Convergent synthesis of functionalized fluoroallylamines by the Julia-Kocienski reaction

Article abstract of DOI:10.1016/j.tet.2010.12.061

The synthesis of β-fluoroallylamines is reported from aminofluorobenzothiazolylsulfones. These open a new route for a short synthesis of vinylic fluoride containing highly functionalized amino residues.

Full text of DOI:10.1016/j.tet.2010.12.061

Tetrahedron 67 (2011) 1398e1405
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convergent synthesis of functionalized fluoroallylamines by the JuliaeKocienski
reaction
*
ꢀ
Charlene Calata, Emmanuel Pfund, Thierry Lequeux
ꢁ
ꢁ
ꢁ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR CNRS 6507 & FR3038, ENSICAEN, Universite de Caen Basse-Normandie, 6 Bd du Marechal Juin, 14050 Caen cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of b-fluoroallylamines is reported from aminofluorobenzothiazolylsulfones. These open
Received 26 November 2010
Received in revised form 17 December 2010
Accepted 21 December 2010
Available online 30 December 2010
a new route for a short synthesis of vinylic fluoride containing highly functionalized amino residues.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Modified Julia reaction
Fluoropeptidomimetic
Conjugated addition
1. Introduction
F
F
R2
R2
Peptides are not suitable as therapeutic agents due to their in
vivo degradation by peptidases, thus synthetic peptidomimetics,
stable toward enzymatic cleavage, were designed as potential drug
substance.1 Fluorinated peptide mimics represent an important
class and it is established that the replacement of a specific amide
bond by a fluorinated carbonecarbon double bond acted as a sur-
rogate of a natural peptide.2,3 Almost synthetic routes for the
preparation of fluorinated peptidomimetics and for instance the
formation of the fluoroalkylidene moiety, involved the synthesis of
functionalized allylamine intermediates.
OR3
OR3
(A)
(B)
NR2
EtO2C
F
F
R1
F
R2N
R2
R1
O
N
O
OR3
S
R2N
(C)
S
peptidomimetic
O2
R1
1: R1 = H, alkyl
These latter were obtained from a-fluoro-a,b-unsaturated esters
after further chemical modifications, or from corresponding allylic
alcohols through a sigmatropic rearrangement (Fig. 1A), and from
gem-difluoroallyl unsaturated-amides, -esters through a defluori-
nation reaction (Fig. 1B).4
Fig. 1. Fluoroolefins as peptidomimetics.
only one example related to the preparation of alkenes as peptide
mimics from tetrazolyl-aminosulfones was reported.7 Based on the
success of the JuliaeKocienski reaction to prepare fluoroethylidene
derivatives in one step from heteroaromatic fluoroalkylsulfones,8
reagents, such as benzothiazolylsulfones 1 (Fig. 1C) appeared attrac-
tive to open a new access to fluorinated allylamines and peptide
mimics.
The most straightforward and convergent approach to prepare
allylamines in one step is the Wittig and related reactions. However, it
has been reported that the HWE reaction cannot be applied
to the direct synthesis of fluoroalkylidene derivatives from fluo-
roalkyl-phosphonates,5 and up to date the derivation of fluo-
rovinylphosphonium salts by conjugated addition of amines is the
sole possibility to produce the corresponding allylamines by trapping
the intermediate ylide by aldehydes.5c The JuliaeKocienski reaction
was commonly used for the synthesis of highly functionalized in-
termediates involved in the total synthesis of natural products,6 and
Since its first report, the modified Julia fluoroolefination reaction
was extended to a large variety of
p-deficient aromatic fluo-
rosulfones substituted by an electron-withdrawing or aromatic
groups to produce the corresponding
a-fluoro-a,b-unsaturated
esters, sulfones, nitriles, amides, and aryles.9 The replacement of the
sulfonyl moiety by a sulfoximine, or the use of pyridinylsulfone
derivatives have been proposed as an alternative.10 However, the
* Corresponding author. E-mail address: thierry.lequeux@ensicaen.fr (T. Lequeux).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.061

C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
1399
Table 1
major limitation of the JuliaeKocienki reaction is the availability of
Synthesis of aliphatic secondary and tertiary fluoroallylamines
functionalized reagents, such as substituted fluoroalkylsulfones, to
prepare functionalized fluoroalkylidenes in one step. Previously we
Entry
RCOR0
Yield (%)a from 3a,
Z/Ec
Yield (%)a from 3b,
Z/Ec
(method)b
(method)b
reported the preparation of benzothiazolyl aminosulfones
3
1
2
4
5
4a
68, (A)
5a
4b
60, (A)
5b
53, (A)
70, (B)d
6b
31, (A)
74, (B)
7b
73, (B)
8b
34, (A)
95, (B)
(Scheme 1) as potential reagents for the preparation of functional-
ized fluoroalkylidenes as precursors of peptidomimetics or
bioconjugates through the modified Julia reaction.11 We report our
recent progress in this field, and in particular the use of these sul-
fones to develop a straightforward synthesis of functionalized fluo-
roallylamines and a short synthesis of a peptide mimic precursor.
85:15
30:70
45:55
40:60
88, (A)
3
6
6a
79, (A)
55:45
55:45
4
5
7
8
7a
62, (A)
8a
24, (A)
78, (B)
60:40
d
60:40
d
3a: NR2 = cC6H11NH
1) amine
3b: NR2 = N-pyrrolidinyl
S
N
S
N
2) NH4Cl
3c: NR2 = diterbutyl aspartate
3d: NR2 = ethyl phenylalanilate
3e : NR2 = phtalimido
a
Isolated yield by flash chromatography.
(Method A) experiment realized in the presence of t-BuOK (1.3 equiv) at ꢀ17 ꢁC,
F
SO2
61-95%
F
SO2
b
1 h, THF. (Method B) experiment realized in the presence of NaHMDS
(1.3e2.6 equiv) at ꢀ78 ꢁC to 0 ꢁC, 3 h, THF.
NR2
c
Determined by 19F NMR spectroscopy of the crude product.
See Ref. 11.
2
3
d
Scheme 1. Synthesis of functionalized aminosulfones by aza-Michael addition
reaction.
Michael addition was observed and from secondary aminosulfone
3a and aromatic aldehydes corresponding fluoroallylamines 4a and
5a were isolated in 68% and 88% yields, respectively (Table 1, entries
1 and 2). The addition onto aliphatic aldehydes afforded the cor-
responding amines 6a and 7a in 62e79% (Table 1, entries 3 and 4).
In both cases a mixture of Z/E alkenes was obtained.
2. Results and discussion
The synthesis of the aminosulfones 3 was not straightforward
and we showed that the aza-Michael addition reaction onto
vinylsulfone 2 allowed the introduction of a large variety of amines
(Scheme 1).11
Study of the chemical behavior of functionalized fluoroalkyl-
sulfones 3aee in the modified Julia reaction was investigated to
prepare substituted fluoroalkylidene derivatives. Aminosulfones 3a
and 3b, obtained from secondary and primary amines, were tested
first (Scheme 2, Table 1).
The reaction with cyclic ketone 8 was more difficult, and product
8a was isolated in low yield even after 12 h under stirring at room
temperature (Table 1, entry 5). From tertiary aminosulfone 3b, in the
presence of t-BuOK, similar results were observed from aromatic
aldehydes 4e5 (Table 1, entries 1 and 2), but not from aliphatic ones.
From aldehyde 6 corresponding alkene 6bwas obtained in 31% yield,
and no product was formed from sterically hindered aldehyde 7. In
theses cases, the alkene formation was improved by using NaHMDS
instead of t-BuOK. Thus, from 3b, in the presence of NaHMDS
at ꢀ78 ꢁC (method B), the isolated yields were increased and fluo-
roallylamines 4be8b were obtained in 73e95% yields, and good
yields were observed from aliphatic aldehydes 6, 7 (Table 1, entries 4
and 5). As shown inTable 1, even if NaHMDS is a less convenient base
than t-BuOK, this was necessary to produce alkenes in acceptable
yields.
The use of NaHMDS was also efficient when applied to 4-tert-
butylcyclohexanone 8. In this case the corresponding alkenes were
isolated in 78e95% yields from sulfones 3a,b.
However, poor E/Z selectivity was observed, and no influence of
the nature of the base on the selectivity was noted. Some efforts
were done to control the carbonecarbon double bond geometry. By
using NaHMDS in the presence of MgBr2, in THF or DME no effect
was observed and the Z/E ratio was found mainly unchanged. It is
well known that the JuliaeKocienski reaction is substrate-de-
pendent and the selectivity is solved on a case-by-case.6
1)R1COR2,
Method
N
F
R1
2) NH4Cl
S
SO2
NR2
R2
NR2
F
4(a-e)-8(a-e)
3
a: NR2 = cC6H11NH
b: NR2 = N-pyrrolidinyl
c: NR2 = HNCH(CH2CO2tBu)CO2tBu
d: NR2 = HNCH(CH2Ph)CO2Et
e : NR2 = phtalimido
O
O
Br
O
8
6
4
5
The reaction with sulfones 3c,d derived from racemic amino
acids was then tested (Scheme 2, Table 2). As observed from sulfone
3a,b, the reaction reached completion when t-BuOK or NaHMDS
were used as base at ꢀ17 ꢁC and ꢀ78 ꢁC, respectively. However,
these substrates seem to be more sensitive to the reaction tem-
perature and the nature of the base and better yields were obtained
with NaHMDS. In the presence of t-BuOK, side products appeared
in the crude 19F NMR analysis. In the presence of NaHMDS, from
sulfone 3c containing a ditertiobutyl aspartate residue and aliphatic
or aromatic aldehydes, the corresponding fluoroalkenes 4ce7c
were isolated in moderate to excellent yields (Table 2, entries 1e4),
despite some difficulties occurring during their purification by
flash column chromatography. In contrast from the sulfone 3d
O
O
CO2Me
7
8
Scheme 2. JuliaeKocienski reaction from aminosulfones and carbonyl compounds.
Four bases (DBU, TMG, t-BuOK, NaHMDS) were screened. DBU
and TMG induced no reaction and the starting materials were
partially recovered. However, when a solution of t-BuOK (1.3 equiv)
in THF was slowly added to a solution of sulfone 3a and carbonyl
compound at ꢀ17 ꢁC (method A), the reaction reached completion
after 1 h of stirring. Under this Babier type conditions, no retro-

1400
C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
Table 2
The JuliaeKocienski reaction was realized from the protected
3-silyloxy-propanal (PG¼TBDPS) and 3e. The reaction reached
completion after 2 h under stirring, however a mixture mainly
composed of compound 9 and partially O-deprotected compound
9 was obtained. In a second approach the protected 3-benzyloxy-
propanal was used, and in this case, the reaction afforded the
expected olefin 10 as the sole reaction product. The compound 10
was isolated in 77% yield as a mixture of Z/E alkenes (54:46). The
precursor of the GlyeGly peptidomimetic was then prepared in
two additional steps involving a deprotection of the primary al-
cohol in the presence of a Lewis acid (TiCl4), followed by a Jones
oxidation to produce the known protected acid 12 in 85% yield.2b
This first straightforward synthesis of fluorinated allylamines
from phtalimidosulfone 3e and protected aldehyde illustrates the
synthetic potential of the modified Julia reaction to prepare pep-
tidomimetics. However, some limitations appeared due to the
difficulties occurring in the preparation of sulfones containing
other protected amino group (BocNH group). The aza-Michael
addition onto vinylsulfone 2 is strongly dependent on the nucle-
ophilic character of the nitrogen atom.11 However, the depro-
tection and protection by a Boc protecting group will be achieved
following previous method reported in the literature.2d Current
works are underway to apply this approach for dipeptide mimics
synthesis.
Preparation of aminoacid and phtalimidoyl derivatives by method B
Entry
RCOR’
Yield (%)
Z/Eb
Yield (%)
Z/Eb
Yield (%)
Z/Eb
from 3ca
from 3da
from 3ea
1
2
3
4
5
4
5
6
7
8
4c
74
5c
72
6c
75
7c
77
8c
27
70:30
60:40
75:25
69:41
d
4d
60
5d
58
6d
21
7dc
20
8dd
20:80
52:48
60:40
70:30
d
4e
70
5e
56
6e
66
7e
50
8e
63
85:15
90:10
62:38
48:52
d
a
Isolated yield by flash chromatography.
b
c
Determined by 19F NMR spectroscopy of the crude product.
Not isolated.
No reaction.
d
containing a phenylalanine residue, the reaction performed from
aromatic aldehydes 4, 5 afforded the corresponding allylamines 4d,
5d in 61% and 58%, but from aliphatic aldehydes 6, 7, compounds 6c,
7c were obtained in lower yields (Table 2, entries 3 and 4). Fur-
thermore, the reaction realized with cyclic ketone 8 afforded the
corresponding alkene 8c in moderate yield from 3c, and no product
was formed from 3d. It is noteworthy that as previously reported,8a
no racemisation of the stereogenic center occurred during the re-
action. In the crude 19F NMR, from aldehyde 7 the only products
formed were the corresponding E/Z alkenes.
The olefination of carbonyl compounds was extended to the
phtalimidosulfone 3e in the presence of NaHMDS at ꢀ78 ꢁC (Table 2,
entries 1e5). The reaction afforded the corresponding fluoroallyl-
amines 4ee7e in good yields (50e70%) from aliphatic and aromatic
aldehydes 4e7. The E/Z selectivity was poor to good. In contrast to
the previous results obtained from 3c or 3d, the reaction performed
from4-tert-butylcyclohexanone afforded alkene 8e in 63% yield, and
the product was easier to purify. Having in hand the phtalimido-
sulfone 3e, a short preparation of a potent glycidyl dipeptide pre-
cursor was explored from 3-alkoxy-propanal (Scheme 3).
3. Conclusion
The first one-step synthesis of functionalized fluoroalkylidene
derivatives, and in particular the synthesis of fluoroallylamines from
carbonyl compounds and heterocyclic fluorosulfones by using the
JuliaeKocienski reaction is reported. The preparation of the GlyeGly
peptide mimic precursor illustrates the interest of this new approach
by a convergent synthesis of a dipeptide precursor in few steps.
Current works are now under progress to generalize this strategy for
the preparation of the most common dipeptide isosters, peptide
nucleic acid mimics, and to find the most adapted heterocycle or
experimental conditions to control the configuration of the alkenes.
4. Experimental section
4.1. General information
All reactions were carried out under an atmosphere of dry ni-
trogen in dried glassware with magnetic stirring. THF was dried by
pressure filtration on a drier apparatus. HPLC grade ethyl acetate
was used without further purification. Flash columns chromatog-
raphy were realized on silica gel 60 (40e63
mm) and were followed
by thin layer chromatography. The spots were visualized by UV-
irradiation and/or KMnO4 solution. NMR spectra were recorded on
a 250 MHz or 400 MHz. NMR data appear in the following order:
chemical shift in parts per million, multiplicity (s, singlet; d, dou-
blet; t, triplet; q, quadruplet; m, multiplet), number of protons,
coupling constant J in hertz. TMS and CFCl3 are the internal stan-
dard for the CDCl3 solutions. High-resolution mass data were
recorded on a high-resolution mass spectrometer in the EI or ESI
mode. All reagents are commercially available and used without
further purification and aldehydes were freshly distilled prior used.
4.2. Method (A): general procedure for the preparation of
fluorinated allylic amines (4ae8a) and (4be8b) in the
presence of t-BuOK
To a solution of aminosulfone 3a or 3b (1 equiv) and aldehyde
(1.05 equiv) in THF at ꢀ17 ꢁC was added slowly in 5 min a THF so-
lution of t-BuOK (1.3 equiv). After 15 min at ꢀ17 ꢁC, the mixture
was stirred for 1 h at 0 ꢁC and quenched by addition of a saturated
Scheme 3. Synthesis of GlyeGly peptidomimetic precursor.

C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
1401
3
3
solution of NH4Cl (1 mL) then extracted with CH2Cl2 (2ꢂ5 mL).
Combined organic layers were washed with a 1 M solution of NaOH
(1 mL) and brine, dried over MgSO4, filtered, and evaporated under
reduced pressure. The crude product was purified by flash column
chromatography to give allylamines 4ae8a and 4be8b.
(dt, JHF¼21.8 Hz, JHH¼8.0 Hz, 1H, E), 5.69e5.79 (m, 2H); 13C NMR
(CDCl3, 100 MHz)
d 22.4, 22.5, 23.7, 23.8, 24.3, 24.5, 24.8, 24.9, 27.8,
27.9, 28.0, 28.15, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.9, 31.4, 31.6, 32.7,
41.0 (d, 2JCF¼28.7 Hz, E), 45.4 (d, 2JCF¼29.6 Hz, Z), 54.1, 54.3, 107.8 (d,
2JCF¼14.1 Hz, E), 108.2 (d, JCF¼19.7 Hz, Z), 113.0, 113.1, 138.1, 138.2,
2
153.7 (d, JCF¼253.0 Hz, Z), 156.1 (d, JCF¼246.1 Hz, E); 19F NMR
1
1
3
4.2.1. (Z/E)-N-Cyclohexyl-3-anthracen-9-yl-2-fluoro-propenamine
(4a). Following the method (A) from sulfone 3a (90 mg, 0.26 mmol),
anthraldehyde (57 mg, 0.27 mmol), and t-BuOK (38 mg, 0.34 mmol)
in THF (5 mL). Purification by flash chromatography (pentane/AcOEt,
gradient from 90:10 to 0:100) afforded successively alkenes (E)-4a
and (Z)-4a (59 mg, 68%) as an orange oil. Compound (E)-4a: 1H NMR
(CDCl3, 376 MHz)
d
ꢀ111.5 (dt, JFH¼21.8 , 18.2 Hz, 1F, E), ꢀ117.0 (dt,
3JFH¼37.4 , 17.4 Hz, 1F, Z); MS (EI) m/z 296 [MþH]þ (47), 214 (50), 95
(100); HRMS (ESI) m/z [MþH]þ calcd for C19H35FN 296.2754, found
296.2752.
4.2.4. (Z/E)-(1S,3S)-Methyl-3-(3-(cyclohexylamino)-2-fluoroprop-1-
enyl)-2,2-dimethyl-cyclopropane-carboxylate (7a). Following the
method (A) from sulfone 3a (100 mg, 0.29 mmol), biocartol-
methylester (48 mg, 0.30 mmol), and t-BuOK (42 mg, 0.37 mmol) in
THF (5 mL). Purification by flash chromatography (pentane/AcOEt,
gradient 90:10 to 0:100) afforded a mixture of (Z/E) 7a (51 mg, 62%)
(CDCl3, 400 MHz) d 0.57e0.84 (m, 6H), 1.16e1.31 (m, 4H),1.86 (s, 1H),
3
3
2.13e2.20 (m, 1H), 3.04 (d, JHF¼19.5 Hz, 2H), 6.74 (d, JHF¼18.4 Hz,
1H), 7.37e7.39 (m, 4H), 7.89e7.91 (m, 2H), 8.05e8.08 (m, 2H), 8.32 (s,
1H); 13C NMR (CDCl3, 100 MHz)
d 23.4, 24.7, 31.7, 42.4 (d,
2JCF¼26.7 Hz), 53.5, 104.1 (d, 2JCF¼25.4 Hz), 124.2, 124.6, 124.8, 125.3,
126.0, 127.6, 129.3, 130.2, 159.7 (d, 1JCF¼258.8 Hz); 19F NMR (CDCl3,
as a yellow oil. 1H NMR (CDCl3, 400 MHz)
d 0.98e1.06 (m, 4H),
1.08e1.16 (m, 18H), 1.55e1.65 (m, 2H), 1.65e1.67 (m, 8H), 1.76e1.79
3
376 MHz)
d
ꢀ104.7 (dt, JFH¼18.4 , 19.5 Hz, 1F); MS (EI) m/z 334
3
[MþH]þ (100), 235 (10); HRMS (ESI) m/z [MþH]þ calcd for C23H25FN
(m, 4H), 2.07 (t, JHH¼9.1 Hz, 2H), 2.37e2.42 (m, 2H), 3.29 (d,
334.1971, found 334.1974. Compound (Z)-4a: 1H NMR (CDCl3,
3JHF¼17.7 Hz, 2H, Z), 3.43 (d, 3JHF¼21.0 Hz, 2H, E), 3.57e3.60 (m, 6H),
3
3
3
400 MHz)
d
1.12e1.34 (m, 6H), 1.60e1.63 (m, 1H), 1.74e1.78 (m, 2H),
5.06 (dd, JHF¼36.7 Hz, JHH¼9.6 Hz, 1H, Z), 5.49 (dd, JHF¼20.7 Hz,
1.95e1.98 (m, 2H), 2.69e2.74 (m,1H), 3.72 (d, 3JHF¼14.6 Hz, 2H), 6.42
3JHH¼8.4 Hz, 1H, E); 13C NMR (CDCl3, 100 MHz)
d 14.6, 24.8, 24.9,
(d, 3JHF¼38.6 Hz, 1H), 7.37e7.44 (m, 4H), 7.92e7.94 (m, 2H), 8.06 (d,
26.0, 26.1, 26.4, 26.5, 27.8, 27.9, 28.4, 28.5, 29.0, 29.1, 30.6, 30.7, 33.1,
3JHH¼7.6 Hz, 2H), 8.35 (s,1H); 13C NMR (CDCl3,100 MHz)
d
24.0, 25.0,
33.2, 33.3, 42.9 (d, JCF¼28.3 Hz, Z), 47.2 (d, JCF¼28.3 Hz, E), 51.2,
2 2
2
2
32.3, 46.2 (d, 2JCF¼28.9 Hz), 54.5, 102.3 (d, 2JCF¼6.9 Hz), 124.1, 124.5,
51.3, 54.9, 55.1, 101.7 (d, JCF¼10.0 Hz, E), 103.3 (d, JCF¼27.3 Hz, Z),
124.9, 125.5, 125.9, 127.6, 128.7, 130.3, 157.2 (d, JCF¼268.4 Hz); 19F
157.8 (d,1JCF¼248.3 Hz, E),160.3 (d,1JCF¼256.8 Hz, Z),171.0,171.5; 19
F
1
NMR (CDCl3, 376 MHz)
d
ꢀ104.9 (dt, 3JFH¼38.6 , 14.6 Hz, 1F, F-9); MS
NMR (CDCl3, 376 MHz)
d
ꢀ107.1 (dt, 3JFH¼20.7 , 21.0 Hz,1F, E), ꢀ116.9
(EI) m/z 334 [MþH]þ (50), 235 (100); HRMS (ESI) m/z [MþH]þ calcd
(dt, 3JFH¼36.7 ,17.7 Hz,1F, Z); MS (EI) m/z 284 [MþH]þ (62),185 (77),
125 (100), 100 (66); HRMS (ESI) m/z [MþH]þ calcd for C16H27FNO2
284.2026, found 284.2015.
for C23H25FN 334.1971, found 334.1969.
4.2.2. (Z/E)-N-Cyclohexyl-3-[4-bromophenyl]-2-fluoro-propenamine
(5a). Following the method (A) from sulfone 3a (70 mg, 0.20 mmol),
4-bromobenzaldehyde (39 mg, 0.21 mmol), and t-BuOK (30 mg,
0.26 mmol) in THF (3 mL). Purification by flash chromatography
(pentane/AcOEt, gradient98:2 to 80:20) afforded successivelyalkenes
(E)-5a and (Z)-5a (56 mg, 88%) as an orange oil. Compound (E)-5a: 1H
4.3. Method (B): general procedure for the preparation of
fluorinated allylic amines (8a), (4bee), (5bee), (6bee), (7bee),
and (8bee) in the presence of NaHMDS
To
a solution of aminosulfone 3 (1 equiv) and aldehyde
NMR (CDCl3, 400 MHz)
d
0.80e1.20 (m, 6H), 1.51e1.54 (m, 1H),
(1.05 equiv) in THF at ꢀ78 ꢁC was added slowly in 5 min a solution
of NaHMDS (1.3 or 2.6 equiv, 1 M in THF). After 15 min at ꢀ78 ꢁC,
the mixture was slowly warmed-up to 0 ꢁC under stirring over 3 h
and quenched by the addition of a saturated solution of NH4Cl
(1 mL) then extracted with CH2Cl2 (2ꢂ5 mL). Combined organic
layers were washed with a 1 M solution of NaOH (1 mL) and brine,
dried over MgSO4, filtered, and evaporated under reduced pressure.
The crude product was purified by flash column chromatography to
give allylamines 8a, 4be8b, 4ce8c, 4de6d, and 4ee7e.
1.61e1.71 (m, 4H), 2.38e2.43 (m, 1H), 3.52 (d, 3JHF¼21.1 Hz, 2H), 6.18
(d, 3JHF¼20.8 Hz, 1H), 7.01 (d, 3JHH¼8.2 Hz, 2H), 7.05 (d, 3JHH¼7.2 Hz,
2H);13CNMR(CDCl3,100 MHz)
d
24.8, 26.0, 33.1, 43.7(d,2JCF¼27.0 Hz),
55.8,109.4 (d, 2JCF¼28.1 Hz),121.0,130.1,131.6,132.5 (d, 3JCF¼13.4 Hz),
1
160.3 (d, JCF¼255.0 Hz); 19F NMR (CDCl3, 376 MHz)
d
ꢀ104.1 (dt,
3JHF¼20.8 , 21.1 Hz,1F); MS (EI) m/z 314 [M(C15H2081BrFN)þH]þ (100),
312 [M(C15H2079BrFN)þH]þ (100), 213 (67), 134 (20); HRMS (ESI) m/z
[MþH]þ calcd for C15H2079BrFN 312.0763, found 312.0777. Compound
(Z)-5a: 1H NMR (CDCl3, 400 MHz)
d 0.76e1.30 (m, 6H), 1.50e1.53 (m,
1H), 1.53e1.56 (m, 2H), 1.56e1.87 (m, 2H), 2.43e2.59 (m, 1H), 3.48 (d,
4.3.1. N-[2-(4-tert-Butyl-cyclohexylidene)-2-fluoroethyl]-cyclohexyl-
amine (8a). Following the method (B) from sulfone 3a (100 mg,
0.29 mmol), tert-butylcyclohexanone (46 mg, 0.30 mmol), and
3JHF¼15.7 Hz, 2H), 5.60 (d, 3JHF¼38.7 Hz,1H), 7.28 (d, 3JHH¼8.6 Hz, 2H),
7.36 (d, 3JHH¼8.5 Hz, 2H); 13C NMR (CDCl3,100 MHz)
d 23.8, 24.8, 31.8,
46.3 (d, 2JCF¼28.9 Hz), 54.6, 105.9 (d, 2JCF¼6.9 Hz), 120.0, 129.1, 130.5,
NaHMDS (380 mL, 0.38 mmol, 1 M in THF) in THF (5 mL). Purifica-
3
1
130.9 (d, JCF¼2.2 Hz), 157.2 (d, JCF¼268.4 Hz); 19F NMR (CDCl3,
tion by flash chromatography (pentane/AcOEt, gradient 90:10 to
3
376 MHz)
d
ꢀ106.8 (dt, JFH¼38.7, 15.7 Hz, 1F); MS (EI) m/z 314 [M
70:30) afforded compound 8a (64 mg, 78%) as a yellow oil. 1H NMR
(C15H2081BrFN)þH]þ (100), 312 [M(C15H2079BrFN)þH]þ (50), 213
(100), 134 (15); HRMS (ESI) m/z [MþH]þ calcd for C15H2079BrFN
312.0763, found 312.0777.
(CDCl3, 400 MHz) d 0.77 (s, 9H), 0.88e1.18 (m, 9H), 1.50e1.56 (m,
2H), 1.65e1.68 (m, 2H), 1.76e1.79 (m, 4H), 1.80e2.10 (m, 1H),
3
2.30e2.42 (m, 2H), 2.84 (m, 1H), 3.36 (d, JHF¼23.2 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) d 24.9, 25.0, 25.6, 25.7, 26.0, 27.5, 27.6, 28.2,
2
4.2.3. (Z/E)-N-Cyclohexyl-2-fluoro-2,12-tridecadienamine (6a). Follo-
wing the method (A) from sulfone 3a (70 mg, 0.20 mmol), undecenal
(43 mg, 0.21 mmol), and t-BuOK (30 mg, 0.26 mmol) in THF (3 mL).
Purification by flash chromatography (pentane/AcOEt, gradient 98:2
to 90:10) afforded a mixture of (Z/E) 6a (47 mg, 79%) as a yellow oil.
28.3, 32.4, 33.0, 33.3, 42.7 (d, JCF¼30.3 Hz), 48.0, 55.1, 118.3 (d,
2JCF¼14.9 Hz), 148.9 (d, 1JCF¼241.7 Hz); 19F NMR (CDCl3, 376 MHz)
3
d
ꢀ121.8 (t, JFH¼23.2 Hz, 1F); MS (EI) m/z 282 [MþH]þ (100), 163
(27), 107 (28), 100 (92); HRMS (ESI) m/z [MþH]þ calcd for C18H33FN
282.2597, found 282.2589.
1H NMR (CDCl3, 400 MHz)
d 0.78e0.81 (m, 3H), 1.08e1.20 (m, 28H),
1.50e2.30 (m, 19H), 2.42e2.58 (m, 2H), 3.02e3.12 (m, 2H), 3.32 (d,
4.3.2. (Z/E)-N-[3-(Anthracen-9-yl)-2-fluoro-2-propenyl]-pyrrolidine
(4b). Following the method (B) from sulfone 3b (100 mg,
0.32 mmol), anthraldehyde (68 mg, 0.33 mmol), and NaHMDS
3JHF¼17.4 Hz, 2H, Z), 3.36 (d, 3JHF¼18.2 Hz, 2H, E), 4.30e4.63 (m, 2H),
3
3
4.70 (dt, JHF¼37.4 Hz, JHH¼7.5 Hz, 1H, Z), 4.84e4.94 (m, 4H), 5.12

1402
C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
(420
m
L, 0.42 mmol, 1 M in THF) in THF (5 mL). Purification by flash
by chromatography (pentane/AcOEt, gradient 90:10 to 70:30)
chromatography (pentane/AcOEt, gradient 90:10 to 0:100) afforded
afforded compound 8b (76 mg, 95%) as a yellow oil. 1H NMR (CDCl3,
successively alkenes (E)-4b and (Z)-4b (80 mg, 83%) as a yellow-
400 MHz) d 0.54 (s, 9H), 0.83e0.90 (m, 1H), 0.90e0.98 (m, 2H), 1.03
(m, 1H), 1.12e1.23 (m, 1H), 1.49e1.52 (m, 1H), 1.71e1.79 (m, 6H),
2.38e2.42 (m,1H), 2.50e2.54 (m, 3H), 2.84e2.88 (m,1H), 3.12e3.29
green oil. Compound (E)-4b: 1H NMR (CDCl3, 400 MHz)
d
1.51e1.54
3
(m, 4H), 2.19e2.20 (m, 4H), 2.93 (d, JHF¼19.3 Hz, 2H), 6.74 (d,
3JHF¼18.7 Hz, 1H), 7.40e7.44 (m, 4H), 7.90e7.93 (m, 2H), 8.05e8.08
(m, 2H); 13C NMR (CDCl3,100 MHz)
d
23.4, 25.6 (d, 3JCF¼7.8 Hz), 27.5,
(m, 2H), 8.34 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d
23.4, 52.7 (d,
28.3 (d, 3JCF¼7.6 Hz), 32.4, 48.0, 51.6 (d, 2JCF¼30.3 Hz), 53.6, 119.4 (d,
2JCF¼24.1 Hz), 53.9, 105.6 (d, JCF¼25.2 Hz), 125.2, 125.8, 125.9,
2JCF¼14.9 Hz), 148.9 (d, 1JCF¼241.7 Hz); 19F NMR (CDCl3, 376 MHz)
2
127.0, 128.7, 130.3, 130.4, 131.3, 160.1 (d, JCF¼260.3 Hz); 19F NMR
d
ꢀ115.0 (t, JFH¼23.07 Hz, 1F); MS (EI) m/z 254 [MþH]þ (58), 163
1
3
(CDCl3, 376 MHz)
d
ꢀ102.3 (dt, 3JFH¼18.7 , 19.3 Hz, 1F); MS (EI) m/z
(22),135 (16), 123 (29),121 (33),113 (33),107 (100), 95 (17), 93 (34);
HRMS (ESI) m/z [MþH]þ calcd for C16H29FN 254.2284, found
254.2272.
306 [MþH]þ (90), 235 (100); HRMS (ESI) m/z [MþH]þ calcd for
C21H21FN 306.1658, found 306.1667. Compound (Z)-4b: 1H NMR
(CDCl3, 400 MHz)
d 1.81e1.85 (m, 4H), 2.73e2.76 (m, 4H), 3.51 (d,
3
3JHF¼15.3 Hz, 2H), 6.41 (d, JHF¼38.1 Hz, 1H), 7.35e7.42 (m, 4H),
4.3.6. (Z/E)-N-[(3-Anthracen-9-yl)-2-fluoro-2-propenyl]-aspartic
acid di-tert-butyl ester (4c). Following the method (B) from sulfone
3c (100 mg, 0.21 mmol), anthraldehyde (46 mg, 0.22 mmol), and
NaHMDS (540 mL, 0.54 mmol, 1 M in THF) in THF (5 mL). Purifica-
tion by flash chromatography (pentane/AcOEt, gradient 95:5 to
90:10) afforded a mixture of (Z/E) 4c (74 mg, 74%) as an orange oil.
7.89e7.91 (m, 2H), 8.03e8.05 (m, 2H), 8.32 (s, 1H); 13C NMR (CDCl3,
100 MHz)
d
23.7, 54.3, 56.7 (d, 2JCF¼28.0 Hz),104.2 (d, 2JCF¼13.5 Hz),
125.1, 125.6, 126.0, 126.6, 127.0, 128.7, 129.7, 131.3, 158.3 (d,
1JCF¼265.0 Hz); 19F NMR (CDCl3, 376 MHz)
d
ꢀ100.6 (dt, 3JFH¼38.1 ,
15.3 Hz, 1F); MS (EI) m/z 306 [MþH]þ (5), 235 (100); HRMS (ESI)
m/z [MþH]þ calcd for C21H21FN 306.1658, found 306.1660.
1H NMR (CDCl3, 400 MHz)
d 1.03 (s, 9H), 1.28 (s, 9H), 1.37 (s, 9H),
2
3
1.44 (s, 9H), 2.23 (dd, JHH¼15.7 Hz, JHH7.2 Hz, 1H, E), 2.33 (dd,
3
2
4.3.3. (Z/E)-N-(2-Fluoro-2,12-tridecadienyl)-pyrrolidine (6b). Follo-
wing the method (B) from sulfone 3b (100 mg, 0.32 mmol), unde-
2JHH¼15.7 Hz, JHH¼5.8 Hz, 1H, E), 2.58 (dd, JHH¼15.7 Hz,
3JHH¼7.4 Hz, 1H, Z), 2.69 (dd, 2JHH¼15.7 Hz, 3JHH¼5.3 Hz, 1H, Z), 2.94
3
3
cenal (56 mg, 0.33 mmol), and NaHMDS (420
mL, 0.42 mmol, 1 M in
(dd, JHF¼23.5 Hz, JHH¼14.6 Hz, 1H, E), 3.13e3.21 (m, 2H, E), 3.54
3 3 3
THF) in THF (5 mL). Purification by chromatography (pentane/AcOEt,
gradient 90:10 to 0:100) afforded a mixture of (Z/E) 6b (63 mg, 74%)
(dd, JHF¼14.3 Hz, JHH¼13.7 Hz, 1H, Z), 3.74 (dd, JHH¼5.3 , 7.0 Hz,
3 3
1H, Z), 3.77 (dd, JHF¼14.6 Hz, JHH¼15.9 Hz, 1H, Z), 6.47 (d,
3JHF¼38.6 Hz,1H, Z), 6.73 (d, 3JHF¼18.3 Hz,1H, E), 7.29e7.46 (m, 9H),
7.91e7.94 (m, 3H), 8.04e8.07 (m, 3H), 8.13 (d, 3JHH¼8.4 Hz,1H), 8.34
as an orange oil. 1H NMR (CDCl3, 400 MHz)
d 1.02e1.49 (m, 24H),
1.74e1.75 (m, 8H), 1.93e2.02 (m, 8H), 2.48e2.50 (m, 8H), 3.06 (d,
3JFH¼18.4 Hz, 2H, Z), 3.18 (d, JHF¼22.4 Hz, 2H, E), 4.63 (dt,
(s, 2H); 13C NMR (CDCl3, 100 MHz)
d
26.6, 26.8, 26.9, 27.0, 38.2, 38.6,
3
3
2
2
3JHF¼37.2 Hz, JHH¼7.6 Hz, 1H, Z), 4.84e4.94 (m, 4H), 5.17 (dt,
44.3, 44.6, 47.7 (d, JCF¼30.9 Hz, Z), 56.8 (d, JCF¼24.9 Hz, E), 79.8,
80.1, 80.2, 80.8, 101.9 (d, 2JCF¼13.0 Hz, E), 104.1 (d, 2JCF¼25.3 Hz, Z),
124.0, 124.2, 124.3, 124.5, 124.6, 124.8, 124.9, 125.0, 125.3, 125.4,
3JHF¼22.4 Hz, 3JHH¼8.0 Hz, 1H, E), 5.80 (ddt, 4JHH¼6.8 Hz,
2
3JHH¼10.4 Hz, JHH¼17.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 22.4,
1
22.5, 24.3, 24.4, 24.5, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.6, 28.7, 28.8,
125.5, 125.8, 126.0, 127.6, 128.6, 130.3, 157.7 (d, JCF¼263.5 Hz, Z),
2
28.9, 32.7, 32.8, 50.5 (d, JCF¼27.1 Hz, E), 52.8, 52.9, 55.3 (d,
159.4 (d, 1JCF¼259.5 Hz, E), 168.8, 169.1, 171.0, 171.6; 19F NMR (CDCl3,
2JCF¼27.9 Hz, Z), 66.9, 107.7 (d, JCF¼14.5 Hz, E), 108.2 (d,
376 MHz)
d
ꢀ103.3 (m, 1F, Z), ꢀ103.8 (ddd, 3JHF¼23.5 Hz, 3JHF¼18.3,
2
2JCF¼20.0 Hz, Z), 113.0, 113.1, 137.8, 138.1, 155.3 (d, 1JCF¼254.8 Hz, Z),
16.0 Hz, 1F, E); MS (EI) m/z 480 [MþH]þ (67), 424 (100), 368 (74);
HRMS (ESI) m/z [MþH]þ calcd for C29H35FNO4 480.2550, found
480.2538.
155.5 (d, 1JCF¼248.1 Hz, E); 19F NMR (CDCl3, 376 MHz)
d
ꢀ105.7 (dt,
3JFH¼22.4 , 22.4 Hz, 1F, E), ꢀ113.2 (dt, JFH¼37.2 , 18.4 Hz, 1F, Z); MS
(EI) m/z 268 [MþH]þ (42), 208 (10), 95 (100), 93 (44), 81 (50); HRMS
(ESI) m/z [MþH]þ calcd for C17H31FN 268.2441, found 268.2441.
3
4.3.7. (Z/E)-N-[3-(4-Bromo-phenyl)-2-fluoro-2propenyl]-aspartic
acid di-tert-butyl ester (5c). Following the method (B) from sulfone
3c (100 mg, 0.21 mmol), 4-bromobenzaldehyde (42 mg, 0.22 mmol),
4.3.4. (Z/E)-(1S,3S)-Methyl3-(2-fluoro-3-(pyrrolidin-1-yl)prop-1-
enyl)-2,2-dimethyl-cyclopropane-carboxylate (7b). Following the
method (B) from sulfone 3b (100 mg, 0.32 mmol), biocartol-
and NaHMDS (540 mL, 0.54 mmol, 1 M in THF) in THF (5 mL). Purifi-
cation by flash chromatography (pentane/AcOEt, gradient 95:5 to
methylester (52 mg, 0.33 mmol), and NaHMDS (420 mL, 0.42 mmol,
90:10) afforded a mixture of (Z/E) 5c (70 mg, 72%) as an orange oil. 1H
1 M in THF) in THF (5 mL). Purification by flash chromatography
(pentane/AcOEt gradient 90:10 to 0:100) afforded a mixture of (Z/E)
7b (61 mg, 73%) as a colorless oil. 1H NMR (CDCl3, 400 MHz)
NMR (CDCl3, 400 MHz) d 1.36e1.41 (m, 36H), 2.03e2.13 (m, 2H),
2.44e2.57 (m, 4H), 3.29e3.53 (m, 6H), 5.59 (d, 3JHF¼38.9 Hz,1H), 6.17
(d, 3JHF¼20.3 Hz, 1H), 7.03e7.10 (m, 4H), 7.17e7.35 (m, 4H); 13C NMR
d
1.13e1.14 (m, 6H), 1.16e1.18 (m, 6H), 1.58e1.66 (m, 2H), 1.69e1.78
(CDCl3, 100 MHz) d 26.9, 27.0, 27.1, 28.6, 38.2, 38.4, 44.2 (d,
(m, 8H), 2.08 (t, 3JHH¼9.0 Hz, 2H), 2.49e2.51 (m, 8H), 3.11 (m, 2H, Z),
2JCF¼12.3 Hz, E), 48.1 (d, JCF¼30.1 Hz, Z), 56.6, 56.8, 80.1, 80.2, 80.7,
80.8, 108.9 (d, 2JCF¼27.8 Hz, E), 110.8, 119.9 (d, 2JCF¼30.8 Hz, Z), 121.4,
122.1, 122.9, 125.4, 129.2, 130.4, 134.4, 157.6 (d, 1JCF¼267.9 Hz, Z),158.7
2
3
3.25 (d, JHF¼22.2 Hz, 2H, E), 3.54e3.61 (m, 6H), 5.08 (dd,
3JHF¼36.1 Hz, JHH¼9.6 Hz, 1H, Z), 5.53 (dd, JHF¼20.8 Hz,
3
3
3JHH¼9.6 Hz, 1H, E); 13C NMR (CDCl3, 100 MHz)
d
14.6, 14.7, 23.5,
(d, JCF¼255.7 Hz, E), 171.3, 171.5, 172.1, 172.2; 19F NMR (CDCl3,
1
26.4, 26.5, 27.8, 27.9, 28.4, 28.5, 28.9, 29.1, 30.7, 30.8, 51.2, 51.3, 52.0
376 MHz)
d
ꢀ101.6 (dt, 3JFH¼20.3 , 23.7 Hz, E), ꢀ106.2 (dt, 3JFH¼38.9,
(d, JCF¼27.2 Hz, Z), 53.8, 56.5 (d, JCF¼26.7 Hz, E), 102.8 (d,
13.9 Hz, Z); MS (EI) m/z 460 [M(C21H3081BrFNO4)þH]þ (90), 458 [M
(C21H3079BrFNO4)þH]þ (90), 402 (100), 346 (69); HRMS (ESI) m/z
[MþH]þ calcd for C21H3079BrFNO4 458.1342, found 458.1343.
2
2
2JCF¼10.1 Hz, E), 104.3 (d, 2JCF¼27.27 Hz, Z), 158.1 (d, 1JCF¼250.2 Hz,
E), 158.6 (d, JCF¼258.0 Hz, Z), 171.0, 171.5; 19F NMR (CDCl3,
1
3
376 MHz)
d
ꢀ100.5 (dt, JFH¼20.8 , 22.2 Hz, 1F, E), ꢀ112.8 (dt,
3JFH¼36.1 , 19.1 Hz, 1F, Z); MS (EI) m/z 256 [MþH]þ (80), 185 (53),
125 (100), 105 (16); HRMS (ESI) m/z [MþH]þ calcd for C14H23FNO2
256.1713, found 256.1720.
4.3.8. (Z/E)-N-(2-Fluoro-2,12-tridecadienyl)-aspartic acid di-tert-
butyl ester (6c). Following the method (B) from sulfone 3c (100 mg,
0.21 mmol), undecenal (38 mg, 0.22 mmol), and NaHMDS (540 mL,
0.54 mmol, 1 M in THF) in THF (5 mL). Purification by flash chro-
matography (pentane/AcOEt, 95:5) afforded a mixture of (Z/E) 6c
4.3.5. N-[2-(4-tert-Butyl-cyclohexylidene)-2-fluoroethyl]-pyrrolidine
(8b). Following the method (B) from sulfone 3b (100 mg,
0.32 mmol), tert-butylcyclohexanone (50 mg, 0.33 mmol), and
(71 mg, 75%) as a yellow oil. 1H NMR (CDCl3, 400 MHz)
d 1.25e1.31
(m, 31H), 1.37 (s, 18H),1.39 (s, 18H), 1.55e1.58 (m, 1H),1.86e1.99 (m,
3
NaHMDS (420
mL, 0.42 mmol,1 M in THF) in THF (5 mL). Purification
6H), 2.42e2.48 (m, 2H), 3.10e3.43 (m, 4H), 4.63 (dt, JHF¼37.5 Hz,

C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
1403
3
3JHH¼7.4 Hz, 1H, Z), 4.84e4.94 (m, 4H), 5.08 (dt, JHF¼21.4 Hz,
(90); HRMS (ESI) m/z [MþH]þ calcd for C28H27FNO2 428.2026,
3JHH¼7.4 Hz, 1H, E), 5.68e5.79 (m, 2H); 13C NMR (CDCl3, 100 MHz)
found 428.2018.
d
22.4, 22.5, 24.2, 24.3, 26.9, 27.0, 27.1, 27.8, 27.9, 28.0, 28.1, 28.2,
28.3, 28.4, 28.5, 28.9, 29.0, 32.7, 38.4, 38.5, 43.3 (d, 2JCF¼28.5 Hz, E),
4.3.12. (Z/E)-N-[3-(4-Bromo-phenyl)-2-fluoro-2propenyl]-phenylala-
nine ethyl ester (5d). Following the method (B) from sulfone 3d
(100 mg, 0.23 mmol), 4-bromobenzaldehyde (45 mg, 0.24 mmol),
and NaHMDS (600 mL, 0.60 mmol, 1 M in THF) in THF (5 mL). Puri-
fication by flash chromatography (pentane/AcOEt, 95:5) afforded
successively alkenes (E)-5d and (Z)-5d (54 mg, 58%) as an orange oil.
47.5 (d, 2JCF¼30.4 Hz, Z), 56.3, 79.9, 80.0, 80.4,106.6 (d, 2JCF¼14.4 Hz,
2
E), 107.9 (d, JCF¼19.9 Hz, Z), 113.0, 113.1, 113.2, 138.0, 138.1, 138.2,
155.5 (d, 1JCF¼253.6 Hz, Z), 155.8 (d, 1JCF¼247.8 Hz, E), 169.0, 169.1,
3
171.5, 171.6; 19F NMR (CDCl3, 376 MHz)
d
ꢀ109.6 (dt, JFH¼21.4 ,
21.5 Hz, 1F, E), ꢀ116.3 (dt, 3JFH¼37.5 , 15.7 Hz, 3F, Z); MS (EI) m/z 442
[MþH]þ (50), 386 (81), 330 (100); HRMS (ESI) m/z [MþH]þ calcd for
C25H45FNO4 442.3333, found 442.3349.
Compound (E)-5d: 1H NMR (CDCl3, 400 MHz)
d
1.05 (t, 3JHH¼7.2 Hz,
3H), 1.12e1.22 (m, 1H), 2.83 (dd, 2JHH¼13.5 Hz, 3JHH¼7.9 Hz, 1H), 2.91
2
3
(dd, JHH¼13.5 Hz, JHH¼6.1 Hz, 1H), 3.27e3.46 (m, 3H), 3.94e4.03
(m, 2H), 6.16 (d, 3JFH¼20.2 Hz, 1H), 6.93e6.96 (m, 2H), 7.09e7.11 (m,
4.3.9. (Z/E)-N-[2-Fluoro-3-(3-methoxycarbonyl-2,2-dimethyl-cyclo-
propyl)-2-propenyl]-aspartic acid di-tert-butyl ester (7c). Following
the method (B) from sulfone 3c (100 mg, 0.21 mmol), bio-
2H), 7.15e7.23 (m, 3H), 7.29e7.36 (m, 2H); 13C NMR (CDCl3,
2
100 MHz)
d
14.1, 39.7, 45.3 (d, JCF¼27.4 Hz), 60.8, 61.9, 110.1 (d,
cartolmethylester (35 mg, 0.23 mmol), and NaHMDS (540
mL,
2JCF¼27.7 Hz),121.2,126.8,128.4,129.2,130.1,130.9,132.2,137.1,159.5
1
0.54 mmol, 1 M in THF) in THF (5 mL). The purification by flash
chromatography (Pentane/AcOEt, 95:5) afforded a mixture of (Z/E)
7c (70 mg, 77%) as a yellow oil. 1H NMR (CDCl3, 400 MHz)
(d, JCF¼255.7 Hz), 173.8; 19F NMR (CDCl3, 376 MHz)
d
ꢀ101.9 (dt,
3JFH¼20.2 , 23.7 Hz, 1F); MS (EI) m/z 408 [M(C20H2281BrFNO2)þH]þ
(100), 406 [M(C20H2279BrFNO2)þH]þ (100), 213 (48), 134 (7); HRMS
(ESI) m/z [MþH]þ calcd for C20H2279BrFNO2 406.0818, found
d
1.12e1.13 (m, 6H), 1.15 (s, 6H), 1.37 (s, 18H), 1.39e1.40 (m, 18H),
1.62e1.71 (m, 3H), 2.03e2.08 (m, 3H), 2.48e2.57 (m, 4H),
3.20e3.42 (m, 6H), 3.45 (s, 3H), 3.55 (s, 3H), 5.08 (dd, 3JHF¼36.2 Hz,
406.0821. Compound (Z)-5d: 1H NMR (CDCl3, 400 MHz)
d 1.10 (t,
3JHH¼7.1 Hz, 3H), 1.43e1.63 (m, 1H), 2.86 (dd, 2JHH¼13.7, 7.4 Hz, 1H),
3JHH¼9.7 Hz, 1H, Z), 5.46 (dd, 3JHF¼20.4 Hz, 3JHH¼9.4 Hz, 1H, E); 13
C
2.94 (dd, JHH¼13.7, 7.4 Hz, 1H), 3.18e3.44 (m, 2H), 3.50 (t,
2
3
3
NMR (CDCl3, 100 MHz)
d
14.6, 26.3, 26.4, 26.5, 27.8, 27.9, 28.0, 28.1,
3JHH¼6.9 Hz, 1H), 4.04 (q, JHH¼7.1 Hz, 2H), 5.39 (d, JFH¼38.8 Hz,
28.4, 28.5, 28.7, 28.8, 30.7, 30.8, 39.4, 39.5, 44.8 (d, 2JCF¼28.2 Hz, E),
1H), 7.12e7.15 (m, 2H), 7.16e7.24 (m, 5H), 7.33e7.34 (m, 2H); 13C
48.8 (d, 2JCF¼28.8 Hz, Z), 51.2 (d, 3JCF¼8.2 Hz, Z), 57.4 (d, 3JCF¼4.5 Hz,
NMR (CDCl3, 100 MHz)
d
14.1, 39.4, 48.9 (d, 2JCF¼27.3 Hz), 60.9, 61.9,
2
E), 80.8, 80.9, 81.4, 81.5, 102.1 (d, JCF¼9.8 Hz, E), 103.9 (d,
106.1 (d, 2JCF¼16.5 Hz), 120.8, 126.8, 128.4, 129.3, 129.9, 130.0, 132.0,
2JCF¼27.1 Hz, Z), 158.5 (d, 1JCF¼249.5 Hz, E), 158.8 (d, 1JCF¼256.9 Hz,
137.1, 159.4 (d, JCF¼255.8 Hz), 174.1; 19F NMR (CDCl3, 376 MHz)
1
Z), 170.0, 170.1, 171.0, 171.3, 172.4, 172.5; 19F NMR (CDCl3, 376 MHz)
d
ꢀ106.4 (dt, JFH¼38.8 , 13.4 Hz, 1F); MS (EI) m/z 408 [M
3
d
ꢀ105.9 (dt, JFH¼20.4 , 22.2 Hz, 1F, E), ꢀ115.9 (dt, JFH¼36.2,
(C20H2281BrFNO2)þH]þ (82), 406 [M(C20H2279BrFNO2)þH]þ (82), 213
(100), 134 (9); HRMS (ESI) m/z [MþH]þ calcd for C20H2279BrFNO2
406.0818, found 406.0807.
3
3
17.2 Hz, 1F, Z); MS (EI) m/z 430 [MþH]þ (100), 374 (97), 318 (60);
HRMS (ESI) m/z [MþH]þ calcd for C22H37FNO6 430.2605, found
430.2609.
4.3.13. (Z/E)-N-(2-Fluoro-2,12-tridecadienyl)-phenylalanine ethyl ester
4.3.10. N-[2-(4-tert-Butyl-cyclohexylidene)-2-fluoro-2-propenyl]-as-
partic acid di-tert-butyl ester (8c). Following the method (B) from
sulfone 3c (100 mg, 0.21 mmol), 4-tert-butylcyclohexanone (35 mg,
(6d). Following the method (B) from sulfone 3d (100 mg,
0.23 mmol), undecenal (41 mg, 0.24 mmol), and NaHMDS (600 mL,
0.60 mmol, 1 M in THF) in THF (5 mL). Purification by flash chro-
matography (pentane/AcOEt, 95:5) afforded a mixture of (Z/E) 6d
0.23 mmol), and NaHMDS (540 mL, 0.54 mmol, 1 M in THF) in THF
(5 mL). Purification by flash chromatography (pentane/AcOEt, 95:5)
(19 mg, 21%) as a yellow oil. 1H NMR (CDCl3, 400 MHz)
d 1.08 (t,
afforded compound 8c (25 mg, 27%) as a yellow oil. 1H NMR (CDCl3,
3JHH¼7.1 Hz, 3H),1.09 (t, 3JHH¼7.1 Hz, 3H),1.18e1.30 (m, 26H), 1.69 (s,
400 MHz)
d 0.84 (s, 9H), 0.92e0.99 (m, 2H), 1.01e1.12 (m, 1H), 1.45
2H), 1.81 (q, 3JHH¼8.0 Hz, 2H), 1.94e1.99 (m, 5H), 2.87e2.90 (m, 3H),
3
3
(s, 9H), 1.50 (s, 9H), 1.55e1.63 (m, 2H), 1.82e1.87 (m, 3H), 2.53e2.56
(m, 1H), 2.60e2.61 (m, 2H), 2.89e2.92 (m, 1H), 3.38e3.50 (m, 3H);
3.03e3.29 (m, 4H), 3.48 (t, JHH¼6.9 Hz, 2H), 4.03 (q, JHH¼7.1 Hz,
2H), 4.04 (t, 3JHH¼7.1 Hz, 2H), 4.54 (dt, 3JFH¼37.1 Hz, 3JHH¼7.5 Hz, 1H,
13C NMR (CDCl3, 125 MHz)
d
25.5, 25.6, 27.5, 28.0, 28.1, 32.4, 39.6,
Z), 4.83e4.96 (m, 4H), 5.05 (dt, JFH¼21.3 Hz, JHH¼8.0 Hz, 1H, E),
3
3
2
2
44.5 (d, JCF¼30.1 Hz), 57.3, 80.9, 81.3, 81.4, 118.8 (d, JCF¼14.5 Hz),
5.69e5.77 (m, 2H), 7.10e7.20 (m, 10H); 13C NMR (CDCl3, 125 MHz)
1
148.7 (d, JCF¼243.2 Hz), 170.0, 172.7; 19F NMR (CDCl3, 470 MHz)
d 13.0, 21.9, 22.3, 22.4, 22.7, 24.1, 24.2, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2,
d
ꢀ119.6 (m, 1F); MS (EI) m/z 428 [MþH]þ (100), 372 (83), 316 (43),
28.3, 28.4, 28.5, 28.6, 28.9, 32.7, 32.8, 38.6, 38.7, 43.1 (d, 2JCF¼28.6 Hz,
E), 47.3 (d, 2JCF¼30.7 Hz, Z), 60.4, 60.6, 106.7 (d, 2JCF¼14.3 Hz, Z),108.1
(d, 2JCF¼19.7 Hz, Z), 113.0, 113.1, 125.7, 125.8, 127.3, 127.4, 128.1, 128.2,
211 (43); HRMS (ESI) m/z [MþH]þ calcd for C24H43FNO4 428.3176,
found 428.3188.
1
136.0, 136.1, 138.1, 138.2, 155.3 (d, JCF¼253.6 Hz, Z), 155.7 (d,
4.3.11. (Z/E)-N-[3-(Anthracen-9-yl)-2-fluoro-2-propenyl]-phenylala-
nine ethyl ester (4d). Following the method (B) from sulfone 3d
(100 mg, 0.23 mmol), anthraldehyde (49 mg, 0.24 mmol), and
1JCF¼247.8 Hz, E), 172.9, 173.1; 19F NMR (CDCl3, 376 MHz)
d
ꢀ109.9
(dt, 3JFH¼21.3 , 21.6 Hz,1F, E), ꢀ116.5 (dt, 3JFH¼37.1,15.8 Hz,1F, Z); MS
(EI) m/z 390 [MþH]þ (100), 316 (50), 194 (12); HRMS (ESI) m/z
[MþH]þ calcd for C24H37FNO2 390.2808, found 390.2824.
NaHMDS (600 mL, 0.60 mmol, 1 M in THF) in THF (5 mL). Purifi-
cation by flash chromatography (pentane/AcOEt, gradient 95:5 to
70:30) afforded (E)-4d (59 mg, 60%) as an orange oil, the Z alkene
appeared as traces. Compound (E)-4d: 1H NMR (CDCl3, 400 MHz)
4.3.14. (Z/E)-N-[3-(Anthracen-9-yl)-2-fluoro-2-propenyl]-isoindole-
1,3-dione (4e). Following the method (B) from sulfone 3e (90 mg,
0.23 mmol), anthraldehyde (49 mg, 0.24 mmol), and NaHMDS
3
3
d
0.76 (t, JHH¼7.1 Hz, 3H), 1.65 (s, 1H), 2.64 (d, JHH¼6.8 Hz, 2H),
3
2.85e3.11 (m, 2H), 3.22 (t, JHF¼6.8 Hz, 1H), 3.55e3.69 (m, 2H),
6.72 (d, 3JHF¼18.4 Hz, 1H, E), 6.82e6.87 (m, 2H), 7.06e7.10 (m, 3H),
7.36e7.41 (m, 4H), 7.91e7.93 (m, 3H), 8.00e8.02 (m, 1H),
(300 mL, 0.3 mmol, 1 M in THF) in THF (4 mL). The crude product
was purified by flash chromatography (pentane/AcOEt, gradient
95:5 to 70:30) to afford a mixture of (Z/E) 4e (62 mg, 70%) as
8.07e8.10 (m, 1H), 8.34 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d
12.7,
a yellow oil. 1H NMR (CDCl3, 400 MHz)
d
4.16 (d, 3JHF¼11.7 Hz, 2H),
38.3, 44.3 (d, 2JCF¼26.3 Hz, E), 59.3, 60.5, 104.2 (d, 2JCF¼25.2 Hz, E),
4.19 (d, JHF¼12.0 Hz, 2H), 6.55 (d, JHF¼37.2 Hz, 1H, Z), 6.88 (d,
3JHF¼18.4 Hz, 1H, E), 7.36e7.48 (m, 9H), 7.52e7.53 (m, 5H),
7.69e7.71 (m, 2H), 7.86e7.93 (m, 6H), 8.03e8.04 (m, 2H), 8.09e8.13
(m, 2H), 8.24 (s, 1H, E), 8.33 (s, 1H, Z); 13C NMR (CDCl3, 100 MHz)
3
3
124.2, 124.6, 124.9, 125.0, 125.5, 126.0, 127.2, 127.7, 128.0, 129.3,
130.3, 135.9, 159.3 (d, JCF¼259.2 Hz, E), 172.5; 19F NMR (CDCl3,
1
376 MHz)
d
ꢀ103.8 (m, 1F, E); MS (EI) m/z 428 [MþH]þ (100), 235

1404
C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
2
2
d
38.7 (d, JCF¼33.5 Hz), 105.2 (d, JCF¼12.9 Hz), 123.6, 123.7, 125.2,
51.3, 104.3 (d, 2JCF¼7.8 Hz, E), 105.8 (d, 2JCF¼25.1 Hz, Z), 123.4, 132.0,
1
1
125.9, 126.0, 127.3, 128.6, 129.7, 131.3, 132.0, 134.4, 152.6 (d,
134.0, 134.1, 154.5 (d, JCF¼257.5 Hz, Z), 154.6 (d, JCF¼250.1 Hz, E),
1JCF¼264.4 Hz), 167.6; 19F NMR (CDCl3, 376 MHz)
d
ꢀ104.3 (dt,
167.4, 167.5, 171.1, 171.2; 19F NMR (CDCl3, 376 MHz)
d
ꢀ107.4 (dt,
3JFH¼18.4 , 11.7 Hz, 1F, E), ꢀ106.5 (dt, JFH¼37.2 , 12.0 Hz, 1F, Z); MS
(EI) m/z 382 [MþH]þ (100), 362 (26), 215 (11); HRMS (ESI) m/z
[MþH]þ calcd for C25H18FNO2 382.1243, found 382.1254.
3JFH¼19.6 , 19.7 Hz, 1F, E), ꢀ118.0 (ddd, JFH¼13.4 , 18.4 , 35.5 Hz, 1F,
FZ); MS (EI) m/z 332 [MþH]þ (100), 318 (38), 300 (93), 280 (7); HRMS
(ESI) m/z [MþH]þ calcd for C18H19FNO4 332.1298, found 332.1290.
3
3
4.2.15. (Z/E)-N-[3-(4-Bromo-phenyl)-2-fluoro-2-propenyl]-iso-
indole-1,3-dione (5e). Following the method (B) from sulfone 3e
(100 mg, 0.25 mmol), 4-Bromobenzaldehyde (49 mg, 0.26 mmol),
4.3.18. N-[2-(4-tert-Butyl-cyclohexylidene)-2-fluoro-ethyl]-iso-
indole-1,3-dione (8e). Following the method (B) from sulfone 3e
(90 mg, 0.23 mmol), 4-tert-butylcyclohexanone (37 mg, 0.24 mmol),
and NaHMDS (320
mL, 0.32 mmol, 1 M in THF) in THF (4 mL). The
and NaHMDS (300 mL, 0.30 mmol, 1 M in THF) in THF (4 mL). The
crude product was purified by flash chromatography (pentane/
AcOEt, gradient 95:5 to 90:10) to afford successively alkenes (E)-5e
and (Z)-5e (50 mg, 56%) as a yellow oil. Compound (E)-5e: 1H NMR
crudeproductwaspurifiedbyflashchromatography(pentane/AcOEt,
95:5) to afford compound 8e (48 mg, 63%) as a yellow oil. 1H NMR
(CDCl3, 400 MHz) d 0.92 (s, 9H), 0.97e1.04 (m,1H),1.11e1.29 (m, 2H),
(CDCl3, 400 MHz)
d
4.54 (d, 3JHF¼15.4 Hz, 2H), 6.30 (d, 3JHF¼20.1 Hz,
1.59e1.63 (m,1H),1.82e1.83 (m,1H),1.92e1.97 (m, 2H), 2.79 (m,1H),
1H), 7.24e7.27 (m, 2H), 7.41e7.42 (m, 2H), 7.65e7.67 (m, 2H),
2.87 (m, 1H), 4.49 (d, 3JHF¼20.9 Hz, 2H), 7.72e7.37 (m, 2H), 7.85e7.87
7.77e7.79 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d
35.5 (d,
(m, 2H); 13C NMR (CDCl3, 100 MHz)
d
2
25.7 (d, 3JCF¼7.8 Hz), 27.6, 28.4
2
3
2JCF¼28.6 Hz), 110.4 (d, JCF¼25.8 Hz), 121.5, 123.5, 130.5, 131.5,
(d, JCF¼4.6 Hz), 32.5, 34.9 (d, JCF¼32.0 Hz), 47.9, 120.7 (d,
131.8, 131.9, 134.2, 154.6 (d, 1JCF¼256.0 Hz), 167.5; 19F NMR (CDCl3,
2JCF¼13.1 Hz), 123.4, 132.1, 134.0, 145.2 (d, 1JCF¼243.1 Hz), 167.7; 19F
3
3
376 MHz)
d
ꢀ107.5 (dt, JFH¼15.4 , 20.1 Hz, 1F). Compound (Z)-5e:
NMR (CDCl3, 376 MHz)
analyzable.
d
ꢀ121.9 (t, JFH¼20.9 Hz, 1F); HRMS not
1H NMR (CDCl3, 400 MHz)
d
4.44 (d, JHF¼15.3 Hz, 2H), 5.70 (d,
3
3JHF¼37.3 Hz, 1H), 7.23e7.25 (m, 2H), 7.32e7.35 (m, 2H), 7.65e7.67
(m, 2H), 7.79e7.81 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d
35.5 (d,
4.4. Preparation of dipeptide precursor 12
2JCF¼28.6 Hz), 110.5 (d, JCF¼25.8 Hz), 121.6, 123.5, 130.5, 131.4,
2
131.8, 131.9, 134.2, 154.6 (d, 1JCF¼256.0 Hz), 167.6; 19F NMR (CDCl3,
4.4.1. (Z/E)-N-(5-Benzyloxy-2-fluoro-2-pentenyl)-isoindole-1,3-di-
one (10). To a solution of sulfone 3e (150 mg, 0.38 mmol, 1 equiv)
and 3-benzyloxy-propionaldehyde (66 mg, 0.40 mmol, 1.05 equiv)
in THF (6 mL) at ꢀ17 ꢁC was added t-BuOK (0.056 g, 0.49 mmol,
1.3 equiv). After 5 min at ꢀ17 ꢁC, the mixture was stirred for 2 h at
20 ꢁC, quenched with a saturated solution of NH4Cl (1 mL) and
extracted with CH2Cl2 (2ꢂ5 mL). Combined organic layers were
washed with a 1 M solution of NaOH, dried over MgSO4, filtered,
and evaporated under reduced pressure. The crude residue was
purified by flash silica gel chromatography (pentane/AcOEt, 9:1) to
afford a mixture of (Z/E)-N-(5-benzyloxy-2-fluoro-2-pentenyl)-
isoindole-1,3-dione 10 (100 mg, 77%) as a yellow oil. 1H NMR
3
376 MHz)
analyzable.
d
ꢀ108.3 (dt, JFH¼15.3 , 37.3 Hz, 1F); HRMS not
4.3.16. (Z/E)-N-(2-Fluoro-2,12- tridecadienyl)-isoindole-1,3-dione (6e).
Following the method (B) from sulfone 3e (90 mg, 0.23 mmol),
undecenal (41 mg, 0.24 mmol), and NaHMDS (300 mL, 0.30 mmol,
1 M in THF) in THF (4 mL). The crude product was purified by flash
chromatography (pentane/AcOEt, 95:5) to afford successively alkenes
(E)-6e and (Z)-6e (52 mg, 66%) as a yellow oil. Compound (E)-6e: 1H
NMR (CDCl3, 400 MHz)
d 1.18e1.52 (m, 12H), 1.94e2.00 (m, 2H),
2.12e2.16 (m, 2H), 4.38 (d, 3JHF¼19.2 Hz, 2H), 4.84e4.95 (m, 2H), 5.18
(dt, 3JHH¼8.1 Hz, 3JHF¼20.7 Hz, 1H), 5.69e5.78 (m, 1H), 7.64e7.67 (m,
(CDCl3, 400 MHz)
d
2.33 (q, 3JHH¼6.6 Hz, 2H), 2.46 (q, 3JHH¼6.8 Hz,
2H), 7.78e7.80 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d
25.3 (d,
2H), 3.39 (t, JHH¼6.7 Hz, 2H), 3.49 (t, JHH¼6.8 Hz, 2H), 4.29 (d,
3
3
3JCF¼7.6 Hz), 28.9, 29.1, 29.3, 29.4, 29.7, 29.8, 33.8, 34.5 (d,
3JHF¼14.3 Hz, 2H, E), 4.38 (d, 3JHF¼20.7 Hz, 2H, Z), 4.41 (s, 2H), 4.45
2JCF¼30.4 Hz), 110.5 (d, 2JCF¼18.0 Hz), 114.1, 123.4, 132.0, 134.0, 139.2,
(s, 2H), 4.91 (dt, JHF¼36.1 Hz, JHH¼7.4 Hz, 1H, Z), 5.27 (dt,
3JHF¼19.7 Hz, 3JHH¼6.2 Hz, 1H, E), 7.18e7.29 (m, 10H), 7.63e7.66 (m,
3
3
152.8 (d, 1JCF¼248.3 Hz), 167.6; 19F NMR (CDCl3, 376 MHz)
d
ꢀ112.1
(dt, 3JFH¼19.2 , 20.7 Hz, 1F); MS (EI) m/z 344 [MþH]þ (100), 324 (74),
172 (65); HRMS (ESI) m/z [MþH]þ calcd for C21H27FNO2 344.2026,
4H), 7.75e7.80 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d 23.3 (d,
3JCF¼4.1 Hz, E), 25.1 (d, 3JCF¼8.0 Hz, Z), 33.6 (d, 2JCF¼30.2 Hz, E), 37.2
(d, 2JCF¼33.5 Hz, Z), 67.9 (d, 4JCF¼1.9 Hz, E), 68.4 (d, 4JCF¼2.7 Hz, Z),
71.8, 71.9, 104.7 (d, 2JCF¼13.1 Hz, E), 106.1 (d, 2JCF¼20.2 Hz, Z), 122.4,
122.5,126.5,126.6,127.3,127.4,127.5,130.9,133.0,133.1,133.2,134.1,
137.3, 137.4, 152.8 (d, 1JCF¼256.6 Hz, Z), 153.2 (d, 1JCF¼250.1 Hz, E),
found 344.2025. Compound (Z)-6e: 1H NMR (CDCl3, 400 MHz)
3
d
1.26e1.37 (m, 12H), 2.01e2.09 (m, 4H), 4.37 (d, JHF¼14.9 Hz, 2H),
4.92e5.01 (m, 3H), 5.77e5.85 (m, 1H), 7.73e7.75 (m, 2H), 7.87e7.89
(m, 2H); 13C NMR (CDCl3, 100 MHz)
d
23.5 (d, 3JCF¼3.8 Hz), 28.9, 29.0,
2
29.1, 29.2, 29.3, 29.4, 33.8, 38.4 (d, JCF¼33.5 Hz), 109.6 (d,
166.4, 166.5; 19F NMR (CDCl3, 376 MHz)
d
ꢀ109.6 (dt, 3JFH¼19.7 Hz,
2JCF¼13.6 Hz), 114.1, 123.5, 132.0,134.1, 139.2,152.7 (d, 1JCF¼254.6 Hz),
3JFH¼20.7 Hz, 1F, E), ꢀ115.6 (dt, JFH¼36.1 , 14.3 Hz, 1F, Z); MS (EI)
m/z 340 [MþH]þ (49), 302 (100), 173 (45), 160 (99), 155 (42); HRMS
(ESI) m/z [MþH]þ calcd for C20H19O3NF 340.1349, found 340.1344.
3
167.5; 19F NMR (CDCl3, 376 MHz)
d
ꢀ118.0 (dt, JFH¼14.9 , 36.3 Hz,
3
1F); MS (EI) m/z 344 [MþH]þ (100), 324 (74), 172 (65); HRMS (ESI)
m/z [MþH]þ calcd for C21H27FNO2 344.2026, found 344.2033.
4.4.2. (Z/E)-N-(2-Fluoro-5-hydroxy-pent-2-enyl)-isoindole-1,3-dione
(11). To a solution of compound 10 (84 mg, 0.25 mmol, 1 equiv) in
CH2Cl2 (14 mL) was added TiCl4 (0.28 mL, 2.55 mmol, 10 equiv) at
20 ꢁC. After 16 h under stirring, the mixture was added to a solution
of NaHCO3/Et2O (1:9, 10 mL) and stirred over 30 min then the
resulting mixture was dried and filtered on Celite. The filtrate was
evaporated under reduced pressure to afford a mixture of (Z/E) 11
4.3.17. (Z/E)-3-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-fluoro-
propenyl]-2,2-dimethyl-cyclopropane carboxylic acid methyl ester
(7e). Following the method (B) from sulfone 3e (90 mg, 0.23 mmol),
biocarptolmethylester (37 mg, 0.24 mmol), and NaHMDS (300 mL,
0.30 mmol,1 M inTHF) inTHF (4 mL). The crude product was purified
by flash chromatography (pentane/AcOEt, gradient 95:5 to 90:10) to
afford a mixture of (Z/E) 7e (38 mg, 50%) as a yellow oil. 1H NMR
(56 mg, 90%) as a colorless oil. 1H NMR (CDCl3, 400 MHz)
d 2.05 (s,
3
3
(CDCl3, 400 MHz)
d
1.08e1.22 (m,12H),1.65 (d, 3JHH¼8.5 Hz,1H),1.75
2H), 2.26 (q, JHH¼6.0 Hz, 2H), 2.42 (q, JHH¼6.0 Hz, 2H), 3.57 (t,
3
3
3
(d, JHH¼8.6 Hz, 1H), 1.96e2.09 (m, 2H), 3.57 (s, 6H), 4.26e4.45 (m,
4H), 5.28 (dd, 3JHH¼9.7 Hz, 3JHF¼35.5 Hz,1H, Z), 5.61 (dd, 3JHH¼9.4 Hz,
3JHF¼19.7 Hz, 1H, E), 7.63e7.68 (m, 4H), 7.76e7.81 (m, 4H); 13C NMR
3JHH¼6.3 Hz, 2H), 3.67 (t, JHH¼5.6 Hz, 2H), 4.31 (d, JHF¼14.3 Hz,
3
3
2H, E), 4.36 (d, JHF¼13.0 Hz, 2H, Z), 4.90 (dt, JHF¼36.1 Hz,
3JHH¼7.4 Hz, 1H, Z), 5.25 (dt, JHF¼20.3 Hz, JHH¼8.2 Hz, 1H, E),
3
3
(CDCl3, 100 MHz)
d 14.7, 26.6, 26.7, 26.8, 27.5, 27.6, 28.3, 28.4, 28.5,
7.66e7.67 (m, 4H), 7.78e7.79 (m, 4H); 13C NMR (CDCl3, 100 MHz)
3
3
28.6, 30.8, 31.0, 35.0 (d, 2JCF¼30.6 Hz, E), 38.6 (d, 2JCF¼31.3 Hz, Z), 51.2,
d
29.0 (d, JCF¼5.2 Hz, E), 31.9 (d, JCF¼7.8 Hz, Z), 34.7 (d,

C. Calata et al. / Tetrahedron 67 (2011) 1398e1405
1405
2
4
2JCF¼29.6 Hz, E), 38.4 (d, JCF¼33.3 Hz, Z), 61.7 (d, JCF¼3.0 Hz, E),
These data include MOL files and InChIKeys of the most important
compounds described in this article.
4
2
61.8 (d, JCF¼2.6 Hz, Z), 105.4 (d, JCF¼13.0 Hz, E), 107.3 (d,
2JCF¼19.8 Hz, Z), 123.6, 126.0, 129.7, 129.9, 131.9, 134.2, 154.8 (d,
1JCF¼262.4 Hz, Z), 154.9 (d, 1JCF¼242.6 Hz, E), 167.5, 167.6; 19F NMR
References and notes
(CDCl3, 376 MHz)
d
ꢀ109.1 (dt, 3JFH¼20.3 , 13.0 Hz, 1F, E), ꢀ115.4 (dt,
3JFH¼36.1 , 14.3 Hz, 1F, Z); MS (EI) m/z 250 [MþH]þ (37), 232 (10),
230 (100), 104 (13); HRMS (ESI) m/z [MþH]þ calcd for C13H13O3NF
250.0879, found 250.0873.
1. Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241.
2. (a) Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107; (b) Allmendinger, T.;
€
Furet, P.; Hungerbuhler, E. Tetrahedron Lett. 1990, 31, 7297; (c) Allmendinger, T.;
€
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4.4.3. (Z/E)-5-Phtalimido-4-fluoro-pent-3-enoic acid (12). To a solu-
tion of compound 11 (20 mg, 0.08 mmol, 1 equiv) in acetone
(0.6 mL) was added Jones oxidant (0.1 mL) at 0 ꢁC. After 1 h at 20 ꢁC,
the mixture was diluted in AcOEt and water (9:1, 5 mL) and
extracted with CH2Cl2 (3ꢂ5 mL). Combined organic layers were
washed with a saturated solution of NaCl, dried over MgSO4, fil-
tered, and evaporated under reduced pressure to afford a mixture
of (Z/E)-5-phtalimido4-fluoro-pent-3-enoic acid 12 (18 mg, 85%) as
3. (a) Hollenstein, M.; Leumann, C. J. Org. Chem. 2005, 70, 3205; (b) Hollenstein, M.;
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Leumann, C. Org. Lett. 2003, 5, 1987; (c) Van der Veken, P.; Stenten, K.; Kertesz, I.;
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De Meester, I.; Lambeir, A.-M.; Maes, M.-B.; Scharpe, S.; Haemers, A.;
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(d) Dutheuil, G.; Paturel, C.; Lei, X. S.; Couve-Bonnaire, S.; Pannecoucke, X. J. Org.
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Bonnaire, S.; Pannecoucke, X. Angew. Chem., Int. Ed. 2007, 46, 1290; (h) Otaka, A.;
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Saito, K.; Ose, Y.; Nagao, Y. Tetrahedron 2006, 62, 11881.
a yellow oil. 1H NMR (CDCl3, 400 MHz)
d
3.13 (d, 3JHH¼15.4 Hz, 2H,
Z), 3.32 (d, 3JHH¼7.7 Hz, 2H, E), 4.35 (d, 3JHF¼14.2 Hz, 2H, Z), 4.39 (d,
3JHF¼20.0 Hz, 2H, E), 5.11 (dt, 3JHH¼7.1 Hz, 3JHF¼34.7 Hz, 1H, Z), 5.42
(dt, 3JHH¼7.1 Hz, 3JHF¼18.9 Hz, 1H, E), 7.64e7.71 (m, 4H), 7.77e7.85
(m, 4H), 9.4e9.8 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d 27.9 (d,
3JCF¼5.0 Hz, E), 29.5 (d, 3JCF¼9.2 Hz, Z), 33.5 (d, 2JCF¼30.2 Hz, E), 36.9
(d, 2JCF¼32.6 Hz, Z), 99.8 (d, 2JCF¼11.9 Hz, E), 101.9 (d, 2JCF¼25.7 Hz,
Z), 110.6, 121.6, 122.3, 122.5, 125.5, 130.8, 133.2, 153.8 (d,
1
1JCF¼260.3 Hz, Z), 154.5 (d, JCF¼253.5 Hz, E), 166.4, 166.5, 174.4,
ꢀ
5. (a) Van der Verken, P.; Senten, K.; Kertesz, I.; Haemers, A.; Augustyns, K.
3
174.5; 19F NMR (CDCl3, 376 MHz)
d
ꢀ106.3 (dt, JFH¼20.0 Hz,
Tetrahedron Lett. 2003, 44, 969; (b) Blackburn, G. M.; Parratt, J. J. Chem. Soc.,
Chem. Commun. 1983, 886; (c) Hanamoto, T.;Shindo, K.;Matsuoka,M.;Kiguchi,Y.;
Kondo, M. J. Chem. Soc., Perkin Trans. 1 2000, 103.
6. (a) Bellingham, R.; Jarowicki, K.; Kocienski, P. J.; Martin, V. Synthesis 1996, 285;
(b) Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327; (c) Smith, N. D.;
Kocienski, P. J.; Street, S. D. A. Synthesis 1996, 652; (d) Liu, P.; Jacobsen, E. N.
J. Am. Chem. Soc. 2001, 123, 10772; (e) Trost, B. M.; Chisholm, J. D.; Wrobleski, S.
T.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420; (f) van Summeren, R. P.; Moody,
D. B.; Ferringa, B. L.; Minnaard, A. J. J. Am. Chem. Soc. 2006, 128, 4546; (g) Aïssa, C.
Eur. J. Org. Chem. 2009, 1831.
2JFH¼18.9 Hz, 1F, E), ꢀ112.6 (dt, JFH¼14.2 Hz, JFH¼34.7 Hz, 1F, Z);
MS (EI) m/z 262 [MꢀH]ꢀ (100), 242 (71), 218 (9), 146 (98), 114 (22);
HRMS (ESI) m/z [MꢀH]ꢀ calcd for C13H9O4NF 262.0516, found
262.0517.
3
2
Acknowledgements
7. Bandur, N. G.; Harms, K.; Koert, U. Synthesis 2007, 2720.
This work was supported by the CNRS and the Crunch (in-
8. (a) Chevrie, D.; Lequeux, T.; Pazenok, S.; Demoute, J. P. Tetrahedron Lett. 2003,
44, 8127; (b) Pazenok, S.; Demoute, J.P.; Zard, S.; Lequeux, T. PCT Int. Appl. WO
0240459 A1, 2002; Chem. Abstr. 2002, 136, 386131; (c) Zajc, B.; Kumar, R. Syn-
thesis 2010, 1822.
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Gomez-Bengoa, E.; Najera, C. Adv. Synth. Catal. 2008, 350, 1823; (c) del Solar, M.;
Ghosh, A. K.; Zajc, B. J. Org. Chem. 2008, 73, 8206; (d) He, M.; Ghosh, A. K.; Zajc,
B. Synlett 2008, 999; (e) Ghosh, A. K.; Banerjee, S.; Sinha, S.; Kang, S. B.; Zajc, B.
J. Org. Chem. 2009, 74, 3689; (f) Calata, C.; Catel, J. M.; Pfund, E.; Lequeux, T.
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ꢁ
terregional organic chemistry network). The ‘Region Basse-Nor-
mandie’ and ERDF funding (ISCE-Chem & INTERREG IVa program)
are gratefully thanked for their financial support.
Supplementary data
Copies of 1H, 13C NMR spectra of compounds 4aee to 8aee,
10e12 are available. Supplementary data associated with this ar-
ticle can be found in online version at doi:10.1016/j.tet.2010.12.061.
11. Calata, C.; Pfund, E.; Lequeux, T. J. Org. Chem. 2009, 74, 9399.