, 939 – 944
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T. Billard, B. R. Langlois, et al.
N-Trifluoroacetyl-N-benzyl-O-trimethylsilylephedrine (3b): (2 rotamers:
Attempts to model the transition states with 3 (cyclic
Zimmermann–Traxler type or linear Mukaiyama type)
seemed to confirm the weakness of the influence of the sub-
stituents other than the nitrogen one. In the case of sulfina-
mides 4, the unknown geometry of the sulfur atom in the in-
termediate reactive species made the modeling more diffi-
cult.
1
3
80/20; yellow oil). H NMR: d = 7.40–7.00 (m, 10H), 5.25 (d, J(H,H) =
7.9 Hz, 0.8H), 5.05 (d, 2J(H,H) = 15.4 Hz, 0.2H), 4.99 (d, 3J(H,H) =
3.6 Hz, 0.2H), 4.73 (d, 2J(H,H) = 15.4 Hz, 0.2H), 4.50 (d, 2J(H,H) =
15.4 Hz, 0.8H;
H
3a), 4.20 (m, 0.2H), 3.50–3.30 (m, 1.6H), 1.28 (d,
6.7 Hz, 0.6H), 0.02 (s,
3J(H,H) 6.7 Hz, 2.4H), 1.19 (d, 3J(H,H)
=
=
7.2H), 0.01 ppm (s, 1.8H); 13C NMR: d = 157.6 (q, 2J(C,F) = 35.1 Hz),
142.6, 141.6, 137.8, 135.6, 129.1, 129.0, 128.8, 128.6, 128.4, 128.1, 127.49,
127.45, 127.0, 126.9, 126.8, 126.6, 117.2 (q, 1J(C,F) = 287.8 Hz), 117.0 (q,
1J(C,F) = 288.3 Hz), 79.0, 74.4, 63.8, 59.4 (q, 4J(C,F) = 3.4 Hz), 52.8 (q,
4J(C,F) = 3.5 Hz), 48.1, 14.1, 12.9, 0.4, 0.0 ppm; 19F NMR: d = À68.00
(0.20), À69.50 ppm (0.80); elemental analysis calcd (%) for
C21H26F3NO2Si: C 61.59, H 6.40, N 3.42, Si 6.86; found: C 61.71, H 6.45,
N 3.31, Si 6.74.
Conclusion
Although the trifluoroacetamides and trifluoromethanesulfi-
namides arising from silylated amino alcohols constitute a
family of powerful reagents for nucleophilic trifluoromethy-
lation, their propensity to induce stereoselectivity seems to
be limited, since the maximum achieved ee is 30%.
The design of a chiral reagent efficient for highly enantio-
selective nucleophilic trifluoromethylation appears to be a
challenge that cannot be solved by the present strategy.
Other strategies must be now envisaged, and we are now fo-
cusing our interest on these new routes.
N-Trifluoroacetyl-N-pentyl-O-trimethylsilylephedrine (3c): (2 rotamers:
80/20; yellow oil). 1H NMR: d = 7.40–7.20 (m, 5H), 5.25 (d, 3J(H,H) =
3
3
8.0 Hz, 0.8H), 4.83 (d, J(H,H) = 4.5 Hz, 0.2H), 4.00 (qd, J(H,H) = 4.5,
3J(H,H) = 6.6 Hz, 0.2H), 3.57 (m, 0.2H), 3.37 (bq, 3J(H,H) = 6.6Hz,
0.8H), 3.05 (td, 2J(H,H)
2J(H,H) 15.2, 3J(H,H)
3J(H,H) = 6.6 Hz, 2.4H), 1.40–1.00 (m, 6.6H), 0.91 (t, J(H,H) = 6.8 Hz,
0.6H), 0.83 (t, 3J(H,H)
7.2 Hz, 2.4H), 0.02 (s, 1.8H), 0.01 ppm (s,
=
15.2, 3J(H,H)
=
7.3 Hz, 0.8H), 2.46 (td,
= 7.3 Hz, 0.8H), 1.78 (m, 0.2H), 1.50 (d,
=
3
=
7.2H); 13C NMR: d = 157.1 and 156.9 (q, 2J(C,F) = 35.4 Hz), 142.5,
141.7, 128.6, 128.3, 128.2, 128.1, 126.6, 126.5, 117.0 and 116.6 (q, 1J(C,F)
= 286.7 Hz; CF3), 78.6, 74.4, 60.8, 58.9 (q, 4J(C,F) = 3.2 Hz), 29.8, 29.1,
29.0, 28.9, 22.7, 22.52, 22.49, 22.4, 14.3, 14.1, 0.29, 0.27 ppm; 19F NMR: d
= À68.33 (0.20), À70.60 ppm (0.80); elemental analysis calcd (%) for
C19H30O2F3NO2Si: C 58.58, H 7.76, N 3.60, Si 7.21; found: C 58.65, H
7.94, N 3.7, Si 6.83.
Experimental Section
N-Trifluoroacetyl-N-methyl-O-trimethylsilylpseudoephedrine (3d): (2 ro-
tamers: 60/40; white solid). Mp: 60–618C; 1H NMR: d = 7.38–7.33 (m,
5H), 4.78 (d, 3J(H,H)
= 7.5 Hz, 0.6H), 4.63 (brs, 0.6H), 4.56 (dq,
General: DME and THF were dried over Na/benzophenone and freshly
distilled. CsF was dried at 3008C overnight and stored at 1008C. Benzal-
dehyde was freshly purified by distillation prior to use. Other reagents
were used as purchased.
1H, 13C, and 19F NMR spectra were recorded in CDCl3 at 300, 75, and
282 MHz, respectively.
3J(H,H)
3J(H,H)
=
8.2, 6J(H,F)
6.8, 4J(H,F)
=
1.2 Hz, 0.4H), 4.10 (dqq, 3J(H,H)
=
8.2,
=
1.2 Hz, 0.4H), 3.08 (q, 4J(H,F)
=
3
6.8 Hz,
=
3
1.8H), 2.97 (s, 1.2H), 1.11 (d, J(H,H) = 6.8 Hz, 1.8H), 1.04 (d, J(H,H)
= 6.8 Hz, 1.2H), 0.01 (s, 5.4H), À0.04 ppm (s, 3.6H); 13C NMR: d =
158.2 and 157.3 (q, 2J(C,F) = 34.9 Hz), 141.9 and 141.8, 128.9 and 128.6,
128.6 and 128.2, 127.5 and 127.3, 117.3 (q, 1J(C,F) = 287.7 Hz), 117.1 (q,
Chemical shifts are given in ppm relative to TMS (1H, 13C) or CFCl3 (19F)
as internal references. Coupling constants are given in Hertz.
1J(C,F) = 288.3 Hz), 76.3 and 76.1, 59.2 (q, J(C,F) = 2.9 Hz), 58.0 (brs),
4
31.0 (brs), 28.4, 14.9, and 13.6 (C3), À0.1 and À0.12 ppm; 19F NMR: d =
À67.87 (0.40), À70.69 ppm (0.60); elemental analysis calcd (%) for
C15H22F3NO2Si: C 54.03, H 6.65, N 4.20, Si 8.42; found: C 54.09, H 6.46,
N 4.37, Si 8.28.
Flash chromatography was performed on silica gel 60 M (0.04–
0.063 mm). Melting points (uncorrected) were determined in capillary
tubes on a Bꢄchi apparatus.
Typical procedure: synthesis of 3a: A flame-dried three-necked vessel
was successively charged, under nitrogen, with ephedrine (6.6 g,
40 mmol) and dichloromethane (40 mL). The resulting mixture was
cooled to 08C before addition of N-(trimethylsilyl)imidazole (6 mL,
41 mmol). The reaction medium was stirred at 08C for 40 min and then
allowed to warm to room temperature and kept stirring for 2 h. After
this period, diisopropylethylamine (7.2 mL, 41.4 mmol) was added, and
the mixture was again cooled to 08C. A solution of trifluoroacetic anhy-
dride (5.6 mL, 40 mmol) in CH2Cl2 (16 mL) was then added dropwise
over 1.5 h. After this addition, the temperature was kept at 08C for
10 min, then raised to room temperature. After stirring for 4 h, the reac-
tion medium was washed with 6% aqueous NaHCO3. The organic phase
was dried over Na2SO4 and evaporated in vacuo. The crude residue was
purified by chromatography over silica gel.
(1S,2R)-N-Trifluoroacetyl-N-methyl-O-trimethylsilyl-1,2-diphenylethanol
(3 f): (2 rotamers: 90/10; white solid). M.p. 1068C; 1H NMR: d = 7.60–
7.00 (m), 5.74 (d, 3J(H,H) = 7.5 Hz, 0.9H), 5.51 (d, 3J(H,H) = 7.5 Hz,
0.9H), 5.39 (d, 3J(H,H) = 6.2 Hz, 0.1H), 5.21 (d, 3J(H,H) = 6.2 Hz,
0.1H), 3.05 (s, 0.3H), 2.89 (t, 5J(H,F) = 1.7 Hz, 2.7H), 0.04 (s, 0.9H),
0.02 ppm (s, 8.1H); 13C NMR: d = 157.4 (q, 2J(C,F) = 35.5 Hz), 157.3
(q, 2J(C,F)
= 35.1 Hz), 141.0, 140.8, 136.1, 135.9, 130.3, 129.8, 129.0,
128.8, 128.7, 128.64, 128.58, 128.5, 127.3, 127.1, 116.8 (q, 1J(C,F)
=
288.3 Hz), 117.1 (q, 1J(C,F) = 288.1 Hz), 74.91, 74.86, 66.2 (q, 4J(C,F) =
4
2.7 Hz), 65.8, 32.7 (q, J(C,F) = 3.8 Hz), 32.4, 0.4, 0.3 ppm; 19F NMR: d
= À66.61 (0.10), À70.43 ppm (0.90); elemental analysis calcd (%) for
C20H24F3NO2Si: C 60.74, H 6.12, N 3.54, Si 7.10; found: C 60.47, H 6.25,
N 3.75, Si 6.93.
(1S,2R)-N-Trifluoroacetyl-N-benzyl-O-trimethylsilyl-1,2-diphenyl-ethanol
(3h): (2 rotamers: 95/5; yellow oil). 1H NMR: d = 7.40–7.17 (m, 13H),
7.15–7.14 (m, 2H), 5.96 (d, 3J(H,H) = 8.9 Hz, 1H), 4.30 (d, 1J(H,H) =
N-Trifluoroacetyl-O-trimethylsilylephedrine (3a): (2 rotamers: 80/20;
white solid). M.p. 51–528C; 1H NMR: d = 7.25–7.38 (m, 5H), 5.01 and
4.84 (d, 3J(H,H) = 4.4 Hz, 1H), 4.38 (qd, 3J(H,H) = 6.9, 3J(H,H) =
15.9 Hz, 1H), 4.21 (d, 3J(H,H)
=
8.9 Hz, 1H), 3.95 (d, 1J(H,H)
158.1 (q, 2J(C,F)
=
4.6 Hz, 0.8H), 4.07 (qqd, 3J(H,H)
=
6.8, 5J(H,F)
=
1.1, 3J(H,H)
=
15.9 Hz, 1H), 0.26 ppm (s, 9H); 13C NMR: d
=
=
5
3
4.6 Hz, 0.2H), 3.05 (q, J(H,F) = 1.6 Hz, 3H); 1.26 and 1.19 (d, J(H,H)
=
6.6 and 7.1 Hz, 3H), 0.03 ppm (s, 9H); 13C NMR: d
= 157.5 (q,
35.1 Hz), 142.2, 137.8, 134.5, 130.7, 129.02, 128.99, 128.6, 128.5, 128.4,
128.3, 127.4, 127.2, 116.8 (q, 1J(C,F)
= 288.5 Hz), 73.4, 71.8, 53.0 (q,
2J(C,F) = 35.4 Hz), 141.9 and 141.6, 128.7 and 128.5, 128.3 and 127.9,
126.5 and 126.5, 117.0 and 116.9 (q, 1J(C,F) = 287.6 and 288.1 Hz), 78.1
and 76.2, 59.0, 58.7 (q, 4J(C,F) = 3.1 Hz), 32.2 (q, 4J(C,F) = 3.8 Hz),
30.8, 12.8 and 10.2, 0.3 and 0.2 ppm; 19F NMR: d = À68.28 (0.2) and
À70.57 ppm (0.8); elemental analysis calcd (%) for C15H22F3NO2Si: C
54.03, H 6.65, N 4.20, Si 8.42; found: C 53.75, H 6.58, N 4.21, Si 8.90.
4J(C,F) = 3.6 Hz), 0.09 ppm; 19F NMR: d = À66.62 (0.05), À69.07 ppm
(0.95); elemental analysis calcd (%) for C26H28F3NO2Si: C 66.22, H 5.98,
N 2.97, Si 5.96; found: C 66.38, H 6.02, N 2.86, Si 5.87.
(R)-N-Trifluoroacetyl-N-benzyl-O-trimethylsilylphenylglycinol (3i): (2 ro-
tamers: 50/50; yellow oil). 1H NMR: d = 7.00–7.50 (m, 10H), 5.36 (br. t,
942
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Chem. Eur. J. 2005, 11, 939 – 944

Towards Enantioselective Nucleophilic Trifluoromethylation
FULL PAPER
3
3
3J(H,H) = 6.7 Hz, 0.5H), 4.96 (br. dd, J(H,H) = 8.0, J(H,H) = 6.3 Hz,
0.5H), 4.69 (d, 2J(H,H) = 15.1 Hz, 0.5H), 4.67 (s, 2H), 4.43 (dd, 2J(H,H)
= 10.4, 3J(H,H) = 8.0 Hz, 0.5H), 4.27 (d, 2J(H,H) = 15.1 Hz, 0.5H),
3.94–4.12 (m, 1.5H), 0.12 and 0.11 ppm (s, 9H); 13C NMR: d = 158.6
and 158.1 (q, 2J(C,F) = 34.9 Hz), 137.1, 136.6, 135.9, 135.8, 129.3, 129.0,
128.9, 128.61, 128.58, 128.45, 128.42, 128.2, 128.0, 127.6, 117.4 and 117.1
(q, 1J(C,F) = 288.2 Hz), 61.9, 62.2, 61.2 (q, 4J(C,F) = 2.6 Hz), 61.4, 51.5
6.4 Hz, 0.2H), 4.54–4.40 (m, 1H), 4.37–4.21 (m, 1.8H), 4.09 (d, 2J(H,H)
= 15.3 Hz, 0.2H), 0.04 (s, 7.2H), À0.1 ppm (s, 1.8H); 13C NMR: d =
141.2, 140.8, 136.8, 136.6, 135.5, 135.2, 130.4, 130.0, 129.7, 129.6, 129.2,
129.1, 128.9, 128.81, 128.75, 128.7, 128.57, 128.55, 128.43, 128.40, 128.38,
128.2, 127.8, 124.9 (q, 1J(C,F)
= =
343.0 Hz), 124.7 (q, 1J(C,F)
341.0 Hz), 77.0, 76.0, 69.6, 69.3, 48.6, 48.4, 0.5, 0.2 ppm; 19F NMR: d =
À73.16 (0.20), À73.56 ppm (0.80); elemental analysis calcd (%) for
C25H28F3NO2SSi: C 61.07, H 5.74, N 2.85, S 6.52, Si 5.71; found: C 61.17,
H 5.67, N 2.73, S 6.44, Si 5.68.
(q, J(C,F) = 3.5 Hz), 47.5, À0.3, À0.5 ppm; 19F NMR: d = À66.55 (0.5),
4
À68.69 ppm (0.5); elemental analysis calcd (%) for C20H24F3NO2Si: C
60.74, H 6.12, N 3.54, Si 7.10; found: C 60.62, H 6.23, N 3.61, Si 6.85.
(R)-N-Trifluoromethanesulfinyl-N-benzyl-O-trimethylsilylphenylglycinol
(4c): (Yellow oil/dia. Maj.). 1H NMR: d = 7.43–7.18 (m, 10H), 4.54 (d,
2J(H,H) = 15.4 Hz, 1H), 4.53 (bdd, 3J(H,H) = 8.9, 3J(H,H) = 5.6 Hz,
(S)-N-Trifluoroacetyl-O-trimethylsilyl-2-pyrrolidinemethanol (3j): (2 ro-
tamers: 90/10; yellow oil). 1H NMR: d = 4.22 (brm, 1H), 3.80 (dd,
2J(H,H)
=
10.3, 3J(H,H)
=
5.5 Hz, 1H); 3.70 (dd, 2J(H,H)
=
10.3,
3J(H,H) = 2.9 Hz, 1H), 3.65 (m, 2H), 2.25–1.80 (m, 4H), 0.13 (s, 8.1H),
0.11 ppm (s, 0.9H); 13C NMR: d 156.2 and 155.9 (q, 2J(C,F)
1H), 4.23 (d, 2J(H,H)
= = 10.9,
15.4 Hz, 1H), 4.01 (dd, 2J(H,H)
3J(H,H) = 8.9 Hz, 1H), 3.86 (dd, 2J(H,H) = 10.9, 3J(H,H) = 5.6 Hz,
1H), 0,14 ppm (s, 9H); 13C NMR: d = 137.5, 135.9, 129.3, 129.2, 128.99,
128.93, 128.5, 128.3, 127.1 (q, 1J(C,F) = 342.0), 65.1, 63.7, 47.5, 0.4 ppm;
=
=
36.6 Hz), 116.8 and 116.7 (q, 1J(C,F) = 287.5 Hz), 63.6 (q, 5J(C,F) =
1.3 Hz), 61.6, 60.7, 59.6 (q, 4J(C,F) = 2.4 Hz), 48.0, 47.8 (q, 4J(C,F) =
3.5 Hz), 28.7, 26.8, 24.9 (q, 5J(C,F) = 1.0 Hz), 20.9, À0.4, À0.5 ppm; 19F
NMR: d = À70.91 (0.10), À73.02 ppm (0.90); elemental analysis calcd
(%) for C10H18F3NO2Si: C 44.59, H 6.74, N 5.20, Si 10.43; found: C 44.47,
H 6.83, N 5.36, Si 10.22.
19F NMR:
d
=
À74.09 ppm; elemental analysis calcd (%) for
C19H24F3NO2SSi: C 54.92, H 5.82, N 3.37, S 7.72, Si 6.76; found: C 54.68,
H 6.07, N 3.13, S 7.89, Si 6.53.
(1R,2S)-N-Trifluoromethanesulfinyl-N-benzyl-O-trimethylsilylephedrine
(4d): (Yellow oil/de = 80%). 1H NMR: d = 7.49–7.09 (m, 10H), 4.88
3
2
(1R,2S)-N-Trifluoroacetyl-O-trimethylsilyl-2-benzylamino-cyclohexane-
methanol (3k): (2 rotamers: 70/30; colorless oil). 1H NMR: d = 7.41–
(d, J(H,H) = 3.0 Hz, 0.9H), 4.72 (d, J(H,H) = 15.6 Hz, 0.9H), 4.56 (d,
2J(H,H) = 14.9 Hz, 0.1H), 4.54 (d, 3J(H,H) = 6.0 Hz, 0.1H), 4.24 (d,
2J(H,H) = 15.6 Hz, 0.9H), 4.07 (d, 2J(H,H) = 14.9 Hz, 0.1H), 3.56 (m,
2
7.22 (m, 3H), 7.21–7.14 (m, 2H), 5.12 (d, J(H,H) = 15.8 Hz, 0,3H), 4.80
(d, 2J(H,H) = 18.1 Hz, 0.7H), 4.66 (d, 2J(H,H) = 18.1 Hz, 0.7H), 4.40
(d, 2J(H,H) = 15.8 Hz, 0.3H), 4.22 (m, 1H), 3.80 (m, 2H), 2.41 (brs,
0.7H), 2.16 (brs, 0.3H), 2.04–1.66 (m, 3H), 1.64–1.12 (m, 5H), 0.15 ppm
0.1H), 3.36 (qd, 3J(H,H)
=
3.0, 3J(H,H)
=
7.1 Hz, 0.9H), 1.42 (d,
3J(H,H) 7.0 Hz, 0.3H), 1.20 (d, 3J(H,H)
=
= 7.2 Hz, 2.7H), 0.15 (s,
8.1H), 0.00 ppm (s, 0.9H); 13C NMR: d = 141.7, 136.1, 129.3, 129.1,
128.5, 128.4, 128.0, 126.8, 124.8 (q, 1J(C,F) = 340.9 Hz), 74.9, 61.2, 47.8,
14.0, 0.5 ppm; 19F NMR: d = À73.30 (0.10), À75.73 ppm (0.90); elemen-
tal analysis calcd (%) for C20H26F3NO2SSi: C 55.92, H 6.10, N 3.26, S
7.46, Si 6.54; found: C 56.01, H 5.89, N 3.40, S 7.27, Si 6.38.
(s, 9H); 13C NMR: d = 158.2 (q, J(C,F) = 35.1 Hz), 158.1 (q, J(C,F) =
34.9 Hz), 138.4, 137.7, 129.0, 128.9, 127.7, 127.3, 126.7, 126.1, 117.3 (q,
1J(C,F) = 287.1 Hz), 116.9 (q, 1J(C,F) = 288.9 Hz), 61.7, 61.5, 60.7, 59.7
(q, 4J(C,F) = 2.7 Hz), 49.8 (q, 4J(C,F) = 3.8 Hz), 49.0, 43.1, 38.8, 29.5,
28.6, 27.6, 26.7, 26.6, 25.5, 21.03, 21.0, À0.3 ppm; 19F NMR: d = À68.67
(0.30), À69.21 ppm (0.70); elemental analysis calcd (%) for
C19H28F3NO2Si: C 58.89, H 7.28, N 3.61, Si 7.25; found: C 59.07, H 7.33,
N 3.88, Si 7.13.
1
1
(S)-N-Trifluoromethanesulfinyl-O-trimethylsilyl-2-pyrrolidinemethanol
1
(4e): (Yellow oil/de = 0%). H NMR: d = 3.88 (m, 2H), 3.62 (m, 2H),
3.28 (m, 0.5H), 3.07 (m, 0.5H), 2.17–1.70 (m, 4H), 0.15 (s, 4.5H),
0.11 ppm (s, 4.5H); 13C NMR: d = 126.6 (q, 1J(C,F) = 338.5 Hz), 124.2
(q, 1J(C,F) = 337.0 Hz), 65.9, 65.5, 64.0, 61.5, 46.6, 43.8, 28.7, 26.0, 24.6,
23.1, 0.45, 0.45 ppm; 19F NMR: d = À74.03 (0.50), À75.20 ppm (0.50); el-
emental analysis calcd (%) for C9H18F3NO2SSi: C 37.35, H 6.27, N 4.84, S
11.08, Si 9.71; found: C 37.51, H 6.36, N 5.03, S 10.95, Si 9.37.
Synthesis of N-trifluoromethanesulfinyl-O-trimethylsilylephedrine (4a)
[CF3SO+] solution: A flame-dried three-necked vessel was successively
charged, under nitrogen, with potassium triflinate (CF3SO2K, 3.5 g,
20 mmol), dichloromethane (60 mL), and POCl3 (935 mL, 10 mmol). The
reaction medium was stirred at room temperature for 40 min.
(S)-N-Trifluoromethanesulfinyl-O-trimethylsilyl-1,1-diphenyl-2-pyrrolidi-
nemethanol (4 f): (Yellow oil/dia. maj.). 1H NMR: d = 7.52–7.27 (m,
10H), 4.89 (dd, 3J(H,H) = 9.2, 3J(H,H) = 4.0 Hz, 1H), 3.69 (m, 1H),
2.16 (m, 1H), 2.09–1.87 (m, 2H), 1.55 (m, 1H), 0.95 (m, 1H), À0.19 ppm
(s, 9H); 13C NMR: d = 142.5, 141.8, 130.03, 129.98, 128.6, 128.3, 128.0,
127.5, 124.3 (q, 1J(C,F) = 336.5 Hz), 83.4, 73.3, 43,1, 28.6, 26.0, 2.0 ppm;
Synthesis: A flame-dried three-necked vessel was successively charged,
under nitrogen, with ephedrine (1.65 g, 10 mmol) and dichloromethane
(47 mL). The resulting mixture was cooled to 08C before addition of N-
(trimethylsilyl)imidazole (1.5 mL, 10.2 mmol). The reaction mixture was
stirred at 08C for 20 min and was then allowed to warm to room temper-
ature and kept stirring for 2 h. After this period, diisopropylethylamine
(3.5 mL, 20 mmol) was added and the mixture was again cooled to 08C.
The [CF3SO+] solution was then added over 1 h. After the addition, the
temperature was kept at 08C for 10 min, then raised to room tempera-
ture. After stirring for 24 h, the reaction mixture was washed with 6%
aqueous NaHCO3. The organic phase was dried over Na2SO4 and evapo-
rated in vacuo. The crude residue was purified by chromatography over
silica gel.
19F NMR:
d
=
À73.78 ppm; elemental analysis calcd (%) for
C21H26F3NO2SSi: C 57.12, H 5.93, N 3.17, S 7.26, Si 6.36; found: C 57.29,
H 5.72, N 3.33, S 6.92, Si 6.69.
(S)-N-Trifluoromethanesulfinyl-O-trimethylsilyl-1,1-diphenyl-2-pyrrolidi-
nemethanol (4 f): (Yellow oil/dia. Min.). 1H NMR: d = 7.56–7.29 (m,
10H), 4.87 (dd, 3J(H,H) = 8.9, 3J(H,H) = 2.7 Hz, 1H), 3.16 (m, 1H),
2.54 (m, 1H), 2.20 (ddd, 3J(H,H) = 17.1, 3J(H,H) = 8.9, 2J(H,H) =
13.5 Hz, 1H), 1.97 (m, 1H), 1.56 (m, 1H), 0.81 (dddd, 3J(H,H) = 17.1,
2J(H,H) = 12.5, 3J(H,H) = 8.3, 3J(H,H) = 6.1 Hz, 1H), À0.13 ppm (s,
9H); 13C NMR: d = 142.4, 141.6, 130.2, 129.9, 128.7, 128.5, 128.1, 127.8,
125.4 (q, 1J(C,F) = 346.5 Hz), 83.7, 68.9, 45.8, 28.2, 23.6, 2.0 ppm; 19F
NMR: d = À72.33 ppm; elemental analysis calcd (%) for C21H26F3NO2S-
Si: C 57.12, H 5.93, N 3.17, S 7.26, Si 6.36; found: C 56.99, H 5.85, N
3.26, S 7.36, Si 6.51.
N-Trifluoromethanesulfinyl-O-trimethylsilylephedrine (4a): (Colorless
oil/de = 20%). 1H NMR: d = 7.23–7.35 (m, 5H), 4.85 (d, 3J(H,H) =
3
3
3.9 Hz, 0.6H), 4.68 (d, J(H,H) = 5.7 Hz, 0.4H), 3.70 (dq, J(H,H) = 5.7,
3J(H,H) = 7.0 Hz, 0.4H), 3.58 (dq, 3J(H,H) = 3.9, 3J(H,H) = 7.0 Hz,
0.6H), 2.84 (q, 5J(H,H) = 1.4 Hz, 1.8H), 2.70 (q, 5J(H,H) = 1.8 Hz,
1.2H), 1.32 (d, 3J(H,H) = 7.0 Hz, 1.2H), 1.22 (d, 3J(H,H) = 7.0 Hz,
1.8H), 0.06 (s, 5.4H), 0.04 ppm (s, 3.6H); 13C NMR: d = 141.8, 141.4,
128.7, 128.6, 128.4, 128.1, 127.0, 126.8, 124.5 (q, 1J(C,F) = 343.1 Hz),
(1R,2S)-N-Trifluoromethanesulfinyl-O-trimethylsilyl-2-benzylaminocyclo-
hexanemethanol (4g): (Colorless oil/de = 20%). 1H NMR: d = 7.45–
7.24 (m, 5H), 4.67 (d, 2J(H,H) = 15.6 Hz, 0.6H), 4.66 (d, 2J(H,H) =
15.8 Hz, 0.4H), 4.35 (d, 2J(H,H) = 15.8 Hz, 0.4H), 4.24 (d, 2J(H,H) =
15.6 Hz, 0.6H), 3.91 (dd, 3J(H,H) = 6.0, 2J(H,H) = 12.0 Hz, 0.4H), 3.70
(m, 1.6H), 3.37 (m, 1H), 2.15 (m, 0.4H), 2.03 (m, 0.6H), 1.97–1.59 (m,
5H), 1.49–1.11 (m, 3H), 0.16 ppm (s, 9H); 13C NMR: d = 135.8, 135.7,
129.3, 129.2, 128.7, 128.6, 128.4, 128.2, 124.7 (q, 1J(C,F) = 342.0 Hz),
124.5 (q, 1J(C,F) = 340.9 Hz), 60.9, 60.8, 60.6, 60.1, 47.3, 46.8, 39.3, 38.7,
1
124.5 (q, J(C,F) = 341.6 Hz), 77.9, 77.0, 64.5 (brs), 62.8, 29.1, 26.6, 13.9,
13.2, 0.34, 0.32 ppm; 19F NMR: d = À75,03 (0.6), À75.27 ppm (0.4); ele-
mental analysis calcd (%) for C14H22F3NO2SSi: C 47.57, H 6.27, N 3.96, S
9.07, Si 7.95; found: C 47.69, H 6.56, N 3.91, S 9.40, Si 8.20.
(1S,2R)-N-Trifluoromethanesulfinyl-N-benzyl-O-trimethylsilyl
1,2-di-
phenyl-ethanol (4b): (Yellow oil/de = 60%). 1H NMR: d = 7.47–6.92
(massif, 10H), 5.32 (d, 3J(H,H)
= =
5.1Hz, 0.8H), 5.21 (d, 3J(H,H)
Chem. Eur. J. 2005, 11, 939 – 944
www.chemeurj.org
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
943

T. Billard, B. R. Langlois, et al.
28.9, 28.8, 28.0, 26.9, 26.49, 26.41, 21.5, 21.1, À0.2 ppm; 19F NMR: d =
À74.40 (0.40), À75.24 ppm (0.60); elemental analysis calcd (%) for
C18H28F3NO2SSi: C 53.04, H 6.92, N 3.44, S 7.87, Si 6.89; found: C 53.13,
H 7.06, N 3.71, S 7.74, Si 7.05.
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Berlin, 2000, chapter 5, pp. 137–182; f) A. Becker, Inventory of In-
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CsF (15 mg, 0.1 equiv) was added to a solution of 3 or 4 (1 mmol) and
the electrophile (1 mmol) in DME (1 mL). After 24 h, the crude product
was desilylated with TBAF in THF (1m, 1 mL) for 1 h and extracted with
pentane and brine. The organic phase was dried over Na2SO4, and the
solvent was evaporated in vacuo. The crude products were purified by
chromatography over silica gel.
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of tetrabutylammonium triphenyldifluorosilicate (TBAT, 54 mg,
0.1 equiv) in THF (0.5 mL) was added dropwise over 15 min to a stirred
solution of 3 or 4 (1 mmol) and the electrophile (1 mmol) in THF
(1 mL). After 6 h, the crude mixture was desilylated with TBAF in THF
(1m, 1 mL) for 1 h, and then extracted with pentane and brine. The or-
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vacuo. The crude products were purified by flash chromatography over
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Acknowledgement
We thank the CNRS and Rhodia Co. for financial support and Rhodia -
Co. for a generous gift of potassium triflinate.
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Received: July 29, 2004
Published online: December 15, 2004
944
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 939 – 944