Lithiated fluorinated styrene oxides: Configurational stability, synthetic applications, and mechanistic insight

Article abstract of DOI:10.1002/chem.201000897

The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents α-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, α-5-Li, and α-6-Li) are all configurationally stable in the reaction time scale, whereas a-lithiated ortho-, meta-, and paratrifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated ssamino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.

Full text of DOI:10.1002/chem.201000897

DOI: 10.1002/chem.201000897
Lithiated Fluorinated Styrene Oxides: Configurational Stability, Synthetic
Applications, and Mechanistic Insight
Vito Capriati,* Saverio Florio,* Filippo Maria Perna, and Antonio Salomone[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
9778
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Chem. Eur. J. 2010, 16, 9778 – 9788

FULL PAPER
Abstract: The configurational stability
of some lithiated fluorinated styrene
oxides has been investigated. Chemical
studies have shown that in ethereal sol-
vents a-lithiated ortho-, meta-, and
para-fluorostyrene oxides (2-Li, a-5-Li,
and a-6-Li) are all configurationally
stable in the reaction time scale, where-
as a-lithiated ortho-, meta-, and para-
trifluoromethylstyrene oxides (9-Li, 13-
Li, and 14-Li) are configurationally un-
stable. Optically active oxiranyllithiums
2-Li and 9-Li, could be stereospecifi-
cally generated and quenched with
electrophiles. The corresponding deriv-
atives were then successfully subjected
to regiospecific ring-opening reactions
with amines to give fluorinated b-
amino alcohols with a stereodefined
quaternary carbinol center, which are
useful synthons in medicinal chemistry.
The barriers of inversion have been
calculated (Eyring equation) for oxira-
nyllithiums 9-Li, 13-Li, and 14-Li by
determining the enantiomeric ratios
after electrophilic quenching on aging
the enantioenriched organolithium for
different times in THF; in the case of
9-Li, activation parameters have also
been determined. Mechanisms that
may be responsible of the racemization
oxiranyllithiums 9-Li, 13-Li, and 14-Li
undergo once generated are also dis-
cussed.
Keywords: amino alcohols · Eyring
equation · fluorinated substituents ·
kinetics · oxiranyllithiums
Introduction
which has been related to the different aggregation states
depending on the experimental conditions employed.[8] Opti-
cally active a-lithiated styrene oxide retains its absolute con-
figuration when coupled in THF at 175 K with a large
number of electrophiles. The stereochemical integrity is yet
preserved in reactions with boronic esters in Et2O at 158 K[9]
but not in THF, thus suggesting that the stereochemical
pathway of its trapping reactions surprisingly depends upon
the solvent used, the temperature, and also the nature of the
electrophile. As part of our recent studies aimed at investi-
gating the substitution effect at the aryl group on the config-
urational stability of a-lithiated aryloxiranes, it has been
quite recently reported that the ortho-positioned para-tolyl-
sulfinyl group of a-lithiated styrene oxide induces, surpris-
ingly, epimerization.[10] The influence of the sulfinyl group is
remarkable not only from a stereochemical point of view
but also considering the acidity enhancement occurring at
the oxirane ring (in the presence of such a substituent)
which could be lithiated, for the first time, also by lithium
diisopropyl amide (LDA) at 195 K. Herein, we wish to
report the effect of ortho-, meta-, and para-positioned fluori-
nated groups on the configurational stability of the corre-
sponding lithiated derivatives, trapping reactions with elec-
trophiles, and amine-promoted ring-opening reactions on
the newly functionalized epoxides to give key synthons
(such as chiral fluorinated aromatic b-aminoalcohols) having
a stereogenic quaternary carbinol atom. In addition, for
those lithiated intermediates proven to be configurationally
unstable (ortho-, meta-, and para-trifluoromethyl deriva-
tives) barriers to inversion and activation parameters have
been calculated and discussed.
Fluorine holds a special place not only in the heart of the
close-knit community of organic “fluorine chemists” but
also in that of biologists, medicinal chemists, and people in-
volved in the fields of materials and life sciences.[1] This is
because the introduction of fluorine (which has unique
steric and electronic properties),[2] as well as of fluorinated
substituents in an organic molecule, can dramatically change
its reactivity and/or modulate some biological activities such
as physicochemical and pharmacokinetic properties,[3] and
improve drug delivery.[4] The properties of fluorinated aro-
matic molecules have also made them suitable for wide-
spread applications as agrochemicals, in particular, for
modern crop protection and as insecticides, fungicides, and
herbicides.[5] In addition, the employment of bioactive aro-
matic fluorinated compounds (whose availability in an opti-
cally pure form is still poor) is also challenging in biochem-
istry because of their potential chelating properties toward
alkali and alkaline earth metal ions;[1d] thus, a stereocon-
trolled preparation of such compounds is of great interest.
a-Lithiated styrene and stilbene oxides are configuration-
ally stable intermediates[6] and have been successfully em-
ployed as chiral synthons in asymmetric synthesis over the
past few years.[7] With special reference to lithiated styrene
oxide, a recent multinuclear magnetic resonance study, sup-
ported by density functional theory calculations, has been
used to investigate its configurational stability as well as its
dichotomic reactivity (carbanionic/carbene-like character),
[a] Prof. Dr. V. Capriati, Prof. Dr. S. Florio, Dr. F. M. Perna,
Dr. A. Salomone
Dipartimento Farmaco-Chimico, Universitꢁ di Bari “A. Moro”
Consorzio Interuniversitario Nazionale Metodologie
e Processi Innovativi di Sintesi C.I.N.M.P.I.S.
Via E. Orabona 4, 70125 Bari (Italy)
Results and Discussion
Synthetic studies: Optically active ortho-fluorostyrene oxide
(R)-2 (Scheme 1) was prepared in two steps by the reaction
E-mail: capriati@farmchim.uniba.it
florio@farmchim.uniba.it
of ortho-fluorobenzaldehyde
1 with dimethylsulfonium
Supporting information for this article (1H and 13C NMR spectra for
compounds 3b,c, 4a–d, 8, and 10) is available on the WWW under
http://dx.doi.org/10.1002/chem.201000897.
methylide in DMSO (Corey–Chaykovsky epoxidation)[11] at
room temperature to give racemic epoxide (ꢀ)-2 (70%
Chem. Eur. J. 2010, 16, 9778 – 9788
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9779

S. Florio, V. Capriati et al.
yield) followed by hydrolytic kinetic resolution (HKR) ac-
cording to the Jacobsen[12] protocol (48 h, overall yield 18%)
(Scheme 1).
terium incorporation were similarly obtained at variable
times (15 min: 95% D and 90% yield; 180 min: 95% D and
10% yield) deprotonating (R)-2 with sBuLi in the absence
of TMEDA, which, therefore, does not act in this case as a
modifier of sBuLi reactivity.
The nucleophilicity of (R)-2-Li toward other electrophiles
was then investigated. The reactions with MeI, Me3SiCl, and
acetone occurred smoothly, leading to the corresponding
a,a-disubstituted epoxides 3a–c in moderate to good yields
(entries 1–3, Table 2).
Scheme 1.
Table 2. Synthesis of a,a-disubstituted ortho-fluorostyrene oxides 3.
Oxiranyllithium (R)-2-Li (Table 1) was smoothly generat-
ed by treatment of a precooled THF solution of (R)-2 and
N,N,N’,N’-tetramethylethylenediamine
(TMEDA)
with
sBuLi.[13] Quenching the reaction mixture after 15 min with
MeOD gave deuterated epoxide [D]-(R)-2 (90% yield, 95%
D) with complete retention of configuration of the starting
oxirane (>98:2 enantiomeric ratio (e.r.)) (entry 1, Table 1).
Entry
Electrophile
Epoxide 3 (yield [%])[a]
1
2
3
MeI
Me3SiCl
AHCTUNGRTEG(NNUN CH3)2CO
3a (90)
3b (40)
3c (57)
Table 1. Lithiation–deuteration of (R)-2.
[a] Isolated yield after column chromatography.
With terminal epoxides 3a–c in hand, we reasoned they
could represent useful synthons for the preparation of fluo-
rinated b-aminoalcohols (Scheme 2). Epoxide 3a was used
as a probe. Dissolving 3a in EtOH followed by treatment
with diethylamine, pyrrolidine, benzylamine and morpholine
at 608C for 48 h, resulted in the highly regioselective forma-
tion of the corresponding b-aminoalcohols 4a–d in very
good yields (80–95%, Scheme 2). Similarly, starting from
enantioenriched epoxide (R)-3a (prepared in 92% yield
and> 98:2 e.r. by quenching (R)-2-Li with MeI), it was pos-
sible to prepare highly enantioenriched (> 98:2 e.r.) b-ami-
noalcohols (R)-4c (85% yield) and (R)-4d (88% yield)
(Scheme 2). Such fluorinated phenylpropanolamines have
recently attracted considerable interest either as agrochemi-
cal bioregulators or as agonists on octopamine receptors in
cockroach ventral nerve cords.[16] A microwave-assisted syn-
thesis of N-substituted indoles which exploits an amine-pro-
moted epoxide ring-opening reaction of ortho-fluoro-substi-
tuted styrene oxides has also been reported.[17]
In principle, fluoro-substituted styrene oxides would have
three types of centers capable of being lithiated: the benzyl-
ic position and the sites ortho to the fluorine substituent and
to the oxiranyl ring. A fluorine atom itself, however, occu-
pies a very low position in the hierarchy of directed ortho
metalation (DoM) groups.[18] Therefore, the fact that ortho-
fluorostyrene oxide undergoes a highly regioselective ben-
zylic lithiation when treated with sBuLi/THF may most
probably be the result of the synergistic cooperation of an
oxiranyl-driven complex-induced proximity effect[8a] and a
fluorine-promoted electron-withdrawing inductive effect;
that is, the benzylic hydrogen atom in 2 is more acidic than
the hydrogen atom ortho to fluorine.[19] Optically active
meta-fluorostyrene oxide (R)-5 (Table 3) (>98:2 e.r.) was
Entry
T [K]
t [min]
D [%][a]
Yield [%][b]
e.r.[c]
1
2
3
175
175
195
15
180
15
95
95
95
90
10
38
>98:2
>98:2
>98:2
[a] Calculated by 1H NMR of the crude reaction mixture. [b] Isolated
yield after column chromatography. [c] Enantiomeric ratio evaluated by
chiral HPLC (see Experimental Section).
This fact proves that (R)-2-Li is configurationally stable[14]
at least on the time scale of its generation and addition to
an electrophile at 175 K. The chemical and configurational
stabilities of (R)-2-Li were also checked at longer reaction
times. After stirring the above reaction mixture for 180 min
at 175 K and quenching with MeOD, [D]-(R)-2 was recov-
ered with 95% D and, again, with the configuration at the
benzylic-type carbon unaffected (>98:2 e.r.); however, the
isolated yield after column chromatography was only 10%
(entry 2, Table 1). A careful inspection of the crude product
revealed a complex mixture of products (mainly enediols
and alkenes), most probably originating by the reported
“eliminative dimerization” and “reductive alkylation” pro-
cesses.[15] Therefore, oxiranyllithium (R)-2-Li, at longer reac-
tion time, decomposes rather than racemizes. This behavior
is in line with that found for other a-lithiated aryloxiranes.[6]
A higher temperature than 175 K favored the carbenoid
nature of (R)-2-Li as well; indeed, after only 15 min stirring
at 195 K, followed by quenching with MeOD, [D]-(R)-2 was
again isolated in poor yield (38%, entry 3, Table 1) although
with high deuterium incorporation (95% D) and high e.r.
(>98:2). It is worth noting that comparable yields and deu-
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Lithiated Fluorinated Styrene Oxides
FULL PAPER
(entry 4, Table 3)[20] that raised up to 85:5 employing 3 equiv
of nBuLi (entry 7, Table 3).
By contrast, lithiation of optically active para-fluorostyr-
ene oxide (R)-6 with sBuLi (2 equiv, THF, 175 K, 15 min)
(see Experimental Section) took place mainly at the benzyl-
ic position to give, after MeOD quenching, [D]-(R)-a-6 in
70% and [D]-(R)-ortho-6 in 20% yield, the remaining 10%
being unreacted starting epoxide (1H NMR analysis of the
crude reaction mixture) (entry 1, Table 4).
Table 4. Lithiation–deuteration of para-fluorostyrene oxide (R)-6.
Scheme 2.
Entry Base
Solvent
THF
T
t
[D]-(R)-a-6
[D]-(R)-o-6
[K] [min] [%][a]
[%][a]
Table 3. Lithiation–deuteration of meta-fluorostyrene oxide (R)-5.
1
2
sBuLi
175 10
70
70
20
20
sBuLi/
hexane 183 10
TMEDA[b]
LDA/
3
THF 175 30
–
30
tBuOK
[a] Calculated by 1H NMR. [b] Lithiation performed in the presence of
3 equiv of TMEDA.
Entry Base
Solvent
T
[K]
t
[D]-(R)-a- [D]-(R)-o-
[min] 5[a]
5[a]
However, the isolation by column chromatography of the
mixture of deuterated compounds, [D]-(R)-a-6 and [D]-(R)-
ortho-6, confirmed that no racemization occurred at the
benzylic position. a-Lithiated para-fluorostyrene oxide (R)-
a-6-Li was shown to be configurationally stable up to a reac-
tion time of 90 min. The use of the sBuLi/TMEDA complex
in hexane at 183 K gave results similar to those obtained
with sBuLi in THF (entry 2, Table 4), whereas the mixture
LDA/tBuOK furnished only [D]-(R)-ortho-6 in 30% yield
(THF, 175 K, 30 min), the remaining being unreacted start-
ing epoxide (entry 3, Table 4). Other metalating agents such
as LDA and lithium 2,2,6,6-tetramethylpiperidide were inef-
fective (THF, 175 K, 30 min). Lithiation of compound 7
(Scheme 3), bearing two fluorine atoms in a meta orienta-
1
2
3
4
sBuLi
sBuLi
sBuLi
sBuLi/
TMEDA
LDA/tBuOK THF
nBuLi
(1 equiv)
nBuLi
(3 equiv)
THF
Et2O
hexane 183
hexane 183
195
175
0.5
10
10
5
30
50
[b]
[b]
[c]
[c]
–
–
30
70
5
6
175
175
30
10
–
<2
15
60
THF
7
THF
175
10
5
85
[a] Evaluated by 1H NMR analysis of the crude reaction mixture.
[b] Complex mixture. [c] No deprotonation occurred.
prepared by HKR of the corresponding racemic epoxide
(see Experimental). Deprotonation with sBuLi in THF at
195 K and quenching with a deuterium source after 30 s af-
forded (1H NMR analysis) [D]-(R)-ortho-5 (50%) from (R)-
ortho-5-Li and [D]-(R)-a-5 (30%) from (R)-a-5-Li; about
20% of 5 remained unreacted (entry 1, Table 3). The mix-
ture of the two deuterated compounds, [D]-(R)-a-5 and [D]-
(R)-ortho-5, once isolated by column chromatography,
turned out to be highly enantiomerically enriched with the
configuration at the benzylic stereogenic centers unaffected
(>98:2 e.r., GC analysis, see Experimental Section). A
number of bases and parameters were also screened (en-
tries 1–7, Table 3). With respect to this, it is worth noting
that: tBuLi and lithium diisopropylamide (LDA) were inef-
fective, a mixture of sBuLi/TMEDA in hexane gave a mix-
ture of [D]-(R)-ortho-5 and [D]-(R)-a-5 in a 70:30 ratio
Scheme 3.
tion, with sBuLi (THF, 175 K), followed by quenching with
Me3SiCl after 15 min, gave adduct 8 in almost quantitative
yield after column chromatography (Scheme 3). Most likely,
in this case, the regioselectivity of lithiation is achieved by
cooperation of both complexation and inductive effects.
Chem. Eur. J. 2010, 16, 9778 – 9788
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S. Florio, V. Capriati et al.
Table 5. Lithiation-deuteration of meta-trifluoromethylstyrene oxide (S)-
9 at different temperatures and times.
Attention was next turned to investigating lithiation of
ortho-, meta-, and para-trifluoromethyl-substituted deriva-
tives. Optically active meta-trifluoromethylstyrene oxide (S)-
9 (>98:2 e.r.) (see Experimental Section), when treated
with sBuLi (THF, 175 K, 15 min), could be quantitatively a-
deprotonated to give only (S)-9-Li so furnishing, after
quenching with MeOD, [D]-(S)-9 (>98% D) with 93:7 e.r.
(Scheme 4). This result is in line with the fact that the tri-
fluoromethyl substituent, in spite of being a strong electron-
withdrawing group, is, however, a weaker DoM activator
than the fluorine atom itself.[21] Lowering the temperature to
157 K, (S)-9-Li could be quenched with MeI after 15 min to
give (S)-9a (Scheme 4) in 95% yield and 96:4 e.r. The latter
was subjected to a ring-opening reaction with Et2NH to give
aminoalcohol (S)-10 in 85% isolated yield and 96:4 e.r.
However, no deprotonation occurred when (S)-9 was treat-
ed with sBuLi employing hexane or Et2O as the solvent.
Therefore, unlike lithiated ortho-, meta-, and para-fluoros-
tyrene oxides, which are configurationally stable on the time
scale of the reaction, (S)-9-Li in part loses its original con-
figurational integrity (93:7 e.r. at 175 K and 96:4 e.r. at
157 K).
Entry
T [K]
Solvent
t [min]
e.r.[a]
1
2
3
4
5
6
7
8
195
195
195
195
195
175
175
175
175
157
157
157
157
THF
THF
THF
THF
THF
THF
THF
THF
3
5
71:29
68:32
61:39
58:42
54:46
93:7
85:15
80:20
71:29
97:3
10
15
20
15
30
40
60
20
30
40
60
9
THF
10
11
12
13
THF/Et2O 3:2
THF/Et2O 3:2
THF/Et2O 3:2
THF/Et2O 3:2
95:5
94:6
92:8
[a] Determined by chiral stationary phase HPLC.
discussion above), racemization of (S)-9-Li was found to
proceed slowly and, at 195 K, [D]-9 was recovered with
71:29–54:46 e.r. between 3 and 20 min (entries 1–5, Table 3),
1
each time with >98% D (evaluated by H NMR analysis of
the crude reaction mixture). The plot of ln
(j2XR(9)ꢁ1j)
versus t showed a very good linear relationship (R2 =0.993)
and was found to obey strictly the kinetics of first-order rac-
emization;[22] the slope, corresponding to ꢁkrac, indicated an
estimated half-life of racemization, t1/2, of 7.2 min at 195 K
(Figure 1). Application of the Eyring equation[23] to the esti-
mated kenant (calculated as krac/2), for the oxiranyllithium
¼
(S)-9-Li indicates a barrier to inversion (DG (enant)) of
14.01ꢀ0.04 kcalmolꢁ1 at 195 K in THF.
Scheme 4.
Thus, we found it instructive to study in detail the kinetics
of the racemization of (S)-9-Li in THF as well as that of
lithiated ortho- and para-trifluoromethylstyrene oxides
(which were shown to be configurationally unstable in THF
(see below)), especially because a knowledge of the stereo-
chemical stability and the rate of interconversion of chiral
organolithiums is critical to asymmetric substitution chemis-
try as well as for dynamic kinetic/thermodynamic resolu-
tions.
Kinetic studies: The approximate racemization half-life of
configurationally unstable lithiated styrene oxides was in all
cases determined by performing deprotonation/quenching
experiments with a deuterium source.
meta-Trifluoromethylstyrene oxide (S)-9 (>98:2 e.r.) was
first deprotonated at 195 K with sBuLi (1.5 equiv) in THF
for a time t followed by MeOD quench. The recovered ep-
oxide was then analyzed, each time, by a chiral stationary
phase HPLC to calculate its e.r. (Table 5). As expected (see
Figure 1. Plot of ln
G
~
&
(157 , 175 , and 195 K ) in lithiation–deuteration exchange on (S)-9:
estimation of the racemization half-life of the oxiranyllithium (S)-9-Li.
All reactions run at [(S)-9]=0.05m. XR(9) is the mole fraction of (R)-9,
and j2XR(9)ꢁ1j is equivalent to the % ee of 9 expressed as a number be-
tween 0 and 1. T = 157 K, krac = 4.24ꢂ10ꢁ5 sꢁ1, t1/2 = 272.4 min, R2
=
¼
0.998, DG (enant) = 12.34ꢀ0.03 kcalmolꢁ1; T = 175 K, krac = 2.70ꢂ
10ꢁ4 sꢁ1, t1/2 = 43.4 min, R2 = 0.995, DG (enant) = 13.16ꢀ0.04 kcal
¼
molꢁ1; T = 195 K, krac = 1.59ꢂ10ꢁ3 sꢁ1, t1/2 = 7.2 min, R2 = 0.993 , DG
¼
(enant) = 14.01ꢀ0.04 kcalmolꢁ1
.
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Lithiated Fluorinated Styrene Oxides
FULL PAPER
Similar deprotonation/deuteration experiments were also
carried out on (S)-9 after lowering the temperature to 175
and 157 K (Table 5). At longer reaction times (15–60 min),
[D]-(S)-9 was recovered with ever increasing e.r. ranging
from 93:7–71:29 (175 K) (entries 6–9, Table 5) to 97:3–92:8
Scheme 5. Indirect dynamic interconversion between the two lithiated h3-
aza-allyl enantiomeric monomers (R)- and (S)-h3-11-Li.
(157 K) (entries 10–13, Table 5). The plot of ln
(j2XR(9)ꢁ1j)
¼
¼
enantiomerization barriers DG (enant) of 13.16ꢀ0.04 and
version barrier DG (enant) was 8.8 kcalmolꢁ1 (143 K, 3:2
12.34ꢀ0.03 kcalmolꢁ1 at 175 and 157 K, respectively (at
THF/Et2O): an indirect dynamic interconversion mediated
by higher aggregates between two lithiated h3-aza-allyl
enantiomeric monomers has been proposed[28] and an invert-
ing tetrahedral configuration is very likely to take place
rather than an inverting planar configuration.
¼
195 K: t1/2
=
7.2 min, DG (enant)
=
14.01ꢀ0.04 kcal
molꢁ1).
From these studies, activation parameters for the enantio-
merization of (S)-9-Li could then be determined. To this
end, the above free energies of enantiomerization were plot-
ted as a function of temperature (Figure 2). A very good re-
lationship was found (R2 =0.999), corresponding to an en-
To prove that, (S)-9 was also deprotonated with sBuLi in
THF but at a higher concentration (0.5m vs 0.05m) to favor
the formation of higher aggregates, if any. Surprisingly, after
quenching the mixture with MeOD, 30 min being the reac-
tion time, [D]-(S)-9 was recovered with 98% D and the
same e.r. (85:15) obtained in the case of the reaction run at
a lower (0.05m) concentration, although the amount of by-
products in the crude mixture (mainly alkenes and enediols)
increased to about 20% in the former case. Most probably,
as observed for lithiated styrene oxide,[8a] at a higher con-
centration, (S)-9-Li may be similarly more prone to self-as-
sociate to give higher aggregates with a more pronounced
“carbene-like” reactivity.
¼
thalpy of activation (DH ) of 5.45ꢀ0.13 kcalmolꢁ1 and an
¼
entropy of activation (DS ) of ꢁ43.92ꢀ0.75 calmolꢁ1 Kꢁ1.
3,5-Bis(trifluoromethyl)styrene oxide (R)-12 (98:2 e.r.)
was prepared by means of Noyoriꢃs asymmetric reduction of
the corresponding a-chloroketone (see Experimental Sec-
tion).[29] After treating (R)-12 with sBuLi (1.5 equiv) in
THF/Et2O (3:2), followed by quenching with MeOD, com-
pletely racemic [D]-12 was recovered (90% yield and 89%
D) even at 157 K after a reaction time of 5 s (Scheme 6).
Figure 2. Eyring plot and activation parameters for enantiomerization of
(S)-9-Li.
The measured small enthalpy of activation along with a
strong negative entropy of activation are both consistent
with either additional solvation of the transition state or for-
mation of a larger dipole resulting in electrostatic restriction
of the solvent.[24] Therefore, in this case, the transformation
of a contact ion pair into a solvent-separated ion pair
(SSIP)[25] may be conceived as the rate-determining step.
However, epimerization through
a higher aggregate
Scheme 6.
cannot be ruled out.[26] In the case of 1-lithio-1-phenyl-2,2-
dimethylcyclopropane (which exhibits a topomerization bar-
rier markedly lower than that of the configurationally stable
cyclopropyllithium), for example, the large negative activa-
tion entropy (ca. ꢁ32 calmolꢁ1 Kꢁ1)) points toward just the
participation of aggregate structures.[27] As an additional ex-
ample, it is worth noting that in contrast to a-lithiated aryl-
oxiranes, which are usually configurationally stable (with the
restriction discussed above), a-lithiated oxazolinyloxiranes
are not; the bias that lithium has to be strongly coordinated
by the iminic oxazoline moiety was found to be a crucial
factor in causing a fast racemization for the latter lithium
carbenoids. In particular, in the case of 1-lithio-1-(2-oxazo-
linyl)-2,2-dimethyloxirane 11 (Scheme 5), the estimated in-
The trifluoromethyl group is known to be one of the most
powerful electron-withdrawing groups in structural organic
chemistry.[30] Thus, the presence of two such groups in a
meta orientation is most probably enough to lead to the
SSIP directly on deprotonation, thereby allowing anion 12-
Li to be configurationally unstable.
We then turned to ortho-trifluoromethylstyrene oxide
(R)-13 (>98:2 e.r., see Experimental Section (Table 6); it
was similarly investigated by deprotonation/deuteration se-
quences at variable times with sBuLi (1.5 equiv) in THF/
Et2O (3:2). As shown in Table 6 (entries 1–4), only after a
3 s deprotonation time at 157 K, the addition of MeOD es-
Chem. Eur. J. 2010, 16, 9778 – 9788
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9783

S. Florio, V. Capriati et al.
sentially gave racemic [D]-13. This is consistent with a con-
figurational instability of 13-Li, which undergoes racemiza-
tion even faster than 9-Li. Eyring analysis of the data
(Figure 3) gave a racemization half-life of 1.6 s at 157 K
mechanism in which the lithium is “escorted” from one face
to the other face of the oxiranyllithium.[32] However, it is
worth pointing out that, in general, although internal coordi-
nation is often known to influence the barrier for intercon-
version at a stereogenic lithiated carbon atom, it is not
always predictable whether such an interconversion will be
faster or slower.[33,34] Alternatively, for anions such as 13-Li,
¼
(R2 =0.9953), corresponding to an inversion barrier DG
(enant) of 9.46ꢀ0.01 kcalmolꢁ1.
ꢁ
one could also think of a plausible carbon fluorine no-bond
resonance (hyperconjugation) as a stabilizing mesomeric
mechanism (Scheme 7).
ꢁ
Scheme 7. Carbon fluorine no-bond resonance in lithiated oxiranyllithi-
um 13-Li.
Figure 3. Plot of ln
deuteration exchange on (R)-13: estimation of the racemization half-life
G
of the oxiranyllithium 13-Li. All reactions run at [(R)-13]=0.05m. krac
=
Indeed, fluorine hyperconjugation has frequently been in-
voked for interpreting various bond lengths and solvolytic
reactivities of polyhalogenated compounds.[35] However, re-
lying on the 13C NMR resonances of C-ortho and C-para
phenyl as a criterion for ascertaining effective (or no) deloc-
alization of the p-charge into the phenyl ring,[8a,25a] prelimi-
nary NMR investigations on 13-Li[34] indicate that such car-
bons were shifted upfield with respect to those of the neu-
tral 13 (falling at 128.0–129.0 ppm) by about 10 ppm only.
This would be consistent with a negligible transfer of the
carbanion charge into the phenyl p-system as similarly ob-
¼
0.434 sꢁ1, t1/2 = 1.6 s, R2 = 0.9953, DG (enant) = 9.46ꢀ0.01 kcalmolꢁ1
.
Table 6. Lithiation–deuteration of ortho-trifluoromethylstyrene oxide
(R)-13 at different times at 157 K.
served in lithiated styrene oxide.[8a] C F anionic hyperconju-
ꢁ
entry
t [s]
e.r.[a]
% D[b]
gation has also been found not to play a significant role in
the stabilization of other trifluoromethyl anion deriva-
tives.[36]
1
2
3
4
3
4
5
7
56:44
54:46
53:47
51:49
84
85
92
95
Finally, the configurational stability of a-lithiated para-tri-
fluoromethyl-substituted styrene oxide 14-Li (Table 7) was
also investigated.
[a] Determined by chiral stationary phase HPLC and corrected for the
1
percent deuterium found. [b] Evaluated by H NMR analysis of the crude
reaction mixture.
Lithiation (sBuLi, 1.5 equiv) of optically active (R)-14 (>
98:2 e.r.) (Table 7) (see Experimental Section) at 157 K
(THF/Et2O 3:2), followed by electrophilic quenching with
At lower temperatures than 157 K and at very short reac-
tion times (less than 10 s), the kinetics of deprotonation
competes with that of racemization, thereby rendering the
calculation of activation parameters for this lithiated system
impractical.
Table 7. Lithiation–deuteration of para-trifluoromethylstyrene oxide (R)-
14 at different times at 157 K.
The lower inversion barrier found for 13-Li compared
with 9-Li raises the possibility that an alternative or cooper-
ative mechanism is under way for racemization of the
former oxiranyllithium other than those discussed above.
Actually, if one looks at the lithiated system 13-Li, the close
spatial proximity of lithium to the ortho-trifluoromethyl
group opens the opportunity for an intramolecular coordina-
tion of lithium to such a group. Organic fluorine can be,
indeed, regarded as an efficient donor atom in the coordina-
tion of both alkali and alkaline earth metal ions.[1d,31] In our
case, one possibility is that fluorine may really be involved
in promoting what is usually called a “conducted tour”-type
Entry
t [s]
e.r.[a]
% D[b]
1
2
3
4
5
67:33
61:39
57:43
53:47
64
75
83
88
10
20
30
[a] Determined by chiral stationary phase HPLC and corrected for the
percent deuterium found. [b] Evaluated by H NMR analysis of the crude
reaction mixture.
1
9784
www.chemeurj.org
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Chem. Eur. J. 2010, 16, 9778 – 9788

Lithiated Fluorinated Styrene Oxides
FULL PAPER
MeOD on aging the enantioenriched organolithium for dif-
ferent times (Table 7), proved that 14-Li, similarly to 13-Li,
is configurationally unstable; indeed, the e.r. of the corre-
sponding deuterated [D]-14 dropped back to 67:33 soon
after 5 s. The activation free energy for enantiomerization
tive position of the CF3 group on the phenyl ring. With
regard to that, it is of interest to observe that the barriers to
inversion in the case of lithiated meta- and para-trifluorome-
thylstyrene oxides 9-Li (12.34 kcalmolꢁ1 at 157 K) and 14-Li
(10.13 kcalmolꢁ1 at 157 K) parallel those of sm and sp of the
CF3 group, which are 0.43 and 0.53, respectively; that is, a
lower barrier value corresponds to a higher Hammett s
value. Lithiated meta- and para-fluorostyrene oxides 5-Li
and 6-Li, which are both configurationally stable, do have
the lowest Hammett s values, that is 0.34 and 0.06, respec-
tively. In the case of lithiated ortho-trifluoromethylstyrene
oxide 13-Li, a possible synergistic cooperation of another
competing mechanism, such as a “conducted tour” mecha-
nism, may justify the lowest activation free energy found for
racemization (9.46 kcalmolꢁ1 at 157 K).
¼
DG (enant) of 14-Li, calculated from the corresponding
Eyring plot (R2 =0.9812) (Figure 4) was 10.13ꢀ0.03 kcal
molꢁ1 at 157 K, which gives a t1/2 (rac) of 13.5 s.
The calculation of the barriers to inversion for such oxira-
nyllithiums, the intimate knowledge of their racemization
mechanisms, and the possibility of slowing down their rate
of interconversion in the presence of ligands or different sol-
vents, is quite interesting for setting up either stereoselective
synthesis of interesting target molecules or useful and effi-
cient dynamic resolutions. These issues will be subject of
future investigations.
Figure 4. Plot of ln
deuteration exchange on (R)-14: estimation of the racemization half-life
G
of the oxiranyllithium 14-Li. All reactions run at [(R)-14]=0.05m. krac
0.0512 sꢁ1, t1/2 = 13.5 s, R2 = 0.9812, DG (enant) = 10.13ꢀ0.03 kcal
molꢁ1
.
Conclusion
Experimental Section
In conclusion, a study on the configurational stability of
some lithiated fluorinated styrene oxides has been carried
out. a-Lithiated ortho-, meta-, and para-fluorostyrene oxides
(2-Li, a-5-Li, and a-6-Li) were all shown to be configura-
tionally stable. Optically active oxiranyllithium (R)-2-Li, in
particular, could be deprotonated and stereospecifically
quenched with some electrophiles. Then, the corresponding
functionalized derivatives so obtained were successfully sub-
jected to regiospecific ring-opening reactions with amines to
give fluorinated b-aminoalcohols having a stereodefined
quaternary carbinol center. In the case of the meta- and
para-fluorinated derivatives (5 and 6), benzylic lithiation
competes to a variable extent with ortho-lithiation to the
fluoro-adjacent position depending on the base and the sol-
vent used. In contrast, a-lithiated ortho-, meta-, and para-tri-
fluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) proven
to be configurationally unstable. Among them, optically
active lithiated meta-trifluoromethylstyrene oxide (S)-9-Li
racemizes much slower than the corresponding ortho- and
para-isomers 13-Li and 14-Li. However, when two trifluoro-
methyl groups are in a meta orientation to each other, as in
the case of (R)-12, the corresponding anion 12-Li undergoes
a very fast racemization thus showing a configurational in-
stability. The barriers to inversion were calculated for oxira-
nyllithiums 9-Li, 13-Li, and 14-Li and, in the case of 9-Li,
also activation parameters. Most likely, strong inductive
field effects provided by a group such as the trifluoromethyl
group may play a major role in stabilizing all of the above
regioisomeric benzylic-type oxiranyllithiums, thereby pro-
moting racemization at a rate that is dependent on the rela-
General: Tetrahydrofuran (THF) was freshly distilled under a nitrogen
atmosphere over sodium/benzophenone. Petroleum ether refers to the
1
40–608C boiling fraction. For the H, 13C and 19F NMR spectra (1H NMR
400, 600 MHz; 13C NMR 150 MHz; 19F NMR 376 MHz), CDCl3 was used
as the solvent. 19F NMR spectra were recorded using trichlorofluorome-
thane (CFCl3) as an internal standard (d=0 ppm). GC-MS spectrometry
analyses were performed on a gas chromatograph (dimethylsilicon capil-
lary column, 30 m, 0.25 mm i.d.) equipped with a mass selective detector
operating at 70 eV (EI). Optical rotation was measured with a polarime-
ter using a cell of 1 dm path length at 258C; the concentration (c) is ex-
pressed in g per 100 mL. Melting points were uncorrected. Elemental
analyses were performed by using a Carlo Erba CHNS-O EA1108-Ele-
mental Analyzer. Analytical thin-layer chromatography (TLC) was car-
ried out on precoated 0.25 mm thick plates of Kieselgel 60 F254; visuali-
zation was accomplished by UV light (254 nm) or by spraying with a so-
lution of 5% (w/v) ammonium molybdate and 0.2% (w/v) ceriumACHTUNGTRENNUNG(III)
sulfate in 100 mL 17.6% (w/v) aq. sulphuric acid and heating to 2008C
for some time until blue spots appear. All reactions involving air-sensitive
reagents were performed under nitrogen in oven-dried glassware using
syringe-septum cap technique. Lithiation-deuteration reactions were per-
formed using an ethanol/liquid N2 (157 K) or methanol/liquid N2 (175 K)
or acetone/dry ice (195 K) cold bath. The enantiomeric ratios were deter-
mined as follows: compound (S)-10, by 1H NMR analysis (600 MHz,
CCl4 with [D4]MeOH as the external standard) in the presence of the
Chiral Solvating Agent (CSA) (R)-(ꢁ)-2,2,2-trifluoro-1-(9-anthryl)etha-
nol,[37] (CSA/(10) molar ratio 2:1); compounds 4c,d, by HPLC analysis
employing a Daicel Chiralcel OD-H column (250ꢂ4.6 mm); compounds
5, 9, 9a, and 14, by HPLC analysis employing a Cellulose Lux-2 column
(250ꢂ4.6 mm); compounds 2, 3a, 6, and 13, by GC analysis employing a
Chirasil-DEX CB column (250ꢂ0.25 mm, column head pressure 18 psi,
He flow 1.5 mLminꢁ1, oven temperature 100–! 1108C). Racemic oxir-
anes were prepared either according to the Corey–Chaykovsky[11] epoxi-
dation procedure starting from the corresponding benzaldehyde deriva-
tives (epoxides 2, 5, 6, and 14) or according to Durst[38] methodology (ep-
oxides 9 and 13). The following optically active epoxides were synthe-
sized as follows: compounds 2, 5, and 14 starting from the corresponding
Chem. Eur. J. 2010, 16, 9778 – 9788
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9785

S. Florio, V. Capriati et al.
racemic mixtures by using the Jacobsen hydrolytic kinetic resolution,[12]
whereas compounds 9, 12, and 13 starting from the corresponding a-
chloroketones exploiting the Noyori asymmetric reduction.[29] a-Chloro-
ketones were prepared from the commercially available acetophenone
ACTHNGUTERNNUG
(COH), 62.7 (C), 50.6 (d, 4J(C,F)=1 Hz; CH2), 26.4 (CH3), 24.9 (d, 5J-
A
FT-IR (KBr): n˜ =3483, 2986, 1492, 1450, 1189, 762 cmꢁ1; GC-MS (70 eV):
m/z (%): 196 (1) [M+], 138 (100), 123 (92), 109 (54), 59 (33); elemental
analysis calcd (%) for C11H13FO2: C 67.33, H 6.68; found: C 67.64, H
6.98.
(C,F)=2 Hz; CH3); 19F NMR (376 MHz, CDCl3, 298 K): d =ꢁ112.95;
derivatives, likewise as reported.[39] (R)-(a)-4-Fluorostyrene oxide
6
(99.5:0.5 e.r.) is commercially available. Spectroscopic data of compounds
2,[40] 3a,[17] 5,[40] 7,[41] 9,[42] 9a,[42] 12,[43] 13,[42] and 14[42] have been reported.
Synthesis of b-aminoalcohols 4a–d and 10—General procedure: The re-
spective and freshly distilled amine (Et2NH, Bn2NH, pyrrolidine or mor-
pholine) (1.4 mmol) was added to a solution of the respective epoxide
(3a or 9a) (0.7 mmol in 2 mL of absolute EtOH), then the mixture was
refluxed for 48 h. After this time, the solvent was evaporated in vacuo
and the crude product was purified by column chromatography (silica
gel, CH2Cl2/MeOH 97:3 ! 92:8) to afford b-aminoalcohols 4a–d and 10.
Kinetic studies: All kinetics experiments were conducted in a closed
vessel immersed in a given cold bath according to the temperature em-
ployed (see above). The temperature was monitored using a calibrated
digital thermometer. The rate constants for the racemization of optically
active oxiranylithiums (S)-9-Li, (R)-13-Li and (R)-14-Li were determined
by plotting enantiomeric ratios over time after performing a series of lith-
iation–deuteration experiments on the corresponding epoxides (S)-9, (R)-
13 and (R)-14 at different temperatures and times as reported in the
main text. Each point in the plot corresponds to a single experiment. The
detected enantiomeric ratios at very short reaction times (less than 30 s,
Tables 6 and 7) proven to be reproducible within the limits of 5% of the
stated ratio.
(ꢀ)-1-(Diethylamino)-2-(2-fluorophenyl)propan-2-ol (4a): colorless oil,
95%; 1H NMR (600 MHz, CDCl3, 298 K): d =7.73–7.70 (m, 1H; ArH),
7.22–7.18 (m, 1H; ArH), 7.12–7.10 (m, 1H; ArH), 6.98–6.94 (m, 1H;
ArH), 4.97 (brs, 1H; OH), 3.13 (dd, 2J
(H,H)=13.5, 5J
N
2
1H; CHH), 2.62 (d, J
A
CH2), 1.52 (s, 3H; CH3), 0.88 (t, 3J
ACHTUNGTRENNUNG
Lithiation–deuteration sequence on epoxides (S)-9, (R)-12, (R)-13 and
(R)-14—General kinetic run: Standard solutions (0.05m) of the respec-
tive optically active epoxide (0.1 mmol in 2 mL of dry THF for reactions
performed at 175 K or 195 K and of dry THF/Et2O 3:2 for reactions per-
formed at 157 K) were prepared and treated with sBuLi (0.15 mmol,
1.3m solution in cyclohexane) under N2. After stirring the resulting mix-
ture for the measured time period (see Tables 5–7), MeOD (10 mmol)
was added all at once. The cooling bath was removed and the reaction
mixture was allowed to warm to room temperature, then diluted with
brine (5 mL) and extracted with Et2O (3ꢂ5 mL). The combined organic
phases were dried with Na2SO4 and concentrated in vacuo. The crude
product was analyzed without further purification to check the enantio-
meric ratio as described above.
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
E
G
ACHTUNGTRENNUNG
3
4
ACHUTNGRENNU(G C,F)=5 Hz; COH), 62.9 (d, JACTHUNGTRENNUNG
AHCTUNGTRENNUNG
(376 MHz, CDCl3, 298 K): d =ꢁ114.36; FT-IR (film): n˜ =3368, 2972,
1385, 1482, 1448, 1204, 1062, 819, 759 cmꢁ1; GC-MS (70 eV): m/z (%):
225 (1) [M+], 210 (6) [M+ꢁCH3], 86 (100) [C5H12N+], 58 (11); elemental
analysis calcd (%) for C13H20FNO: C 69.30, H 8.95, N 6.22; found: C
69.65, H 9.11, N 6.30.
(ꢀ)-2-(2-Fluorophenyl)-1-(pyrrolidin-1-yl)propan-2-ol (4b): colorless oil,
95%; 1H NMR (400 MHz, CDCl3, 298 K): d =7.76–7.71 (m, 1H; ArH),
7.24–7.19 (m, 1H; ArH), 7.14–7.10 (m, 1H; ArH), 6.99–6.94 (m, 1H;
Synthesis of epoxides 3a-c, 8 and 9a—General procedure: A solution of
epoxide 2, 7 or 9 (0.5 mmol) in dry THF (5 mL) was treated at 175 K
and under N2 with sBuLi (0.6 mmol, 1.3m solution in cyclohexane). After
stirring for 15 min, the electrophile (MeI, Me3SiCl or acetone)
(1.0 mmol) was added all at once and the mixture stirred for additional
30 min at 175 K. After this time, the cooling bath was removed and the
reaction mixture was allowed to warm to room temperature, then diluted
with brine (5 mL) and extracted with Et2O (3ꢂ10 mL). The combined or-
ganic phases were dried with Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography (silica gel, petro-
leum ether/Et2O 8:2!95:5) to afford a-functionalized epoxides 3a–c, 8
and 9a.
ArH), 3.11 (dd, 2J
2J
AHCTUNGTRENNUNG
4H; 2ꢂCH2), 1.52 (s, 3H; CH3); 13C NMR (125 MHz, CDCl3, 298 K): d
=159.3 (d, 1J
(C,F)=244 Hz; C), 134.7 (d, 2J
(C,F)=13 Hz; CCF), 128.4
3
4
(d, J
N
N
ACHTUNGTRENNUNG(C,F)=
2 Hz; CH), 115.5 (d, 2J
G
ACHTUNGTRENNUNG
COH), 65.2 (d, 4J
AHCTUNGTRENNUNG
(CH2), 23.8 (CH3); 19F NMR (376 MHz, CDCl3, 298 K): d =ꢁ113.23; FT-
IR (film): n˜ =3400, 2971, 2803, 1482, 1446, 1296, 1206, 1076, 820,
759 cmꢁ1; GC-MS (70 eV): m/z (%): 223 (1) [M+], 208 (4) [M+ꢁCH3],
123 (3), 84 (100) [C5H10N+], 55 (6); elemental analysis calcd (%) for
C13H18FNO: C 69.93, H 8.13, N 6.27; found: C 69.80, H 8.37, N 6.27.
(R)-(ꢁ)-2-(2-Fluorophenyl)-2-methyloxirane (3a): 92%; [a]2D5 = ꢁ44 (c
(ꢀ)-1-(Benzylamino)-2-(2-fluorophenyl)propan-2-ol (4c): colorless oil,
85%; 1H NMR (600 MHz, CDCl3, 298 K): d =7.73–7.70 (m, 1H; ArH),
7.32–7.22 (m, 6H; 6ꢂArH), 7.16–7.12 (m, 1H; ArH), 7.00–6.97 (m, 1H;
= 0.8, CHCl3); HPLC: Cellulose Lux 2 (250ꢂ4.6 mm), n-hexane/iPrOH
99.5:0.5, flow 0.5 mLminꢁ1
13.0 min; e.r. 99.5:0.5.
, l=260 nm, tR minor = 12.1 min, tR major =
ArH), 3.71 (s, 2H; CH2), 3.35 (d, 2J
2J
298 K): d =159.3 (d, J
13 Hz; CCF), 128.7 (d, 4J
3J
(C,F)=5 Hz; CH), 128.0 (2ꢂCH), 127.1 (CH), 124.0 (d, J
CH), 115.7 (d, 2J(C,F)=24 Hz; CH), 71.6 (d, 3J
(C,F)=5 Hz; COH), 57.7
(d, 4J(C,F)=4 Hz; CH2), 53.9 (CH2), 26.3 (d, 4J
(C,F)=4 Hz; CH3);
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(ꢀ)-2-(2-Fluorophenyl)-2-trimethylsilyloxirane (3b): Colorless oil, 40%;
1H NMR (600 MHz, CDCl3, 298 K): d=7.31–7.28 (m, 1H; ArH), 7.22–
7.19 (m, 1H; ArH), 7.11–7.08 (m, 1H; ArH), 7.01–6.98 (m, 1H; ArH),
1
2
U
ACHTUNGTRENNUNG(C,F)=
AHCTUNGTRENNUNG
4
3.02 (d, 2J(H,H)=5.5 Hz, 1H; CHH), 2.86 (d, 2J
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
A
ACHTUNGTRENUN(NG C,F)=2 Hz;
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
19F NMR (376 MHz, CDCl3, 298 K): d =ꢁ113.70; FT-IR (film): n˜ =3338,
3063, 2931, 1579, 1484, 1451, 1210, 819, 759, 699 cmꢁ1; GC-MS (70 eV):
m/z (%): 241 (3) [M+ꢁ18], 120 (67) [C8H10N+], 91 (100) [C7H7+], 65 (7);
elemental analysis calcd (%) for C16H18FNO: C 74.11, H 7.00, N 5.40;
found: C 74.23, H 7.19, N 5.49.
A
E
ACHTUNGTRENNUNG
(C,F)=21 Hz; CH), 51.43 (CH2), 51.41 (C), ꢁ4.0
(3ꢂCH3); 19F NMR (376 MHz, CDCl3, 298 K): d=ꢁ115.78; FT-IR (film):
n˜ = 3040, 2959, 1614, 1580, 1488, 1250, 842 cmꢁ1; GC-MS (70 eV): m/z
(%): 210 (30) [M+], 195 (35) [M+ꢁCH3], 139 (13), 77 (100).
(R)-(ꢁ)-(4c): 83%, [a]2D5 =ꢁ5.6 (c=0.9, CHCl3): HPLC: Chiralcel OD-H
(ꢀ)-2-[2-(2-Fluorophenyl)oxiran-2-yl]propan-2-ol (3c): White solid,
57%, m.p. 55–568C (hexane); 1H NMR (400 MHz, CDCl3, 298 K): d
=7.45–7.43 (m, 1H; ArH), 7.32–7.29 (m, 1H; ArH), 7.14–7.12 (m, 1H;
(250ꢂ4.6 mm), n-hexane/iPrOH 95:5, flow 0.5 mLminꢁ1
, l=230 nm,
tR minor =19.2 min, tR major =21.1 min; e.r. 99.5:0.5.
ArH), 7.06–7.02 (m, 1H; ArH), 3.41 (d, 2J
2.79 (d, 2J
6J(H,F)=2.4 Hz, 3H; CH3), 1.27 (s, 3H; CH3); 13C NMR (150 MHz,
N
(ꢀ)-2-(2-Fluorophenyl)-1-(morpholin-4-yl)propan-2-ol (4d): white solid,
88%, m.p. 69–708C (hexane); 1H NMR (600 MHz, CDCl3, 298 K): d
=7.71–7.68 (m, 1H; ArH), 7.24–7.14 (m, 1H; ArH), 7.13–7.10 (m, 1H;
ArH), 7.00–6.95 (m, 1H; ArH), 3.85 (brs, 1H, OH), 3.57–3.54 (m, 4H;
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CDCl3, 298 K): d =160.3 (d, 1J
G
ACHTUNGTRNE(NUNG C,F)=
3 Hz; CH), 129.8 (d, 3J
A
E
2ꢂCH2), 3.14 (dd, 2J
2J
(H,H)=13.2, 5J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
4
CCF), 123.6 (d, J
A
U
ACHTUNGTRENNUNG
9786
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9778 – 9788

Lithiated Fluorinated Styrene Oxides
FULL PAPER
(m, 2H; 2ꢂCHH), 1.52 (d, 5J
(150 MHz, CDCl3, 298 K): d =159.2 (d, 1J
2J(C,F)=13 Hz; CCF), 128.6 (d, 3J(C,F)=8 Hz; CH), 127.3 (d, 3J
4 Hz; CH), 124.2 (d, J
70.3 (d, 3J(C,F)=5 Hz; COH), 67.41 (CH2), 67.4 (CH2), 67.0 (CH2), 54.8
N
[3] a) B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11; b) B. K. Park,
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[13] Treatment of 2 with LDA at 175 K for 15 min followed by quench-
ing with MeOD was ineffective in the case of this substrate.
[14] The term “configurationally stable/unstable” used throughout the
manuscript refers to the time scale set by the reaction rate of addi-
tion of oxiranyllithium to the electrophile shown also with reference
to the temperature employed.
AHCTUNGTRENNUNG
E
G
ACHTUNGTRENNUNG
4
2
ACHTUNGTRENNUNG
(2ꢂCH2), 27.4 (CH3); 19F NMR (376 MHz, CDCl3, 298 K): d =ꢁ113.38;
FT-IR (KBr): n˜ =3366, 2974, 2859, 1479, 1447, 1300, 1199, 1117, 864,
780 cmꢁ1; GC-MS (70 eV): m/z (%): 239 (3) [M+], 208 (4), 123 (3), 84
(100) [C5H10N+], 55 (6); elemental analysis calcd (%) for C13H18FNO2: C
65.25, H 7.58, N 5.85; found: C 65.49, H 7.63, N 5.71.
(R)-(ꢁ)-(4d): 85%, [a]2D5 =ꢁ2.0 (c = 0.9, CHCl3); HPLC: Chiralcel OD-
H (250ꢂ4.6 mm), n-hexane/iPrOH 95:5, flow 0.5 mLminꢁ1, l=230 nm,
t
R minor =13.3 min, tR major =14.2 min; e.r. 99.5:0.5.
(ꢀ)-2-(2,4-Difluoro-3-trimethylsilylphenyl)oxirane (8): colorless oil, 90%;
1H NMR (600 MHz, CDCl3, 298 K): d =7.16–7.12 (m, 1H; ArH), 6.80–
6.77 (m, 1H; ArH), 4.08 (brs, 1H; CH), 3.15–3.14 (m, 1H; CHH), 2.75–
2.73 (m, 1H; CHH), 0.38 (s, 9H; 3ꢂCH3); 13C NMR (150 MHz, CDCl3,
298 K): d =166.7 (dd, 1J
G
ACHTUNGTRENNUNG
1J
3J
A
U
ACHTUNGTRENNUNG
N
N
ACHTUNGTRENNUNG
113.4 (t, 2J
N
A
ACHTUNGTRENNUNG
CH), 50.3 (CH), 47.0 (d, 4J
ACHTUNGTRENNUNG
(376 MHz, CDCl3, 298 K): d =ꢁ98.35, ꢁ105.22; FT-IR (film): n˜ =3051,
2918, 1610, 1460, 1370, 1252, 1124, 982, 846 cmꢁ1; GC-MS (70 eV): m/z
(%): 228 (42) [M+], 199 (41),136 (33), 117 (64), 77 (100).
(ꢀ)-1-(Diethylamino)-2-(3-(trifluoromethyl)phenyl)propan-2-ol (10): col-
orless oil, 85%; 1H NMR (600 MHz, CDCl3, 298 K): d =7.75 (brs, 1H;
ArH), 7.62–7.61 (m, 1H; ArH), 7.47–7.46 (m, 1H; ArH), 7.43–7.41 (m,
1H; ArH), 4.72 (brs, 1H; OH), 2.84 (d, 2J
2.66 (d, 2J
(s, 3H; CH3), 0.89 (t, 3J
(150 MHz, CDCl3, 298 K):
CCF3), 128.4 (CH), 128.2 (CH), 124.3 (q, 1J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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AHCTUNGTRENNUNG
d
ACHTUNGTRENNUNG
(CH), 121.7 (CH), 70.8 (COH), 65.2 (CH2), 48.1 (2ꢂCH2), 29.5 (CH3),
11.9 (2ꢂCH3); 19F NMR (376 MHz, CDCl3, 298 K): d =ꢁ63.02; FT-IR
(film): n˜ =3338, 3063, 2931, 1579, 1484, 1451, 1210, 819, 759, 699 cmꢁ1
;
GC-MS (70 eV): m/z (%): 275 (3) [M+], 120 (67), 91 (100), 65 (7); ele-
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(S)-(ꢁ)-(10): 85%, [a]2D5 =ꢁ2.0 (c
=
1, CHCl3); 1H NMR (600 MHz,
298 K, CCl4 with CD3OD as external standard) in the presence of the
CSA (R)-(ꢁ)-2,2,2-trifluoro-1-(9-anthryl)ethanol, (CSA/10 molar ratio=
2:1), dminor =0.89 ppm, dmajor =0.86 ppm; e.r. 96:4.
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Acknowledgements
This work was carried out under the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni” and
financially supported by the University of Bari and by the Interuniversi-
ties Consortium C.I.N.M.P.I.S. The authors would like to acknowledge
Dr. Rosalba Altamura, Dr. Rocco Paparella, and Dr. Maria Giovanna
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Received: April 9, 2010
Published online: July 19, 2010
9788
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Chem. Eur. J. 2010, 16, 9778 – 9788