Chiral and achiral lithium amides having a fluorous ponytail: Preparation and evaluation as a recycling reagent for lithium enolate generation

Article abstract of DOI:10.1055/s-2007-983877

Diisopropylamine derivatives bearing a perfluoroalkyl chain were prepared and converted to the corresponding lithium amides by treatment with n-butyllithium. The fluorous lithium amides reacted with ketones to efficiently produce lithium enolates. Asymmetric deprotonation of prochiral ketones was also studied using lithium amides derived from chiral fluorous amines, which gave optical yields comparable with the parent nonfluorous chiral lithium amides. These reusable fluorous amines can be easily recovered by liquid-liquid extraction or chromatographic separation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983877

FEATURE ARTICLE
2901
Chiral and Achiral Lithium Amides Having a Fluorous Ponytail: Preparation
and Evaluation as a Recycling Reagent for Lithium Enolate Generation
R
ecyclable Fluor
u
i
s-Tagg
r
o
and
A
chiral
s
L
ithium
Amides i Matsubara,* Louis Maeda, Hiroyuki Sugiyama, Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: ryu@c.s.osakafu-u.ac.jp
Received 4 June 2007; revised 25 June 2007
acylations, and transmetalations to other useful metal eno-
Abstract: Diisopropylamine derivatives bearing a perfluoroalkyl
chain were prepared and converted to the corresponding lithium
amides by treatment with n-butyllithium. The fluorous lithium
amides reacted with ketones to efficiently produce lithium enolates.
lates.8 Since diisopropylamine is soluble in water, the
workup procedure of the reaction of LDA involves treat-
ment with water to remove diisopropylamine from organ-
Asymmetric deprotonation of prochiral ketones was also studied us- ic solution generally without recovery. In pursuit of useful
ing lithium amides derived from chiral fluorous amines, which gave
methods to prepare chiral compounds, the recent work
optical yields comparable with the parent nonfluorous chiral lithium
surrounding lithium enolate chemistry focuses on chiral
amides. These reusable fluorous amines can be easily recovered by
lithium amide reagents available for the enantioselective
liquid-liquid extraction or chromatographic separation.
generation of lithium enolates,9,10 in which a precious
chiral function is embedded by appropriate molecular de-
sign. This study reports on the preparation and testing of
Key words: fluorous, chiral amine, enolate, LDA, asymmetric
deprotonation, recycling
recyclable fluorous-tagged substitutes for chiral and
achiral LDA-type reagents, whose concept is outlined in
Scheme 1. Consequently we found that a-phenethyl
amines having a fluorous ponytail on the benzene ring
worked equally well with non-fluorous reagents and were
easily recovered and recycled.
Introduction
Since the pioneering work of Horváth and Rábai,1 the con-
cept of the fluorous biphasic system (FBS) has been pro-
posed in organic chemistry as an environmentally benign
recycling process.2 This concept is based on the physical
phenomena that highly fluorinated compounds (fluorous
materials) are immiscible with organic solvents, while
they exhibit a thermomorphic nature to give a homoge-
neous solution upon heating. Thus, a variety of organic
compounds in which perfluorinated alkyl chains (fluorous
pony tails) are introduced and used as reagents, are easily
separable from organic products by extraction using per-
fluorinated solvents such as FC-72 (perfluorohexanes) or
liquid/solid extraction using fluorous silica gel.3 Work in
our laboratories in this area has been directed toward the
carbonyl
compound
n-BuLi
N
R
N
R
H
Li
fluorous tag
organic solvent
enol silyl ether
fluorous amine
lithium enolate
TMSCl
+
fluorous amine
fluorous solvent
recycling
design, synthesis, and application of novel environmen- Scheme 1 Concept of recycling fluorous amines acting as fluorous
LDA precursors by FBS
tally benign fluorous reaction media as well as effective
fluorous reagents and catalysts. To this end, our group has
recently reported fluorous versions of diethyl ether and
DMF that function as easily recyclable reaction media.4,5
Our group has also established phase-vanishing methods
based on the use of fluorous solvents as a liquid mem-
brane, which permits transport of reagents and regulates
the reactions in triphasic and quadraphasic.6
Results and Discussion
Preparation and Properties of Fluorous Amines:
(5-Perfluorooctyl-2-pentyl)-2-propylamine (1) and
2-(4-Perfluoroalkylphenyl)ethyl-2-propylamine (2)
Lithium diisopropylamide (LDA)7 and its analogues are
frequently used for the generation of lithium enolates
from corresponding carbonyl compounds by proton ab-
straction. Lithium enolates can be used in a variety of syn-
thetic reactions including O- and C-alkylations,
We started our fluorous LDA project by preparing the
fluorous amine 1 where a perfluorooctyl chain is attached
to a diisopropylamine core as a ponytail in order to ac-
quire a light fluorous character. Fluorous amine 1 was
synthesized according to the procedure outlined in
Scheme 2. Thus, perfluorooctyl iodide was treated with
but-3-en-2-ol under radical conditions to give 3-iodo-4-
perfluorooctylbutan-2-ol (4) in 82%, whose iodine was re-
moved by tin hydride reduction to give 4-perfluorooctyl-
butan-2-ol (5). Butanol 5 was then converted into the
SYNTHESIS 2007, No. 18, pp 2901–2912
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.08.2007
DOI: 10.1055/s-2007-983877; Art ID: F10107SS
© Georg Thieme Verlag Stuttgart · New York

2902
H. Matsubara et al.
FEATURE ARTICLE
corresponding tosylate 6 in 88% yield, which was subject- We also prepared a-phenethyl type fluorous amines 2a
ed to an SN2 reaction with isopropylamine in the presence and 2b, whose synthetic pathway is shown in Scheme 3.
of potassium carbonate in acetonitrile11 to afford the de- Perfluorooctyl iodide was treated with 4-iodoethylben-
sired amine 1 in 63% yield. Fluorous amine 1 is a pale yel- zene in the presence of copper12 to give 4-perfluorooctyl-
low, clear, and slightly viscous liquid with a boiling point ethylbenzene (7a) in 70% yield, which was converted to
of 65–65 °C at 5 mmHg. This compound is miscible with a-phenethyl bromide 8a by NBS bromination in 76%
a wide range of organic solvents, such as hexane, benzene, yield. The bromide was treated with isopropylamine to af-
diethyl ether, ethyl acetate, acetone, and ethanol, and is ford fluorous amine 2a in 64% yield. Fluorous amine 2a
poorly soluble in water.
is a pale yellow, viscous liquid with a boiling point of
Biographical Sketches
Hiroshi Matsubara was in 1991 and was a visiting Osaka Prefecture Universi-
born in Shiga, Japan in researcher at the University ty, in 2005. His research in-
1963. He received his PhD of Melbourne in the re- terests include development
from Osaka University in search group of Professor of synthetic methodologies
1991 under the supervision Carl H. Schiesser from 2002 utilizing fluorous chemistry
of Professor Shigetoshi Ta- to 2003. He was promoted and computational investi-
kahashi. He was appointed to Lecturer in 2002 and to gations into radical reac-
as a Research Associate at Associate Professor in the tions.
Osaka Prefecture University Graduate School of Science,
Louis Maeda was born in received his MSc in 2006 working as a research chem-
Hyogo, Japan in 1980 and under the guidance of Pro- ist at Osaka Organic Chemi-
studied chemistry at Osaka fessor Ilhyong Ryu. Since cal Industry, Ltd., Japan.
Prefecture University. He April 2006, he has been
Hiroyuki Sugiyama was 2004 under the guidance of tic Industry Co., Ltd., Japan
born in Shizuoka, Japan in Professor Ilhyong Ryu. (2004–2007) and Sumitomo
1979 and studied chemistry Since April 2004, he has Bakelite Co., Ltd., Japan
at Osaka Prefecture Univer- been working as a research (2007–).
sity. He received his MSc in chemist at Tsutsunaka Plas-
Ilhyong Ryu received his Professor at Osaka Univer- ic Organic Chemistry, Japan
BSc from Nagoya Universi- sity in 1988 and promoted to (1990), and the Chemical
ty in 1973. He then moved Associate Professor in Society of Japan Award for
to the Graduate School of 1995. He also had the expe- Creative Work (2004). His
Osaka University, where he rience of working with Pro- research interests include
received his PhD in 1978 fessor
Howard
Alper new synthetic methodolo-
under the direction of Pro- (1991–1992) at the Univer- gies based on radical reac-
fessors Noboru Sonoda and sity of Ottawa as a Visiting tions, new catalytic trans-
Shinji Murai. After serving Scientist. In 2000, he moved formations, the utilization
as a JSPS Postdoctoral Fel- to Osaka Prefecture Univer- of green reaction media, and
low and a Research Associ- sity as a Full Professor. He micro devices in organic
ate at Osaka University, he has been the recipient of the synthesis.
was appointed Assistant Progress Award in Synthet-
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

FEATURE ARTICLE
Recyclable Fluorous-Tagged Chiral and Achiral Lithium Amides
2903
C8F17
I
Bu3SnH
C8F17
OH
C8F17
OH
OH
Et3B, 99%
Et3B, 82%
I
4
5
NH2
p-TsCl
pyridine, 88%
C8F17
OTs
C8F17
N
K2CO3, 63%
MeCN
H
6
1
Scheme 2
100–105 °C at 3 mmHg. Fluorous amine 2b bearing a per- these two diastereomers. It is generally perceived that
fluorodecyl chain was synthesized by a similar three-step more than 60% of the fluorine (in weight) is required to
procedure, which started with the use of perfluorodecyl show fluorous character.14 However, the results from
iodide. Fluorous amine 2b is a white solid with a melting Table 1 show that by choosing polar organic solvent,
point of 48.0–49.0 °C.
fluorous amines 2 and 3 can be recovered from the FC-72
layer.
Fluorous compounds having perfluorooctyl or perfluoro-
decyl chains are called light fluorous compounds. Ap-
Generation of Lithium Enolates with Lithium
proximate partition coefficients of light fluorous amines Amides Derived from Fluorous Amine 1 and 2
prepared in this study were determined by the Curran’s
Using fluorous amine 1, our group attempted to generate
method13 and listed in Table 1. Table 1 also lists partition
lithium enolate 9 from cyclohexanone using fluorous lith-
coefficients of chiral fluorous amines, (R,S)-3 and (S,S)-3,
ium amide 10 (Scheme 4). Fluorous amine 1 was treated
the preparation of which is referred below.
with n-butyllithium at –78 °C in THF giving fluorous lith-
When fluorous amine 1 was treated with a 1:1 mixture of
FC-72 and cyclohexane, some 80% of fuorous amine 1
was distributed in FC-72 phase, indicating that the amine
can be recovered from the reaction mixture through re-
peated biphasic treatment. Bearing a benzene ring, amine
2a became less fluorous than 1, whereas the introduction
of a longer perfluorodecyl group increased distribution of
the resulting amine 2b in the fluorous phase. Interestingly,
as more polar solvent, such as acetone, methanol, and
acetonitrile, was used, a greater amount of fluorous amine
was distributed in the FC-72 phase. This tendency is sim-
ilar to that of fluorous ether, F-626.4 As expected, chiral
fluorous amines 3, which have two phenyl rings, are less
fluorous than 2b; however, the amine (R,S)-3 and the dia-
stereomer (S,S)-3 are distributed mainly in the fluorous
phase when acetonitrile is used in the organic phase. Little
difference in the partition coefficient is observed between
ium amide 10. Cyclohexanone was added to the lithium
amide solution at –78 °C. After quenching the reaction
mixture with chlorotrimethylsilane, the resulting mixture
was subjected to aqueous workup using hexane and aque-
ous NaHCO3. After drying and concentration of the hex-
ane phase, biphasic treatment of the crude mixture with
benzene and perfluorohexane (FC-72) was carried out.
The product, 1-trimethylsiloxycyclohexene (11), was ob-
tained in 49% yield from the benzene solution, whereas
88% of fluorous amine 1 was recovered from the FC-72
solution. We found that the 1H NMR spectrum of the re-
covered fluorous amine contained small signals assigned
to olefinic protons bearing spin coupling with fluorine
(d = 5.69, and double-triplet, JH,F(trans) = 33.9 Hz and
JC,H = 8.0 Hz), suggesting the occurrence of an intramo-
lecular proton abstraction pathway under the reaction con-
ditions (Scheme 4).
Cu, 2,2-dipyridyl
NBS, BPO
RfI
+
DMSO
CCl4
I
Rf
Rf = C8F17, C10F21
7a: Rf = C8F17 (70%)
7b: Rf = C10F21 (54%)
NH2
Br
N
H
Rf
K2CO3, MeCN
Rf
8a: Rf = C8F17 (76%)
2a: Rf = C8F17 (64%)
8b: Rf = C10F21 (80%)
2b: Rf = C10F21 (85%)
Scheme 3
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

2904
H. Matsubara et al.
FEATURE ARTICLE
Table 1 Partition Coefficient of Fluorous Amines Prepared for this Studya
Fluorus amine
FC-72/cyclohexane FC-72/C6H6
FC-72/acetone FC-72/MeOH FC-72/MeCN % Fb
c
c
c
87/13
59/41
82/18
57/43
–
–
–
61
56
C8F17
N
H
1
N
58/42
80/20
67/33
90/10
63/37
66/34
93/7
H
C8F17
2a
N
77/23
47/53
40/60
66/34
97/3
59
54
54
H
C10F21
2b
N
H
c
c
–
–
86/14
73/27
C10F21
(R,S)-3
N
H
c
c
–
–
C10F21
(S,S)-3
a Measured at 23 3 °C. Average of two runs. To a biphasic mixture of organic solvent (3 mL) and FC-72 (3 mL) was added fluorous amine
(300 mg), and the mixture was stirred vigorously for 30 min. After standing for 5 min, the two layers were separated and evaporated, then
weighed.
b Percent fluorine by molecular weight.
c Not determined.
The observation of a partial decomposition of 1 led to the reaction conditions as fluorous amine 1, we obtained the
use of fluorous amines 2a and 2b in which a benzene ring desired enol silyl ether 11 in 92% yield from the cyclohex-
had been inserted between the perfluorooctyl chain and ane phase (Scheme 5, Procedure A). Quantitative recov-
the amine moiety to eliminate a self-decomposition path- ery of 2b from the FC-72 phase was also achieved. We
way. When fluorous amine 2b was exposed to the same also examined separation using silica gel chromatography
(Procedure B), which also worked well. The results of the
synthesis of enol silyl ethers from a variety of cyclic ke-
tones using fluorous amine 2a and 2b are summarized in
Table 2.
n-BuLi, THF
–78 °C
C8F17
N
C8F17
N
Li
H
1
10
Both 2a and 2b were found to serve as effective fluorous
lithium amide precursors, which effectively generated
lithium enolates from ketones. Quenching the enolates
with chlorotrimethylsilane gave enol silyl ethers 11–16 in
good to high yields. Due to the less fluorous character, the
organic/fluorous biphasic treatment (Procedure A) for re-
covery of fluorous amine 2a from the product was not
necessarily satisfactory (92%, Table 2, entry 1). However,
the use of column chromatography on silica gel (Proce-
dure B) resulted in nearly quantitative recovery of 2a (en-
try 2). On the other hand, fluorous amine 2b bearing a
perfluorodecyl chain gave satisfactory results both in
yield of the product and in the recovery of the amine even
for the liquid/liquid workup (entries 3 and 4). Reaction
with 2-methylcyclohexanone gave the kinetically formed
enolate (entry 9) exclusively, demonstrating that fluorous
OLi
OSiMe3
Me3SiCl
–78 °C to r.t.
cyclohexanone
–78 °C
1
+
9
11 49%
88%
N
Li
N
F
F
C7F15
H
H
H
C7F15
F
10
Scheme 4
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

FEATURE ARTICLE
Recyclable Fluorous-Tagged Chiral and Achiral Lithium Amides
2905
OSiMe3
1. n-BuLi, THF, –78 °C
LiCl THF
N
2. cyclohexanone, –78 °C
H
3. Me3SiCl, –78 °C to r.t.
2b
C10F21
11
2b
OSiMe3
cyclohexane
layer
Procedure A
11
OSiMe3
92%
hexane layer
2b
2b
>99%
11
FC-72 layer
hexane
OSiMe3
NaHCO3
aq layer
LiCl THF
11
Procedure B
>99%
(silica gel
chromatography)
2b
methanol
96%
Scheme 5
lithium amide generated from amine 2b has the same se- 2b and n-butyllithium is a useful substitute for LDA in the
lectivity as LDA.15 As shown in Table 2, a variety of enol generation of lithium enolates; also, it can be recovered
silyl ethers were prepared in excellent yields using lithium easily and reused for the next reaction.
amide derived from fluorous amine 2b and n-butyllithi-
Preparation of Chiral Fluorous Amines: (R)-2-(4-
um, with excellent recovery of 2b in an essentially pure
Perfluorodecylphenyl)ethyl-2-propylamine [(R)-2b]
form.
and [1-(4-Perfluorodecylphenyl)ethyl](1-pheneth-
yl)amine (3)
Scheme 6 outlines the model recycling study. After ob-
taining 14 (entry 9), fluorous amine 2b recovered by Pro-
cedure B was dried under reduced pressure for six hours
and subjected to use for the next reaction. The second re-
action afforded enol silyl ether 14 in 88% yield after iso-
lation by silica gel column chromatography (entry 10).
The amine 2b was recovered in 97% yield from the reac-
tion mixture of the second run. In summary, fluorous lith-
ium amide derived from perfluorodecyl substituted amine
Based on the pioneering efforts of two research groups,
Koga16 and Simpkins,17 asymmetric deprotonation of
prochiral ketones using chiral lithium amide bases has
been pursued by many researchers.9,10 Having successful
results with achiral fluorous lithium amides derived from
2a and 2b, our group advanced our fluorous LDA chem-
istry to synthesize chiral fluorous amine (R)-2b, the R-
OSiMe3
1. n-BuLi, THF
–78 °C
hexane
silica gel
chromatography
2.
O
14
hexane
aq NaHCO3
75%
95%
N
H
3. Me3SiCl
–78 °C to r.t.
C10F21
MeOH
2b
2b
'' dried under reduced pressure''
Reuse
1. n-BuLi, THF, –78 °C
2.
O
hexane
MeOH
14
2b
3. Me3SiCl, –78 °C to r.t.
4. hexane, aq NaHCO3
88%
97%
silica gel
chromatography
Scheme 6
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

2906
H. Matsubara et al.
FEATURE ARTICLE
Table 2 Preparation of Enol Silyl Ethers Using Fluorous Lithium Amide
Entry
Substrate
Amine
2a
Workupa
Product
Yield (%)
89b
Recovery of amine (%)
1
2
3
4
5
6
7
8
A
B
A
B
B
A
B
B
92
O
OSiMe3
2a
71
98
2b
92
>99
96
2b
>99
76
2a
>99
>99
>99
>99
O
OSiMe3
OSiMe3
OSiMe3
2b
99
2b
>99
96
2b
O
9
2b
2b
B
B
75c
88c
95
97
O
10d
11
12
13
14
15
16
2b
2b
2b
2b
2b
2b
A
B
C
A
B
C
>99
>99
96
>99
97
O
OSiMe3
>99
99
92
O
Me3SiO
>99
89
>99
97
a Procedure A: biphasic workup using cyclohexane as the organic solvent. Procedure B: silica gel column chromatography using hexane to give
the products, then using methanol to recover fluorous amine. Procedure C: biphasic workup using acetonitrile as the organic solvent.
b Determined by 1H NMR spectroscopy.
c 1-Trimethylsiloxy-2-methylcyclohex-1-ene (thermodynamically stable enolate) was obtained in less than 1% yield.
d Second run of entry 9 using recovered amine 2b.
enantiomer of 2b, with the hope of using the amine in the (Figure 1), respectively. These ‘parent’ amines, made
enantioselective formation of lithium enolates. (R)-2b popular by Simpkins,17b are still important chiral bases for
was prepared by the fractional crystallization of a racemic enantioselective deprotonation of ketones. The synthetic
mixture of amine 2b with (R)-tartaric acid. (R)-Tartaric pathway toward chiral fluorous amines 3 is summarized in
acid salt of the racemic amine 2b was recrystallized three Scheme 7. 1-(4-Perfluorodecylphenyl)ethyl bromide (8b)
times from ethanol to give pure (R)-2b (>99% ee). The ab-
solute configuration of (R)-2b was determined to be R by
comparison of its CD spectrum with that of chiral phen-
N
R
ethylamine.18 R-Configuration of amine (R)-2b was also
supported by its specific rotation: reported S-enantiomer
of 2-phenethyl-2-propylamine (S)-17 (Figure 1), the par-
ent compound of fluorous amine (R)-2b, showed a specif-
ic rotation of –59.7 (levorotatory),19 while the chiral
amine (R)-2b provided a specific rotation of +14.0 (dex-
trorotatory).
S
N
H
H
C10F21
[α]D = +14.0°
(R)-2b
(S)-17
*
N
*
H
A set of fluorous chiral amines 3 bearing two chiral cen-
ters were prepared to provide a larger asymmetric envi-
ronment than amine (R)-2b. Fluorous amines (R)-2b and
3 are fluorous derivatives of chiral amines 17 and 18
[α]D = +167.6°
[α]D = –168°
(R,R)-18
(S,S)-18
Figure 1 Chiral amines (R)-2b, (S)-17, (R,R)-18, and (S,S)-18
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

FEATURE ARTICLE
Recyclable Fluorous-Tagged Chiral and Achiral Lithium Amides
2907
H2N
H
H
N
H
N
N
column
chromatography
(silica gel)
Br
(S)
, K2CO3
77%
hexane–Et2O (8:2)
MeCN
C10F21
C10F21
C10F21
C10F21
8b
(R,S) + (S,S) mixture
(S,S)-3
(R,S)-3
[α]D = –61.9°
[α]D = +3.6°
H2N
H
H
N
H
N
column
chromatography
(silica gel)
N
Br
(R)
, K2CO3
69%
MeCN
hexane–Et2O (8:2)
C10F21
C10F21
C10F21
C10F21
8b
(R,R) + (S,R) mixture
(S,R)-3
(R,R)-3
[α]D = –3.5°
[α]D = +61.5°
Scheme 7
was treated with (S)-phenethylamine to give an R,S- and the transition states for generating S-lithium enolate of 4-
S,S-mixture of amine 3, which was separated by column methylcyclohexanone are shown in Figure 2. The remote
chromatography on silica gel, affording (R,S)-3 and (S,S)- fluorous group would have essentially no effect on the ste-
3. The fluorous amines, (R,R)-3 and (S,R)-3, were pre- reoselectivity of the lithiations involving the chiral
pared by a similar procedure starting from 8b and (R)- amines, affording the same configuration of lithium eno-
phenethylamine.
late in either case.
The absolute configurations of chiral amines 3 were deter- Enantioselective Generation of Lithium Enolates
mined by comparison of their specific rotations relative to with Lithium Amides Derived from Chiral Fluorous
those of the parent amines. Parent amines 18 with R,R or Amines
S,S configuration have specific rotations of +167.6 (dex-
Generation of chiral lithium enolate of 4-tert-butylcyclo-
trorotatory)20 or –168 (levorotatory),21 respectively, while
hexanone using chiral fluorous amines (R)-2b and 3 has
R,S-amine shows no optical activity,22 since the amine is
been accomplished.16b The conditions employed for (R)-
a meso compound. Since the perfluoroalkyl chain of the
2b were similar to those for the reaction using fluorous
fluorous amines 3 is located far from the chiral center, it
amine 2. Since chiral fluorous amines 3 precipitated be-
was expected that the fluorous ponytail attached to the
low –50 °C in THF, the fluorous lithium amides had to be
para position of the benzene ring might exert a bit of in-
prepared from 3 and n-butyllithium at –40 °C, then the re-
fluence on the specific rotations. Chiral amines with very
sulting amide solution was cooled to –78 °C, and reacted
small rotations were assigned to meso-related compounds,
with ketones. The results of the enantioselective reaction
(R,S)-3 and (S,R)-3. Chiral fluorous amine with a specific
involving fluorous amine (R)-2b and 3 are listed in
rotation of +61.5 was derived from (R)-phenethylamine,
Table 3. With the exception of entry 5, which employed a
and was determined to be (R,R)-3, That with –61.9 of ro-
reaction temperature of –94 °C, all reactions for generat-
tation was derived from (S)-phenethylamine, and was de-
ing chiral lithium enolate using chiral fluorous amines
termined to be (S,S)-3. As mentioned above, the parent
were carried out at –78 °C. Quenching the generated
amine 18 with R,R-configuration was dextrorotatory,
chiral enolates with chlorotrimethylsilane at –78 °C gave
while that with S,S-configuration was levorotatory. Thus,
the corresponding enol silyl ethers, with enantioselectivi-
we concluded that the prepared chiral fluorous amines
ties determined by GC equipped with a chiral column (J &
with specific rotations of +3.6, –61.9, +61.5, and –3.5 can
W CYCLOSILB).
be assigned the R,S-, S,S-, R,R-, and S,R-configurations,
respectively.
Fluorous amine (R)-2b gave (S)-19 in approximately 60%
ee (Table 3, entries 1 and 2). On the other hand, amine
(S,S)-3 gave (R)-19 with much higher enantioselectivity
(up to 86% ee) (entries 3 and 4). In each case, the fluorous
amines used could be recovered in 92–99% yield using ei-
ther of two procedures (A: biphasic workup with FC-72
and acetonitrile; B: silica gel chromatography with hex-
Because of a single fluorous chain, C2 symmetry was lost
and therefore two geometries are available in the lithiation
step for chiral lithium amides derived from (R,R)-3. Our
group constructed a model of transition states for the ste-
reoselective lithiation. Predicted molecular structures23 of
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

2908
H. Matsubara et al.
FEATURE ARTICLE
Figure 2 Two possible transition states leading to S-lithium enolate of 4-methylcyclohexanone with (R,R)-3
ane and EtOAc). Although there was little difference in (R,S)-3 and (S,R)-3 gave R- and S-enolate, respectively, in
the recovery efficiency of 3 between these two proce- much lower enantioselectivity (entries 7 and 8). Table 3
dures, a rather tedious extraction with FC-72 had to be re- also demonstrates that lithium enolates of cyclohexanone
peated five times when procedure A was employed. derivatives with various substituents at the 4-position
Lowering the reaction temperature to –94 °C did not im- were prepared by a similar protocol (entries 9–11). These
prove enantioselectivity of the product (entry 5). As ex- results are comparable to those reported in the previous
pected, fluorous amine (R,R)-3 afforded S-enolate as the work, in which (R,R)-18 was used to obtain (S)-19 in 87%
major product (entry 6), while the ‘meso-type’ amine ee.16b
Table 3 Enantioselective Silylation Using Chiral Fluorous Amine
O
OSiMe3
OSiMe3
19: R = t-Bu
20: R = Me
21: R = i-Pr
22: R = Ph
1) fluorous LDA, LiCl, –78 °C
2) Me3SiCl
R
R
R
(S)
(R)
Entry
R
Amine
Workupa
Configuration Yield (%)
of productb
ee (%)c
Recovery of
amine (%)
1
2
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
(R)-2b
(R)-2b
(S,S)-3
(S,S)-3
(S,S)-3
(R,R)-3
(R,S)-3
(S,R)-3
(S,S)-3
(S,S)-3
(S,S)-3
A
B
A
B
B
B
B
B
B
B
B
S
93
86
73
82
66
81
78
70
74
75
86
57
60
83
86
85
83
21
25
85
76
90
99
98
92
95
94
99
95
99
99
99
99
S
3
R
R
R
S
4
5d
6
7
R
S
8
9
R
R
R
10
11
i-Pr
Ph
a Procedure A: biphasic workup using acetonitrile as the organic solvent. Procedure B: silica gel column chromatography using hexane to give
the products, then using ethyl acetate to recover fluorous amine.
b Determined by comparison of specific rotations with the reported data.16b
c Determined by GC attached with a J & W CYCLOSILB chiral column.
d Carried out at –94 °C.
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

FEATURE ARTICLE
Recyclable Fluorous-Tagged Chiral and Achiral Lithium Amides
2909
Table 4 Enantioselective Silylation with Recycling Chiral Fluorous Aminea
O
OSiMe3
OSiMe3
1) fluorous LDA, LiCl, –78 °C
2) Me3SiCl
t-Bu
t-Bu
(R)-19
t-Bu
(S)-19
Entry
Amine
Run
Configuration of Yield (%)
productb
ee (%)c
Recovery of amine
(%)
1
2
3
4
5
(R)-2b
(R)-2b
(S,S)-3
(S,S)-3
(S,S)-3
1st
S
86
85
75
76
76
60
65
82
84
84
98
95
99
99
99
2nd
1st
S
R
R
R
2nd
3rd
a Workup procedure: silica gel column chromatography using hexane to give the products, then using ethyl acetate to recover fluorous amine.
b Determined by comparison of specific rotations with the reported data.16b
c Determined by GC attached with a J & W CYCLOSILB chiral column.
Our group performed the preparation of lithium enolate tyllithium at –78 °C. Thus, fluorous substitutes of second-
using recovered fluorous chiral amines (R)-2b and (S,S)- ary amines have proven useful even for lithium enolate
3. Recycling of the amine was carried out using procedure formation.
B (silica gel, hexane and ethyl acetate). As shown in
Table 4, the yields and enantioselectivities of reactions
Melting points were obtained with a Yanako micro melting point
using recovered amines were almost identical to those of
the first run, indicating that fluorous amine (R)-2b and
(S,S)-3 can be recycled without any loss of the ability to
form enantioselective enolates.
apparatus and are not corrected. Products were purified by flash
chromatography on silica gel (Kanto Chemical Co., Inc., Silica Gel
1
60N, 70–230 mesh). H NMR spectra were recorded with either a
JEOL JMN ECP-500 (500 MHz) or an EX-270 (270 MHz) spec-
trometer in CDCl3 or C6D6. Chemical shifts were reported in parts
per million (d) downfield from internal TMS at 0.00. 13C NMR
spectra were recorded with either a JEOL JMN ECP-500 (125
MHz) or an EX-270 (68 MHz) spectrometer in CDCl3 and refer-
enced to the solvent peak at 77.00 ppm. 19F NMR spectra were re-
corded with a JEOL JMN ECP-500 (471 MHz) spectrometer and
referenced to external CFCl3 at 0.00 ppm. Coupling constants, J, are
reported in Hertz (Hz), and splitting patterns are designated as s
(singlet), d (doublet), t (triplet), q (quartet), sept (septet), dd (double
doublet), and m (multiplet). IR spectra were obtained on a JASCO
FT/IR 4100 spectrometer; absorptions are reported in reciprocal
centimeters. Both conventional and high-resolution mass spectra
were recorded with a JEOL MS-700 spectrometer. Determination of
enantiomeric purity was accomplished by analytical GC using a
SHIMADZU GC-14A; column: J & W CYCLOSILB (ID: 0.25
mm, length: 30 m, film: 0.25 mm) and N2 (100 kPa). Determination
of diastereomeric purity and product purity was accomplished by
analytical GC using a SHIMADZU GC-18A; column: J & W DB-1
(ID: 0.32 mm, length: 30 m, film: 1 mm), N2 (700 kPa); temperature
program: 60 °C for 6 min, then 60 °C to 250 °C at 20 °C/min. Opti-
cal rotations were measured with a JASCO DIP-370 polarimeter.
All enol silyl ethers prepared in this study are known compounds:
11,24 12,25 13,25 14,26 15,27 16,28 and 19–21;29 their spectral data are
in agreement with the literature.
Conclusions
A series of diisopropylamine derivatives bearing a per-
fluorooctyl or perfluorodecyl chain (fluorous ponytail)
were prepared and considered for use in the generation of
lithium enolates. Although fluorous amine 1, in which a
perfuluorooctyl chain is attached to a diisopropylamine
core, suffers from decomposition of the corresponding
lithium amide 10 at –78 °C, the fluorous-tagged a-phen-
ethylamines 2a and 2b can nevertheless be used for the ef-
ficient generation of lithium enolates. These amines can
be recovered almost quantitatively by liquid/liquid (or-
ganic/fluorous) or liquid/solid (organic/SiO2) extraction,
and reused for the next reaction. Chiral fluorous amines
(R)-2b, (S,S)-3, and (R,R)-3 were prepared and used for
asymmetric deprotonation of ketones. These amines af-
ford similar performance in asymmetric reactions as non-
fluorous mother compounds. Again, the fluorous chiral
amines can be separated effectively by the two kinds of
workup procedures and reused without any loss of both
optical and isolated yields of enol silyl ethers. It was dem-
onstrated that fluorous ponytails attached to the benzene
ring can survive under strong basic conditions using n-bu-
Isopropyl(4-perfluorooctyl-2-butyl)amine (1)
Bp 60–65 °C/5 mmHg.
IR (neat): 3300, 2950, 2860, 1450, 1375, 1365, 1320, 1240, 1200,
1140, 1105, 1060, 990, 880, 710, 700, 650 cm–1.
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

2910
H. Matsubara et al.
FEATURE ARTICLE
1H NMR (270 MHz, CDCl3): d = 1.03–1.11 (m, 9 H, 3 CH3), 1.29
(br s, 1 H, NH), 1.60–1.84 (m, 2 H, CH2CH2C8F17), 2.04–2.42 (m,
2 H, CH2C8F17), 2.79 [m, 1 H, CH(CH3)2], 2.92 (m, 1 H, CHCH3).
HRMS-EI: m/z calcd for C18H8BrF21 [M]+: 701.9474; found:
701.9433.
1-(1-Bromoethyl)-4-perfluorooctylbenzene (8a)
1-(1-Bromoethyl)-4-perfluorooctylbenzene (8a) was prepared in a
manner similar to that described for 8b; colorless oil.
13C NMR (68 MHz, CDCl3): d = 20.81, 23.13, 23.73, 27.45 (t,
JC,F = 22.4 Hz, CH2C8F17), 27.62, 45.37, 49.01, 110.65–119.19
(C8F17).
IR (neat): 2990, 2920, 2855, 1615, 1510, 1445, 1420, 1370, 1330,
1300, 1200, 1150, 1115, 1090, 1040, 960, 945, 845, 820, 705, 680,
660, 595, 560, 530 cm–1.
HRMS-EI: m/z calcd for C15H16F17N [M – H]+: 532.0933; found:
532.0905.
1-Ethyl-4-perfluorodecylbenzene (7b)
1H NMR (500 MHz, CDCl3): d = 2.06 (d, J = 6.8 Hz, 3 H, CH3),
5.21 (q, J = 6.8 Hz, 1 H, CHBr), 7.54–7.61 (m, 4 H, ArH).
13C NMR (125 MHz, CDCl3): d = 26.45, 47.24, 108–119 (C8F17),
127.20, 127.41, 129.11, 147.52.
HRMS-EI: m/z calcd for C16H8BrF17 [M]+: 601.9538; found:
601.9555.
A mixture of 1-ethyl-4-iodobenzene (6.90 g, 29.7 mmol), perfluo-
rodecyl iodide (21.1 g, 32.7 mmol), copper powder (300 mesh, 6.23
g, 98.0 mmol), 2,2¢-dipyridyl (0.93 g, 5.94 mmol), and DMSO (50
mL) was heated to 120 °C under N2 for 2 days. After cooling to r.t.,
H2O (100 mL) and Et2O (100 mL) were added, and the mixture was
filtered through a pad of Celite. The insoluble solid on the pad was
washed with Et2O (150 mL) . The organic layer of the filtrate was
separated, washed with H2O (2 × 100 mL), dried (MgSO4), and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent: hexane) to yield 7b
(14.3 g, 77%) as white crystals; mp 47.0–48.0 °C.
[1-(4-Perfluorodecylphenyl)ethyl]isopropylamine (2b)
Compound 8b (14.1 g, 20.0 mmol), i-PrNH2 (3.76 g, 64.0 mmol),
K2CO3 (2.77 g, 20.0 mmol), and MeCN (200 mL) were placed in a
500 mL stainless steel autoclave together with a magnetic stirring
bar. The autoclave was closed and heated at 80 °C for 4 days. After
cooling, the mixture was diluted with Et2O (300 mL) and filtered.
H2O (500 mL) was then added to the filtrate. The aqueous layer was
separated and extracted with Et2O (3 × 200 mL). The combined or-
ganic layer was dried (MgSO4), and evaporated under reduced pres-
sure. The residue was distilled under reduced pressure (110 °C/2
mmHg) to yield racemic fluorous amine 2b (10.9 g, 64%) as white
crystals. Retention time (tR) in the GC-14A with the chiral column
(130 °C isothermal); (S)-2b: tR = 37.9 min, (R)-2b: tR = 38.8 min.
IR (KBr): 2970, 2930, 1620, 1375, 1245, 1200, 1150, 1115, 1090,
1055, 880, 830, 650, 640, 555, 530 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.5 Hz, 3 H, CH3),
2.71 (q, J = 7.5 Hz, 2 H, CH2), 7.33 (d, J = 8.2 Hz, 2 H, ArH), 7.50
(d, J = 8.2 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 15.00, 28.70, 105–120 (C10F21),
126.44, 126.84, 128.08, 148.35.
HRMS-EI: m/z calcd for C18H9F21 [M]+: 624.0369; found:
624.0352.
Fractional Crystallization of Fluorous Amine 2b
Racemic fluorous amine 2b (3.70 g, 5.43 mmol) and (R)-tartaric
acid (818 mg, 5.43 mmol) were dissolved in EtOH (40 mL) under
reflux, then allowed to stand at r.t. for 12 h. The separated white sol-
id was collected by filtration and subjected to a second recrystalli-
zation. After a third recrystallization, the solid was partitioned
between 10% aq NaOH (20 mL) and Et2O (20 mL). The aqueous
layer was separated and extracted with Et2O (3 × 20 mL). The com-
bined organic layers were dried (MgSO4) and evaporated under re-
duced pressure to yield (R)-2b, the R-enantiomer of 2b (296 mg,
99% ee).
1-Ethyl-4-perfluorooctylbenzene (7a)
1-Ethyl-4-perfluorooctylbenzene (7a) was prepared in a manner
similar to that described for 1-ethyl-4-perfluorodecylbenzene (7b);
colorless oil.
IR (neat): 2930, 2855, 1620, 1515, 1460, 1420, 1370, 1300, 1245,
1210, 1150, 1115, 1090, 1050, 1030, 1015, 960, 940, 920, 870, 835,
725, 705, 655 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.3 Hz, 3 H, CH3),
2.72 (q, J = 7.3 Hz, 2 H, CH2), 7.33 (d, J = 8.2 Hz, 2 H, ArH), 7.50
(d, J = 8.2 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 15.08, 28.74, 108–118 (C8F17),
126.32, 126.86, 128.11, 148.56.
HRMS-EI: m/z calcd for C16H9F17 [M]+: 524.0433; found:
(R)-[1-(4-Perfluorodecylphenyl)ethyl]isopropylamine [(R)-2b]
Mp 48.0–49.0 °C; [a]D28 +14.0 (c 5.5, CHCl3).
IR (KBr): 640, 770, 840, 880, 980, 1020, 1060, 1200, 1340, 1380,
1620, 2980 cm–1.
524.0449.
1H NMR (500 MHz, CDCl3): d = 1.00 [d, J = 6.4 Hz, 6 H,
CH(CH3)2], 1.33 (d, J = 6.5 Hz, 3 H, CHCH3), 2.61 [sept, J = 6.4
Hz, 1 H, CH(CH3)2], 3.96 (q, J = 6.5 Hz, 1 H, CHCH3), 7.43 (d,
J = 8.3 Hz, 2 H, ArH), 7.52 (d, J = 8.3 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 22.12, 23.80, 24.68, 45.94, 55.01,
105–120 (C10F21), 126.73, 126.98, 127.57, 150.97.
19F NMR (471 MHz, CDCl3): d = –125.99, –122.59, –121.78,
–121.63, –121.17, –110.25, –80.62.
HRMS-EI: m/z calcd for C21H16F21N [M]+: 681.0947; found:
681.0917.
1-(1-Bromoethyl)-4-perfluorodecylbenzene (8b)
A mixture of 7b (14.33 g, 23.0 mmol), N-bromosuccinimide (3.88
g, 21.8 mmol), benzoyl peroxide (0.20 g), and CCl4 (60 mL) was
heated under reflux. After 12 h, the hot mixture was filtered using a
Büchner funnel under suction. The solid on the funnel was washed
with hot CCl4 (40 mL). The filtrate was evaporated under reduced
pressure and the residue was purified by column chromatography
on silica gel (eluent: hexane) to yield 8b (15.7 g, 97%) as white
crystals; mp 65.8–67.0 °C.
IR (KBr): 2980, 2925, 2865, 1615, 1445, 1420, 1375, 1340, 1310,
1285, 1245, 1205, 1150, 1110, 1095, 1055, 1020, 975, 880, 835,
770, 655, 640, 555, 530 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.06 (d, J = 6.8 Hz, 3 H, CH3),
5.20 (q, J = 6.8 Hz, 1 H, CHBr), 7.56 (m, 4 H, ArH).
13C NMR (125 MHz, CDCl3): d = 26.47, 47.33, 105–120 (C10F21),
127.18, 127.41, 129.12, 147.47.
[1-(4-Perfluorooctylphenyl)ethyl]isopropylamine (2a)
The title compound 2a was prepared in a manner similar to that de-
scribed for 2b.
Bp 100–105 °C/3 mmHg.
IR (neat): 1200, 1510, 2860, 2925, 2950, 3310 cm–1.
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

FEATURE ARTICLE
Recyclable Fluorous-Tagged Chiral and Achiral Lithium Amides
2911
1H NMR (500 MHz, CDCl3): d = 1.03 [d, J = 5.9 Hz, 6 H,
CH(CH3)2], 1.23–1.34 (d, J = 6.2 Hz, 3 H, CHCH3), 2.60–2.62 [m,
1 H, CH(CH3)2], 3.97 (q, J = 6.2 Hz, 1 H, CHCH3), 7.44–7.46 (m, 2
H, ArH), 7.53–7.55 (m, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 21.37, 23.94, 24.37, 45.86, 54.90,
108.58–118.30 (C8F17), 126.73–126.97 (Ar), 150.81.
(S)-1-(4-Perfluorodecylphenyl)ethyl-(R)-1-phenethylamine
[(S,R)-3] and (R)-1-(4-Perfluorodecylphenyl)ethyl-(R)-1-phen-
ethylamine [(R,R)-3]
The title compounds were prepared from 8a and (R)-(+)-1-phenyl-
ethylamine in a manner similar to that described for (R,S)-3] and
(S,S)-3.
MS (EI, 70 eV): m/z (%) = 581 (M+, 5), 566 ([M – CH3]+, 100), 523
(S)-1-(4-Perfluorodecylphenyl)ethyl-(R)-1-phenethylamine
([M – NHCH(CH3)2]+, 33).
[(S,R)-3]
[a]D23 –3.5 (c 5.6, CHCl3).
HRMS-EI: m/z calcd for C19H16F17N [M]+: 581.1011; found:
HRMS-EI: m/z calcd for C26H18F21N [M]+: 743.1104; found:
581.1037.
743.1102.
Fluorous Amines 3
A mixture of 8b (15.7 g, 22.4 mmol), (S)-(–)-1-phenethylamine
(2.74 g, 22.6 mmol), K2CO3 (3.09 g, 22.4 mmol), and MeCN (80
mL) was heated under reflux for 1 day. The mixture was evaporated
under reduced pressure. Et2O (80 mL) and H2O (80 mL) were added
to the residue and the aqueous layer was separated and then extract-
ed with Et2O (3 × 80 mL). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure to yield the crude
mixture. The crude mixture was purified by column chromatogra-
phy on silica gel (hexane to EtOAc) to afford an S,S and R,S mixture
of fluorous amine 3 (12.9 g, 77%). Separation of S,S- and R,S-fluo-
rous amine 3 was achieved by column chromatography on silica gel
(hexane–Et2O, 8:2) affording (R,S)-3 (1.96 g, 98% ee) and (S,S)-3
(1.78 g, 99% ee); retention time (tR) in the GC-18A; (R,S)-3:
tR = 16.16 min, (S,S)-3: tR = 16.03 min.
(R)-1-(4-Perfluorodecylphenyl)ethyl-(R)-1-phenethylamine
[(R,R)-3]
[a]D17 +61.5 (c 5.2, CHCl3).
HRMS-EI: m/z calcd for C26H18F21N [M]+: 743.1104; found:
743.1134.
Determination of Partition Coefficients of Fluorous Amine
Partition coefficients were determined according to the procedure
reported by the Curran group.13 To a biphasic mixture of organic
solvent (3 mL) and FC-72 (3 mL) was added fluorous amine (300
mg), and stirred vigorously for 30 min. After standing for 5 min, the
two layers were separated, evaporated to dryness, and then
weighed.
Isolation of Silyl Enol Ether 20 by Column Chromatography;
Typical Procedure
(R)-1-(4-Perfluorodecylphenyl)ethyl-(S)-1-phenethylamine
[(R,S)-3]
To a solution of amine (S,S)-3 (887.1 mg, 1.20 mmol) and LiCl
(25.5 mg, 0.60 mmol) in anhyd THF (15 mL) was added n-BuLi
(0.95 mL, 1.50 mmol, 1.60 M in hexane) dropwise under N2 at –40
°C. The resulting yellowish solution was then cooled to –78 °C and
4-methylcyclohexanone (112.2 mg, 1.00 mmol) in anhyd THF (5
mL) was added dropwise. After 30 min, chlorotrimethylsilane
(133.5 mg, 1.23 mmol) was added dropwise and the mixture was
warmed slowly to r.t. Then, sat. aq NaHCO3 (20 mL) and hexane
(30 mL) were added; the aqueous layer was separated and extracted
with hexane (2 × 30 mL). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (eluent: hexane to
EtOAc) to yield (R)-4-methyl-1-trimethylsiloxycyclohexene (20;
136 mg, 74%, 85%ee) and the fluorous amine (S,S)-3 (884.2 mg,
99% recovery).
Mp 36.5–37.1 °C; [a]D26 +3.6 (c 5.2, CHCl3).
IR (KBr): 669, 701, 759, 835, 884, 928, 973, 1019, 1089, 1108,
1154, 1216, 1244, 1616, 2869, 2929, 2970, 3020, 3429 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.34 (d, J = 6.4 Hz, 3 H, CH3),
1.36 [d, J = 6.8 Hz, 3 H, CH3 (fluorous tail side)], 3.78 (q, J = 6.4
Hz, 1 H, CH), 3.82 [q, J = 6.8 Hz, 1 H, CH (fluorous tail side)], 7.15
(m, 1 H), 7.23–7.25 (m, 4 H, ArH), 7.37 (d, J = 8.2 Hz, 2 H, ArH),
7.48 (d, J = 8.2 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 23.41, 23.43, 55.03, 55.53, 108–
118 (C10F21), 126.61, 126.89, 127.53 [t, JC,F = 23.9 Hz, C(Ar)–CF2],
128.45, 145.64, 150.51.
19F NMR (471 MHz, CDCl3): d = –126.55, –123.03, –122.19,
–122.00, –121.86, –121.46, –110.60, –81.40.
HRMS-EI: m/z calcd for C26H18F21N [M]+: 743.1104; found:
743.1066.
Preparation of Enol Silyl Ether 19 Using Organic/Fluorous
Biphasic Workup; Typical Procedure
To a solution of amine (S,S)-3 (898 mg, 1.21 mmol) and LiCl (26.5
mg, 0.63 mmol) in anhyd THF (15 mL) was added n-BuLi (0.95
mL, 1.50 mmol, 1.60 M in hexane) dropwise under N2 at –40 °C.
The resulting yellowish solution was then cooled at –78 °C, and 4-
tert-butylcyclohexanone (155 mg, 1.00 mmol) in anhyd THF (5
mL) was added dropwise. After 30 min, chlorotrimethylsilane (132
mg, 1.21 mmol) was added dropwise and the mixture was warmed
slowly to r.t. Then, sat. aq NaHCO3 (20 mL) and hexane(30 mL)
were added; the aqueous layer was separated and extracted with
hexane (2 × 30 mL). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. The residue was
diluted with MeCN (20 mL), and perfluorohexanes (FC-72, 20 mL)
were added to the solution. The FC-72 layer was separated, and the
acetonitrile layer was extracted with FC-72 (4 × 20 mL). The com-
bined FC-72 layer was evaporated under reduced pressure to yield
the amine (825 mg, 92% recovery), while the MeCN layer was
evaporated under reduced pressure to yield (R)-4-tert-butyl-1-tri-
methylsiloxycyclohexene (19; 161 mg, 73%, 83%ee).
(S)-1-(4-Perfluorodecylphenyl)ethyl-(S)-1-phenethylamine
[(S,S)-3]
Mp 40.5–41.2 °C; [a]D26 –61.9 (c 5.0, CHCl3).
IR (KBr): 441, 481, 669, 759, 929, 1019, 1057, 1154, 1216, 1243,
1526, 1639, 2400, 2927, 2976, 3020, 3423 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.27 (d, J = 6.8 Hz, 3 H, CH3),
1.29 [d, J = 6.4 Hz, 3 H, CH3 (fluorous tail side)], 3.46 (q, J = 6.8
Hz, 1 H, CH), 3.59 [q, J = 6.4 Hz, 1 H, CH (fluorous tail side)], 7.18
(d, J = 7.4 Hz, 2 H, ArH), 7.22–7.26 (m, 1 H, ArH), 7.31–7.36 (m,
4 H, ArH), 7.54 (d, J = 8.2 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 24.79, 54.90, 55.40, 108–118
(C10F21), 126.54, 126.95, 127.52 [t, JC,F = 23.9 Hz, C(Ar)-CF2],
128.54, 145.42, 150.30.
19F NMR (471 MHz, CDCl3): d = –126.36, –122.88, –122.08,
–121.90, –121.78, –121.39, –110.43, –81.11.
HRMS-EI: m/z calcd for C26H18F21N [M]+: 743.1104; found:
743.1147.
Synthesis 2007, No. 18, 2901–2912 © Thieme Stuttgart · New York

2912
H. Matsubara et al.
FEATURE ARTICLE
Oulyadi, H.; Desjardins, S.; Fressigne, C.; Maddaluno, J.
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Acknowledgment
We gratefully acknowledge a Grant-in-Aid for Scientific Research
from MEXT Japan and JSPS for funding. We also thank the Nogu-
chi Foundation for partial financial support.
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