Synthesis of new fluorous modular chiral ligand derivatives from amino alcohols and application in enantioselective carbon-carbon bond-forming alkylation reactions

Article abstract of DOI:10.1016/j.tetasy.2010.05.015

N-Trifluoracyl β-chalcogeno amides and N-perfluoracyl β-thio amide ligands were prepared by a simple and efficient reaction sequence. These new ligands were evaluated in palladium-catalyzed alkylation of rac-(E)-1,3-diphenyl-2-propenyl acetate in the pres

Full text of DOI:10.1016/j.tetasy.2010.05.015

Tetrahedron: Asymmetry 21 (2010) 997–1003
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new fluorous modular chiral ligand derivatives from amino
alcohols and application in enantioselective carbon–carbon bond-forming
alkylation reactions
Jasquer A. Sehnem a, Priscila Milani b, Vanessa Nascimento c, Leandro H. Andrade b, Luciano Dorneles a,
,
*
Antonio L. Braga a,c,
*
a Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS 97105-900, Brazil
b Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, CEP 05508-900, São Paulo, SP, Brazil
c Departamento de Química, Universidade Federal de Santa Catarina, CEP 88040-970, Florianópolis, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Trifluoracyl b-chalcogeno amides and N-perfluoracyl b-thio amide ligands were prepared by a simple
and efficient reaction sequence. These new ligands were evaluated in palladium-catalyzed alkylation of
rac-(E)-1,3-diphenyl-2-propenyl acetate in the presence of dimethyl malonate and an enantioselectivity
of up to 99% was obtained. After catalysis, the fluorous ligand can be easily recovered by liquid–liquid
extraction and reused without loss in the activity.
Received 29 April 2010
Accepted 13 May 2010
Available online 16 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
soluble in the fluorous phase any product that will be in the organ-
ic phase can be separated by simple decantation. Then, the recov-
Transition metal-catalyzed allylic substitution is one of the most
efficient and versatile methods for carbon–carbon bond formation,
and hence it is the focus of intense synthetic attention.1 The inherent
problem with this reaction is to separate the catalyst, without
decomposition, from the other reaction components once the pro-
cess has gone to completion. This is important both for facilitating
the purification of products and for recycling the catalyst.
Therefore, there is a growing interest in the use of unusual sol-
vents such as fluorous solvents in organometallic catalysis.2 This
methodology can offer a cleaner technology for a chemical indus-
try, as well as to promote reactions with improved selectivity. This
class of solvent has unusual chemical and physical proprieties,
such as low isoelectric constant, chemical and thermal stability,
and lack of toxicity.2f
The concept of Fluorous Biphasic Catalysis (FBC) was first intro-
duced by Horváth and Rabai in 1994.3 A metal complex bearing
one or more fluorinated ligands is dissolved in a fluorous solvent,
and this is mixed with the substrate in an organic solvent. The cat-
alytic reaction is then effected under biphasic conditions. In a sig-
nificant variant, warming renders the organic and fluorous phases
miscible and the reaction occurs under homogeneous conditions.
The two phases are readily separated at lower temperature, allow-
ing a very easy method. So, if a catalyst is designed to be selectively
ered catalyst can be easily separated and recycled.
FBC methods have advanced rapidly, and a large number of flu-
orous catalysts have been reported4 and have already been applied
to several important organic reactions, for example, Heck,5 oxida-
tion,6 metathesis,7 alkylation of aldehydes via Et2Zn,8 and the
hydrogenation of olefins.9
At the same time, several compounds were employed as ligands
in asymmetric allylic alkylation using fluorous solvents.10 Deriva-
tives of BINAP 1,11 MOP 2,12 and bisoxazolines 313 have been the
main examples applied as catalysts for this class of reaction during
the last decade and are depicted in Figure 1.
Organoselenium compounds have been found to function as
antioxidants and chemopreventors in biology14 and are employed
as powerful ligands in asymmetric catalysis.15 We have recently
described the synthesis of a wide range of chiral b-seleno amides
and their derivatives by the ring-opening reaction of 2-oxazolines
and 2-oxazolidinones, as depicted in Figure 2. The organoselenium
compounds were successfully applied in the palladium-catalyzed
asymmetric allylic alkylation and in the microwave-accelerated
version of this reaction, furnishing the corresponding alkylated
products in excellent yields and enantiomeric excesses.16
In the course of our growing interest in the preparation of a
wide range of chiral organoselenium compounds and their applica-
tion in asymmetric synthesis, we describe herein the synthesis of
b-chalcogeno amides containing fluorinated chain in order to ob-
tain an easy, inexpensive, modular, and straightforward access to
compounds that can act as recyclable ligands in the palladium-
catalyzed asymmetric allylic alkylation. With this project, we could
* Corresponding authors. Tel.: +55 55 32208761; fax: +55 48 3721 6850 (A.L.B.).
E-mail addresses: lu221066@terra.com.br (L. Dorneles), albraga@qmc.ufsc.br
(A.L. Braga).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.015

998
J. A. Sehnem et al. / Tetrahedron: Asymmetry 21 (2010) 997–1003
CF
FH2C
P(Ph-p-OCH2C7F15 2
)
P(Ph-p-OCH2C7F15 2
OCH2C7F15
)
O
O
P(Ph-p-OCH2C7F15 2
)
N
N
Ph
Ph
1
2
Ligand a; CF = C8F17
Ligand b; CF = C10F21
3
Figure 1. Main examples applied as catalysts in asymmetric allylic alkylation using fluorous solvents.
same methodology. This class of compound is well known as a very
R
R
good ligand in palladium-catalyzed allylic alkylation reactions.17
The phosphine 7d was obtained in reasonable yield by treatment
of compound 6 with Ph2PLi, prepared with Ph2PH and n-BuLi using
THF as a solvent. Compounds 7e and 7f containing an electron-
donating and an electron-withdrawing substituents, respectively,
were also synthesized, using the same conditions employed on
compound 7b, these compounds were obtained in good yields.
Additionally, the synthesis of N-trichloroacyl b-thio amide 10a
and b-thio amide 10b was accomplished by the same strategy, as
depicted in Scheme 2. Compound 10a was obtained by reacting
R
+
YR
YR
PG
YR
+
N
O
N
O
GP
HN
Ph
O
Figure 2. Synthesis of a wide range of chiral b-seleno amides and their derivatives
by ring-opening reaction.
complement our recent studies concerning b-chalcogeno amines
and amides as catalyst in asymmetric allylic alkylation reactions.
L-valinol with trichloroacetic anhydride, furnishing compound 8a
2. Results and discussion
in high yield. A tosylation reaction of compound 8a and later nucle-
ophilic substitution of tosylate 9a with PhSꢀ led to compound 10a
in good yield. The N-trifluoracyl b-thio amide 10b was obtained in
Initially, commercially available L-valinol was submitted to an
acylation reaction using trifluoroacetic anhydride in the presence
of K2CO3 as described in Scheme 1. The crude product was used
without any further purification. The reaction of compound 5 with
tosyl chloride using Et3N and DMAP furnished the desired tosylate
6 in 73% yield. With the N-trifluoracyl tosylate 6 in hand, we
turned our attention to investigate the reactivity of this compound
in the presence of chalcogen nucleophiles (RYꢀ) as depicted in
Scheme 1.
high yield by employing the same sequence, but starting from
phenylalaninol (Scheme 2).
L-
With the b-chalcogeno amides in hands, we turn our attention
to evaluate the activity of this class of compound as chiral ligand
in the palladium-catalyzed asymmetric allylic alkylation reaction.
Initially, the allylic alkylation reaction was performed using the li-
gands 7a–d in order to verify the effect of the chalcogeno atom in
the ligand. We studied the palladium-catalyzed asymmetric allylic
alkylation (AAA) of 1,3-diphenyl-2-propenylacetate with dimethyl
Using the same substrate we could obtain thio, seleno, and
tellurocompounds.
malonate in the presence of 2.5 mol % of [Pd(g
3C3H5)Cl]2 using
The reaction was initially studied with compound 6 and phenyl
selenolate, easily generated by reduction of PhSeSePh with NaBH4
in THF/EtOH (3:1). Under these conditions, the desired organosele-
nium compound 7a was obtained in excellent yield (93%). On the
other hand, sulfur anion was generated starting from the commer-
cially available thiophenol using t-BuOK as base and the respective
product 7b was obtained in very good yield. The tellurium nucleo-
phile was generated from PhTeTePh and NaBH4 and, under this
condition, the desired organotellurium compound 7c was obtained
in 78% yield (Scheme 1). In order to get a closer look at this reac-
tion, ligand containing phosphine was also synthesized using the
NaH and THF. The results are summarized in Scheme 3.
As exemplified above, asymmetric alkylation reaction per-
formed with ligand 7a led to the desired product in excellent yield
but in reasonable enantiomeric excess. When compound 7b was
employed as ligand the alkylated product was afforded in very
good enantioselectivity. On the other hand, the b-phenyltelluro
amide 7c did not promote the product formation, while the phos-
phine 7d has shown only moderate activity.
After determining the chalcogeno atom, which furnishes a bet-
ter enantioselectivity, we started to study the influence of the sub-
stituents attached to the sulfur moiety and the influence of the
O
O
K2CO3
TsCl
OTs
CF3
OH
CF3
OH
+
F3C
O
CF3
CH2Cl2; r.t.; 24h
Et3N; DMAP; CH2Cl2
r.t.; 24h
HN
HN
NH2
73%
O
O
L- Valinol
6
5
RY-
7a; YR = SePh; 91%
7b; YR = SPh; 93%
7c; YR = TePh; 78%
7d; YR = PPh; 65%
YR
CF3
7e; YR = SPhOMe-p; 87%
7f; YR = SPhCl-p; 85%
HN
O
7a-f
Scheme 1.

J. A. Sehnem et al. / Tetrahedron: Asymmetry 21 (2010) 997–1003
999
R
O
O
R
K2CO3
R
TsCl
OTs
CX3
OH
CX3
OH
+
CH2Cl2; r.t. 24h
CY3
HN
Y3C
O
HN
Et3N; DMAP; CH2Cl2
r.t.; 24h
NH2
O
O
9a-b
8a-b
8a, R = i-Pr, CX3 = CCl3; 90%
8b, R = Bz, CX3 = CF3; 95%
PhSH, t-BuOK
THF, reflux
48h
9a, R = i-Pr, CX3 = CCl3; 73%
9b, R = Bz, CX3 = CF3; 77%
10a, R = i-Pr, CX3 = CCl3; 81%
10b, R = Bz, CX3 = CF3; 83%
R
SPh
CX3
HN
O
10a-b
Scheme 2.
O
O
[PdCl(n3-C3H5)]2 (5 mol%)/Lig. (20 mol%)
THF, NaH, r.t., 24h
OAc
Ph
O
O
+
MeO
Ph
OMe
PPh2
Ph
MeO
OMe
F3C
Ph
SePh
TePh
SPh
F3C
NH
F3C
NH
F3C
NH
NH
O
O
O
O
7d
7a
7c
7b
56% ee; 93% yield
not catalyzed
78% ee; 97% yield
91% ee; 95% yield
Scheme 3.
reaction media on the activity of these ligands. The results are
shown in Table 1.
donating substituents (Table 1, entries 12 and 13) the enantiomeric
excess obtained was lower than that compared with ligand 7b.
In order to check the viability of recovering the ligand using a
liquid–liquid extraction or reaction in a biphasic system using a
perfluorinated solvent, the b-thio amide 14 containing a long fluo-
rinated chain was synthesized, as depicted in Scheme 4. The N-Boc
oxazolidinone 11 was submitted to a ring-opening reaction using
thiophenol as a nucleophile, furnishing the desired N-Boc b-thio
amine 12 in good yield. The Boc moiety was removed using triflu-
oroacetic acid leading to the amine 13 in quantitative yield.14c Per-
fluore acid 14 was initially reacted with methyl chloroformate in
the presence of NMP and then with the b-thio amine 13. The N-per-
fluoracyl b-thio amide 15 was obtained in reasonable yield as
shown in Scheme 4.
Based on the results obtained with ligands 7 and 10, we exam-
ine the activity of compound 15 as a ligand in the palladium-cata-
lyzed asymmetric allylic alkylation using the same conditions
employed for ligands 7a–f, THF as a solvent, and NaH as base as de-
picted in Scheme 5. The respective alkylated products were ob-
tained in only moderate yields but with 99% ee, when compound
15 was used as a ligand under these conditions (Scheme 5; reaction
A). The catalytic performance of the ligands 15 was also performed
in the biphasic system THF/CF-72 using NaH base (Scheme 5; reac-
tion B). Under this condition the desired product was obtained in
95% enantiomeric excess but only 56% yield, probably due to a dif-
ficulty in mixing the solvents at room temperature.
The system used to generate the dimethyl malonate anion had a
strong influence on the activity of ligand 7b. When the reaction
was performed using THF and NaH as base, the alkylated product
was furnished in high enantiomeric excess (Table 1, entry 1).
Changes in the method to generate the malonate anion led to prod-
uct with low enantiomeric excess when compared to the results
obtained with the NaH/THF system (Table 1, entries 2–5). Reaction
with Cs2CO3 and CH2Cl2 also promoted the reaction in a high level
of enantioselectivity. On the other hand, the use of Et2Zn as a base
gives the desired product in a racemic form.
After the evaluation of the anion production, the amount of li-
gand and palladium catalyst was studied. The results indicate that
the best ratio between ligand and Pd catalyst is 4:1, respectively, as
shown in Table 1, entries 1 and 7. Changing this proportion gave
the desired product in moderate enantiomeric excess (Table 1,
entry 7). Variation in the temperature decreases the activity of
the b-thio amide 7b (Table 1, entry 9).
With the better conditions determined, we turned our attention
to the evaluation of the influence of the substituents attached to
the nitrogen atom and to the phenyl group. When the asymmetric
alkylation reaction was performed using ligand 10a the alkylated
product was obtained in only moderate ee (Table 1, entry 10) indi-
cating that the nature of the substituent attached to the nitrogen
atom plays an important role in the ligand activity. Modification
in the side chain of b-thio amide also leads to disappointing results
(Table 1, entry 11). Additionally, when the reaction was conducted
with b-thio amides containing electron-withdrawing and electron-
This result prompted us to evaluate the recovery of N-perfluori-
nated b-thio amide 15 with a liquid–liquid extraction using the
fluorinated solvent CF-72. After perform the allylic alkylation

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J. A. Sehnem et al. / Tetrahedron: Asymmetry 21 (2010) 997–1003
Table 1
N-Fluoracyl b-thio amides as chiral ligands in the palladium-catalyzed asymmetric allylic alkylation (AAA)
O
O
OAc
Ph
[PdCl(n3-C3H5)]2/Lig.
Base, Solvent
O
O
+
MeO
Ph
OMe
Ph
MeO
F3C
OMe
SPh
Ph
SPh
Ph
SPh
Cl3C
NH
F3C
NH
NH
O
O
O
10a
10b
7b
SPhCl-p
SPhOMe-p
F3C
NH
F3C
NH
O
O
7f
7e
Entry
Ligand (mol %)
Pd cat. (mol %)
Solvent
THF
CH2Cl2
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
Base
Yielda (%)
eeb (%)
1
2
3
7b (20)
7b (20)
7b (20)
7b (20)
7b (20)
7b (10)
7b (10)
7b (4)
7b (10)
10a (10)
10b (10)
7e (10)
7f (10)
5
5
5
5
5
5
2.5
1
2.5
2.5
2.5
2.5
2.5
NaH
96
75
25
90
96
95
95
85
80
91
87
95
97
90
83
rac
rac
rac
83
91
74
78
79
43
77
82
Cs2CO3
BSA/KOAc
Et2Zn
Et2Zn
NaH
NaH
NaH
NaH
NaH
4
5c
6
7
8
9c
10
11
12
13
NaH
NaH
NaH
THF
a
b
c
Isolated yield.
Determined by HPLC with a Chiralcel OD column.
Reaction conducted at ꢀ78 °C.
PhSH, t-BuOK
TFA, CH2Cl2
4h, r.t.
SPh
N
O
SPh
Boc
THF, Reflux, 48h
78%
NH2
NH
Boc
O
13
12
11
O
1.
MeO
Cl
O
SPh
NH
NMP, CH2Cl2, r.t., 12H
C6F13
OH
O
2. Compound 13, r.t., 24h
14
80%
(CF2)5
F3C
15
Scheme 4.
[PdCl(n3-C3H5)]2 (2.5 mol%)/Lig. (10 mol%)
O
O
OAc
O
O
+
MeO
OMe
Ph
Ph
Ph
MeO
OMe
THF, NaH, r.t., 24h
Ph
Solvent: reaction A: THF; 99% ee, 71% yield
reaction B: THF/CF-72; 95% ee, 56% yield
SPh
C6F13 NH
Recovered ligand: reaction C: 97% ee, 61% yield,
O
15
solvent THF
Scheme 5.

J. A. Sehnem et al. / Tetrahedron: Asymmetry 21 (2010) 997–1003
1001
reaction using THF as the solvent (Scheme 5; reaction A), the ligand
was extracted by washing the reaction with fluorinated solvent
(3 ꢁ 2 mL), furnishing the desired ligand in 70%. The recovered li-
gand was used in the alkylation reaction leading to the desired
product with 97% ee, indicating that the activity does not change
in the recovery process (Scheme 5).
4.3. Procedure for the synthesis of N-trifluoracyl b-seleno amide
7a
Under an argon atmosphere, the diphenyl diselenide anion
was generated by reaction of the corresponding diselenide
(1 mmol) with NaBH4 (2.5 mmol) in a mixture of THF (10 mL)
and EtOH (2 mL) and stirred for 10 min. After this period, com-
pound 6 (1.5 mmol) was added to the mixture. The resulting solu-
tion was stirred for 48 h at reflux. The reaction was quenched
with a saturated NH4Cl solution (10 mL) and the reaction mixture
was extracted with CH2Cl2 (2 ꢁ 10 mL). The organic fractions
were combined, dried over MgSO4, and filtered. The solvent was
removed in vacuum, yielding the crude product 7a, which was
purified by flash chromatography, using ethyl acetate/hexane
3. Conclusion
In summary, we have shown an easy, modular and straight-
forward synthesis of N-trifluoracyl b-chalcogeno amides and
N-perfluoracyl b-thio amides from amino alcohol. All the new
compounds were evaluated as chiral ligands in the palladium-
catalyzed asymmetric allylic alkylation and furnished the corre-
sponding alkylated products in good yields and ee. The addition
of a perfluoroalkyl chain to b-chalcogeno amide ligand has a great
effect on the enantioselectivity of the catalyst system. This modifi-
cation allows achievement of the desired product in high enantio-
meric excess. Additionally, this ligand can be separated from the
organic product(s) on the FBC, without compromising enantiose-
lectivity and reused in the catalytic process.
(10:90). Yield: 93%. ½a D20
ꢂ
¼ þ4 (c 3, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d = 7.53–7.51 (m, 2H), 7.27–7.25 (m, 3H), 6.49 (d,
J = 7.6 Hz, 1H), 4.01–3.94 (m, 1H), 3.11–3.05 (m, 2H), 1.94 (oct,
J = 6.4 Hz, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H).
13C NMR (CDCl3, 100 MHz): d = 156.9 (qua, J = 146.8 Hz), 133.2,
132.8, 129.2, 127.6, 115.7 (qua, J = 1146.0 Hz), 55.4, 31.4, 30.7,
19.0, 18.0. HRMS m/z calculated for
C
13H16F3NOSe + Na+
362.0247; found 362.0241.
The importance of this work lies in the fact that this is the first
study involving organochancogeno compounds in asymmetric
allylic alkylation using the fluorous biphasic catalytic methods.
This study opens a new frontier for the development of heterobid-
entate ligands containing a chalcogen atom.
4.4. Procedure for the synthesis of N-trifluoracyl b-thio amide
7b
In
a two-necked round-bottomed flask, under argon and
equipped with magnetic stirrer, a solution of PhSH (2 mmol), THF
(10 mL), and t-BuOK (2 mmol) was added. The reaction mixture
was stirred for 30 min. After this period, compound 6 (1.5 mmol)
was added into the mixture. The resulting solution was stirred
for 48 h at reflux. The reaction was quenched with a saturated
NH4Cl solution (10 mL) and the reaction mixture was extracted
with CH2Cl2 (2 ꢁ 10 mL). The organic fractions were combined,
dried over MgSO4, and filtered. The solvent was removed in vac-
uum, yielding the crude product 7b which was purified by flash
chromatography, using ethyl acetate/hexane (10:90). Yield: 91%.
4. Experimental
4.1. Procedure for the synthesis of N-trifluoracyl L-valinol 5
In
a
two-necked round-bottomed flask, under argon and
-valinol (10 mmol)
equipped with a magnetic stirrer, a solution of
L
and K2CO3 (4.2 g; 30 mmol) in dry dichloromethane (40 mL) was
added. Trifluoroacetic anhydride (11 mmol) was slowly added.
The mixture was stirred for 24 h at room temperature. After this
period, the reaction was quenched with a saturated NH4Cl solution
(15 mL) and the reaction mixture was extracted with CH2Cl2
(3 ꢁ 15 mL). The organic fractions were combined, dried over
MgSO4, and filtered. The solvent was removed under vacuum,
yielding the desired product. No further purification was needed.
½
a 2D0
ꢂ
¼ ꢀ0:8 (c 3, CH2Cl2). 1H NMR (CDCl3, 400 MHz): d = 7.46–
7.43 (m, 2H), 7.31–7.21 (m, 3H), 6.75 (d, J = 8.8 Hz, 1H), 3.91–
3.85 (m, 1H), 2.98 (dd, J1 = 13.2 Hz, J2 = 6.4 Hz, 1H), 2.79 (dd,
J1 = 13.2 Hz, J2 = 5.6 Hz, 1H), 1.89 (oct, J = 6.8 Hz, 1H), 0.75 (d,
J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3,
100 MHz): d = 166.8, 135.8, 131.9, 131.2, 129.4, 58.0, 53.9, 36.3,
30.0, 19.1, 17.3. HRMS m/z calculated for C13H16F3NOS + Na+
314.0802; found 314.0796.
4.2. Procedure for the synthesis of N-trifluoracyl L-valinol
tosylate 6
In
a two-necked round-bottomed flask, under argon and
4.5. Procedure for the synthesis of N-trifluoracyl b-telluro amide
equipped with a magnetic stirrer, compound 5 (10 mmol), dichlo-
romethane (50 mL), Et3N (12 mmol), and DMAP (0.5 mmol,
5 mol %) were added, respectively. The mixture was stirred for 10
min at room temperature. After this period, tosyl chloride
(11 mmol) was added and the reaction mixture was stirred for
24 h at the same temperature. The reaction was quenched with a
saturated NH4Cl solution (15 mL), NaOH 1.0 M (15 mL), and NaClaq
(15 mL). The aqueous layers were extracted with CH2Cl2 (10 mL)
and organic fractions were combined, dried over MgSO4, and fil-
tered. The solvent was removed under vacuum, yielding the crude
product 6, which was purified by flash chromatography, using
7c
This compound was prepared using the same conditions of
compound 7a. In this case, the source of nucleophile was PhTe-
TePh. Yield: 78%. ½a D20
ꢂ
¼ þ13 (c 3, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d = 7.76–7.74 (m, 2H), 7.33–7.29 (m, 1H), 7.23–7.19
(m, 2H), 6.34 (d, J = 7.2 Hz, 1H), 3.97–3.90 (m, 1H), 3.14–3.05 (m,
2H), 1.88 (oct, J = 6.8 Hz, 1H), 0.90 (t, J = 7.0 Hz, 6H). 13C NMR
(CDCl3, 100 MHz): d = 156.7 (qua, J = 148.0 Hz), 138.8, 129.4,
128.2, 115.7 (qua, J = 1148.0 Hz), 110.5, 55.9, 32.9, 19.1, 17.9,
12.6. HRMS m/z calculated for C13H16F3NOTe + Na+ 412.0144;
found 412.0296.
ethyl acetate/hexane (20:80). Yield: 73%. ½a D20
¼ ꢀ9 (c 3, CH2Cl2).
ꢂ
1H NMR (CDCl3, 400 MHz): d = 7.77 (d, J = 8 Hz, 2H), 7.36 (d,
J = 8 Hz, 2H), 4.20 (dd, J1 = 4 Hz, J2 = 8 Hz, 1H), 4.08–4.04 (m, 1H),
3.90–3.85 (m, 1H), 2.44 (s, 3H), 1.96 (oct, J = 6.8 Hz, 1H), 0.93–
0.91 (m, 6H). 13C NMR (CDCl3, 100 MHz): 156.2 (qua, J = 71 Hz),
145.1, 130.8, 128.7, 127.9, 115.9 (qua, J = 1113.0 Hz), 68.7, 51.4,
36.4, 19.8, 17.7. HRMS m/z calculated for C14H18F3NO4S + Na+
376.0806; found 376.0801.
4.6. Procedure for the synthesis of N-trifluoracyl b-phosphino
amide 7d
To a cooled solution (ꢀ78 °C) of Ph2PH (2 mmol) in 10 mL of
THF was added, dropwise, n-butyllithium (2 mmol, in hexanes).
After stirring for 30 min compound 6 (1.5 mmol) was added into

1002
J. A. Sehnem et al. / Tetrahedron: Asymmetry 21 (2010) 997–1003
the mixture. The resulting solution was stirred for 48 h at reflux.
The reaction was quenched with a saturated NH4Cl solution
(10 mL) and the reaction mixture was extracted with CH2Cl2
(2 ꢁ 10 mL). The organic fractions were combined, dried over
MgSO4, and filtered. The solvent was removed under vacuum,
yielding the crude product 7d which was purified by flash chroma-
tography using ethyl acetate/hexane (10:90). Yield: 65%.
19.8, 17.3. HRMS m/z calculated for
423.9920; found 423.9915.
C
14H18Cl3NO4S + Na+
4.12. Procedure for the synthesis of N-trifluoracyl L-
phenylalaninol tosilate 9b
This compound was prepared using the same conditions of
½
a 2D0
ꢂ
¼ þ25 (c 1, CH2Cl2). 1H NMR (CDCl3, 400 MHz): 7.41–7.29
compound 6. In this case, the starting material was compound
(m, 4H), 7.01–6.77 (m, 6H), 6.81 (d, J = 7.2 Hz, 1H), 4.20–4.10 (m,
1H), 2.51–2.35 (m, 2H), 1.65 (oct, J = 6.2 Hz, 1H), 0.77 (d,
J = 7.5 Hz, 3H), 0.73 (d, J = 7.5 Hz, 3H). 13C NMR (CDCl3,
100 MHz): 156.8 (qua, J = 73 Hz), 138.2 (d, J = 82 Hz), 130.5,
129.4, 123.9, 119.0 (qua, J = 270 Hz), 64.4, 35.2, 29.6 (d,
J = 50 Hz), 18.7, 17.5. HRMS m/z calculated for C19H21F3NOP + Na+
390.1211; found 390.1204.
8b. Yield: 77%.
½
a 2D0
ꢂ
¼ ꢀ15 (c 3, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d = 7.77 (d, J = 8 Hz, 2H), 7.36 (d, J = 8 Hz, 2H), 7.32–
7.21 (m, 3H), 7.11–7.09 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 4.36–
4.28 (m, 1H), 4.07 (dd, J1 = 10.6 Hz, J2 = 3.2 Hz, 1H), 3.99 (dd,
J1 = 10.6 Hz, J2 = 3.6 Hz, 1H), 2.96 (dd, J1 = 13.6 Hz, J2 = 6.8 Hz, 1H),
2.89 (dd, J1 = 13.6 Hz, J2 = 8.4 Hz, 1H), 2.46 (s, 3H). 13C NMR (CDCl3,
100 MHz): d = 156.9, 145.6, 135.3, 131.8, 130.1, 129.0, 128.8, 127.9,
127.2, 116.8, 68.5, 50.4, 36.2, 21.6. HRMS m/z calculated for
4.7. Procedure for the synthesis of N-trifluoracyl b-thio amide
C
18H18F3NO4S + Na+ 424.0806; found 424.0800.
7e
4.13. Procedure for the synthesis of N-trichloroacyl b-thio
This compound was prepared using the same conditions of
amide 10a
compound 7b. In this case, the source of nucleophile was p-MeOP-
hSH. Yield: 87%.
½
a 2D0
ꢂ
¼ þ19 (c 3, CH2Cl2). 1H NMR (CDCl3,
This compound was prepared using the same conditions of
400 MHz): d = 7.36 (d, J = 8 Hz, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.82
(d, J = 8 Hz, 2H), 3.94–3.85 (m, 1H), 3.73 (s, 3H), 3.04–2.89 (m,
2H), 1.96–1.87 (m, 1H), 0.91–0.85 (m, 6H). 13C NMR (CDCl3,
100 MHz): d = 159.2, 157.0 (qua, J = 144.0 Hz), 133.8, 124.9, 115.7
(qua, J = 1146.8 Hz), 114.5, 55.1, 54.9, 38.1, 30.8, 18.7, 17.6. HRMS
m/z calculated for C14H18F3NO2S + Na+ 344.0908; found 344.0902.
compound 7b. In this case, the starting material was compound
9a. Yield: 81%.
½
a 2D0
ꢂ
¼ þ32 (c 3, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d = 7.47–7.43 (m, 2H), 7.31–7.21 (m, 3H), 6.75 (d,
J = 8 Hz, 1H), 3.91–3.85 (m, 1H), 2.97 (dd, J1 = 8 Hz, J2 = 12 Hz,
1H), 2.79 (dd, J1 = 5.6 Hz, J2 = 12 Hz, 1H), 1.89 (oct, J = 7.4 Hz, 1H),
0.75 (d, J = 8 Hz, 3H), 0.73 (d, J = 8 Hz, 3H). 13C NMR (CDCl3,
100 MHz): d = 166.8, 135.8, 131.2, 129.5, 127.9, 58.2, 53.9, 36.3,
30.0, 19.1, 17.4. HRMS m/z calculated for C13H16Cl3NOS + Na+
361.9916; found 361.9909.
4.8. Procedure for the synthesis of N-trifluoracyl b-thio amide 7f
This compound was prepared using the same conditions of
compound 7b. In this case, the source of nucleophile was p-ClPhSH.
4.14. Procedure for the synthesis of N-trifluoracyl b-thio amide
10b
Yield: 85%. ½a 2D0
ꢂ
¼ þ10 (c 3, CH2Cl2). 1H NMR (CDCl3, 400 MHz):
d = 7.29–7.22 (m, 4H), 7.02 (d, J = 8.8 Hz, 1H), 3.95–3.88 (m, 1H),
3.12 (dd, J1 = 13.8 Hz, J2 = 4.4 Hz, 1H), 3.00 (dd, J1 = 13.8 Hz,
J2 = 8.8 Hz, 1H), 1.93 (oct, J = 6.4 Hz, 1H), 0.92 (d, J = 6.8 Hz, 3H),
0.89 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d = 157.2
(qua, J = 146.4 Hz), 133.6, 132.7, 131.5, 129.0, 115.7 (qua,
J = 1142.0 Hz), 54.9, 36.5, 30.9, 18.9, 17.6. HRMS m/z calculated
for C13H15ClF3NOS + Na+ 348.0413; found 348.0408.
This compound was prepared using the same conditions of
compound 7b. In this case, the starting material was compound
9b. Yield: 83%.
½
a 2D0
ꢂ
¼ þ39 (c 3, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d = 7.38–7.35 (m, 2H), 7.32–7.20 (m, 6H), 7.15–7.13
(m, 2H), 6.38 (d, J = 6.8 Hz, 1H), 4.39–4.30 (m, 1H), 3.11 (dd,
J1 = 13.8 Hz, J2 = 5.6 Hz, 1H), 3.05 (dd, J1 = 13.8 Hz, J2 = 6.0 Hz, 1H),
2.99 (d, J = 6.8 Hz, 2H). 13C NMR (CDCl3, 100 MHz): d = 156.6
(qua, J = 150 Hz), 135.9, 134.6, 130.2, 129.2, 129.2, 128.8, 127.1,
127.0, 115.5 (qua, J = 1146.4 Hz), 51.0, 38.4, 36.8. HRMS m/z calcu-
lated for C17H16F3NOS + Na+ 362.0802; found 36.0796.
4.9. Procedure for the synthesis of N-trichloroacyl L-valinol 8a
This compound was prepared using the same conditions of
compound 5. In this case, the electrophile was trichloroacetic
anhydride. Yield: 90%.
4.15. Procedure for the synthesis of N-perfluoracyl b-thio amide
15
4.10. Procedure for the synthesis of N-trifluoroacyl L-
phenylalaninol 8b
In a two-necked round-bottomed flask, under argon and
equipped with a magnetic stirrer, a solution of tridecafluoro-hepta-
noic acid (1 mmol) in dry dichloromethane (7 mL) was added. After
this, N-methyl pyrrolidinone (1.2 mmol) was added and the system
was cooled to 0 °C. Slowly, ethyl chloroformate was added. The
reaction mixture was stirred for 12 h at room temperature. After
this, compound 13 was added and the mixture was stirred for
24 h at the same temperature. The reaction was quenched with a
saturated NH4Cl solution and the reaction mixture was extracted
with CH2Cl2, and the combined organic fractions were collected,
dried over MgSO4, and filtered. The solvent was removed in
vacuum, yielding the crude product 15 which was purified by flash
This compound was prepared using the same conditions of
compound 5. In this case, the starting material was L-phenylalani-
nol. Yield: 95%.
4.11. Procedure for the synthesis of N-trichloroacyl L-valinol
tosylate 9a
This compound was prepared using the same conditions of
compound 6. In this case, the starting material was compound
8a. Yield: 73%.
½
a 2D0
ꢂ
¼ ꢀ5 (c 3, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d = 7.81 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 7.01 (d,
J = 7.6 Hz, 1), 4.27 (dd, J1 = 4 Hz, J2 = 8 Hz, 1H), 4.11–4.04 (m, 1H),
3.87–3.83 (m, 1H), 2.40 (s, 3H), 1.85 (oct, J = 6.8 Hz, 1H), 0.91 (d,
J = 7.7 Hz, 3H), 0.87 (d, J = 7.7 Hz, 3H). NMR 13C (CDCl3,
100 MHz): 156.5, 145.7, 130.1, 128.7, 127.3, 87.1, 68.7, 51.3, 36.1,
chromatography. Yield: 80%. ½a D20
ꢂ
¼ þ39 (c 3, CH2Cl2). 1H NMR
(CDCl3, 300 MHz): d = 7.40–7.38 (m, 2H), 7.33–7.21 (m, 3H),
6.389 (d, J = 7.8 Hz, 1H), 4.10–3.98 (m, 1H), 3.17–3.08 (m, 2H),
2.03 (oct, J = 6.0 Hz, 1H), 0.94 (d, J = 6.0 Hz, 3H), 0.89 (d,
J = 6.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d = 157.3 (t,

J. A. Sehnem et al. / Tetrahedron: Asymmetry 21 (2010) 997–1003
1003
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J = 25.5 Hz), 135.0, 130.9, 129.2, 127.1, 119.0 (t, J = 32.2 Hz), 115.2
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564.0635.
4.16. General procedure for the palladium-catalyzed
asymmetric allylic alkylation
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A THF (1 mL) solution of [Pd(g
3-C3H5)Cl]2 (10 mg, 2.5 mol %),
catalyst (10 mol %) was stirred for 30 min under an argon atmo-
sphere and then 1,3-diphenyl-2-propenyl acetate (252 mg,
1.0 mmol) was added. The mixture was stirred for 10 min and a
solution of sodium dimethyl malonate, prepared from dimethyl
malonate (264 mg, 2.0 mmol) and sodium hydride (36 mg,
1.5 mmol) in THF (3 mL), was added at room temperature. The
reaction mixture was then stirred for 24 h at room temperature.
After this time, saturated NH4Cl(aq) was added and the aqueous
solution was extracted with CH2Cl2 (3 ꢁ 15 mL). The combined or-
ganic layers were dried with MgSO4, the solvent was evaporated,
and the crude product was purified by flash chromatography elut-
ing with hexane/ethyl acetate (98:2). Enantiomeric excess was
determined by chiral HPLC (Chiralcel OD column, 0.5 mL/min, hex-
ane/2-propanol 99:1, 254 nm).
4.17. General procedure for the palladium-catalyzed
asymmetric allylic alkylation using the FBC
This reaction mixture was prepared under the same conditions
of the reaction described above the only difference is the way by
which it was extracted. At the end of the reaction, the solvent
was removed under reduced pressure, and the residue was ex-
tracted with FC72 (3 ꢁ 2 mL). The fluorous phase was washed with
CH2Cl2 (3 ꢁ 2 mL) and the fluorous solvent was removed under re-
duced pressure to afford the corresponding catalyst. The alkylated
product was purified by flash chromatography eluting with hex-
ane/ethyl acetate (98:2).
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Acknowledgments
The authors gratefully acknowledge CAPES, CNPq (INCT-Catá-
lise), FAPESC, and FAPESP for financial support.
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