Highly Stereoselective Synthesis of Fluoroalkene Dipeptides via the Novel Chromium(II)-Mediated Carbon-Fluorine Bond Cleavage/New Carbon-Carbon Bond Formation

Article abstract of DOI:10.1055/s-0035-1560390

An efficient chromium(II)-mediated reductive coupling reaction of various CBrF₂-containing molecules and aldehydes has been developed. This reaction proceeds presumably via the monofluorinated dichromium(III) intermediate generated by the carbon-fluorine bond activation, and provides a general and straightforward access to synthesize a variety of (E)- or (Z)-β-fluoroallylic alcohols in a highly stereoselective manner. Based on the novel reductive coupling, four types of fluoroalkene dipeptide analogues could be stereoselectively prepared.

Full text of DOI:10.1055/s-0035-1560390

SYNTHESIS
0
0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 865–881
paper
865
T. Nihei et al.
Paper
Synthesis
Highly Stereoselective Synthesis of Fluoroalkene Dipeptides
via the Novel Chromium(II)-Mediated Carbon–Fluorine Bond
Cleavage/New Carbon–Carbon Bond Formation
Takashi Niheia
Yuji Nishia
F
R2CHO, CrCl2, LiI
DMF, r.t., 4 h
F
F
R2
R1
R1
Br
Natsumi Ikedaa
Saya Yokotania
Takashi Ishiharaa
Satoru Arimitsub
Tsutomu Konno*a
HO
H
E or Z
highly stereoselective
(44–94%, 36 examples)
F
O
R
1 = (CH2)2OTBDPS
5 steps
R2
OH
R2
OH
N
a Faculty of Molecular Chemistry and Engineering, Kyoto Institute of
Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
konno@kit.ac.jp
b Department of Chemistry Biology and Marine Science, University
of the Ryukyus, Nishihara, Okinawa 903-0123, Japan
NH2
H
O
NH2
H
O
R2 = Me, i-Pr, i-Bu, HOCH2
Received: 02.10.2015
Accepted after revision: 20.11.2015
Published online: 29.12.2015
active peptides. Although such synthetic procedures abso-
lutely play an important role in synthesizing a variety of
stereochemically defined fluoroalkenes, they also have var-
ious drawbacks, like difficulties on the preparation of the
substrates, narrow range of applicable substrates, etc. As a
consequence, it has still been a very important subject to
explore a new methodology for constructing fluoroalkene
frameworks stereoselectively.
Carbon–fluorine (C–F) bond has a very large bond ener-
gy and has been known as the most chemically stable bond.
Accordingly, reactions that efficiently cleave this C–F bond
and subsequently create a new carbon–carbon (C–C) bond
are significantly attractive from the viewpoint of a new
synthetic methodology. In recent years, such carbon elon-
gations have come under the spotlight.6
DOI: 10.1055/s-0035-1560390; Art ID: ss-2015-f0577-op
Abstract An efficient chromium(II)-mediated reductive coupling reac-
tion of various CBrF2-containing molecules and aldehydes has been de-
veloped. This reaction proceeds presumably via the monofluorinated
dichromium(III) intermediate generated by the carbon–fluorine bond
activation, and provides a general and straightforward access to syn-
thesize a variety of (E)- or (Z)-β-fluoroallylic alcohols in a highly stereo-
selective manner. Based on the novel reductive coupling, four types of
fluoroalkene dipeptide analogues could be stereoselectively prepared.
Key words β-fluoroallylic alcohol derivatives, carbon–fluorine bond
activation, chromium(II) chloride, stereoselective, fluoroalkene bio-
isosteres
Fluoroalkenes have been well recognized as among the
most important and valuable peptide bond bioisosteres be-
cause the fluoroalkene and the peptide bond frameworks
are closely similar in the structural and electronic proper-
ties. More specifically, an amide bond in bioactive peptides
is sometimes easily hydrolyzed by an enzyme in vivo, re-
sulting in the inactivation of the peptide, but due to hydro-
lytic stability of the fluoroalkene framework, peptidomi-
metics, in which the amide bond is replaced with the fluo-
roalkene unit, maintain the original bioactivity and often
simultaneously provoke very interesting additional biologi-
cal activities.1 For this reason, a large number of synthetic
methods, such as electrophilic fluorination of various vinyl-
metal species,2 Horner–Wadsworth–Emmons reaction of
monofluorinated phosphonate with aldehydes,3 SN2′ reac-
tion of α,α-difluoroallylic compounds with organocopper
reagents,4 and others,5 have been developed for the incor-
poration of a fluoroalkene skeleton into a wide range of bio-
In this article, we describe a highly stereoselective syn-
thesis of various (E)- or (Z)-β-fluoroallylic alcohols based
on C–F bond cleavage of CBrF2-containing molecules in the
presence of the early transition metal, chromium(II)7 fol-
lowed by the addition reaction of the resultant α-fluorovi-
nyl chromium species with various aldehydes in detail.8 Ad-
ditionally, we also report the stereoselective synthesis of
various fluoroalkene dipeptides through the above Cr(II)-
mediated reductive coupling reaction.
Scope and Limitations
For this investigation, we first selected several CBrF2-
containing substrates, such as the imide 1,9 the esters 210
and 4,11 the silyl ethers 3 and 5,10 and also the alkane 6.12
These substrates were easily prepared as shown in Scheme
1. Treatment of 3,3,3-trifluoropropanoyloxazolidinone with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 865–881

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T. Nihei et al.
Paper
Synthesis
1.5 equivalents each of TMSOTf and Et3N in CH2Cl2 at 0 °C
for 0.5 hour afforded the corresponding silyl enol ether,
which was subsequently subjected to 2.0 equivalents of
TiBr4 in CH2Cl2 at –20 °C for 2 hours, leading to 3-(3-bromo-
3,3-difluoropropanoyl)-2-oxazolidinone (1) in 75% isolated
yield over two steps. The radical addition of CBr2F2 toward
ethyl vinyl ether in the presence of NaHCO3 and Na2S2O4 in
EtOH at the reflux temperature for 2 hours, followed by
treating the resultant reaction mixture with an excess
amount of Caro’s acid for 24 hours, gave ethyl 3-bromo-3,3-
difluoropropionate (2) in 36% combined yield. This ester 2
was reduced with 2.3 equivalents of DIBAL-H to provide the
corresponding alcohol, which was subjected to 2.0 equiva-
lents each of TBDPSCl and imidazole in THF for 20 hours to
afford the desired 1-bromo-3-(tert-butyldiphenylsilyloxy)-
1,1-difluoropropane (3) in 49% yield over two steps. The
radical addition of CBr2F2 toward ethyl acrylate in the pres-
ence of Zn and CuBr in Et2O also proceeded to give the cor-
responding ethyl 4-bromo-4,4-difluorobutyrate (4) in an
acceptable yield, which could be converted to 1-bromo-4-
(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5) by the
similar procedure used to prepare compound 3. Finally, the
radical adduct, which could be readily prepared through
the reaction of CBr2F2 with oct-1-ene in the presence of
CuCl (0.01 equiv) and 2-aminoethanol (0.5 equiv) in tert-
BuOH at 85 °C for 48 hours, was treated with 2.0 equiva-
lents of NaBH4 in DMSO at 70 °C for 6 hours to afford 1-bro-
mo-1,1-difluorononane (6) in 38% yield.
With various substrates 1–6 in hand, the reaction of 1
with benzaldehyde in the presence of CrCl2 was first exam-
ined as shown in Table 1. On treating 1 with 2.0 equivalents
of benzaldehyde in the presence of 3.0 equivalents of CrCl2
and a catalytic amount of LiI (0.2 equiv) in DMF at –20 °C
for 4 hours, the corresponding β-fluoroallylic alcohol 7a
was obtained in only 15% yield (Table 1, entry 1). Longer re-
action time was not effective to increase the yield (entry 2).
In each case, the starting material 1 was completely con-
sumed. The yield of 7a was greatly improved from 18% to
84–86% when the reaction was carried out at 0 °C to room
temperature (entries 3 and 4), though higher temperature
such as 60 °C rather decreased the yield (entry 5). Using
only 2.0 equivalents of CrCl2 brought about a significant
drop in the yield (entry 6). The yield somewhat decreased
even when only 1.2 equiv of benzaldehyde was used or LiI
was not used13 (entries 7 and 8). Finally, the use of 4.0 equiv
of CrCl2 led to the best reaction yield (entry 9). In all cases,
only the E-isomer was obtained.14
1) TMSOTf (1.5 equiv)
O
Et3N (1.5 equiv)
O
O
O
F
F
CH2Cl2, 0 °C, 0.5 h
F3C
N
O
Br
N
O
2)
TiBr4 (2.0 equiv)
CH2Cl2, –20 °C, 2 h
(75% yield over 2 steps)
1
1) NaHCO3 (3.0 equiv)
Na2S2O4 (1.5 equiv)
EtOH, reflux, 2 h
O
F
F
Table 1 Reaction of 1 with Benzaldehyde in the Presence of CrCl2
CBr2F2
+
OEt
2) Caro's acid (excess)
EtOH, r.t., 24 h
(36% yield over 2 steps)
Br
OEt
2
F
PhCHO (2.0 equiv)
CrCl2 (3.0 equiv)
LiI (0.2 equiv)
Ph
H
N
O
O
F
F
1) DIBAL-H (2.3 equiv)
CH2Cl2
–78 °C to 0 °C, 5 h
HO
F
F
Br
N
O
DMF, temp., time
O
TBDPSCl (2.0 equiv)
imidazole (2.0 equiv)
THF, r.t., 20 h
2)
Br
OTBDPS
1
O
O
3
7a (E/Z = 100:0)
(49% yield over 2 steps)
Entry
Temp (°C)
Time (h)
Yield (%)a,b of Recovery (%)a of
7a
O
1
(1.0 equiv)
OEt
F
F
Zn (3.60 equiv)
+
CBr2F2 (2.88 equiv)
1
–20
–20
0
4
20
4
15
trace
trace
trace
0
OEt
Br
Et2O, reflux
1 h
Et2O, r.t., 2 h
then reflux, 1 h
(50% yield)
2
18
CuBr (0.36 equiv)
O
4
3
86
1) DIBAL-H (2.3 equiv)
CH2Cl2
–78 °C to 0 °C, 5 h
4
r.t.
60
0
4
84
F
F
5
4
27
0
OTBDPS
2) TBDPSCl (1.2 equiv)
imidazole (1.2 equiv)
THF, r.t., 20 h
Br
6c
7d
8e
9f
4
13
21
4
5
(50% yield over 2 steps)
0
4
76
0
4
64
9
CuCl (0.01 equiv)
2-aminoethanol (0.5 equiv)
Br
F
F
0
4
89 (84)
0
CBr2F2
+
n-C6H13
t-BuOH, 85 °C, 48 h
Br
n-C6H13
a Determined by 19F NMR spectroscopy. Value in parentheses is of isolated
yield.
69% yield
F
F
b In all cases, (E)-7a was obtained as the sole isomer.
c Only 2.0 equiv of CrCl2 was used.
d Only 1.2 equiv of PhCHO was used.
e Without LiI.
NaBH4 (2.0 equiv)
DMSO, 70 °C, 6 h
38% yield
Br
n-C6H13
6
f Four equiv of CrCl2 was used.
Scheme 1 Preparation of various CBrF2-containing substrates
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Synthesis
Upon optimization of the reaction conditions (Table 1,
entry 9), a series of aldehydes were tested by using 1 to ex-
plore the generality of this Cr(II)-mediated reductive cou-
pling reactions. The results are summarized in Table 2.
Table 3 Reaction of 3 with Various Aldehydes
R1CHO (2.0 equiv)
CrCl2 (6.0 equiv), LiI (0.5 equiv)
OTBDPS
DMF, r.t., 4 h
F
F
F
R1
HO
OTBDPS
Br
H
3
8
Table 2 Reaction of 1 with Various Aldehydes
Entrya
R1
Product
Yieldb,c (%)
Ratio (E/Z)b
F
R1CHO (2.0 equiv)
CrCl2 (4.0 equiv), LiI (0.2 equiv)
R1
H
N
O
O
1d
2
Ph
8a
8a
8b
8c
8d
8e
8f
44e
0:100
0:100
0:100
0:100
0:100
0:100
1:99
F
F
HO
Br
N
O
DMF, 0 °C, 4 h
Ph
68 (56)
64 (48)
78 (52)
64 (56)
10
O
O
1
3
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-F3CC6H4
n-Pr
O
7
4
5
Entrya
R1
Product
Yield (%)b,c
Ratio (E/Z)b
6
1
2
3
4
5
6
7
8
9
Ph
4-MeC6H4
7a
7b
7c
7d
7e
7f
89 (84)
77 (64)
73 (69)
94 (90)
26
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
7
79 (57)
77 (59)
78 (63)
17
8
i-Pr
8g
8h
8i
1:99
4-MeOC6H4
4-FC6H4
4-F3CC6H4
n-Pr
9
t-Bu
0:100
0:100
10
(E)-MeCH=CH
a Reaction conditions: 3 (0.3 mmol), aldehyde (0.6 mmol), CrCl2 (1.8 mmol),
LiI (0.15 mmol), DMF (1.2 mL) at r.t. for 4 h under argon.
b Determined by 19F NMR spectroscopy.
70 (68)
80 (77)
88 (77)
23
c Values in parentheses are of isolated yield.
i-Pr
7g
7h
7i
d Reaction conditions: 3 (0.3 mmol), aldehyde (0.6 mmol), CrCl2 (1.2 mmol),
LiI (0.06 mmol), DMF (1.2 mL) at 0 °C for 4 h under argon.
e The starting material 3 was recovered in 40% yield.
t-Bu
(E)-MeCH=CH
a Reaction conditions: 1 (0.5 mmol), R1CHO (1.0 mmol), CrCl2 (2.0 mmol),
LiI (0.1 mmol), DMF (1.5 mL) at 0 °C for 4 h under argon.
b Determined by 19F NMR spectroscopy.
4.0 to 6.0 equivalents and from 0.2 to 0.5 equivalent, re-
spectively. As a result, the starting material 3 was complete-
ly consumed and the corresponding β-fluoroallylic alcohol
8a was obtained in 68% yield (entry 2). Surprisingly, only
the Z-isomer was obtained14 and no trace of E-isomer was
detected. The reactions with various aromatic aldehydes,
such as p-tolualdehyde, p-anisaldehyde, and 4-fluorobenz-
aldehyde, also took place smoothly to give the correspond-
ing adducts in an exclusive Z-selective manner (entries 3, 4,
and 5). Similarly, various aliphatic aldehydes, such as butyr-
aldehyde, isobutyraldehyde, and pivalaldehyde, also gave
the corresponding β-fluoroallylic alcohol derivatives with
high Z-selectivity in high yields (entries 7–9). As observed
in the Cr(II)-mediated reductive coupling of 1, both 4-triflu-
oromethylbenzaldehyde and crotonaldehyde gave poor
yields (entries 6 and 10).
In an analogous way, ethyl 3-bromo-3,3-difluoropropio-
nate (2), ethyl 4-bromo-4,4-difluorobutyrate (4), 1-bromo-
4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5), and
1-bromo-1,1-difluorononane (6) were also subjected to the
same reaction conditions as used in Table 3. The results are
listed in Table 4.
The reaction of 2 with benzaldehyde did not give any
desired coupling product 9a, and ethyl β,β-difluoroacrylate
(13) was obtained in only 18% yield (Figure 1).15 On the oth-
er hand, the ester 4, in which the carbon framework has
one carbon extension from 2, underwent a smooth reduc-
tive coupling with benzaldehyde to give the corresponding
c Values in parentheses are of isolated yield.
The reaction with aromatic aldehydes bearing an elec-
tron-donating group (Me, MeO; Table 2, entries 2 and 3) or
an electron-withdrawing group (F substituent, entry 4) at
the para position of the benzene ring proceeded efficiently
to give the corresponding β-fluoroallylic alcohols 7b–d in
good to high yields. Various aliphatic aldehydes, such as bu-
tyraldehyde (entry 6) and isobutyraldehyde (entry 7), also
showed satisfactory results. Notably, even much bulkier
pivalaldehyde provided the corresponding adduct 7h in a
high yield (entry 8). Disappointingly, a strongly electron-
withdrawing group, like a CF3 group, on the benzene ring
hampered the desired reaction proceeding (entry 5). In ad-
dition, α,β-unsaturated aldehyde, like crotonaldehyde, re-
sulted in a significant decrease of the yield (entry 9). In all
cases, only (E)-β-fluoroallylic alcohols were observed and
no Z-isomer was detected.
Next, our attention was directed toward the Cr(II)-me-
diated reaction of 1-bromo-3-(tert-butyldiphenylsilyloxy)-
1,1-difluoropropane (3) with various aldehydes under the
same reaction conditions as employed in Table 2. The re-
sults are collected in Table 3.
First of all, the desired β-fluoroallylic alcohol 8a was ob-
tained in only 44% yield under the reaction conditions em-
ployed for the reaction of 1 (Table 3, entry 1). In this case,
40% of the starting material 3 still remained unreacted.
Therefore, the amounts of CrCl2 and LiI were increased from
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Synthesis
Table 4 Reaction of 2, 4–6 with Various Aldehydes
adduct 10a in 76% yield. Furthermore, various aromatic as
well as aliphatic aldehydes could participate well in the re-
ductive coupling reaction to afford the corresponding ad-
ducts 10b–d,f–h in acceptable yields. As observed in the re-
action of 1 and 3, however, neither 4-trifluoromethylbenz-
aldehyde nor crotonaldehyde afforded the desired products
10e and 10i in good yields.
R1CHO (2.0 equiv)
CrCl2 (6.0 equiv)
F
F
F
LiI (0.5 equiv)
R2
R1
R2
DMF, r.t., 4 h
Br
R2 = CO2Et (2)
HO
R2 = CO2Et (9)
H
CH2CO2Et (4)
CH2CH2OTBDPS (5)
n-C7H15 (6)
CH2CO2Et (10)
CH2CH2OTBDPS (11)
n-C7H15 (12)
F
O
Entrya Substrate R1
Product Yield (%)b,c Ratio (E/Z)b
F
OEt
13
1
2
2
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
Ph
9a
0d
–
Figure 1 Ethyl β,β-difluoroacrylate
Ph
10a
10b
10c
10d
10e
10f
76 (55)
47 (40)
52 (51)
59 (49)
4e
2:98
1:99
1:99
0:100
3
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-F3CC6H4
n-Pr
4
In the same way, the other starting materials 5 and 6
could be also successfully applied for the reductive coupling
reaction with various aldehydes, except for 4-trifluoro-
methylbenzaldehyde and crotonaldehyde, with various β-
fluoroallylic alcohols 11a,c,g,h,j–m, and 12a–d,f–h being
obtained in high to excellent yields. In all cases, a high Z-
stereoselection was observed.
With the highly selective preparation of fluoroalkenes
in hand, the investigation was next shifted to their synthet-
ic application. As mentioned previously, fluoroalkene is one
of the important bioisosteres found occasionally in medici-
nal chemistry (Figure 2).
5
f
6
–
7
53 (42)
58 (54)
44 (31)
26
0:100
1:99
8
i-Pr
10g
10h
10i
9
t-Bu
0:100
1:99
10
11
12
13
14
15
16g
17
18g
19
20
21
22
23
24
25
26
27
(E)-MeCH=CH
Ph
11a
11c
11j
78 (67)
80 (54)
83 (69)
81 (67)
71 (61)
64 (49)
57 (38)
75
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
2:98
4-MeOC6H4
Me
i-Pr
11g
11h
11k
11l
O
i-Bu
F
R
OH
R
OH
s-Bu
N
H
NH2
O
NH2
O
CH2OPMB
CHMe(OBn)
Ph
glycine dipeptide
fluoroalkene bioisostere
of glycine dipeptide
11m
12a
12b
12c
12d
12e
12f
94 (76)
75
Figure 2 Glycine dipeptide and its fluoroalkene bioisostere
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-F3CC6H4
n-Pr
2:98
90 (80)
93 (78)
6h
0:100
0:100
To prove our concept, (Z)-fluoroalkene 11 was chosen as
the ideal starting material.16 First, alcohol moiety was re-
acted with sodium azide to afford β-fluoroallylic azides as a
regioisomeric mixture of 14 and 15, which were generated
through an SN2 and SN2′ reaction pathway, respectively5j,17
(Table 2). Regioselectivity was highly dependent on the
substrates. If R1 is aromatic, compound 15 is the major
product, if R1 is aliphatic, the major product is the desired
product 14, and interestingly, when R1 is CH2OPMB, only
the SN2 type of product 14 was observed. The products 14
and 15 were unable to separate by the standard condition
of silica gel chromatography, therefore the following reduc-
tion step was conducted with a mixture of starting materi-
als. However, fortunately, their amine products after reduc-
tion were easily separated and used for further chemical
transformation (Table 5). Next, after protection of amine
moiety by Boc, the desilylation was conducted smoothly,
f
–
94 (81)
91 (70)
82
2:98
1:99
1:99
i-Pr
12g
12h
12i
t-Bu
f
(E)-MeCH=CH
18i
–
a Reaction conditions: 2 and 4–6 (0.3 mmol), aldehyde (0.6 mmol), CrCl2
(1.8 mmol), LiI (0.15 mmol), DMF (1.2 mL) at r.t. for 4 h under Ar atmo-
sphere.
b Determined by 19F NMR spectroscopy.
c Values in parentheses are of isolated yield.
d Ethyl β,β-difluoroacrylate (13) was obtained in 18% yield.
e The starting material 4 was recovered in 47% yield.
f Not determined.
g The diastereomeric ratio was at 45:55 (entry 16) and at 62:38 (entry 18).
h The starting material 6 was recovered in 44% yield.
i The starting material was recovered in 7% yield.
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Synthesis
and Jones oxidation, followed by esterification with diazo-
methane, gave the desired fluoroalkene bioisosteres of Boc-
protected glycine dipeptide analogues (Scheme 2).
Based on our experimental results, the reaction mecha-
nism can be proposed as follows (Scheme 3). Thus, the
starting CBrF2-containing substrates can be converted into
the corresponding difluorinated chromium species Int-1
via the single electron-transfer mechanism. In Int-1, the C–
F bond may be a little bit longer than that in the starting
CBrF2-containing substrates due to the nature of a carben-
oid. Therefore, the C–F bond activation by CrCl2 presumably
takes place to provide the corresponding dichromium spe-
cies Int-2.
Table 5 Synthesis of β-Fluoroamine Analogues
F
F
R1
R2
R1
H2N
R2
N3
MsCl (2.5 equiv)
DMPA (4.0 equiv)
NaN3 (30 equiv)
F
16
+
14 (SN2 type)
PPh3 (2.0 equiv)
R1
HO
R2
+
F
THF–H2O
50 °C, 24 h
C–F bond activation
F
R1
R2
R1
R2
NH2
11
R2 = (CH2)2OTBDPS
2 CrCl2
2CrCl2
F
Cl2Cr
F
N3
15 (SN2' type)
F
F
F
R2
R2
R2
17
Cl2Cr
Int-2
Br
Cl2Cr
Int-1
CrCl2Br
CrCl2F
Entry R1
Yielda of 14 and 15 Combined yield (%)a
(ratio 14/15)b
(yield (%) of 16 and 17)
1
2
3
4
5
6
7
8
Ph
a
c
60 (0:100)
45 (0:100)
69 (52:48)
74 (49:51)
85 (78:22)
40 (68:32)c
85 (100:0)
28 (52:48)e
85 (0, 85)
p-MeOC6H4
i-Pr
84 (0, 84)
O
g
h
j
52 (35, 17)
82 (28, 54)
82 (49, 33)
83 (52, 31)d
85 (85, 0)
CrCl2
O
R2
H
i-Bu
Cl2Cr
N
Me
F
CrCl2
F
Cl2Cr
O
H
H
s-Bu
k
l
CH2OPMB
CHMe(OBn)
syn
elimination
(– CrHCl2)
syn
elimination
(– CrHCl2)
m
88f (40, 48)g
a Isolated yield.
O
O
F
b Values in parentheses are the ratio of regioisomer determined by 19F NMR
spectroscopy.
R2
Cl2Cr
N
Cl2Cr
c The diastereomeric ratio was 50:50.
d The diastereomeric ratios of 16 and 17 were 48:52 and 49:51, respectively.
e The diastereomeric ratios of 14 and 15 were 30:70 and 31:69, respectively.
f Isolation of the product was not possible. The yield was determined by
19F NMR spectroscopy.
H
O
F
H
(Z)-Int-3
(E)-Int-3
g The diastereomeric ratios of 16 and 17 were 27:73 and 27:73, respectively.
R1CHO
R1CHO
F
F
R1
H
R1
R2
Boc2O (1.2 equiv)
Et3N (1.2 equiv)
CH2Cl2, 0 °C, 1 h
1)
F
R1
OH
CrIII
O
R2
CrIII
O
H
16
2) TBAF (1.1 equiv)
THF, r.t., 2 h
Int-4
NHBoc
R1
=
i-Pr (g)
i-Bu (h)
Me (j)
CH2OPMB (l)
18g : 65%
H2O
H2O
18h : 86%
18j : 74%
18l : 96%a
F
F
1)
2)
CrO3 (5.0 equiv), H2SO4
acetone–H2O, 0 °C, 3 h
CH2N2 (excess), Et2O
R1
H
R1
R2
OH R2
OH
H
F
7
8, 10–12
R1
OMe
Scheme 3 Proposed reaction mechanism
NHBoc
O
19g : 68%
19h : 69%
19j : 45%b
19l : 27%
When 1 was employed as the substrate, the Lewis acidic
chromium metal can coordinate with the carbonyl oxygen
of the oxazolidinone moiety in Int-2 to form a stable seven-
membered intermediate. Additionally, this intermediate is
more stabilized because the dipole moment vectors on each
carbonyl group facing the opposite direction cancel each
a) Determined by 19F NMR. b) Isolated yield for the corresponding carboxylic acid.
Scheme 2 Synthesis for bioisosteres of glycine dipeptide
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 865–881

870
T. Nihei et al.
Paper
Synthesis
other. Then, syn-elimination of CrHCl2 takes place to afford
the corresponding (Z)-fluorovinyl chromium reagent (Z)-
Int-3,18 which can react with aldehydes to produce the cor-
responding (E)-β-fluoroallylic alcohols 7.
In the case of 3–6, which do not have any functionality
capable of coordinating with the chromium metal, β-elimi-
nation of CrHCl2 from the most stable conformer, in which
R2 and CrCl2 substituents are located in the antiperiplaner
position, avoiding a large steric repulsion, occurs in a syn-
fashion, resulting in the formation of a thermodynamically
stable (E)-fluorovinyl chromium reagents (E)-Int-3, which
can react with various aldehydes to yield the corresponding
(Z)-β-fluoroallylic alcohols 8 and 10–12.
In summary, we have investigated the highly stereose-
lective synthesis of (E)- or (Z)-β-fluoroallylic alcohol deriv-
atives based on CrCl2-mediated C–F bond activation reac-
tion. As a result, the substrate 1 having a Lewis basic group,
like an oxazolidinone substituent, afforded E-isomers in a
highly stereoselective manner, while substrates 3–6 with-
out a Lewis basic substituent gave the Z-isomers stereose-
lectively. It was proposed that this stereoselection was de-
rived from the interaction of chromium metal and a car-
bonyl oxygen in the dichromium intermediates. In addition,
the novel Cr(II)-mediated reductive coupling reaction could
be successfully applied to the stereoselective synthesis of
fluoroalkene dipeptide analogues.
In the reaction of 1, β-elimination of HF from Int-1 by
the chromium alkoxide Int-4 may also be possible due to a
highly acidic α-proton of the carbonyl (Scheme 4). In this
case, Int-1 can be directly converted into (Z)-Int-3, bypass-
ing the formation of the dichromium species Int-2.
IR spectra were recorded as a liquid film between NaCl plates or KBr
disk method for solids with a JASCO FT/IR-4100 type A spectrometer.
1H and 13C NMR spectra were recorded on a JEOL JNM-AL 400 NMR
spectrometer in CDCl3 solution with TMS as an internal reference. A
JEOL JNM-AL 400 NMR spectrometer was used for determining the
yield of the products with C6F6. 19F NMR (376.05 MHz) spectra were
recorded on a JEOL JNM-AL 400 NMR spectrometer in CDCl3 solution
with CFCl3 as an internal standard. High-resolution mass spectra
(HRMS) were recorded on a JEOL JMS-700MS spectrometer by elec-
tron impact (EI), chemical ionization (CI), and fast atom bombard-
ment (FAB) methods.
All reactions were routinely monitored by 19F NMR spectroscopy or
TLC, and carried out under an atmosphere of argon. EtOH was fleshly
distilled from Mg. DMF were freshly distilled from CaH2. All chemicals
were of reagent grade and, if necessary, were purified in the usual
manner prior to use. TLC was done with Merck silica gel 60 F254
plates, and column chromatography was carried out with Wako gel C-
200.
Given that the reaction of 1 with benzaldehyde in the
presence of only 3.0 equivalents of CrCl2 proceeded effi-
ciently, this β-elimination may play an important role in
the Cr(II)-mediated reductive coupling. In fact, some of the
steps of this new reaction mechanism depicted in Scheme 3
conflicts with the one described in our previous paper,8
thus the difluoroalkene could be possibly formed after β-
elimination from Int-1, which was initially thought as the
key intermediate transformed to fluorovinylchromium spe-
cies (Z)- or (E)-Int-3 via single electron transfer. In fact, ac-
cording to the control reaction described in Scheme 5,
treating difluoroalkene 2019 with benzaldehyde under the
standard reaction condition did not give the corresponding
desired product 12a with almost quantitative recovery of
starting material 20. This fact strongly indicates that the re-
action does not proceed via a 1,1-difluoroalkene intermedi-
ate.
1-Bromo-3-(tert-butyldiphenylsilyloxy)-1,1-difluoropropane (3);
Typical Procedure
Under an argon atmosphere, a solution of ethyl 3-bromo-3,3-difluo-
ropropanoate (2; 0.65 g, 3.0 mmol) in CH2Cl2 was added dropwise to
DIBAL-H (6.9 mmol) at –78 °C. The reaction mixture was stirred at
that temperature for 2 h and then stirred at 0 °C for 3 h. The reaction
was quenched with aq 10% HCl and the mixture was extracted with
CH2Cl2 (3 ×). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated under reduce pressure. The resulting residue
was used in the next step without further purification. A mixture of
the above crude alcohol, t-BuPh2SiCl (1.65 g, 6.0 mmol), and imidaz-
ole (0.41 g, 6.0 mmol) in THF (6 mL) was stirred at r.t. for 20 h. Addi-
tion of H2O followed by extractive workup and purification by silica
gel column chromatography (hexane–EtOAc, 80:1) afforded the de-
sired product; yield: 0.60 g (49%, 1.46 mmol) over two steps; colorless
oil.
O
O
F
F
F
Cl2Cr
N
R2
R1
H
+
Cl2Cr
CrIII
O
R2
Int-4
H
H
O
F
H
Int-1
(Z)-Int-3
Scheme 4 β-Elimination
F
Ph
n-C7H15
OH
IR (neat): 3072, 3000, 2932, 2858, 1960, 1590, 1472, 1428, 1362,
CrCl2 (6.0 equiv)
LiI (0.5 equiv)
PHCHO (2.0 equiv)
1283, 1188, 1114, 998, 880, 823, 702, 613 cm–1
.
12a : 0%
F
1H NMR (400 MHz, CDCl3): δ = 1.07 (9 H, s), 2.63–2.69 (2 H, tt, J = 6.59,
+
n-C7H15
F
DMF, r.t., 4 h
13.35 Hz), 3.93 (2 H, t, J = 6.59 Hz), 7.39–7.46 (6 H, m), 7.67–7.69 (4 H,
m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.7, 46.7 (t, J = 20.7 Hz), 58.8 (t,
J = 4.1 Hz), 121.2 (t, J = 305.4 Hz), 127.8, 129.8, 133.1, 135.5.
19F NMR (376 MHz, CDCl3): δ = –42.39 (2 F, t, J = 13.35 Hz).
recovery of 20
20
93%
[determined by 19F NMR]
Scheme 5 Control reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 865–881

871
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Synthesis
HRMS (FAB+): m/z [M + H]+ calcd for C19H24BrF2OSi: 413.0748; found:
413.0751.
13C NMR (100 MHz, acetone-d6): δ = 43.6, 63,2, 69.0 (d, J = 22.0 Hz),
101.8 (d, J = 30.2 Hz), 127.2, 128.7, 129.1, 140.5 (d, J = 1.3 Hz), 154.4,
164.5 (d, J = 24.7 Hz), 175.4 (d, J = 280.6 Hz).
19F NMR (376 MHz, acetone-d6): δ = –97.43 (1 F, dd, J = 21.33, 27.23
Hz).
HRMS (FAB+): m/z [M]+ calcd for C13H12FNO4: 265.0750; found:
265.0750.
1-Bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5)
Yield: 3.72 g (69%, 8.70 mmol) over two steps; colorless oil.
IR (neat): 3071, 2932, 2858, 1472, 1428, 1216, 1186, 1112, 1023, 997,
932, 823, 740, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.81–1.88 (2 H, m), 2.45–
2.55 (2 H, m), 3.72 (2 H, t, J = 5.99 Hz), 7.38–7.46 (6 H, m), 7.64–7.66
(4 H, m).
3-[(E)-3-Fluoro-4-hydroxy-4-(4-methylphenyl)but-2-enoyl]-2-ox-
azolidinone (7b)
Yield: 0.089 g (64%, 0.32 mmol); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 27.1 (d, J = 2.5 Hz), 41.2 (t,
J = 21.5 Hz), 62.0, 123.2 (d, J = 304.5 Hz), 127.7, 129.7, 133.5, 135.5.
19F NMR (376 MHz, CDCl3): δ = –43.76 (2 F, t, J = 14.67 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C20H26BrF2OSi: 427.0904; found:
427.0896.
1H NMR (400 MHz, acetone-d6): δ = 2.36 (3 H, s), 4.13 (2 H, t, J = 8.06
Hz), 4.48–4.52 (2 H, m), 5.26 (1 H, d, J = 6.11 Hz), 6.47 (1 H, dd,
J = 6.11, 27.13 Hz), 7.11 (1 H, d, J = 21.36 Hz), 7.22 (2 H, d, J = 7.97 Hz),
7.51 (2 H, d, J = 7.97 Hz).
13C NMR (100 MHz, acetone-d6): δ = 21.1, 43.6, 63.1, 69.0 (d, J = 22.1
Hz), 101.6 (d, J = 30.2 Hz), 127.2, 129.7, 137.5, 138.3, 154.4, 164.5 (d,
J = 24.7 Hz), 175.6 (d, J = 280.6 Hz).
1-Bromo-1,1-difluorononane (6)
Under an argon atmosphere, a three-necked, round-bottomed flask
equipped with an efficient magnetic stirring bar was charged with
CuCl (0.040 g, 0.4 mmol), 2-aminoethanol (1.22 g, 20.0 mmol), t-
BuOH (6.6 mL), oct-1-ene (4.49 g, 40 mmol), and CBr2F2 (16.8 g, 80
mmol), and the mixture was stirred at 85 °C for 48 h. Then, all organic
materials were filtered through silica gel, which was rinsed with hex-
anes. The resulting colorless filtrate was concentrated by evaporation
and subjected to fractional distillation under reduced pressure, af-
fording 1,3-dibromo-1,1-difluorononane (8.86 g, 27.7 mmol, 69%) as
a colorless liquid. Under an argon atmosphere, a three-necked round-
bottomed flask equipped with an ice-H2O condenser was charged
with 1,3-dibromo-1,1-difluorononane (8.86 g, 27.7 mmol) dissolved
in anhydrous DMSO (28 mL). NaBH4 (1.51 g, 40 mmol) was then add-
ed in small portions with vigorous stirring over the course of 15 min.
After the addition was complete, the bath temperature was raised to
70 °C and the mixture was stirred at this temperature for 6 h. The
flask was cooled to r.t., the contents were transferred to an Erlenmey-
er flask, and the reaction was quenched with chips of ice. The result-
ing mixture was carefully acidified with concd HCl, and the aqueous
DMSO layer was extracted with Et2O (3 ×). The combined Et2O layers
were washed with H2O, dried (Na2SO4), and subjected to fractional
distillation under the ambient pressure affording the known com-
pound, 1-bromo-1,1-difluorononane (contaminated with a small
amount of 1,1-difluorononane); yield: 1.87 g (38%, 7.7 mmol) as a col-
orless liquid. The analytical and spectral data were in conformity with
the literature.12
19F NMR (376 MHz, acetone-d6): δ = –98.73 (1 F, dd, J = 21.36, 27.13
Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H14FNO4: 279.0907; found:
279.0916.
3-[(E)-3-Fluoro-4-hydroxy-4-(4-methoxylphenyl)but-2-enoyl]-2-
oxazolidinone (7c)
Yield: 0.10 g (69%, 0.35 mmol); yellow oil.
1H NMR (400 MHz, acetone-d6): δ = 3.79 (3 H, s), 4.11 (2 H, t, J = 8.05
Hz), 4.46–4.51 (2 H, m), 5.18 (1 H, d, J = 6.00 Hz), 6.39 (1 H, dd,
J = 6.00, 27.01 Hz), 6.92 (2 H, d, J = 8.58 Hz), 7.04 (1 H, d, J = 21.31 Hz),
7.49 (2 H, d, J = 8.58 Hz).
13C NMR (100 MHz, acetone-d6): δ = 43.6, 55.5, 63.1, 68.7 (d, J = 22.0
Hz), 101.4 (d, J = 30.2 Hz), 114.5, 128.5, 132.5, 154.4, 160.5, 164.1 (d,
J = 24.7 Hz), 175.6 (d, J = 280.6 Hz).
19F NMR (376 MHz, acetone-d6): δ = –98.67 (1 F, dd, J = 21.31, 27.01
Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H14FNO5: 295.0856; found:
295.0863.
3-[(E)-3-Fluoro-4-(4-fluorophenyl)-4-hydroxybut-2-enoyl]-2-ox-
azolidinone (7d)
Yield: 0.13 g (90%, 0.45 mmol); yellow oil.
1H NMR (400 MHz, acetone-d6): δ = 4.13 (2 H, t, J = 8.17 Hz), 4.47–
4.53 (2 H, m), 5.37 (1 H, d, J = 5.84 Hz), 6.46 (1 H, dd, J = 5.84, 27.09
Hz), 7.06 (1 H, d, J = 21.29 Hz), 7.14 (2 H, m), 7.58–7.63 (2 H, m).
13C NMR (100 MHz, acetone-d6): δ = 43.6, 63.2, 68.3 (d, J = 21.9 Hz),
101.9 (d, J = 29.8 Hz), 115.8 (d, J = 21.6 Hz), 129.2 (d, J = 8.2 Hz), 136.6,
154.4, 163.3 (d, J = 244.4 Hz), 164.5 (d, J = 24.4 Hz), 175.6 (d, J = 280.4
Hz).
19F NMR (376 MHz, acetone-d6): δ = –115.06 to –114.87 (1 F, m),
–98.29 (1 F, dd, J = 21.29, 27.09 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C13H12F2NO4: 284.0734; found:
E-Selective Chromium(II)-Mediated Reductive Coupling Reaction
of 3-(3-Bromo-3,3-difluoropropanoyl)-2-oxazolidinone (1) with
Aldehydes; 3-[(E)-3-Fluoro-4-hydroxy-4-phenylbut-2-enoyl]-2-
oxazolidinone (7a); Typical Procedure
To a suspension of anhydrous CrCl2 (0.25 g, 2.0 mmol) and LiI (0.013
g, 0.1 mmol) in DMF (1.5 mL) were added benzaldehyde (0.11 g, 1.0
mmol) and imide (0.13 g, 0.5 mmol) at 0 °C. After stirring at that tem-
perature for 4 h, the reaction was quenched with ice-cold H2O. The
mixture was extracted with Et2O (3 ×). The combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo. The result-
ing residue was purified by silica gel column chromatography (ben-
zene–EtOAc, 3:1) to afford the pure product 7a; yield: 0.11 g (84%,
0.42 mmol); yellow oil.
284.0726.
3-[(E)-3-Fluoro-4-hydroxyhept-2-enoyl]-2-oxazolidinone (7f)
1H NMR (400 MHz, acetone-d6): δ = 4.12 (2 H, t, J = 8.03 Hz), 4.48–
4.52 (2 H, m), 5.31 (1 H, d, J = 6.00 Hz), 6.47 (1 H, dd, J = 6.00, 27.23
Hz), 7.04 (1 H, d, J = 21.33 Hz), 7.31–7.59 (5 H, m).
Yield: 0.079 g (68%, 0.34 mmol); yellow oil.
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1H NMR (400 MHz, acetone-d6): δ = 0.94 (3 H, t, J = 7.38 Hz), 1.35–
1.78 (4 H, m), 4.07 (2 H, t, J = 8.05 Hz), 4.43–4.49 (3 H, m), 5.10–5.25
(1 H, m), 6.99 (1 H, d, J = 22.83 Hz).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 57.1 (d, J = 6.6 Hz), 72.3 (d,
J = 32.2 Hz), 107.0, (d, J = 10.7 Hz), 126.7, 127.6, 128.4, 128.5, 129.6,
133.5, 135.5, 139.1, 158.8 (d, J = 260.3 Hz).
13C NMR (100 MHz, acetone-d6): δ = 14.1, 19.3, 36.6, 43.5, 63.1, 67.6
(d, J = 22.9 Hz), 101.3 (d, J = 30.9 Hz), 154.4, 164.2 (d, J = 25.02 Hz),
177.5 (d, J = 280.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.05 (1 F, dd, J = 11.91, 36.72 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C26H29FO2SiNa : 443.1819;
found: 443.1815.
19F NMR (376 MHz, acetone-d6): δ = –97.38 (1 F, dd, J = 22.83, 26.89
Hz).
(Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methylphe-
nyl)but-2-en-1-ol (8b)
HRMS (FAB+): m/z [M + H]+ calcd for C10H15FNO4: 232.0985; found:
232.0993.
Yield: 0.063 g (48%, 0.14 mmol); yellow oil.
IR (neat): 3395, 3071, 2930, 2858, 1079, 1513, 1472, 1428, 1362,
1163, 1111, 1062, 800, 740, 702 cm–1
.
3-[(E)-3-Fluoro-4-hydroxy-5-methylhex-2-enoyl]-2-oxazolidi-
none (7g)
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 2.31 (1 H, br s), 2.35 (3 H,
s), 4.36 (2 H, dd, J = 1.60, 6.49 Hz), 5.09 (1 H, d, J = 11.86 Hz), 5.19 (1 H,
dt, J = 36.52, 6.49 Hz), 7.15–7.44 (10 H, m), 7.64–7.70 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 21.2, 26.7, 57.1 (d, J = 6.6 Hz),
72.2 (d, J = 32.2 Hz), 106.9 (d, J = 9.9 Hz), 126.6, 127.6, 129.2, 129.6,
133.6, 135.6, 136.2, 138.2, 158.8 (d, J = 259.5 Hz).
Yield: 0.088 g (77%, 0.38 mmol); yellow oil.
1H NMR (400 MHz, acetone-d6): δ = 0.92 (3 H, d, J = 6.82 Hz), 1.05 (3
H, d, J = 6.66 Hz), 1.91–1.99 (1 H, m), 4.06 (2 H, t, J = 8.03 Hz), 4.48 (2
H, t, J = 8.03 Hz), 4.57 (1 H, d, J = 7.08 Hz), 4.80–4.90 (1 H, m), 7.05 (1
H, d, J = 21.83 Hz).
13C NMR (100 MHz, acetone-d6): δ = 18.85, 18.86, 32.4, 43.5, 63.0,
73.1 (d, J = 22.5 Hz), 102.2 (d, J = 30.7 Hz), 154.3, 164.4 (d, J = 25.5 Hz),
177.0 (d, J = 280.6 Hz).
19F NMR (376 MHz, CDCl3) δ = –119.12 (1 F, dd, J = 11.86, 36.52 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C27H31FO2SiNa: 457.1975;
found: 457.1972.
19F NMR (376 MHz, acetone-d6): δ = –95.00 (1 F, dd, J = 21.83, 29.33
Hz).
(Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphe-
nyl)but-2-en-1-ol (8c)
HRMS (FAB+): m/z [M + H]+ calcd for C10H15FNO4: 232.0985; found:
232.0984.
Yield: 0.070 g (52%, 0.16 mmol); yellow oil.
IR (neat): 3419, 3071, 2931, 2857, 1709, 1611, 1512, 1464, 1428,
3-[(E)-3-Fluoro-4-hydroxy-5,5-dimethylhex-2-enoyl]-2-oxazolidi-
none (7h)
1250, 1111, 1036, 739, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.04 (9 H, s), 2.00 (1 H, br s), 3.82 (3 H,
s), 4.36 (2 H, dd, J = 2.20, 6.59 Hz), 5.09 (1 H, dd, J = 3.20, 10.09 Hz),
5.19 (1 H, dt, J = 36.63, 6.59 Hz), 6.88–6.90 (2 H, m), 7.23–7.44 (8 H,
m), 7.63–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 55.3, 57.8 (d, J = 6.6 Hz),
72.0 (d, J = 32.2 Hz), 106.8 (d, J = 11.6 Hz), 113.9, 127.6, 128.1, 129.6,
131.3, 133.6, 135.6, 158.9 (d, J = 259.5 Hz), 159.7.
Yield: 0.095 g (77%, 0.39 mmol); yellow oil.
1H NMR (400 MHz, acetone-d6): δ = 1.00 (9 H, s), 4.07 (2 H, dt, J = 2.11,
8.00 Hz), 4.48 (2 H, t, J = 8.00 Hz), 4.63 (1 H, d, J = 6.93 Hz), 5.04 (1 H,
dd, J = 6.93, 30.24 Hz), 7.09 (1 H, d, J = 23.08 Hz).
13C NMR (100 MHz, acetone-d6): δ = 26.5, 36.3, 43.6, 63.0, 74.4 (d,
J = 20.5 Hz), 103.0 (d, J = 31.3 Hz), 154.4, 164.5 (d, J = 25.9 Hz), 176.6
(d, J = 282.8 Hz).
19F NMR (376 MHz, acetone-d6): δ = –87.58 (1 F, dd, J = 23.08, 30.24
Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C11H17FNO4: 246.1142; found:
19F NMR (376 MHz, CDCl3): δ = –118.95 (1 F, dd, J = 10.09, 36.63 Hz).
HRMS (FAB+): m/z [M – H]+ calcd for C27H30FO3Si: 449.1948; found:
449.1938.
246.1141.
(Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-fluorophe-
nyl)but-2-en-1-ol (8d)
Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction
of 1-Bromo-3-(tert-butyldiphenylsilyloxy)-1,1-difluoropropane
(3) with Aldehydes; (Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-
phenylbut-2-en-1-ol (8a); Typical Procedure
Yield: 0.073 g (56%, 0.17 mmol); yellow oil.
IR (neat): 3402, 3071, 2931, 2858, 1709, 1605, 1509, 1472, 1428,
1227, 1111, 1064, 908, 739, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 2.17 (1 H, br s), 4.37 (2 H,
d, J = 6.39 Hz), 5.12 (1 H, d, J = 12.11 Hz), 5.18 (1 H, dt, J = 36.72, 6.39
Hz), 7.03–7.07 (2 H, m), 7.32–7.46 (8 H, m), 7.64–7.72 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 57.0 (d, J = 6.6 Hz), 71.7 (d,
J = 32.2 Hz), 107.3 (d, J = 11.7 Hz), 115.4 (d, J = 27.8 Hz), 127.6, 128.5
(d, J = 8.2 Hz), 129.7, 133.5, 134.8 (d, J = 2.4 Hz), 135.5, 158.5 (d,
J = 258.5 Hz), 162.6 (d, J = 246.2 Hz).
To a suspension of anhydrous CrCl2 (0.22 g, 1.8 mmol) and LiI (0.020
g, 0.15 mmol) in DMF (1.2 mL) were added benzaldehyde (0.064 g, 0.6
mmol) and the silyl ether 3 (0.12 g, 0.30 mmol) at 0 °C. After stirring
at r.t. for 4 h, the reaction was quenched with H2O. The mixture was
extracted with Et2O (3 ×). The combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. The resulting residue
was purified by silica gel column chromatography (hexane–
EtOAc, 5:1) to afford the pure product; yield: 0.071 g (56%, 0.17
mmol); yellow oil.
19F NMR (376 MHz, CDCl3): δ = –119.38 (1 F, dd, J = 12.11, 36.72 Hz).
HRMS (FAB+): m/z [M]+ calcd for C26H28F2O2Si: 438.1827; found:
IR (neat): 3392, 3070, 2931, 2858, 1709, 1589, 1494, 1472, 1428,
438.1833.
1262, 1164, 1111, 1060, 885, 740, 701, 612 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.95 (9 H, s), 2.01 (1 H, br s), 4.26 (2 H,
dd, J = 2.00, 6.79 Hz), 5.03 (1 H, d, J = 11.91 Hz), 5.09 (1 H, dt, J = 36.72,
6.79 Hz), 7.20–7.34 (11 H, m), 7.56–7.57 (4 H, m).
(Z)-1-(tert-Butyldiphenylsilyloxy)-3-fluorohept-2-en-4-ol (8f)
Yield: 0.066 g (57%, 0.17 mmol); yellow oil.
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IR (neat): 3389, 3071, 3050, 2999, 2959, 2932, 2859, 1709, 1589,
1471, 1428, 1305, 1264, 1185, 1112, 939, 852, 822, 740, 702 cm–1
IR (neat): 3448, 3032, 2983, 1736, 1495, 1454, 1372, 1266, 1189,
.
1094, 1060, 1027, 955, 887, 804, 701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.95 (3 H, t, J = 7.39 Hz), 1.07 (9 H, s),
1.26–1.70 (4 H, m), 1.79 (1 H, br s), 4.00–4.07 (1 H, m), 4.37 (2 H, dd,
J = 2.20, 6.59 Hz), 5.07 (1 H, dt, J = 37.41, 6.59 Hz), 7.36–7.47 (6 H, m),
7.68–7.73 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 13.8, 18.5, 19.1, 26.8, 35.8, 57.0 (d,
J = 7.43 Hz), 70.2 (d, J = 29.8 Hz), 106.1 (d, J = 11.7 Hz), 127.6, 129.6,
133.6, 135.5, 159.8 (d, J = 261.2 Hz).
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.09 Hz), 2.50 (1 H, br
s), 3.17 (2 H, d, J = 7.19 Hz), 4.15 (2 H, q, J = 7.09 Hz), 5.22 (1 H, dt,
J = 35.26, 7.19 Hz), 5.24 (1 H, d, J = 11.25 Hz), 7.29–7.45 (5 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 29.2 (d, J = 4.9 Hz), 60.9, 72.4 (d,
J = 31.4 Hz), 99.5 (d, J = 9.8 Hz), 126.7, 128.4, 128.5, 139.1, 160.4 (d,
J = 260.3 Hz), 171.2 (d, J = 2.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.34 (1 F, dd, J = 11.25, 35.26 Hz).
HRMS (FAB+): m/z [M]+ calcd for C13H15FO3: 238.1005; found:
19F NMR (376 MHz, CDCl3): δ = –122.19 (1 F, dd, J = 15.61, 37.41 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C23H31FO2SiNa: 409.1975;
238.1009.
found: 409.1976.
Ethyl (Z)-4-Fluoro-5-hydroxy-5-(4-methylphenyl)pent-3-enoate
(Z)-6-(tert-Butyldiphenylsilyloxy)-4-fluoro-2-methylhex-4-en-3-
(10b)
ol (8g)
Yield: 0.031 g (40%, 0.12 mmol); yellow oil.
Yield: 0.069 g (59%, 0.18 mmol); yellow oil.
IR (neat): 3438, 2982, 2925, 1737, 1514, 1372, 1264, 1186, 1024, 955,
IR (neat): 3404, 3071, 3050, 2960, 2931, 2858, 1708, 1471, 1428,
805, 770, 734 cm–1
.
1264, 1112, 1059, 1026, 939, 876, 822, 782, 740, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.19 Hz), 1.61 (1 H, br
s), 2.35 (3 H, s), 3.17 (2 H, d, J = 6.99 Hz), 4.15 (2 H, q, J = 7.19 Hz),
5.19–5.22 (1 H, m), 5.22 (1 H, dt, J = 35.66, 6.99 Hz), 7.17–7.33 (4 H,
m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 21.2, 29.2 (d, J = 4.9 Hz), 60.9,
72.3 (d, J = 32.2 Hz), 99.3 (d, J = 12.4 Hz), 126.7, 129.3, 136.2, 138.3,
160.5 (d, J = 259.5 Hz), 171.2 (d, J = 1.7 Hz).
1H NMR (400 MHz, CDCl3): δ = 0.92 (3 H, d, J = 6.79 Hz), 0.97 (3 H, d,
J = 6.79 Hz), 1.07 (9 H, s), 1.69 (1 H, br s), 1.87–1.91 (1 H, m), 3.73 (1 H,
dd, J = 6.59, 17.05 Hz), 4.37 (2 H, d, J = 6.49 Hz), 5.07 (1 H, dt, J = 37.12,
6.49 Hz), 7.37–7.46 (6 H, m), 7.69–7.71 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 17.5, 18.8, 19.1, 26.5, 26.8, 57.0 (d,
J = 7.4 Hz), 75.8 (d, J = 28.9 Hz), 107.1 (d, J = 11.6 Hz), 127.7, 129.7,
133.7, 135.6, 159.1 (d, J = 261.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.31 (1 F, dd, J = 11.09, 35.66 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H17FO3: 252.1162; found:
19F NMR (376 MHz, CDCl3): δ = –121.25 (1 F, dd, J = 17.05, 37.12 Hz).
HRMS (FAB): m/z [M + Na]+ calcd for C23H31FO2SiNa: 409.1975; found:
252.1163.
409.1976.
Ethyl (Z)-4-Fluoro-5-hydroxy-5-(4-methoxyphenyl)pent-3-enoate
(Z)-6-(tert-Butyldiphenylsilyloxy)-4-fluoro-2,2-dimethylhex-4-
(10c)
en-3-ol (8h)
Yield: 0.041 g (51%, 0.15 mmol); yellow oil.
Yield: 0.076 g (63%, 0.19 mmol); yellow oil.
IR (neat): 3449, 2982, 2839, 1736, 1611, 1586, 1513, 1465, 1372,
IR (neat): 3442, 3071, 2957, 2958, 1702, 1671, 1472, 1428, 1264,
1304, 1251, 1180, 1113, 1032, 955, 834, 775, 736 cm–1
.
1186, 1070, 1014, 937, 822, 788, 740, 612 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.49 Hz), 2.63 (1 H, br
s), 3.16 (2 H, d, J = 7.19 Hz), 3.80 (3 H, s), 4.14 (2 H, q, J = 7.49 Hz), 5.20
(1 H, dt, J = 36.03, 7.19 Hz), 5.24 (1 H, m), 6.89 (2 H, d, J = 8.59 Hz),
7.35 (2 H, d, J = 8.59 Hz).
1H NMR (400 MHz, CDCl3): δ = 0.94 (9 H, s), 1.05 (9 H, s), 1.71 (1 H, br
s), 3.68 (1 H, d, J = 18.81 Hz), 4.35–4.36 (2 H, m), 5.03 (1 H, dt,
J = 37.38, 6.79 Hz), 7.37–7.44 (6 H, m), 7.67–7.71 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 25.8, 26.8, 34.8, 60.0 (d, J = 7.43
Hz), 78.2 (d, J = 27.31 Hz), 107.5 (d, J = 11.7 Hz), 127.7, 129.6, 133.7,
135.5, 159.1 (d, J = 262.0 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 29.2 (d, J = 4.9 Hz), 55.3, 60.9,
72.0 (d, J = 31.1 Hz), 99.2 (d, J = 11.7 Hz), 113.9, 128.1, 131.3, 159.7,
160.6 (d, J = 259.5 Hz), 171.2 (d, J = 2.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –114.51 (1 F, dd, J = 18.81, 37.38 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.13 (1 F, dd, J = 9.78, 36.03 Hz).
HRMS (FAB+): m/z [M – H]+ calcd for C24H32FO2Si: 399.2156; found:
HRMS (FAB+): m/z [M]+ calcd for C14H17FO4: 268.1111; found:
399.2152.
268.1118.
Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction
of Ethyl 4-Bromo-4,4-difluorobutyrate (4) with Aldehydes; Ethyl
(Z)-4-Fluoro-5-hydroxy-5-phenylpent-3-enoate (10a); Typical Pro-
cedure
Ethyl (Z)-4-Fluoro-5-(4-fluorophenyl)-5-hydroxypent-3-enoate
(10d)
Yield: 0.038 g (49%, 0.15 mmol); yellow oil.
IR (neat): 3431, 2985, 1735, 1604, 1509, 1414, 1373, 1225, 1190,
To a suspension of anhydrous CrCl2 (0.22 g, 1.8 mmol) and LiI (0.020
g, 0.15 mmol) in DMF (1.2 mL) were added benzaldehyde (0.064 g, 0.6
mmol) and the ester 4 (0.065 g, 0.3 mmol) at 0 °C. After stirring at r.t.
for 4 h, the reaction was quenched with H2O and the mixture was ex-
tracted with Et2O (3 ×). The combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. The resulting residue
was purified by silica gel column chromatography (hexane–
EtOAc, 3:1) to afford the pure product; yield: 0.040 g (55%, 0.17
mmol); yellow oil.
1158, 1098, 1027, 956, 839, 784, 736 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.32 (3 H, t, J = 7.19 Hz), 2.84 (1 H, br
s), 3.23 (2 H, d, J = 7.29 Hz), 4.21 (2 H, q, J = 7.19 Hz), 5.27 (1 H, dt,
J = 35.26, 7.29 Hz), 5.28 (1 H, d, J = 11.25 Hz), 7.10–7.14 (2 H, m),
7.46–7.49 (2 H, m).
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13C NMR (100 MHz, CDCl3): δ = 14.1, 29.1 (d, J = 5.8 Hz), 61.0, 71.7 (d,
J = 31.3 Hz), 99.6 (d, J = 11.6 Hz), 115.4, 128.5 (d, J = 8.2 Hz), 134.9 (d,
J = 3.3 Hz), 160.3 (d, J = 260.3 Hz), 162.7 (d, J = 246.3 Hz), 171.2 (d,
J = 2.5 Hz).
Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction
of 1-Bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5)
with Benzaldehyde; (Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-2-
methyloct-5-en-4-ol (11h); Typical Procedure
19F NMR (376 MHz, CDCl3): δ = –114.14 to –114.22 (1 F, m), –119.43
(1 F, dd, J = 11.25, 35.26 Hz).
HRMS (FAB+): m/z [M]+ calcd for C13H14F2O3: 256.0911; found:
To a suspension of anhydrous CrCl2 (1.11 g, 9.0 mmol) and LiI (0.10 g,
0.75 mmol) in DMF (6 mL) were added isovaleraldehyde (0.26 g, 3.0
mmol) and 1-bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobu-
tane (5; 0.64 g, 1.5 mmol) at 0 °C. After stirring at r.t. for 4 h, the reac-
tion was quenched with ice-cold H2O and the mixture was extracted
with Et2O (3 ×). The combined organic layers were dried (Na2SO4); fil-
tered, and concentrated in vacuo. The resulting residue was purified
by silica gel column chromatography (hexane–EtOAc, 5:1) to afford
the pure product 11h; yield: 0.38 g (61%, 0.92 mmol); yellow oil.
256.0914.
Ethyl (Z)-4-Fluoro-5-hydroxyoct-3-enoate (10f)
Yield: 0.026 g (42%, 0.13 mmol); yellow oil.
IR (neat): 3437, 2961, 2874, 1739, 1466, 1372, 1188, 1118, 1028, 953
cm–1
.
IR (neat): 3388, 3071, 2957, 2931, 2859, 1709, 1471, 1428, 1388,
1362, 1111, 937, 823, 738, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.94 (3 H, t, J = 7.39 Hz), 1.26 (3 H, t,
J = 6.79 Hz), 1.37–1.46 (2 H, m), 1.60–1.66 (2 H, m), 2.08 (1 H, br s),
3.14 (2 H, d, J = 7.19 Hz), 4.08–4.17 (3 H, m), 5.07 (1 H, dt, J = 36.77,
7.19 Hz).
13C NMR (100 MHz, CDCl3): δ = 13.8, 14.1, 18.5, 29.1 (d, J = 5.8 Hz),
35.8, 60.9, 70.2 (d, J = 28.9 Hz), 98.5 (d, J = 12.3 Hz), 161.4 (d, J = 261.2
Hz), 171.3 (d, J = 2.5 Hz).
1H NMR (400 MHz, CDCl3): δ = 0.926 (3 H, d, J = 6.39 Hz), 0.932 (3 H,
d, J = 6.39 Hz), 1.05 (9 H, s), 1.45–1.60 (3 H, m), 1.75 (1 H, m), 2.36 (2
H, q, J = 6.66 Hz), 3.69 (2 H, t, J = 6.66 Hz), 4.12 (1 H, dt, J = 15.79, 7.99
Hz), 4.88 (1 H, dt, J = 38.40, 6.66 Hz), 7.36–7.45 (6 H, m), 7.65–7.68 (4
H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 22.1, 23.0, 24.3, 26.8, 42.9, 63.1,
69.3 (d, J = 28.9 Hz), 103.1 (d, J = 14.1 Hz), 127.6, 129.6, 133.8, 135.6,
160.6 (d, J = 257.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.41 (1 F, dd, J = 15.79, 36.77 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C10H17FO3Na: 227.1059; found:
19F NMR (376 MHz, CDCl3): δ = –125.73 (1 F, dd, J = 15.79, 38.40 Hz).
227.1062.
HRMS (FAB+): m/z [M + Na]+ calcd for C25H35FO2SiNa: 437.2288;
Ethyl (Z)-4-Fluoro-5-hydroxy-6-methylhept-3-enoate (10g)
Yield: 0.033 g (54%, 0.16 mmol); yellow oil.
found: 437.2294.
(Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-phenylpent-2-en-1-
ol (11a)
IR (neat) 3445, 2965, 2875, 1738, 1469, 1371, 1259, 1189, 1123, 1123,
1024, 956, 879, 831 cm–1
.
Yield: 0.30 g (67%, 0.68 mmol); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 0.95 (3 H, d, J = 6.59 Hz), 0.99 (3 H, d,
J = 6.59 Hz), 1.26 (3 H, t, J = 7.09 Hz), 1.78 (1 H, br s), 1.89–1.96 (1 H,
m), 3.16 (2 H, dm, J = 7.24 Hz), 3.82 (1 H, dd, J = 6.99, 17.25 Hz), 4.15
(2 H, q, J = 7.09 Hz), 5.07 (1 H, dt, J = 36.58, 7.24 Hz).
Physical and spectral data were in accordance with the literature val-
ues.20
13C NMR (100 MHz, CDCl3): δ = 14.1, 17.6, 18.8, 29.1 (d, J = 5.7 Hz),
31.2, 60.9, 75.9 (d, J = 28.1 Hz), 99.4 (d, J = 12.5 Hz), 160.7 (d, J = 261.2
Hz), 171.3 (d, J = 1.6 Hz).
(Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphe-
nyl)pent-2-en-1-ol (11c)
Yield: 0.13 g (54%, 0.28 mmol); yellow oil.
19F NMR (376 MHz, CDCl3): δ = –119.59 (1 F, dd, J = 17.25, 36.58 Hz).
HRMS (FAB+): m/z [M – H]+ calcd for C10H16FO3: 203.1083; found:
IR (neat): 3405, 3070, 2930, 2857, 1611, 1512, 1471, 1427, 1249,
1174, 1111, 1035, 823, 740, 703 cm–1
.
203.1088.
1H NMR (400 MHz, CDCl3): δ = 1.03 (9 H, s), 2.06 (1 H, d, J = 4.80 Hz),
2.37 (2 H, q, J = 6.59 Hz), 3.68 (2 H, t, J = 6.59 Hz), 3.80 (3 H, s), 4.96 (1
H, dt, J = 37.95, 6.59 Hz), 5.15 (1 H, dd, J = 4.80, 11.34 Hz), 6.87–6.89
(2 H, m), 7.32–7.44 (8 H, m), 7.63–7.67 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 27.0 (d, J = 4.1 Hz), 55.2,
63.0 (d, J = 1.6 Hz), 72.3 (d, J = 32.1 Hz), 104.1 (d, J = 13.3 Hz), 113.9,
127.6, 128.0, 129.6, 131.7, 133.8, 135.5, 159.5, 159.7 (d, J = 256.2 Hz).
Ethyl (Z)-4-Fluoro-5-hydroxy-6,6-dimethylhept-3-enoate (10h)
Yield: 0.020 g (31%, 0.09 mmol); yellow oil.
IR (neat): 3461, 2958, 2908, 2873, 1793, 1479, 1467, 1370, 1330,
1261, 1188, 1076, 1018, 957, 911, 849, 770 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.97 (9 H, s), 1.26 (3 H, t, J = 7.19 Hz),
1.99 (1 H, br s), 3.15 (2 H, m), 3.78 (1 H, d, J = 19.13 Hz), 4.15 (2 H, q,
J = 7.19 Hz), 5.03 (1 H, dt, J = 36.52, 7.29 Hz).
19F NMR (376 MHz, CDCl3): δ = –121.83 (1 F, dd, J = 11.34, 37.95 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C28H33FO3SiNa: 487.2081;
found: 487.2075.
13C NMR (100 MHz, CDCl3): δ = 14.1, 25.8, 29.2 (d, J = 5.7 Hz), 34.9,
60.9, 78.2 (d, J = 28.1 Hz), 100.3 (d, J = 12.5 Hz), 160.7 (d, J = 262.0 Hz),
171.2 (d, J = 1.7 Hz).
(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluorohex-3-en-2-ol (11j)
Yield: 0.39 g (69%, 1.04 mmol); colorless oil.
19F NMR (376 MHz, CDCl3): δ = –114.92 (1 F, dd, J = 19.13, 36.52 Hz).
IR (neat): 3362, 3071, 3050, 2957, 2931, 2858, 1709, 1472, 1428,
HRMS (FAB+): m/z [M + H]+ calcd for C11H20FO3: 219.1396; found:
219.1389.
1389, 1362, 1111, 1005, 937, 823, 738, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.34 (3 H, d, J = 6.31 Hz),
1.55–1.65 (1 H, m), 2.35 (2 H, m), 3.69 (2 H, t, J = 6.79 Hz), 4.26 (1 H,
dq, J = 13.74, 6.31 Hz), 4.88 (1 H, dt, J = 38.93, 6.79 Hz), 7.36–7.45 (6
H, m), 7.65–7.67 (4 H, m).
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13C NMR (100 MHz, CDCl3): δ = 19.1, 20.1 (d, J = 1.7 Hz), 26.8, 26.9 (d,
J = 1.6 Hz), 63.0 (d, J = 1.6 Hz) 66.5 (d, J = 30.5 Hz), 102.0 (d, J = 14.0
Hz), 127.6, 129.6, 133.8, 135.6, 161.3 (d, J = 256.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –124.45 (1 F, dd, J = 13.74, 38.93 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C22H29FO2SiNa: 395.1819;
Major Isomer (more polar)
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.19 (3 H, d, J = 6.39 Hz),
1.50–1.80 (1 H, m), 2.38 (2 H, q, J = 7.06 Hz), 3.68 (2 H, t, J = 7.06 Hz),
3.85–3.95 (1 H, m) 4.20–4.30 (1 H, m), 4.42–4.70 (2 H, m), 5.00 (1 H,
dt, J = 38.43, 7.06 Hz), 7.26–7.44 (11 H, m), 7.65–7.67 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –123.04 (1 F, dd, J = 10.91, 38.43 Hz).
found: 395.1826.
HRMS (FAB+): m/z [M + Na]+ calcd for C30H37FO3SiNa: 515.2389;
(Z)-7-(tert-Butyldiphenylsilyloxy)-4-fluoro-2-methylhept-4-en-3-
found: 515.2394.
ol (11g)
Yield: 0.40 g (67%, 1.00 mmol); yellow oil.
Minor Isomer (less polar)
1H NMR (400 MHz, CDCl3): δ = 5.02 (1 H, dt, J = 37.37, 7.86 Hz).
19F NMR (376 MHz, CDCl3): δ = –123.94 (1 F, dd, J = 15.80, 37.37 Hz).
Physical and spectral data were in accordance with the literature val-
ues.20
(Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-3-methyloct-5-en-4-
ol (11k)
Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction
of 1-Bromo-1,1-difluorononane (6) with Benzaldehyde; (Z)-2-Flu-
oro-1-phenyldec-2-en-1-ol (12a); Typical Procedure
Yield: 0.41 g (49%, 0.99 mmol); diastereomeric ratio: 45:55; yellow
oil.
To a suspension of anhydrous CrCl2 (0.22 g, 1.8 mmol) and LiI (0.020
g, 0.15 mmol) in DMF (1.2 mL) were added benzaldehyde (0.064 g, 0.6
mmol) and the substrate 6 (0.073 g, 0.3 mmol) at 0 °C. After stirring at
r.t. for 4 h, the reaction was quenched with H2O and the mixture was
extracted with Et2O (3 ×). The combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. The resulting residue
was purified by silica gel column chromatography (hexane–
EtOAc, 3:1) to afford the pure product 12a; yield: 0.056 g (76%, 0.22
mmol); yellow oil.
IR (neat): 3404, 3071, 2961, 2931, 2858, 1707, 1463, 1428, 1384,
1362, 1262, 1111, 937, 822, 739, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.87–0.95 (6 H, m), 1.05 (9 H, s), 1.40–
1.84 (4 H, m), 2.39 (2 H, q, J = 6.39 Hz), 3.72 (2 H, t, J = 6.39 Hz), 3.79
and 3.89 (1 H, dd and dd, J = 7.19, 19.48 Hz and J = 5.99, 15.69 Hz),
4.87 and 4.88 (1 H, dt and dt, J = 7.19, 38.64 Hz and J = 7.19, 38.50 Hz),
7.36–7.45 (6 H, m), 7.66–7.68 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –123.86 and –124.94 (1 F, dd and dd,
J = 19.48, 38.64 Hz and 15.69, 38.50 Hz).
IR (neat): 3364, 3032, 2926, 2856, 1708, 1495, 1455, 1379, 1273,
1192, 1111, 1024, 700 cm–1
.
HRMS (FAB+): m/z [M + Na]+ calcd for C25H35FO2SiNa: 437.2288;
found: 437.2285.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 1.27–1.39 (10
H, m), 2.08–2.18 (3 H, m), 4.90 (1 H, dt, J = 37.87, 7.19 Hz), 5.21 (1 H,
d, J = 13.17 Hz), 7.31–7.45 (5 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 29.0, 29.1, 29.2, 31.8,
72.8 (d, J = 32.2 Hz), 107.8 (d, J = 13.3 Hz), 126.6, 128.2, 128.5, 139.7,
158.3 (d, J = 255.4 Hz).
(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluoro-1-(4-methoxybenzyl-
oxy)hex-3-en-2-ol (11l)
Yield: 0.20 g (38%, 0.39 mmol); colorless oil.
IR (neat): 3434, 3070, 2931, 2858, 1616, 1514, 1471, 1428, 1249,
19F NMR (376 MHz, CDCl3): δ = –124.22 (1 F, dd, J = 13.17, 37.87 Hz).
HRMS (FAB+): m/z [M]+ calcd for C16H23FO: 250.1733; found:
1111, 1035, 822, 740, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.04 (9 H, s), 1.40–2.00 (1 H, m), 2.37
(2 H, q, J = 6.66 Hz), 3.50 (1 H, dd, J = 7.59, 9.59 Hz), 3.61 (1 H, dd,
J = 4.00, 9.59 Hz), 3.67 (2 H, t, J = 6.66 Hz), 3.80 (3 H, s), 4.28 (1 H, ddd,
J = 4.00, 7.59, 11.39 Hz), 4.48 (1 H, d, J = 11.99 Hz), 4.52 (1 H, d,
J = 11.99 Hz), 4.99 (1 H, dt, J = 36.71, 6.66 Hz), 6.86–6.89 (2 H, m),
7.23–7.25 (2 H, m), 7.34–7.64 (6 H, m,), 7.65–7.66 (4 H, m).
250.1729.
(Z)-2-Fluoro-1-(4-methylphenyl)dec-2-en-1-ol (12b)
Yield: 76% (19F NMR yield). This compound could not be separated
from the small amount of impurities.
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 26.9 (d, J = 1.7 Hz), 55.3,
63.0 (d, J = 1.7 Hz), 69.4 (d, J = 32.2 Hz), 71.0, 73.1, 104.1 (d, J = 12.4
Hz), 113.9, 127.6, 129.48, 129.58, 129.62, 133.8, 135.5, 157.7 (d,
J = 255.4 Hz), 159.4.
IR (neat): 3368, 2925, 2856, 1708, 1514, 1459, 1273, 1111, 1044, 819,
768 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.90 (3 H, t, J = 5.60 Hz), 1.20–1.40 (10
H, m), 2.12 (2 H, q, J = 7.19 Hz), 2.26 (1 H, br s), 2.37 (3 H, s), 4.90 (1 H,
dt, J = 37.03, 7.19 Hz), 5.16 (1 H, d, J = 12.41 Hz), 7.13–7.33 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –123.36 (1 F, dd, J = 11.39, 36.71 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 21.1, 22.6, 23.3, 29.0, 29.1, 29.2,
31.8, 72.6 (d, J = 32.1 Hz), 107.6 (d, J = 14.1 Hz), 126.6, 129.2, 136.8,
138.0, 158.5 (d, J = 254.6 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H37FO4SiNa: 531.2353;
found: 531.2353.
(Z)-2-Benzyloxy-7-(tert-butyldiphenylsilyloxy)-4-fluorohept-4-
19F NMR (376 MHz, CDCl3): δ = –124.11 (1 F, dd, J = 12.41, 37.03 Hz).
en-3-ol (11m)
HRMS (FAB+): m/z [M]+ calcd for C17H25FO: 264.1889; found:
264.1884.
This compound was inseparable from by-products; yield: 75% (19
F
NMR yield); diastereomeric ratio: 62:38.
(Z)-2-Fluoro-1-(4-methoxyphenyl)dec-2-en-1-ol (12c)
Yield: 0.065 g (80%, 0.23 mmol); yellow oil.
IR (neat): 3399, 2926, 2855, 1707, 1612, 1585, 1512, 1464, 1304,
1249, 1174, 1109, 1036, 832, 774 cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 1.20–1.35 (11
H, m), 2.11 (2 H, q, J = 7.13 Hz), 3.81 (3 H, s), 4.89 (1 H, dt, J = 38.34,
7.13 Hz), 5.15 (1 H, dd, J = 3.60, 12.21 Hz), 6.90 (2 H, d, J = 8.59 Hz),
7.35 (2 H, d, J = 8.59 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 28.99, 29.04, 29.2,
31.8, 55.2, 72.3 (d, J = 32.2 Hz), 107.4 (d, J = 13.3 Hz), 113.8, 127.9,
132.0, 158.6 (d, J = 254.6 Hz), 159.4.
(Z)-4-Fluoro-2,2-dimethyldodec-4-en-3-ol (12h)
Yield: 82% (19F NMR yield). This compound could not be separated
from the small amount of impurities.
IR (neat): 3421, 2956, 2926, 2857, 1703, 1466, 1365, 1288, 1114,
1065, 1013, 910, 848, 768 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.39 Hz), 0.96 (9 H, s),
1.20–1.35 (11 H, m), 2.09 (2 H, q, J = 7.19 Hz), 3.71 (1 H, d, J = 20.64
Hz), 4.75 (1 H, dt, J = 37.88, 7.19 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.2, 26.0, 29.1, 29.31,
29.32, 31.8, 34.8, 78.8 (d, J = 27.3 Hz), 108.5 (d, J = 14.1 Hz), 158.4 (d,
J = 257.9 Hz).
19F NMR (376 MHz, CDCl3): δ = –123.86 (1 F, dd, J = 12.21, 38.34 Hz).
HRMS (FAB+): m/z [M]+ calcd for C17H25FO: 264.1889; found:
264.1894.
(Z)-2-Fluoro-1-(4-fluorophenyl)dec-2-en-1-ol (12d)
Yield: 0.061 g (78%, 0.23 mmol); yellow oil.
19F NMR (376 MHz, CDCl3): δ = –120.38 (1 F, dd, J = 20.64, 37.88 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H27FO: 230.2046; found:
IR (neat): 3358, 2926, 2856, 1707, 1605, 1509, 1465, 1227, 1157,
230.2043.
1097, 1015, 837, 783 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 1.20–1.40 (10
H, m), 2.10 (2 H, q, J = 7.19 Hz), 2.44 (1 H, br s), 4.89 (1 H, dt, J = 37.68,
7.19 Hz), 5.18 (1 H, d, J = 12.79 Hz), 7.03–7.09 (2 H, m), 7.38–7.41 (2
H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 28.99, 29.09, 29.14,
31.8, 72.1 (d, J = 32.2 Hz) 107.9 (d, J = 14.1 Hz), 115.3 (d, J = 21.5 Hz),
128.4 (d, J = 8.3 Hz), 135.5 (d, J = 2.5 Hz) 158.2 (d, J = 254.6 Hz), 162.6
(d, J = 246.4 Hz).
Azide Compounds; (Z)-2-Azido-6-(tert-butyldiphenylsilyloxy)-3-
fluoro-1-(4-methoxybenzyloxy)hex-3-ene (14l), Typical Procedure
To a mixture of β-fluoroallylic alcohol derivative 11l (0.26 g 0.51
mmol), NaN3 (0.96 g, 15 mmol), and DMAP (0.25 g, 2.02 mmol) in
CH2Cl2 (5.1 mL) were added MsCl (0.14 g, 1.26 mmol) at 0 °C. The
mixture was stirred at r.t. for 30 min. Then, DMSO (3.37 mL) was add-
ed to the reaction mixture and the whole was stirred for additional 3
h. The reaction was quenched with H2O and the mixture was extract-
ed with Et2O (3 ×). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting residue was puri-
fied by silica gel column chromatography (hexane–EtOAc, 3:1) to af-
ford the pure product 14l; yield: 0.23 g (85%, 0.43 mmol); pale yellow
oil.
19F NMR (376 MHz, CDCl3): δ = –124.41 (1 F, dd, J = 12.79, 37.68 Hz).
HRMS (FAB+): m/z [M]+ calcd for C16H22F2O: 268.1639; found:
268.1632.
(Z)-5-Fluoro-5-tridecen-4-ol (12f)
In the case of 11a and 11c, the reaction proceeded in a highly regiose-
lective manner to afford the corresponding azide compounds, 15a
and 15c in a pure form. For other substrates, the reaction took place
in a low regioselective manner to give the corresponding adducts as
an inseparable regioisomeric mixture. Therefore, the mixture was
employed for the next reaction without further purification.
Yield: 0.051 g (81%, 0.24 mmol); yellow oil.
IR (neat): 3349, 2959, 2927, 2857, 1708, 1466, 1379, 1253, 1127,
1029, 845 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 0.94 (3 H, t,
J = 7.19 Hz), 1.20–1.45 (12 H, m), 1.61–1.70 (3 H, m), 2.04–2.09 (2 H,
m), 4.06 (1 H, dt, J = 17.25, 13.19 Hz), 4.79 (1 H, dt, J = 37.97, 7.19 Hz).
13C NMR (100 MHz, CDCl3): δ = 13.8, 14.1, 18.7, 22.6, 23.2, 29.0, 29.1,
29.3, 31.8, 36.0, 70.8 (d, J = 29.8 Hz), 106.7 (d, J = 14.1 Hz), 159.2 (d,
J = 255.4 Hz).
IR (neat): 2931, 2857, 2103, 1613, 1514, 1471, 1428, 1362, 1303,
1250, 1173, 1111, 1037, 822, 739, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.04 (9 H, s), 2.38 (2 H, q, J = 6.29 Hz),
3.55 (1 H, dd, J = 7.98, 9.59 Hz), 3.64–3.70 (1 H, m), 3.68 (2 H, t,
J = 6.29 Hz), 3.80 (3 H, s), 4.08 (1 H, ddd, J = 4.79, 7.98, 17.15 Hz), 4.48
(1 H, d, J = 11.49 Hz), 4.52 (1 H, d, J = 11.49 Hz) 5.00 (1 H, dt, J = 36.92,
6.29 Hz), 6.87–6.88 (2 H, m), 7.24–7.45 (8 H, m), 7.65–7.66 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –127.84 (1 F, dd, J = 17.25, 37.97 Hz).
HRMS (EI+): m/z [M]+ calcd for C13H25FO: 216.1889; found: 216.1891.
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 27.1 (d, J = 4.1 Hz), 55.2,
61.6 (d, J = 29.0 Hz), 62.8 (d, J = 1.6 Hz), 69.2, 73.2, 106.9 (d, J = 12.5
Hz), 113.9, 127.6, 129.4, 129.5, 129.6, 133.7, 135.5, 154.4 (d, J = 256.2
Hz), 159.4.
(Z)-4-Fluoro-2-methyldodec-4-en-3-ol (12g)
Yield: 0.044 g (70%, 0.20 mmol); yellow oil.
IR (neat): 3387, 2958, 2926, 2857, 1707, 1467, 1381, 1281, 1168,
1103, 1021, 934, 831 cm–1
.
19F NMR (376 MHz, CDCl3): δ = –120.86 (1 F, dd, J = 17.15, 36.92 Hz).
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 0.91 (3 H, d,
J = 6.79 Hz), 0.98 (3 H, d, J = 6.79 Hz), 1.20–1.40 (10 H, m), 1.70–1.75
(1 H, m), 1.85–1.95 (1 H, m), 2.09 (2 H, q, J = 7.59 Hz), 3.72 (1 H, dt,
J = 19.37, 6.79 Hz), 4.77 (1 H, dt, J = 37.41, 7.59 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 17.9, 18.9, 22.6, 23.2, 29.0, 29.1,
29.3, 31.3, 31.8, 76.5 (d, J = 32.2 Hz), 107.6 (d, J = 14.1 Hz), 158.5 (d,
J = 256.2 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H36FN3O3SiNa: 556.2408;
found: 556.2401.
(Z)-3-Azido-5-(tert-butyldiphenylsilyloxy)-2-fluoro-1-phenyl-
pent-1-ene (15a)
Yield: 0.19 g (60%, 0.41 mmol); yellow oil.
IR (neat): 3070, 2958, 2931, 2857, 2101, 1471, 1428, 1251, 1112, 822,
19F NMR (376 MHz, CDCl3): δ = –126.97 (1 F, dd, J = 19.37, 37.41 Hz).
HRMS (EI+): m/z [M]+ calcd for C13H25FO: 216.1889; found: 216.1897.
739, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.07 (9 H, s), 1.90–2.08 (1 H, m), 2.00–
2.03 (1 H, m), 3.80 (2 H, m), 4.34 (1 H, dt, J = 22.39, 7.29 Hz), 5.77 (1 H,
d, J = 38.65 Hz), 7.29–7.44 (9 H, m), 7.50–7.52 (2 H, m), 7.63–7.68 (4
H, m).
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13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 33.9, 59.7, 60.2 (d, J = 7.2
Hz), 109.2 (d, J = 6.5 Hz), 127.7 (d, J = 4.1 Hz), 127.9 (d, J = 2.5 Hz),
128.6, 128.9 (d, J = 7.4 Hz), 129.8 (d, J = 4.1 Hz), 132.2 (d, J = 2.5 Hz),
133.3 (d, J = 4.9 Hz), 135.5 (d, J = 2.4 Hz), 156.2 (d, J = 268.7 Hz).
19F NMR (376 MHz, CDCl3): δ = –116.84 (1 F, dd, J = 22.39, 38.65 Hz).
HRMS (FAB+): m/z [M]+ calcd for C27H30FN3OSi: 459.2142; found:
13C NMR (100 MHz, CDCl3): δ = 18.4, 19.1, 19.6, 26.8, 27.0 (d, J = 16.6
Hz), 31.1, 59.1 (d, J = 27.3 Hz), 63.3 (d, J = 1.7 Hz), 102.2 (d, J = 14.9
Hz), 127.6, 129.5, 133.8, 135.5, 161.8 (d, J = 257.0 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.52 (1 F, dd, J = 20.23, 38.01 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C24H35FNOSi: 400.2472; found:
400.2481.
459.2148.
(Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-2-methyloct-5-en-4-
(Z)-3-Azido-5-(tert-butyldiphenylsilyloxy)-2-fluoro-1-(4-meth-
amine (16h)
oxyphenyl)pent-1-ene (15c)
Yield: 0.077 g (28%, 0.19 mmol); yellow oil.
Yield: 0.12 g (45%, 0.24 mmol); yellow oil.
IR (neat): 3071, 2956, 2930, 2857, 1703, 1471, 1428, 1386, 1362,
IR (neat): 3071, 2957, 2931, 2857, 2101, 1608, 1513, 1463, 1428,
1111, 1022, 937, 822, 738, 702 cm–1
.
1299, 1254, 1180, 1112, 1034, 860, 823, 739, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.90 (6 H, d, J = 6.39 Hz), 1.05 (9 H, s),
1.26–1.36 (1 H, m), 1.42–1.56 (3 H, m), 1.62–1.72 (1 H, m), 2.34 (2 H,
q, J = 6.69 Hz), 3.32 (1 H, dt, J = 20.63, 7.39 Hz), 3.67 (2 H, t, J = 6.69
Hz), 4.74 (1 H, dt, J = 38.04, 6.69 Hz), 7.36–7.45 (6 H, m), 7.66–7.68 (4
H, m).
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.90–1.98 (1 H, m), 1.99–
2.07 (1 H, m), 3.72–3.89 (2 H, m), 3.83 (3 H, s), 4.32 (1 H, dt, J = 21.99,
7.39 Hz), 5.70 (1 H, d, J = 38.65 Hz), 6.88–6.90 (2 H, m), 7.31–7.47 (8
H, m), 7.62–7.70 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 33.9, 55.3, 59.8, 60.4 (d,
J = 27.3 Hz), 108.8 (d, J = 7.4 Hz), 114.0, 124.8 (d, J = 3.3 Hz), 127.7 (d,
J = 4.2 Hz), 129.8 (d, J = 4.2 Hz), 130.3 (d, J = 7.4 Hz), 133.3 (d, J = 5.7
Hz), 135.5 (d, J = 2.5 Hz), 154.8 (d, J = 226.8 Hz), 159.1 (d, J = 2.5 Hz).
13C NMR (100 MHz, CDCl3): δ = 19.2, 22.4, 22.6, 24.9, 26.8, 27.0 (d,
J = 4.1 Hz), 43.1, 51.2 (d, J = 28.0 Hz), 63.2 (d, J = 1.6 Hz), 101.3 (d,
J = 14.9 Hz), 127.6 (d, J = 5.8 Hz), 129.5, 133.8 (d, J = 1.6 Hz), 135.5,
162.6 (d, J = 257.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.91 (1 F, dd, J = 21.99, 38.65 Hz).
19F NMR (376 MHz, CDCl3): δ = –125.31 (1 F, dd, J = 20.63, 38.04 Hz).
HRMS (FAB+): m/z [M]+ calcd for C28H32FN3O2Si: 489.2248; found:
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found:
489.2245.
414.2630.
β-Fluoroallylic Amines 16 and 17; (Z)-5-(tert-Butyldiphenylsilyl-
oxy)-2-fluoro-1-phenylpent-1-en-3-amine (17a); Typical Proce-
dure
(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluorohex-3-en-2-amine (16j)
Yield: 0.16 g (49%, 0.43 mmol); colorless oil.
IR (neat): 3072, 3049, 2959, 2931, 2858, 1704, 1472, 1428, 1389,
To a solution of the azide compound 15a (0.19 g 0.41 mmol) in THF
(1.37 mL)–H2O (0.075 mL) was added PPh3 (0.22 g, 0.82 mmol) at r.t.
The mixture was stirred at 50 °C for 24 h. The reaction mixture was
purified by silica gel column chromatography (hexane–EtOAc, 2:1) to
afford the pure product 17a; yield: 0.15 g (85%, 0.35 mmol); yellow
oil.
1112, 1027, 937, 823, 791, 737, 703, 613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.23 (3 H, d, J = 6.79 Hz),
1.41 (2 H, br s), 2.31–2.38 (2 H, m), 3.46 (1 H, dq, J = 14.67, 6.79 Hz),
3.68 (2 H, t, J = 6.59 Hz), 4.75 (1 H, dt, J = 37.35, 7.49 Hz), 7.36–7.45 (6
H, m), 7.67–7.69 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 20.4 (d, J = 1.7 Hz), 26.8, 26.9 (d,
J = 4.9 Hz), 48.0 (d, J = 29.8 Hz), 63.2 (d, J = 1.6 Hz), 99.9 (d, J = 15.8
Hz), 127.6, 129.5, 133.8, 135.5, 163.7 (d, J = 256.2 Hz).
IR (neat): 3070, 2930, 2857, 1687, 1589, 1492, 1471, 1448, 1427,
1389, 1111, 1049, 998, 937, 915, 823, 739, 702, 613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.06 ( H, s), 1.70 (2 H, br s), 1.82–1.89
(1 H, m), 1.93–1.98 (1 H, m), 3.74–3.86 (3 H, m), 5.70 (1 H, d, J = 40.20
Hz), 7.22–7.49 (11 H, m), 7.64–7.68 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –121.96 (1 F, dd, J = 14.67, 37.35 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C22H31FNOSi: 372.2159; found:
372.2158.
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 36.9, 51.3 (d, J = 28.1 Hz),
61.1, 105.4 (d, J = 7.4 Hz), 127.0 (d, J = 7.4 Hz), 127.7 (d, J = 2.4 Hz),
128.4, 128.6 (d, J = 6.6 Hz), 129.6 (d, J = 2.4 Hz), 133.3 (d, J = 4.1 Hz),
133.5 (d, J = 4.1 Hz), 135.5, 162.2 (d, J = 267.8 Hz).
(Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-3-methyloct-5-en-4-
amine (16k)
Yield: 0.082 g (52%, 0.20 mmol); yellow oil; diastereomeric ratio:
48:52.
19F NMR (376 MHz, CDCl3): δ = –117.59 (1 F, dd, J = 18.24, 40.20 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C27H33FNOSi: 434.2315; found:
IR (neat): 3071, 2960, 2931, 2858, 1472, 1428, 1111, 1021, 823, 738,
434.2324.
701, 613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.898 (3 H, t, J = 7.19 Hz), 0.900 (3 H, d,
J = 6.79 Hz), 1.05 (9 H, s), 1.16 (1 H, m), 1.44 (2 H, br s), 1.46–1.63 (2 H,
m), 2.35 (2 H, q, J = 7.29 Hz), 3.08 and 3.15 (1 H, dd and dd, J = 6.79,
20.73 Hz and 5.60, 18.19 Hz), 3.68 (2 H, t, J = 7.29 Hz), 4.73 and 4.75
(1 H, dt and dt, J = 38.17, 7.29 Hz), 7.30–7.50 (6 H, m), 7.60–7.70 (4 H,
m).
19F NMR (376 MHz, CDCl3): δ = –121.26 (1 F, dd, J = 18.19, 38.17 Hz),
–122.36 (1 F, dd, J = 20.73, 38.17 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found:
(Z)-7-(tert-Butyldiphenylsilyloxy)-4-fluoro-2-methylhept-4-en-3-
amine (16g)
Yield: 0.095 g (35%); 0.24 mmol; colorless oil.
IR (neat): 3071, 2958, 2930, 2857, 1703, 1589, 1471, 1428, 1386,
1362, 1260, 1111, 936, 822, 738, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.92 (3 H, d, J = 6.79 Hz), 0.95 (3 H, d,
J = 6.79 Hz), 1.05 (9 H, s), 1.41 (2 H, br s), 1.80 (1 H, m), 2.36 (2 H, q,
J = 6.93 Hz), 2.99 (1 H, dd, J = 6.79, 20.23 Hz), 3.68 (2 H, t, J = 6.93 Hz),
4.74 (1 H, dt, J = 38.01, 6.93 Hz), 7.36–7.45 (6 H, m), 7.66–7.68 (4 H,
m).
414.2627.
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Synthesis
(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluoro-1-(4-methoxybenzyl-
HRMS (FAB+): m/z [M + H]+ calcd for C24H35FNOSi: 400.2472; found:
oxy)hex-3-en-2-amine (16l)
400.2481.
Yield: 0.17 g (85%, 0.34 mmol); colorless oil.
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluoro-7-methyloct-4-en-3-
amine (17h)
IR (neat): 3070, 2931, 2857, 1612, 1587, 1514, 1471, 1428, 1362,
1302, 1249, 1173, 1111, 1037, 822, 739, 703 cm–1
.
Yield: 0.150 g (54%, 0.36 mmol); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.55–1.65 (2 H, br s), 2.35
(2 H, q, J = 6.79 Hz), 3.36–3.42 (1 H, m), 3.55–3.64 (1 H , m), 3.66 (2 H,
t, J = 6.79 Hz), 3.80 (3 H, s), 4.47 (2 H, s), 4.86 (1 H, dt, J = 38.11, 6.79
Hz), 6.37 (2 H, d, J = 8.59 Hz), 7.23 (2 H, d, J = 8.59 Hz), 7.27–7.44 (6 H,
m), 7.65–7.67 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 26.9 (d, J = 4.2 Hz), 52.6 (d,
J = 28.9 Hz), 55.1, 63.1 (d, J = 1.7 Hz), 71.9, 72.9, 102.5 (d, J = 14.1 Hz),
113.7, 127.6, 129.3, 129.5, 129.9, 133.5, 133.8, 159.2, 160.0 (d,
J = 255.4 Hz).
IR (neat): 3385, 3071, 2956, 2930, 2858, 1702, 1471, 1428, 1388,
1111, 1048, 823, 737, 702, 613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, d, J = 6.79 Hz), 0.89 (3 H, d,
J = 6.39 Hz), 1.05 (9 H, s), 1.56 (2 H, br s), 1.57–1.60 (1 H, m), 1.70–
1.78 (1 H, m), 1.81–1.91 (1 H, m), 1.92–1.97 (2 H, m), 3.61 (1 H, dt,
J = 19.17, 6.79 Hz), 3.70–3.81 (2 H, m), 4.69 (1 H, dt, J = 38.54, 7.79
Hz), 7.36–7.48 (6 H, m), 7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 22.17, 22.19, 26.8, 28.3 (d, J = 1.6
Hz), 32.3 (d, J = 4.1 Hz), 36.9, 50.4 (d, J = 29.0 Hz), 61.1, 103.7 (d,
J = 14.9 Hz), 127.6 (d, J = 2.4 Hz), 129.6, 133.6 (d, J = 5.0 Hz), 135.5,
161.5 (d, J = 255.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –120.58 (1 F, dd, J = 13.53, 38.11 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H38FNO3SiNa: 530.2503;
found: 530.2493.
19F NMR (376 MHz, CDCl3): δ = –125.85 (1 F, dd, J = 19.17, 38.54 Hz).
(Z)-2-Benzyloxy-7-(tert-butyldiphenylsilyloxy)-4-fluorohept-4-
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found:
en-3-amine (16m)
414.2625.
Yield: 0.028 g (40%, 0.057 mmol); colorless oil; diastereomeric ratio:
27:73.
19F NMR (376 MHz, CDCl3): δ = –119.75 and –121.13 (dd and dd,
J = 14.67, 39.11 Hz).
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluorohex-4-en-3-amine (17j)
Yield: 0.11 g (33%, 0.29 mmol); colorless oil.
IR (neat): 3384, 3071, 3050, 2930, 2858, 1709, 1589, 1482, 1428,
1390, 1112, 1048, 984, 823, 739, 702, 688 cm–1
.
(Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphe-
nyl)pent-1-en-3-amine (17c)
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.55–1.59 (5 H, m), 1.71–
1.76 (1 H, m), 1.80–1.88 (1 H, m), 3.62 (1 H, dt, J = 19.37, 6.79 Hz),
3.75 (2 H, m), 4.71 (1 H, dq, J = 37.42, 6.79 Hz), 7.36–7.45 (6 H, m),
7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 8.5 (d, J = 6.6 Hz), 19.1, 26.8, 36.8, 50.3
(d, J = 28.1 Hz), 61.0, 99.3 (d, J = 15.8 Hz), 127.6, 129.6, 133.6, 135.5,
161.7 (d, J = 255.4 Hz).
Yield: 0.69 g (84%, 0.20 mmol); colorless oil.
IR (neat): 3070, 2999, 2931, 2857, 1608, 1512, 1464, 1428, 1389,
1297, 1251, 1179, 1111, 1036, 937, 855, 823, 739, 703, 613 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.69 (2 H, br s), 1.84 (1 H,
m), 1.95 (1 H, m), 3.80 (3 H, m), 3.82 (3 H, s), 5.63 (1 H, d, J = 40.87
Hz), 6.87 (2 H, m), 7.31–7.44 (8 H, m), 7.65–7.69 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –126.69 (1 F, dd, J = 19.37, 37.42 Hz).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 36.9, 51.2 (d, J = 28.1 Hz),
55.2, 61.1, 104.9 (d, J = 7.4 Hz), 113.8, 125.9 (d, J = 2.5 Hz), 127.7 (d,
J = 2.4 Hz), 129.6 (d, J = 2.5 Hz), 129.8 (d, J = 6.6 Hz), 133.5 (d, J = 2.4
Hz), 135.5, 158.5 (d, J = 2.5 Hz), 160.8 (d, J = 264.5 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C22H31FNOSi: 372.2159; found:
372.2149.
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluoro-6-methyloct-4-en-3-
amine (17k)
19F NMR (376 MHz, CDCl3): δ = –120.64 (1 F, dd, J = 19.55, 40.87 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C28H35FNO2Si: 464.2421; found:
464.2420.
Yield: 0.050 g (31%, 0.12 mmol); colorless oil; diastereomeric ratio:
49:51.
IR (neat): 3071, 2959, 2930, 2857, 1472, 1461, 1428, 1112, 1048, 823,
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluoro-6-methylhept-4-en-3-
738, 702, 613 cm–1
.
amine (17g)
1H NMR (400 MHz, CDCl3): δ = 0.81 and 0.85 (3 H, t and t, J = 7.19 Hz),
0.94 and 1.00 (3 H, d and d, J = 6.79 Hz), 1.05 (9 H, s), 1.16–1.23 (1 H,
m), 1.24–1.40 (1 H, m), 1.50–1.70 (2 H, br s), 1.68–1.80 (1 H, m), 1.80–
1.90 (1 H, m), 2.47 (1 H, m), 3.59 (1 H, m), 3.75 (2 H, m), 4.41 and 4.49
(1 H, dd and dd, J = 8.34, 38.36 Hz and 7.79, 38.86 Hz), 7.35–7.44 (6 H,
m), 7.65–7.68 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –126.21 (1 F, dd, J = 17.11, 38.36 Hz),
–126.95 (1 F, dd, J = 19.55, 39.86 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found:
Yield: 0.045 g (17%, 0.11 mmol); colorless oil.
IR (neat): 3385, 3071, 2958, 2931, 2858, 1702, 1589, 1471, 1428,
1389, 1278, 1112, 1047, 936, 823, 738, 702 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.95 (3 H, d, J = 6.92 Hz), 0.98 (3 H, d,
J = 6.92 Hz), 1.04 (9 H, s), 1.46 (2 H, br s), 1.68–1.76 (1 H, m), 1.80–
1.88 (1 H, m), 2.72 (1 H, dsept, J = 9.65, 6.92 Hz), 3.56 (1 H, dt,
J = 18.51, 6.79 Hz), 3.74 (2 H, m), 4.55 (1 H, dd, J = 9.65, 38.18 Hz),
7.36–7.44 (6 H, m), 7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 23.0, 23.1 (d, J = 1.7 Hz), 23.6 (d,
J = 4.5 Hz), 26.8, 36.9, 50.3 (d, J = 28.9 Hz), 61.1, 112.5 (d, J = 14.9 Hz),
127.7 (d, J = 1.7 Hz), 129.6, 133.7 (d, J = 4.5 Hz), 135.5, 159.5 (d,
J = 254.5 Hz).
414.2627.
(Z)-6-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-4-fluorohept-4-
en-3-amine (17m)
19F NMR (376 MHz, CDCl3): δ = –126.64 (1 F, dd, J = 18.51, 38.18 Hz).
Yield: 0.034 g (48%, 0069 mmol); yellow oil; diastereomeric ratio:
27:73.
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Synthesis
19F NMR (376 MHz, CDCl3): δ = –120.55 and –121.15 (dd and dd,
J = 17.93, 36.66 Hz).
13C NMR (100 MHz, CDCl3): δ = 22.6, 22.7, 25.0, 27.5 (d, J = 3.7 Hz),
28.6, 41.5, 50.8 (d, J = 28.2 Hz), 62.0, 80.0, 103.1 (d, J = 14.1 Hz), 155.5,
159.6 (d, J = 258.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –125.09 (1 F, dd, J = 21.76, 37.41 Hz).
tert-Butyl (Z)-3-Fluoro-6-hydroxyhex-3-en-2-ylcarbamate (18j);
Typical Procedure
HRMS (FAB+): m/z [M + Na]+ calcd for C14H26FNO3Na: 298.1794;
To a solution of (Z)-6-(tert-butyldiphenylsilyloxy)-3-fluorohex-3-en-
2-amine (16j; 0.19 g, 0.5 mmol) and Et3N (0.05 mL, 0.6 mmol) in
CH2Cl2 (1.7 mL) was added (Boc)2O (0.13 g, 0.6 mmol) at 0 °C. The
mixture was stirred at r.t. for 1 h. Then, the reaction was quenched
with H2O and the mixture was extracted with CH2Cl2 (3 ×). The com-
bined organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The resulting residue was used in the next step without fur-
ther purification. To a THF solution of the above alcohol was added
TBAF (0.55 mL, 0.55 mmol) at r.t. After stirring the mixture at that
temperature for 2 h, addition of H2O followed by extractive workup
and purification by column chromatography (hexane–EtOAc, 2:1) af-
forded the desired alcohol 18j; yield: 0.086 g (74%, 0.37 mmol); color-
less oil.
found: 298.1804.
tert-Butyl (Z)-3-Fluoro-6-hydroxy-1-(4-methoxybenzyloxy)hex-3-
en-2-ylcarbamate (18l)
Due to unidentified inseparable by-products, this compound could
not be isolated in pure form; yield: 96% (19F NMR yield).
1H NMR (400 MHz, CDCl3): δ = 1.44 (9 H, s), 1.85–2.05 (1 H, m), 2.29–
2.43 (2 H, m), 3.53 (1 H, dd, J = 4.98, 9.66 Hz), 3.62 (2 H, t, J = 6.32 Hz),
3.60–3.65 (1 H, m), 3.81 (3 H, s), 4.37 (1 H, br s), 4.47 (2 H, s), 4.86 (1
H, dt, J = 37.32, 7.60 Hz), 4.96–5.11 (1 H, m), 6.88 (2 H, d, J = 8.64 Hz),
7.23 (2 H, d, J = 8.64 Hz).
19F NMR (376 MHz, CDCl3): δ = –120.70 (1 F, dd, J = 11.14, 37.32 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C19H28FNO5Na: 392.1849;
found: 392.1850.
IR (neat): 3328, 2979, 2933, 1692, 1527, 1454, 1428, 1391, 1367,
1251, 1171, 1112, 1056, 862, 735, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, d, J = 6.96 Hz), 1.40 (9 H, s),
1.65 (1 H, br s), 2.23–2.36 (2 H, m), 3.61 (2 H, t, J = 6.32 Hz), 4.22–4.26
(1 H, m), 4.63 (1 H, br s), 4.78 (1 H, dt, J = 37.20, 7.52 Hz).
The corresponding carboxylic acid was converted into the methyl es-
ter through treatment of the acid with an excess amount of diazo-
methane.
13C NMR (100 MHz, CDCl3): δ = 18.5, 27.0 (d, J = 3.9 Hz), 28.3, 47.4 (d,
J = 27.7 Hz), 61.7, 79.7, 101.6 (d, J = 14.4 Hz), 154.9, 160.3 (d, J = 257.6
Hz).
Methyl (Z)-5-(tert-Butoxycarbonylamino)-4-fluoro-7-methyloct-
3-enoate (19h); Typical Procedure
19F NMR (376 MHz, CDCl3): δ = –123.24 (1 F, dd, J = 16.18, 37.20 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C11H20FNO3Na: 256.1325;
To a solution of tert-butyl (Z)-5-fluoro-8-hydroxy-2-methyloct-5-en-
4-yl carbamate (18h; 0.21 g, 0.76 mmol) in acetone (9.45 mL) was
added Jones reagent [readily prepared by mixing of CrO3 (0.39 g, 3.91
mmol), H2O (1.15 mL), and H2SO4 (0.38 mL) at 0 °C] at 0 °C. The mix-
ture was stirred at that temperature for 3.5 h. The reaction was
quenched with i-PrOH–H2O (1:1 v/v) and the mixture was extracted
with EtOAc (3 ×), and washed with brine. The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated in vacuo to give
the corresponding carboxylic acid. Thus obtained carboxylic acid was
dissolved in Et2O (10 mL), and the mixture was cooled to 0 °C. To this
reaction mixture was added dropwise an excess amount of an ethere-
al solution of diazomethane [readily prepared via heating the mixture
of KOH (0.56 g, 9.89 mmol), N-methyl-N-nitroso-p-toluenesufon-
amide (1.81 g, 8.45 mmol) in Et2O (ca. 20 mL)/H2O (ca. 1 mL)] at 0 °C.
After about 1 h, the reaction was quenched with AcOH, and the mix-
ture was concentrated in vacuo. The residue was neutralized with sat.
aq NaHCO3 and extracted with EtOAc (3 ×). The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated in vacuo. The
crude material was purified by silica gel column chromatography
(hexane–EtOAc, 3:1) to give 19h; yield: 0.16 g (69%, 0.52 mmol) over
2 steps; yellow oil.
found: 256.1319.
tert-Butyl (Z)-4-Fluoro-7-hydroxy-2-methylhept-4-en-3-ylcarba-
mate (18g)
Yield: 0.39 g (65%, 1.48 mmol); yellow oil.
IR (neat): 3334, 2966, 2933, 2875, 1696, 1504, 1469, 1391, 1367,
1251, 1171, 1044, 1011, 876, 737, 479, 418 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.926 (3 H, d, J = 6.76 Hz), 0.933 (3 H,
d, J = 6.76 Hz), 1.43 (9 H, s), 1.86 (1 H, octet, J = 6.90 Hz), 1.99 (1 H, br
s), 2.31–2.40 (2 H, m), 3.62 (2 H, t, J = 6.36 Hz), 3.86 (1 H, dt, J = 21.91,
8.48 Hz), 4.77 (1 H, dt, J = 37.60, 7.58 Hz).
13C NMR (100 MHz, CDCl3): δ = 18.6, 19.5, 27.2 (d, J = 4.1 Hz), 28.4,
30.1, 58.0 (d, J = 27.6 Hz), 61.9, 79.8, 103.6 (d, J = 14.2 Hz), 155.5,
158.6 (d, J = 258.0 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.98 (1 F, dd, J = 21.91, 37.60 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C13H25FNO3: 262.1818; found:
262.1820.
IR (neat): 3360, 2958, 2871, 1712, 1518, 1439, 1367, 1252, 1170,
1044, 1023, 951, 907, 780 cm–1
.
tert-Butyl (Z)-5-Fluoro-8-hydroxy-2-methyloct-5-en-4-ylcarba-
1H NMR (400 MHz, CDCl3): δ = 0.92 (6 H, d, J = 6.60 Hz), 1.43 (9 H, s),
1.35–1.55 (2 H, m), 1.58–1.70 (1 H, m), 3.10–3.15 (2 H, m), 3.68 (3 H,
s), 4.15–4.35 (1 H, m), 4.62 (1 H, d, J = 8.44 Hz), 5.01 (1 H, dt, J = 36.29,
7.00 Hz).
13C NMR (100 MHz, CDCl3): δ = 22.5, 22.8, 25.0, 28.6, 29.3 (d, J = 5.7
Hz), 41.6, 50.3 (d, J = 28.1 Hz), 52.2, 79.9, 98.6 (d, J = 13.1 Hz), 155.2,
160.2 (d, J = 260.7 Hz), 171.7 (d, J = 1.7 Hz).
mate (18h)
Yield: 0.22 g (86%, 0.80 mmol); yellow oil.
IR (neat): 3330, 2959, 2871, 1692, 1527, 1470, 1391, 1367, 1283,
1252, 1171, 1117, 1046, 872 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.916 (3 H, d, J = 6.60 Hz), 0.919 (3 H,
d, J = 6.52 Hz), 1.43 (9 H, s), 1.35–1.55 (2 H, m), 1.56–1.70 (1 H, m),
1.80–1.95 (1 H, br s), 2.25–2.44 (2 H, m), 3.63 (2 H, t, J = 6.34 Hz),
4.08–4.24 (1 H, m), 4.63–4.67 (1 H, m), 4.80 (1 H, dt, J = 37.41, 7.56
Hz).
19F NMR (376 MHz, CDCl3): δ = –121.50 (1 F, dd, J = 19.54, 36.29 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C12H26FNO4Na: 326.1744;
found: 326.1751.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 865–881

880
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Synthesis
Methyl (Z)-5-(tert-Butoxycarbonylamino)-4-fluoro-6-methylhept-
3-enoate (19g)
References
(1) (a) Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.;
Furman, P. A.; Otto, M. J.; Sofia, M. J. Bioorg. Med. Chem. Lett.
2012, 22, 2938. (b) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011,
5939. (c) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org.
Biomol. Chem. 2007, 5, 1151. (d) Zhao, K.; Lim, D. S.; Funaki, T.;
Welch, J. T. Bioorg. Med. Chem. 2003, 11, 207.
(2) (a) Yang, M.-H.; Matikonda, S. S.; Altman, R. A. Org. Lett. 2013,
15, 3894. (b) Greedy, B.; Gouverneur, V. Chem. Commun. 2001,
233. (c) Tius, M. A.; Kawakami, J. K. Tetrahedron 1995, 51, 3997.
(d) Lee, S. H.; Schwartz, J. J. Am. Chem. Soc. 1986, 108, 2445.
(3) (a) Pfund, E.; Masson, S.; Vazeux, M.; Lequeux, T. J. Org. Chem.
2004, 69, 4670. (b) van Steenis, J. H.; van der Gen, A. Eur. J. Org.
Chem. 2001, 897. (c) Tsai, H.-J. Tetrahedron Lett. 1996, 37, 629.
(4) (a) Nakamura, Y.; Okada, M.; Sato, A.; Horikawa, H.; Koura, M.;
Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 5741. (b) Otaka, A.;
Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe, H.; Kinoshita,
T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org. Chem. 2004, 69, 1634.
(c) Otaka, A.; Watanabe, H.; Yukimasa, A.; Oishi, S.; Tamamura,
H.; Fujii, N. Tetrahedron Lett. 2001, 42, 5443.
Yield: 0.29 g (68%, 0.99 mmol); yellow oil.
IR (neat): 3362, 2970, 1744, 1709, 1513, 1469, 1438, 1391, 1367,
1255, 1171, 1041, 1011, 949, 879, 808, 487 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.93 (3 H, d, J = 6.74 Hz), 0.94 (3 H, d,
J = 6.74 Hz), 1.43 (9 H, s), 1.89 (1 H, octet, J = 6.74 Hz), 3.14 (2 H, m),
3.68 (3 H, s), 3.97 (1 H, dt, J = 19.98, 8.57 Hz), 4.72 (1 H, d, J = 9.16 Hz),
4.97 (1 H, dt, J = 36.49, 7.16 Hz).
13C NMR (100 MHz, CDCl3): δ = 18.2, 19.3, 28.3, 29.0 (d, J = 5.9 Hz),
30.1, 51.8, 57.2 (d, J = 27.2 Hz), 79.5, 99.1 (d, J = 13.0 Hz), 155.2, 159.2
(d, J = 261.0 Hz), 171.4 (d, J = 1.8 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.72 (1 F, dd, J = 19.98, 36.49 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C14H25FNO4: 290.1768; found:
290.1769.
(Z)-5-(tert-Butoxycarbonylamino)-4-fluorohex-3-enoic Acid (19j)
The methyl esterification with diazomethane was not carried out be-
cause the corresponding carboxylic acid could be isolated in a pure
form; yield: 47 mg (45%, 0.19 mmol); colorless oil.
(5) (a) Cao, C.-R.; Ou, S.; Jiang, M.; Liu, J.-T. Org. Biomol. Chem. 2014,
12, 467. (b) Larnaud, F.; Pfund, E.; Linclau, B.; Lequeux, T. Tetra-
hedron 2014, 70, 5632. (c) Yan, X.-W.; Zhang, Q.; Wei, W.; Ji, J.-X.
Tetrahedron Lett. 2014, 55, 3750. (d) Prakash, G. K. S.; Zhang, Z.;
Wang, F.; Rahm, M.; Ni, C.; Iuliucci, M.; Haiges, R.; Olah, G. A.
Chem. Eur. J. 2014, 20, 831. (e) Schneider, C.; Masi, D.; Couve-
Bonnaire, S.; Pannecoucke, X.; Hoarau, C. Angew. Chem. Int. Ed.
2013, 52, 3246. (f) Macé, A.; Tripoteau, F.; Zhao, Q.; Gayon, E.;
Vrancken, E.; Campagne, J.-M.; Carboni, B. Org. Lett. 2013, 15,
906. (g) Kajjout, M.; Smietana, M.; Leroy, J.; Rolando, C. Tetrahe-
dron Lett. 2013, 54, 1658. (h) Lecea, M.; Grassin, A.; Ferreiro-
Mederos, L.; Choppin, S.; Urbano, A.; Carreňo, M. C.; Colobert, F.
Eur. J. Org. Chem. 2013, 4486. (i) Bergeron, M.; Guyader, D.;
Paquin, J.-F. Org. Lett. 2012, 14, 5888. (j) Yanai, H.; Okada, H.;
Sato, A.; Okada, M.; Taguchi, T. Tetrahedron Lett. 2011, 52, 2997.
(k) Bergeron, M.; Johnson, T.; Paquin, J.-F. Angew. Chem. Int. Ed.
2011, 50, 11112. (l) Nikolova, G. S.; Haufe, G. Beilstein J. Org.
Chem. 2008, 4, 12. (m) Ghosh, A. K.; Zajc, B. Org. Lett. 2006, 8,
1553. (n) Saito, A.; Nakagawa, M.; Taguchi, T. J. Fluorine Chem.
2005, 126, 1166. (o) Wang, Z.; Gonzalez, A.; Wnuk, S. F. Tetrahe-
dron Lett. 2005, 46, 5313. (p) Nakagawa, M.; Saito, A.; Soga, A.;
Yamamoto, N.; Taguchi, T. Tetrahedron Lett. 2005, 46, 5257.
(q) Dutheuil, G.; Lei, X.; Pannecoucke, X.; Quirion, J.-C. J. Org.
Chem. 2005, 70, 1911. (r) Nakamura, Y.; Okada, M.; Horikawa,
H.; Taguchi, T. J. Fluorine Chem. 2002, 117, 143. (s) Shimizu, M.;
Hata, T.; Hiyama, T. Tetrahedron Lett. 1999, 40, 7375. (t) Chen,
C.; Wilcoxen, K.; Kim, K.; McCarthy, J. R. Tetrahedron Lett. 1997,
38, 7677. (u) Allmendinger, T.; Felder, E.; Hungarbühler, E. Tet-
rahedron Lett. 1990, 31, 7301.
IR (neat): 3327, 2980, 2934, 1715, 1524, 1455, 1394, 1368, 1252,
1169, 1105, 1059, 951, 914, 864, 735 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.31 (3 H, d, J = 6.96 Hz), 1.44 (9 H, s),
3.18 (2 H, d, J = 7.04 Hz), 4.33–4.35 (1 H, m), 4.68 (1 H, m), 5.02 (1 H,
dt, J = 35.96, 7.04 Hz), 9.20–9.40 (1 H, m).
13C NMR (100 MHz, CDCl3): δ = 18.5, 28.3, 28.9 (d, J = 3.9 Hz), 47.0 (d,
J = 23.6 Hz), 80.0, 97.1 (d, J = 16.5 Hz), 154.8, 160.8 (d, J = 261.2 Hz),
176.1.
19F NMR (376 MHz, CDCl3): δ = –119.48 (1 F, dd, J = 14.34, 35.96 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C11H18FNO4Na: 270.1118;
found: 270.1116.
Methyl (Z)-5-(tert-Butoxycarbonylamino)-4-fluoro-6-(4-methoxy-
benzyloxy)hex-3-enoate (19l)
Yield: 0.25 g (27%, 0.62 mmol); yellow oil.
IR (neat): 3359, 2977, 1741, 1713, 1613, 1586, 1514, 1458, 1391,
1366, 1249, 1172, 1101, 1034, 949, 821, 491 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (9 H, s), 3.16–3.18 (2 H, m), 3.54
(1 H, dd, J = 4.62, 9.70 Hz), 3.61–3.64 (1 H, m), 3.68 (3 H, s), 3.80 (3 H,
s), 4.42 (1 H, br s), 4.46 (2 H, s), 5.00–5.11 (1 H, m), 5.10 (1 H, dt,
J = 36.23, 6.99 Hz), 6.85–6.89 (2 H, m), 7.21–7.24 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 28.4, 29.3 (d, J = 5.8 Hz), 51.2 (d,
J = 31.7 Hz), 52.1, 55.4, 68.8, 73.0, 80.1, 99.2 (d, J = 12.4 Hz), 113.9,
129.4, 129.8, 155.1, 158.2 (d, J = 257.9 Hz), 159.4, 171.5 (d, J = 1.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –117.61 (1 F, dd, J = 8.98, 36.23 Hz).
(6) For reviews, see: (a) Kuehnel, M. F.; Holstein, P.; Kliche, M.;
Krüger, J.; Matthies, S.; Nitsch, D.; Schutt, J.; Sparenberg, M.;
Lentz, D. Chem. Eur. J. 2012, 18, 10701. (b) Clot, E.; Eisenstein,
O.; Jasim, N.; Macgregor, S. A.; Mcgrady, J. E.; Perutz, R. N. Acc.
Chem. Res. 2011, 44, 333. (c) Amii, H.; Uneyama, K. Chem. Rev.
2009, 109, 2119. For recent studies, see: (d) Ohashi, M.; Shibata,
M.; Saijo, H.; Kambara, T.; Ogoshi, S. Organometallics 2013, 32,
3631. (e) Lv, H.; Cai, Y.-B.; Zhang, J. L. Angew. Chem. Int. Ed. 2013,
52, 1. (f) Guo, W.-J.; Wang, Z.-X. J. Org. Chem. 2013, 78, 1054.
(g) Yu, D.; Shen, Q.; Lu, L. J. Org. Chem. 2012, 77, 1798.
(h) Ohashi, M.; Kambara, T.; Hatanaka, T.; Saijo, H.; Doi, R.;
Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 3256. (i) Schaub, T.;
Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964.
HRMS (FAB+): m/z [M + Na]+ calcd for C20H28FNO6Na: 420.1798;
found: 420.1795.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560390.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 865–881

881
T. Nihei et al.
Paper
Synthesis
(7) For Cr(II)-mediated reactions, see: (a) Takai, K. Org. React. 2004,
64, 253. (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem.
Soc. 1986, 108, 5644. (c) Takai, K.; Kimura, K.; Kuroda, T.;
Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281.
(8) Nihei, T.; Yokotani, S.; Ishihara, T.; Konno, T. Chem. Commun.
2014, 50, 1543.
for 10, 12, and 14, which indicate that 9 and 10, 12, 14 possess
E- and Z-configuration, respectively. The details are given in the
Supporting Information.
(15) When the reaction was carried out at –40 °C for 16 h in the
presence of 2.0 equiv of Ti(Oi-Pr)4, instead of a catalytic amount
of LiI, 13 was obtained in 40% yield.
(9) Shimada, T.; Konno, T.; Ishihara, T. Chem. Lett. 2007, 36, 636.
(10) For the preparation of 3, see: Peng, S.; Qing, F.-L.; Li, Y.-Q.; Hu,
C.-M. J. Org. Chem. 2000, 65, 694.
(16) We first attempted the nucleophilic substitution reaction of
NaN3 with 10a under the same conditions as described in Table
5. However, no deisred adduct was detected.
(11) (a) Sasaki, Y.; Hosono, E. Jpn Kokai Tokkyo Koho 04091051,
1992. (b) Chen, J.; Hu, C.-M. J. Chem. Soc., Perkin Trans. 1 1994,
1111.
(12) (a) Bartberger, M. D.; Dolbier, W. R. Jr.; Lusztyk, J.; Ingold, K. U.
Tetrahedron 1997, 53, 9857. (b) Gonzalez, J.; Foti, C. J.;
Elsheimer, S. J. Org. Chem. 1991, 56, 4322.
(13) It has been discussed that LiI plays an important role in the sol-
ubility of CrCl2 in DMF, see: Wessjohann, W.; Gabriel, T. J. Org.
Chem. 1997, 62, 3772.
(14) The stereochemical assignments of 9, 10, 12, and 14 were done
based on the analyses of 1H NMR spectra. The coupling con-
stants between vinyl H and F were 21–23 Hz for 9 and 35–38 Hz
(17) Watanabe, D.; Koura, M.; Saito, A.; Yanai, H.; Nakamura, Y.;
Okada, M.; Sato, A.; Taguchi, T. J. Fluorine Chem. 2011, 132, 327.
(18) It has been reported that trichloroalkanes in the presence of 4.0
equiv of CrCl2 can be converted into the corresponding chlorovi-
nylidene chromium(III) carbenoids, see: (a) Baati, R.; Barma, D.
K.; Krishna, U. M.; Mioskowski, C.; Falck, J. R. Tetrahedron Lett.
2002, 43, 959. (b) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski,
C. J. Am. Chem. Soc. 2001, 123, 9196. (c) Barma, D. K.; Baati, R.;
Valleix, A.; Mioskowski, C.; Falck, J. R. Org. Lett. 2001, 3, 4237.
(19) Pitterna, T.; Böger, M.; Maienfisch, P. Chimia 2004, 58, 108.
(20) Known compounds, see ref. 5n and 5q.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 865–881