An enantio- and diastereoselective synthesis of fluorinated β-aminoalkyloxepine derivatives through Mannich and ring-closing metathesis reactions

Article abstract of DOI:10.1055/s-2006-950345

The combination of a proline-catalyzed Mannich-type reaction between protected fluorinated aldimines and 4-pentenal followed by reduction and regioselective O-allylation gives γ-amino ethers that can then be used as substrates for ring-closing metathesis

Full text of DOI:10.1055/s-2006-950345

SPECIAL TOPIC
4087
An Enantio- and Diastereoselective Synthesis of Fluorinated b-Aminoalkyl-
oxepine Derivatives through Mannich and Ring-Closing Metathesis Reactions
A
a
n
E
nantio-
a
a
e
n
t
nthesis
o
of Fluorina
s
b
-Aminoalky
F
loxepine
D
eri
u
vatives stero,*a,b Elisabet Esteban,a Juan F. Sanz-Cervera,a,b Diego Jiménez,a Fatemeh Mojarrada
Departamento de Química Orgánica, Universidad de Valencia, Burjassot 46100, Spain
Centro de Investigación Príncipe Felipe, Valencia 46013, Spain
Fax +34(96)3544939; E-mail: santos.fustero@uv.es
b
Received 28 July 2006
Dedicated to the memory of Professor Marcial Moreno Mañas
products. Numerous studies toward their synthesis have
been reported because of their frequent natural occurrence
and unusual biological properties.6
Abstract: The combination of a proline-catalyzed Mannich-type
reaction between protected fluorinated aldimines and 4-pentenal
followed by reduction and regioselective O-allylation gives g-ami-
no ethers that can then be used as substrates for ring-closing
metathesis (RCM) reactions to afford fluorinated b-aminoalkyl-
oxepines in a highly stereo- and enantioselective fashion.
We have recently reported a highly diastereo- and enantio-
selective approach to fluorinated syn a-alkyl g-amino al-
cohols by means of an indirect, proline-catalyzed
Mannich-type reaction of fluorinated aldimines and ali-
phatic aldehydes.7 These encouraging results led us to be-
lieve that this same strategy might be used in conjunction
with an RCM reaction for the preparation of fluorinated
seven-membered b-aminoalkyl oxacycles of the type 1
(Scheme 1). Organocatalysis has become one of the key
research areas in synthetic organic chemistry. Its utility in
asymmetric synthesis has been amply demonstrated;
moreover, it has been successfully applied to Mannich re-
actions,8,9 as well as many others.10 The RCM has also
been one of the most successful methods for the prepara-
tion of medium- or large-sized rings from acyclic diene
precursors.11 Thus, we now report on a highly diastereo-
and enantioselective approach to fluorinated b-ami-
noalkyloxepines 1 by means of a synthetic strategy that
uses an indirect, proline-catalyzed Mannich-type reaction
of fluorinated aldimines and aliphatic aldehydes, followed
by an O-allylation reaction, and finally an RCM reaction
(retrosynthetic analysis, Scheme 1).
Key words: amino alcohols, fluorine, organocatalysis, Mannich
reaction, metathesis, oxepines
Enantiopure b-amino acids and derivatives, such as g-
amino alcohols, have become appealing synthetic targets
due to the fact that they are either present in or can be used
as building blocks for a number of compounds with poten-
tial therapeutic properties.1 In fact, several of these com-
pounds have already been shown to display antifungal,
antibiotic, and cytotoxic activity.2 Moreover, because the
presence of fluorine atoms in a potentially bioactive mole-
cule can dramatically change not only its physical, but
also its chemical properties, the preparation of fluorinated
b-amino acids and their derivatives is also an important
objective.3
However, few studies have focused on the preparation of
cyclic, fluorinated b-amino acids. Our group has previ-
ously reported on the preparation of racemic cis seven-
membered g,g-difluorinated b-amino acid derivatives in a
sequence that starts with imidoyl halides.
These are condensed with suitable ester enolates to give
intermediates that can subsequently be cyclized by means
of a ring-closing olefin metathesis reaction. The product is
then stereoselectively reduced to yield the desired com-
pounds in good overall yields.4
PG
PG
RF
NH
NH
O
RF
O
RCM
O-allylation
1
2
PG
At the same time, oxygen- and nitrogen-containing het-
erocyclic compounds have attracted considerable atten-
tion as a result of their biological activity and their
presence in a variety of natural and unnatural products.5
Thus, the asymmetric synthesis of oxygen heterocycles
represents an important task because of the widespread
occurrence of such structural motifs and their use as build-
ing blocks. Among oxygen heterocycles, seven-mem-
bered oxacycles are the central nuclei of numerous natural
PG
RF
PG
RF
N
NH
NH
CH2OH
CHO
RF
H
+
5
CHO
proline-catalyzed
Mannich-type
condensation
[H]
3
4
6
[PG = protecting group]
Scheme 1
SYNTHESIS 2006, No. 23, pp 4087–4091
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950345; Art ID: C04906SS
© Georg Thieme Verlag Stuttgart · New York

4088
S. Fustero et al.
SPECIAL TOPIC
The proline-catalyzed condensation between fluorinated Alternatively, when the O-allyl g-amino ether 2a was
imines 5a–c and 4-pentenal (6) affords the corresponding treated with Grubbs’ second-generation catalyst
fluorinated b-amino aldehydes 4a–c in moderate yield.7 [(IHMes)(PCy3)Cl2Ru=CHPh] in refluxing toluene and
Since fluorinated b-amino aldehydes 4a–c are prone to under a set of reaction conditions that our group has re-
epimerization, we immediately reduced them to the corre- cently shown to favor double bond isomerization after the
sponding g-amino alcohols 3a–c with sodium borohy- RCM reaction,14 isomer 8 was obtained instead of 1a. In-
dride in methanol at 0 °C. Thus, fluorinated g-amino terestingly, this compound can also be prepared from its
alcohols 3a–c were obtained in moderate yields (39– isomer 1a when it is subjected to the same reaction condi-
50%), but with excellent diastereo- and enantioselectivi- tions (Scheme 5).
ties (syn:anti 96:4 and >99% ee in all three cases)
(Scheme 2).
H
H
PMP
F3C
F3C
F3C
N
N
NH
PMP
PMP
O
a
a
1. L-proline (20 mol%),
NMP,
PMP
RF
CHO
75%
80%
PMP
N
O
O
NH
–20 °C to 0 °C
CH2OH
+
2. NaBH4, MeOH
3 h, 0 °C
2a
(a) Grubbs' II (15 mol%), toluene, reflux
1a
8
RF
H
5
6
Scheme 5
RF = CF3 (5a)
CF2CF3 (5b)
CF2Cl (5c)
(2S,3S)-3a (50%)
(2S,3S)-3b (45%)
(2S,3S)-3c (39%)
In summary, the combination of a proline-catalyzed Man-
nich-type reaction between protected fluorinated ald-
imines and 4-pentenal, followed by reduction and O-
allylation affords g-amino ethers 2. These compounds can
then be used as substrates for RCM reactions that ulti-
mately afford seven-membered fluorinated b-aminoalkyl
oxacycles 1 in a highly stereo- and enantioselective fash-
ion. To the best of our knowledge, this is the first time that
compounds with this type of structure have been de-
scribed in the literature.
Scheme 2
For the O-allylation reaction, we decided to use sodium
hydride and allyl bromide in tetrahydrofuran in the pres-
ence of 0.5 molar equivalents of tetrabutylammonium io-
dide (TBAI).12 Thus, when g-amino alcohols 3a,b were
treated with sodium hydride and allyl bromide in the pres-
ence of TBAI, the desired O-allyl g-amino ethers 2a,b
were obtained in excellent yields (Scheme 3) and without
any detectable N-alkylation.13
All solvents were distilled prior to use. 1H NMR, 19F NMR, and 13
C
NMR spectra were measured at 300 MHz, 282.4 MHz, and 75.5
MHz respectively, on a Bruker 300 spectrometer. IR spectra were
recorded with a Thermo Nicolet 380 FT–IR infrared spectrometer.
High resolution mass spectra were obtained on a VG Autospec (mi-
cromass) mass spectrometer. Column chromatography was per-
formed on 100–200 mesh silica gel (Merck) using Hexane–EtOAc
as eluent.
PMP
RF
PMP
RF
NH
NH
CH2=CHCH2Br
NaH, TBAI, THF
CH2OH
O
RF = CF3 (3a)
CF2CF3 (3b)
2a (90%)
2b (73%)
Preparation of Fluorinated g-Amino Alcohols 3a–c; General
Procedure
Scheme 3
To a solution of the starting fluorinated imine7 5 (1 mmol) in N-
methylpyrrolidone (1 mL), L-proline (0.20 mmol) was added and
the resulting solution was stirred at r.t. for 45 min. The temperature
was then lowered to –20 °C and 4-pentenal (2 mmol) was added via
syringe over 1 min. The reaction was kept at –20 °C for 24 h, then
at –10 °C for an additional 24 h, and finally at 0 °C for a further 24
h. The reaction mixture was then hydrolyzed by the addition of sat.
aq NH4Cl solution (5 mL), followed by quick extraction with
EtOAc (3 × 10 mL). The organic phases were pooled together,
washed once with sat. aq NaCl (10 mL) solution, and dried over an-
hydrous Na2SO4. After removal of the solvent under vacuum, the
crude residue was dissolved in dry MeOH (5 mL per mmol of start-
ing fluorinated imine). The solution was cooled to 0 °C and treated
with 5 mol equiv of NaBH4, after which the reaction was allowed to
reach r.t. and stirred for 5 h. Then, the reaction was quenched with
sat. aq NH4Cl solution and extracted into EtOAc. The organic layer
was washed with brine and dried over Na2SO4. The corresponding
fluorinated g-amino alcohols 3 were isolated after silica gel column
purification with hexane–EtOAc (4:1) as eluent.
Finally, when O-allyl g-amino ethers 2a,b were treated
with Grubbs’ first-generation catalyst
[(PCy3)2Cl2Ru=CHPh], an RCM reaction took place
cleanly to afford the corresponding fluorinated b-amino-
alkyl oxepines 1a,b in high yield. (Scheme 4).
PMP
RF
PMP
RF
NH
Grubbs' I
(15 mol%)
NH
O
O
CH2Cl2, reflux
RF = CF3 (2a)
CF2CF3 (2b)
1a (80%)
1b (70%)
Scheme 4
Synthesis 2006, No. 23, 4087–4091 © Thieme Stuttgart · New York

SPECIAL TOPIC An Enantio- and Diastereoselective Synthesis of Fluorinated b-Aminoalkyloxepine Derivatives
4089
(S)-2-[(S)-2,2,2-Trifluoro-1-(4-methoxyphenylamino)eth-
yl]pent-4-en-1-ol (3a)
rified by means of flash column chromatography on silica gel using
hexane–EtOAc (20:1) to afford the desired O-allyl amino ether 2.
Obtained in 50% yield in accordance with the general procedure de-
scribed above. For complete physical and spectroscopic data of this
compound, see ref. 7.
N-[(2S,3S)-3-(Allyloxymethyl)-1,1,1-trifluorohex-5-en-2-yl]-4-
methoxyaniline (2a)
Obtained in 90% yield as a yellowish oil in accordance with the gen-
(S)-2-[(S)-2,2,2,3,3-Pentafluoro-1-(4-methoxyphenylamino)eth-
yl]pent-4-en-1-ol (3b)
Obtained in 45% yield in accordance with the general procedure de-
scribed above. White solid; mp 78–79 °C; [a]D25 +17.5 (c 0.77,
CHCl3).
eral procedure described above. [a]D25 +8.44 (c 0.93, CHCl3).
IR (neat): 3649, 2932, 1647, 1513, 1234, 1133, 1107, 1039, 994,
920, 819, 765, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.90–2.00 (m, 1 H), 2.17–2.34 (m,
2 H), 3.37 (dd, J1 = 9.3 Hz, J2 = 9.3 Hz, 1 H), 3.49 (dd, J1 = 9.3 Hz,
J2 = 3.7 Hz, 1 H), 3.72–3.75 (m, 1 H), 3.75 (s, 3 H), 3.77–3.91 (m,
2 H), 4.13–4.27 (m, 1 H), 4.99–5.21 (m, 4 H), 5.64–5.86 (m, 2 H),
6.67 (d, J = 8.6 Hz, 2 H), 6.78 (d, J = 8.6 Hz, 2 H).
IR (neat): 3385, 1636, 1259, 1189, 1022, 797 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52–1.60 (m, 1 H), 1.97–2.10 (m,
1 H), 2.19–2.30 (m, 1 H), 2.34–2.45 (m, 1 H), 3.49–3.64 (m, 2 H),
3.75 (s, 3 H), 3.76–3.82 (m, 1 H), 4.43–4.57 (m, 1 H), 5.07–5.13 (m,
2 H), 5.73–5.87 (m, 1 H), 6.68 (d, J = 8.9 Hz, 2 H), 6.78 (d, J = 8.9
Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 30.5 (t), 40.5 (d), 53.4 (dd,
2JC–F = 24.2 Hz, 20.3 Hz), 55.7 (q), 61.9 (t), 114.7 (d), 115.0 (d),
117, 3 (t), 135.6 (d), 140.6 (s), 152.9 (s). The d values for the carbon
atoms in the C2F5 group were too weak to be measured because of
their multiplicity, caused by coupling with the fluorine atoms.
13C NMR (75.5 MHz, CDCl3): d = 30.8 (t), 38.6 (d), 55.7 (q), 56.5
(q, 2JC–F = 26.8 Hz), 69.2 (t), 72.0 (t), 114.8 (d), 115.1 (d), 117.1 (t),
1
117.4 (t), 126.7 (q, JC–F = 283.2 Hz), 134.5 (d), 135.6 (d), 141.1
(s), 152.9 (s).
19F NMR (282.4 MHz, CDCl3): d = –72.05 (d, JF–H = 8.0 Hz, 3 F).
HRMS (EI): m/z calcd C17H22NO2F3: 329.16026; found: 329.16061.
N-[(3S,4S)-4-(Allyloxymethyl)-1,1,1,2,2-pentafluorohept-6-en-
3-yl]-4-methoxyaniline (2b)
19F NMR (282.4 MHz, CDCl3): d = –82.65 (s, 3 F), –119.03 (dd,
JF–F = 73.1 Hz, JF–H = 7.2 Hz, 1 F), –123.51 (dd, JF–F = 273.1 Hz,
Obtained in 73% yield as a yellowish oil in accordance with the gen-
JF–H = 19.9 Hz, 1 F).
eral procedure described above. [a]D25 +11.8 (c 0.88, CHCl3).
HRMS–FAB: m/z [M + H]+ calcd for C15H18F5NO2: 340.13360;
found: 340.13257.
IR (neat): 3392, 2932, 1642, 1514, 1186, 1120, 1039, 1019, 918,
817, 730 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.92–2.08 (m, 1 H), 2.29–2.44 (m,
2 H), 3.28 (dd, J1 = 9.5 Hz, J2 = 9.5 Hz, 1 H), 3.48 (dd, J1 = 9.5 Hz,
J2 = 3.8 Hz, 1 H), 3.61 (d, J = 11.2 Hz, 1 H), 3.75 (s, 3 H), 3.78–
3.94 (m, 2 H), 4.39–4.57 (m, 1 H), 5.03–5.29 (m, 4 H), 5.70–5.93
(m, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 6.76 (d, J = 9.0 Hz, 2 H).
(S)-2-[(S)-2-Chloro-2,2-difluoro-1-(4-methoxyphenylami-
no)ethyl]pent-4-en-1-ol (3c)
Obtained in 39% yield in accordance with the general procedure de-
scribed above. White crystals; mp 112–114 °C; [a]D25 –17.1
(c 0.54, CHCl3).
13C NMR (75.5 MHz, CDCl3): d = 30.8 (t), 38.4 (d), 53.3 (dd,
2JC–F = 24.1 Hz, 2JC–F = 19.5 Hz), 55.7 (q), 69.1 (t), 71.8 (t), 114.6
(d), 114.8 (d), 116.9 (t), 117.2 (t), 134.5 (d), 135.6 (d), 140.8 (s),
152.7 (s). The d values for the carbon atoms in the C2F5 group,
which appeared in the d = 100–150 range, were too weak to be mea-
sured because of their multiplicity, caused by coupling with the flu-
orine atoms.
19F NMR (282.4 MHz, CDCl3): d = –82.75 (s, 3 F), –119.04 (dd,
JF–F = 272.5 Hz, JF–H = 6.8 Hz, 1 F), –123.79 (dd, JF–F = 272.5 Hz,
JF–H = 22.8 Hz, 1 F).
IR (neat): 3424, 2924, 1255, 1520, 1198, 1104, 1058, 1026, 957,
917, 897, 818 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.51 (br s, 1 H), 2.00–2.12 (m, 1
H), 2.25–2.35 (m, 1 H), 2.39–2.49 (m, 1 H), 3.56–3.65 (m, 2 H),
3.75 (s, 3 H), 3.80 (dd, J1 = 10.6 Hz, J2 = 3.9 Hz, 1 H), 4.38 (t,
J = 9.6 Hz, 1 H), 5.05–5.15 (m, 2 H), 5.73–5.88 (m, 1 H), 6.71 (d,
J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 30.3 (t), 41.1 (d), 55.7 (q), 62.0
(t, 2JC–F = 23.1 Hz), 62.3 (t), 115.0 (d), 115.3 (d), 117.4 (d), 131.1
(t, 1JC–F = 299.4 Hz), 135.7 (d), 140.9 (s), 153.0 (s).
HRMS–FAB: m/z [M + H]+ calcd for C18H23NO2F5: 380.16490;
found: 380.16070.
19F NMR (282.4 MHz, CDCl3): d = –57.01 (dd, JF–F = 162.0 Hz,
JF–H = 10.2 Hz, 1 F), –57,72 (dd, JF–F = 162.0 Hz, JF–H = 10.2 Hz,
1 F).
Preparation of Fluorinated b-Aminoalkyloxepines 1a–b; Gen-
eral Procedure
HRMS–FAB: m/z [M + H]+ calcd for C14H19ClF2NO2: 306.10724;
found: 306.10502.
A solution of Grubbs first generation ruthenium catalyst
(PCy3)2Cl2Ru=CHPh (15 mol%) in dry CH2Cl2 was added via can-
nula to a solution of amino ethers 2a–c (0.08 mmol) in CH2Cl2 (4
mL, 0.02 M). The resulting dark brown solution was kept at r.t. until
TLC indicated that the starting material was no longer present (usu-
ally 1 h). The solvents were removed under reduced pressure and
the residue was purified by means of flash column chromatography
on silica gel using hexane–EtOAc (9:1).
Preparation of Fluorinated O-Allyl Amino Ethers 2a,b; General
Procedure
The starting fluorinated amino alcohol 3 (0.08 mmol) was dissolved
in anhydrous THF (1 mL), to which TBAI (0.5 mol equiv) was add-
ed. The resulting solution was cooled to 0 °C and NaH (1.2 mol
equiv) was added, the reaction mixture was stirred for 25 min and
then allyl bromide (3 mol equiv) was added. After the addition, the
mixture was stirred at r.t. for 12 h. The reaction mixture was then
hydrolyzed by addition of sat. aq NH4Cl solution (10 mL), followed
by extraction with EtOAc (3 × 10 mL). The organic phases were
pooled together, washed once with sat. aq NaCl solution (10 mL),
and dried over anhydrous Na2SO4. The volatile components were
then removed under vacuum and the crude reaction mixture was pu-
4-Methoxy-N-{(S)-2,2,2-trifluoro-1-[(S)-2,3,4,7-tetrahydro-
oxepin-3-yl]ethyl}aniline (1a)
Obtained in 80% yield as a yellowish oil in accordance with the gen-
eral procedure described above. [a]D25 –30.5 (c 0.93, CHCl3).
IR (neat): 3607, 2925, 2854, 1736, 1716, 1513, 1365, 1231, 1128,
1036, 820, 695 cm–1.
Synthesis 2006, No. 23, 4087–4091 © Thieme Stuttgart · New York

4090
S. Fustero et al.
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3,): d = 2.40–2.51 (m, 3 H), 3.51 (d,
J = 9.8 Hz, 1 H), 3.75 (s, 3 H), 3.76–3.95 (m, 3 H), 4.13–4.30 (m, 2
H), 5.65–5.78 (m, 2 H), 6.63 (d, J = 8.7 Hz, 2 H), 6.80 (d, J = 8.9
Hz, 2 H).
19F NMR (282.4 MHz, CDCl3): d = –72.71 (d, JF–H = 7.2 Hz, 3 F).
HRMS (EI): m/z calcd for C15H18F3NO2: 301.12896; found:
301.12859.
13C NMR (75.5 MHz, CDCl3): d = 26.7 (t), 40.1 (d), 55.7 (q), 57.7
(q, 2J = 27.0 Hz), 70.3 (t), 73.2 (t), 114.9 (d), 115.1 (d), 128.6 (d),
130.1 (q, 1J = 284.8 Hz), 130.5 (d), 140.8 (s), 153.0 (s).
19F NMR (282.4 MHz, CDCl3): d = –72.86 (d, J = 7.2 Hz, 3 F).
Acknowledgment
The authors thank the Ministerio de Educación y Ciencia
(BQU2003-01610 and CTQ2006-01317/BQU) and the Generalitat
Valenciana (GR03-193 and GV05/079) for financial support. E.E.
and D.J. express their thanks for predoctoral fellowships from the
aforementioned institutions.
HRMS (EI): m/z calcd for C15H18F3NO2: 301.12896; found:
301.12900.
4-Methoxy-N-{(S)-2,2,3,3,3-pentafluoro-1-[(S)-2,3,4,7-tetra-
hydrooxepin-3-yl]propyl}aniline (1b)
References
Obtained in 70% yield in accordance with the general procedure de-
scribed above. Yellowish oil; [a]D25 +2.54 (c 0.74, CHCl3).
(1) Reviews: (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev.
1996, 25, 117. (b) Hintermann, T.; Seebach, D. Chimia
1997, 51, 244. (c) Scarborough, R. M. Curr. Med. Chem.
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Maryanoff, C. A. Curr. Med. Chem. 1999, 6, 955.
(e) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.;
Soloshonok, V., Eds.; Wiley-Interscience: New York, 2005.
(2) (a) Fernández, R.; Rodríguez, J.; Quiñoa, E.; Riguera, R.;
Muñoz, L.; Fernández-Suarez, M.; Debitus, C. J. J. Am.
Chem. Soc. 1996, 118, 11635. (b) Hu, T.; Panek, J. J. J. Org.
Chem. 1999, 64, 3000.
(3) (a) Organo-Fluorine Compounds, In Houben-Weyl Methods
of Organic Chemistry, Vol. E10a-c; Georg Thieme Verlag:
Stuttgart, 2000. (b) Fluorine-containing Amino Acids:
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Eds.; Wiley: Chichester, 1995.
(4) Fustero, S.; Bartolome, A.; Sanz-Cervera, J. F.; Sánchez-
Roselló, M.; Soler, J. G.; Ramírez de Arellano, C.; Fuentes,
A. S. Org. Lett. 2003, 5, 2523.
(5) (a) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron
2002, 58, 6795; and references cited therein. (b) Szawkalo,
J.; Zawadzka, A.; Wojtasiewitcz, K.; Leniewski, A.;
Drabowicz, J.; Czarnocki, Z. Tetrahedron: Asymmetry 2005,
16, 3619.
IR (neat): 3456, 3016, 2970, 2943, 1739, 1511, 1366, 1229, 1205,
1181, 1120, 1024, 820, 729 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.41–2.49 (m, 2 H), 2.54–2.67 (m,
1 H), 3.48 (d, J = 9.9 Hz, 1 H), 3.75 (s, 3 H), 3.75–3.79 (m, 1 H),
3.90 (dd, J1 = 12.4 Hz, J2 = 3.3 Hz, 1 H), 3.92–4.03 (m, 1 H), 4.14–
4.22 (m, 2 H), 5.59–5.77 (m, 2 H), 6.58 (d, J = 8.9 Hz, 2 H), 6.77
(d, J = 8.9 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 26.6 (t), 40.4 (d), 55.3 (dd,
2JC–F = 24.7 Hz, 2JC–F = 20.6 Hz), 55.7 (q), 70.2 (t), 73.5 (t), 114.6
(d), 115.0 (d), 128.4 (d), 130.3 (d), 140.3 (s), 152,9 (s). The d values
for the carbon atoms in the C2F5 group, which appeared in the
d = 100–150 range, were too weak to be measured because of their
multiplicity, caused by coupling with the fluorine atoms.
19F NMR (282.4 MHz, CDCl3): d = –82.19 (s, 3 F), –117.57 (dd,
JF–F = 274.0 Hz, JF–H = 6.7 Hz, 1 F), –124.5 (dd,1F, JF–F = 273.8
Hz, JF–H = 20.1 Hz).
HRMS (EI): m/z calcd for C16H18F5NO2: 351.12577; found:
351.12498.
Methoxy-N-{(S)-2,2,3,3,3-pentafluoro-1-[(S)-2,3,4,5-tetra-
hydrooxepin-3-yl]propyl}aniline (8)
This method is analogous to the one used in the preparation of com-
pounds 1a–b, except that Grubbs’ second-generation catalyst
(IHMes)(PCy3)Cl2Ru=CHPh is used and the solvent is toluene un-
der reflux. Either 1a or 2a can be used as starting material. Under
these conditions and with this catalyst (15 mol%), the reaction took
4 h to complete. After flash column chromatography purification on
silica gel using hexane–EtOAc (15:1), the yield was 80% (from 1a)
or 75% (from 2a), obtained as a yellowish oil. [a]D25 +18.8 (c 0.67,
CHCl3).
(6) (a) Batchelor, R.; Hoberg, J. O. Tetrahedron Lett. 2003, 44,
9043; and references cited therein. (b) Wong, J. C. Y.;
Lacombe, P.; Sturino, C. F. Tetrahedron Lett. 1999, 40,
8751. (c) Adams, J. A.; Heron, N. M.; Koss, A.-M.;
Hoveyda, A. H. J. Org. Chem. 1999, 64, 854.
(d) Suginome, M.; Iwanami, T.; Ito, Y. J. Am. Chem. Soc.
2001, 123, 4356. (e) Lecourné, F.; Ollivier, J. Org. Biomol.
Chem. 2003, 1, 3600. (f) Trost, B. M.; Brown, B. S.;
McEachern, E. J.; Kuhn, O. Chem. Eur. J. 2003, 9, 4442.
(7) (a) Fustero, S.; Jiménez, D.; Sanz-Cervera, J. F.; Sánchez-
Roselló, M.; Esteban, E.; Simón-Fuentes, A. Org. Lett.
2005, 7, 3433. (b) Our group has previously described a less
convenient enantioselective synthesis of this class of
compounds that uses (–)-8-phenylmenthol as a chiral
auxiliary, see: Fustero, S.; Pina, B.; Salavert, E.; Navarro,
A.; Ramírez de Arellano, M. C.; Fuentes, A. S. J. Org.
Chem. 2002, 67, 4667.
IR (neat): 3392, 3015, 2970, 2925, 2854, 1738, 1651, 1511, 1365,
1231, 1131, 1037, 820, 758, 731, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.80–1.93 (m, 1 H), 1.94–2.08 (m,
1 H), 2.14–2.23 (m, 2 H), 2.32–2.43 (m, 1 H), 3.62 (d, J = 8.9 Hz, 1
H), 3.75 (s, 3 H), 3.81–3.94 (m, 1 H), 3.96 (dd, J1 = 12.3 Hz,
J2 = 4.7 Hz, 1 H), 4.20 (dd, J1 = 12.3 Hz, J2 = 3.6 Hz, 1 H), 4.73–
4.75 (m, 1 H), 6.29 (d, J = 6.6 Hz, 1 H), 6.66 (d, J = 9.0 Hz, 2 H),
6.79 (d, J = 9.0 Hz, 2 H).
(8) Tanaka, F.; Barbas, C. F. III Enantioselective Synthesis of b-
Amino Acids; Juaristi, E.; Soloshonok, V., Eds.; Wiley-
Interscience: New York, 2005, Chap. 9, 195–214.
13C NMR (75.5 MHz, CDCl3): d = 23.7 (t), 27.2 (t), 40.5 (d), 55.7
2
(q), 59.4 (q, JC–F = 28.0 Hz), 74.0 (t), 108.4 (d), 114.9 (d), 115.1
(d), 126.1 (q, 1JC–F = 285.0 Hz), 140.9 (s), 148.9 (d), 153.0 (d).
Synthesis 2006, No. 23, 4087–4091 © Thieme Stuttgart · New York

SPECIAL TOPIC An Enantio- and Diastereoselective Synthesis of Fluorinated b-Aminoalkyloxepine Derivatives
4091
(9) For representative examples of organocatalyzed Mannich
reactions, see: (a) List, B. J. Am. Chem. Soc. 2000, 122,
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Ashimine, I.; Urushihima, T.; Shoji, M.; Sakai, K. Angew.
Chem. Int. Ed. 2003, 42, 3677. (g) Notz, W.; Tanaka, T.;
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(h) Córdova, A. Acc. Chem. Res. 2004, 37, 102. (i) Wang,
W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7243.
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Eds.; Wiley-VCH: Weinheim, 2005. For reviews, see:
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(13) In the case of g-amino alcohol 2c, however, the yield in the
O-allylation reaction was substantially lower because of
competitive side reactions. As the O-allylation product
turned out to be very difficult to purify, we decided not to
continue with this substrate.
(14) Fustero, S.; Sánchez-Roselló, M.; Jiménez, D.; Sanz-
Cervera, J. F.; del Pozo, C.; Aceña, J. L. J. Org. Chem. 2006,
71, 2706.
Synthesis 2006, No. 23, 4087–4091 © Thieme Stuttgart · New York