Novel synthesis of 4-fluoropyridines based on 2-fluoroallylic alcohols by succeeding Ireland-Claisen and aza-Cope rearrangements as key steps

Article abstract of DOI:10.1055/s-2006-942411

A novel synthetic pathway leads to 4-fluoropyridines bearing aryl substituents in positions 2 and 6 and possibly an additional alkyl group in position 3. 2-Fluoroallylic alcohols were esterified with N-benzoylalanine or N-aroylphenylglycines and the resul

Full text of DOI:10.1055/s-2006-942411

PAPER
2085
Novel Synthesis of 4-Fluoropyridines Based on 2-Fluoroallylic Alcohols by
Succeeding Ireland–Claisen and Aza-Cope Rearrangements as Key Steps
S
ynthesis of 4-Flu
l
oropyri
r
dines fro
i
m2-F
l
c
uoroallylic
hAlcohols Wittmann, Frank Tranel, Roland Fröhlich, Günter Haufe*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: haufe@uni-muenster.de
Received 18 April 2006
Dedicated to Professor Dr. Dieter Hoppe with best wishes on the occasion of his 65th birthday
for the formation of 4-fluoropyridines are chlorine/fluo-
rine displacement9 or Balz–Schiemann fluorodediazotiza-
tion of the corresponding aminopyridines.10
Abstract: A novel synthetic pathway leads to 4-fluoropyridines
bearing aryl substituents in positions 2 and 6 and possibly an addi-
tional alkyl group in position 3. 2-Fluoroallylic alcohols were ester-
ified with N-benzoylalanine or N-aroylphenylglycines and the
resulting esters were transformed to give 4-(2-fluoroallyl)oxazol-
5(4H)-ones in a Steglich-type, Ireland–Claisen rearrangement. The
latter compounds gave either N-aroyl-substituted 2-amino-4-fluoro-
2-methyl- or 2-amino-4-fluoro-2-phenylalk-4-enoic acids in excel-
lent yields by hydrolysis or substituted 2-aryl-4-fluoro-6-phenylpy-
ridines in a cascade reaction initiated by an aza-Cope rearrangement
to form thermally unstable 2-(2-fluoroallyl)oxazol-5(2H)-ones.
Succeeding extrusion of carbon dioxide, intramolecular cyclopro-
panation of the fluorinated double bond with the formed carbene,
ring-opening with formation of a fluorinated dihydropyridine, and
final oxidative aromatization gave the title compounds in moderate
yields.
Amino acid 2-fluoroallyl esters 3, the starting materials
for the planned [3,3]-sigmatropic rearrangement, were
prepared from fluorinated allylic alcohols 1, available ei-
ther in the case of 1a from ammonium 2-fluoroacrylate by
reduction,11 or in the case of 1b–d from terminal olefins
according to our well-established, three-step sequence of
bromofluorination, HBr elimination, and allylic hydroxy-
lation,12 by esterification with N-benzoylalanine (2a) or
N-aroylphenylglycines 2b–f, respectively (Scheme 1).
O
R3
A: DCC, DMAP
CH2Cl2, r.t.
F
O
F
O
R3
NH
O
Key words: heterocycles, 4-fluoropyridines, 2-fluoroallylic alco-
hols, fluorinated a-amino acids, cascade reaction, [3.3]-sigmatropic
rearrangements
NH
+
HO
R1
R1
B: p-TsOH,
toluene, 3 d,
reflux
OH
O
R2
R2
1
2
3
Scheme 1
Fluoro-organic compounds have attracted considerable
attention as intermediates for the synthesis of biologically
active substances, especially in the field of medicinal
chemistry.1 In particular, compounds bearing fluorine at-
tached to sp2-carbon atoms have significant biological ef-
fects.2 For example, a fluorovinyl group is a notably better
bioisostere for a peptide bond then a nonfluorinated ole-
fin;3 the fluorine atom replaces the oxygen and the olefin-
ic CH group equals the NH function.4 Thus, peptide
mimics nonhydrolyzable in this position5 are formed,
which, in some cases, are potent enzyme inhibitors.6
The
N,N¢-dicyclohexylcarbodiimide/4-(dimethylami-
no)pyridine-mediated esterification of allylic alcohols
1a–d with racemic N-benzoylalanine (2a) (Scheme 1)
gave moderate yields of the desired fluorinated amino
acid allylic esters 3 (Table 1, entries 1–4). Two other tri-
als, transesterification of the amino acid methyl esters13a
and nucleophilic ring opening of intermediary formed
azlactones,13b showed very poor yields. For the esterifica-
tion of N-aroylphenylglycines 2b–f, the classical protocol
employing catalytic amounts of p-toluenesulfonic acid
and azeotropic removal of water with toluene was more
successful (Table 1, entries 5–12).14 The esters 3b–d and
3f–l were obtained as 1:1 mixtures of diastereomers. No
efforts were made to separate these mixtures since the ste-
reogenic center of the amino acid moiety will be lost in the
sigmatropic rearrangement of these compounds.
In an ongoing program to study the application of vinyl
fluorides in synthesis,7 we recently described a pathway to
long-chain g-fluoro-a-amino acids utilizing the [3,3]-sig-
matropic rearrangement of glycine esters of 2-fluoroallyl-
ic alcohols.8 Extending this methodology, we now were
interested in rearranging the corresponding esters of other
a-amino acids such as alanine or phenylglycine in order to
obtain N-protected a-substituted a-amino acids bearing a
fluorovinyl moiety in the g-position. Moreover, it was our
aim to rearrange the corresponding intermediate com-
pounds to form 4-fluoro-6-phenylpyridines bearing addi-
tional substituents in positions 2 and 3. Other pathways
Unfortunately, the amino acid esters 3 failed to rearrange
under the usual, fairly basic, conditions of the Kazmaier
variation of the Ireland–Claisen rearrangement with lithi-
um diisopropylamide/zinc chloride or lithium hexameth-
yldisilazanide/zinc chloride in diethyl ether.15 Thus, we
used carbon tetrachloride/triphenylphosphine/triethyl-
amine in acetonitrile at room temperature. This system or,
alternatively, phosgene/pyridine, was used by Steglich et
al. some thirty years ago to rearrange nonfluorinated ami-
SYNTHESIS 2006, No. 13, pp 2085–2096
x
x.
x
x
.
2
0
0
6
Advanced online publication: 08.06.2006
DOI: 10.1055/s-2006-942411; Art ID: C01406SS
© Georg Thieme Verlag Stuttgart · New York

2086
U. Wittmann et al.
PAPER
Table 1 Synthesis of Esters 3 from Allylic Alcohols 1 and N-Protected Amino Acids 2
Entry
1
Alcohol
1a
R1
R2
R3
Ester
3a
3b
3c
3d
3e
3f
Yield (%)
51
H
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
1b
n-Pr
Ph
33
3
1c
n-C7H15
n-C13H27
H
Ph
72
4
1d
Ph
72
5
1a
Ph
67
6
1b
n-Pr
Ph
56
7
1c
n-C7H15
n-C13H27
n-C7H15
n-C7H15
n-C7H15
n-C7H15
Ph
3g
3h
3i
85
8
1d
Ph
96
9
1c
4-ClC6H4
4-O2NC6H4
4-F3CC6H4
4-MeOC6H4
69
10
11
12
1c
3j
41
1c
3k
3l
70
1c
78
no acid allylic esters.13 Thus, the esters 3 were dehydrated
to give intermediate oxazoles 4. The 1,5-diene system of
4 gives rise to spontaneous Ireland–Claisen-type rear-
rangement to obtain the quite hygroscopic 2-fluoroallyl-
substituted oxazol-5(4H)-ones 5 in almost quantitative
yields (Scheme 2, Table 2).
Hydrolysis of 5 in aqueous hydrochloric acid/tetrahydro-
furan gave N-aroyl-substituted 2-amino-2-methyl- or 2-
amino-2-phenyl-4-fluoroalk-4-enoic acids 6 in excellent
yields (Table 2). In addition to spectroscopic analysis the
structure of 6e,f,i was proved by X-ray. As an example the
X-ray structure of 6f is depicted in Figure 1, showing the
Z-configuration of the double bond.
While studying the 4-(2-fluoroallyl)oxazol-5(4H)-ones 5
more closely, it became apparent that these fluorinated
2-aza-1,5-dienes should also undergo [3,3]-sigmatropic re-
arrangement. Steglich et al. observed such a rearrange-
ment in the thermolysis (230 °C) of similar
nonfluorinated compounds yielding 2,6-disubstituted
pyridines16 and starting from 4-(1,1-dimethylallyl)oxazol-
5(4H)-ones the isomeric 2-(3,3-dimethylallyl)oxazol-
5(2H)-ones were obtained, even in refluxing chloro-
form.13a The fluorinated analogues 5e–l were found to be
Figure
acid (6f)
1
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenyloct-4-enoic
much less reactive; heating to 160 °C in decahydronaph-
thalene for 20 hours was necessary to rearrange these
compounds. However, the expected isomeric 2-allylox-
azol-5(2H)-ones 7 were not isolated but, in a consecutive
thermal cascade reaction, the 4-fluoropyridines 11 were
formed in moderate yields (Table 3). The corresponding
F
F
F
O
R1
R1
R1
O
R2
R2
N
R2
N
F
HN
R3
Ph3P, CCl4, Et3N
MeCN, r.t., 16 h
2 N HCl
O
O
O
R1
R3
N
H
CO2H
THF, r.t., 16 h
R2
O
O
O
R3
R3
5
6
3
4
Scheme 2
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Fluoropyridines from 2-Fluoroallylic Alcohols
2087
Table 2 Products of the Ireland–Claisen Rearrangement of Esters 3 to Oxazol-5(4H)-ones 5 and Hydrolysis to N-Aroylamino Acids 6
Entry
1
Ester
3a
3b
3c
3d
3e
3f
R1
R2
R3
Oxazol-5(4H)-one Yield (%)
Amino Acid Yield (%)
H
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
100
100
100
98
6a
6b
6c
6d
6e
6f
96
98
2
n-Pr
Ph
3
n-C7H15
n-C13H27
H
Ph
100
100
92
4
Ph
5
Ph
98
6
n-Pr
Ph
100
99
100
90
7
3g
3h
3i
n-C7H15
n-C13H27
n-C7H15
n-C7H15
n-C7H15
n-C7H15
Ph
5g
5h
5i
6g
6h
6i
8
Ph
100
99
97
9
4-ClC6H4
4-O2NC6H4
4-F3CC6H4
96
10
11
12
3j
5j
99
6j
91
3k
3l
5k
100
100
6k
6l
94
4-MeOC6H4 5l
99
methyl derivatives 5a–d did not react under these condi- chloroform.17b Aromatization to pyridines was not ob-
tions. According to the mechanism proposed by Steglich17 served in their reactions due to the substitution pattern.
we assume that the cascade reaction of 5e–l starts with an
aza-Cope rearrangement to form compounds 7, which are
In summary, we have presented a new synthetic pathway
to 2,6-diaryl-4-fluoropyridines possibly substituted by
not stable under the harsh conditions forming the carbenes
alkyl groups in position 3. Esterification of fluorinated al-
8 by decarboxylation. An intramolecular cyclopropana-
lylic alcohols 1 with N-protected amino acids 2a–f gave
tion of 8 leads to the fluorinated cyclopropanes 9 followed
the corresponding amino acids esters 3. These esters were
by thermal ring opening to the dihydropyridines 10 and,
dehydrated to intermediary oxazoles 4, which underwent
finally, oxidative aromatization yielded the pyridines 11
immediate Ireland–Claisen-type rearrangement to give
the oxazol-5(4H)-ones 5 quantitatively. Subsequent hy-
drolysis of 5 gave N-protected a-disubstituted g-fluorinat-
ed amino acids 6 in high yields. Furthermore, the 4-
fluoropyridines 11 were obtained by heating to 160 °C,
via a cascade reaction starting with an aza-Cope rear-
(Scheme 3, Table 3). None of the mentioned intermedi-
ates could be isolated. However, the presence of a carbene
in the above mentioned reaction sequence of nonfluorinat-
ed compounds was shown by Steglich et al. by trapping
with dimethyl acetylenedicarboxylate.17a The cyclopropa-
nation products of type 9 were reacted to give isomeric di-
rangement of the oxazol-5(4H)-ones 5.
hydropyridines in acetic acid containing refluxing
R3
F
R1
R3
F
N
O
O
decahydronaphthalene, air, 160 °C, 20 h
R1
N
11
5
O
F
R1
R1
R3
O
R1
F
N
N
N
– CO2
R3
R1
N
F
R3
F
R3
7
8
9
10
Scheme 3
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

2088
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PAPER
Table 3 Products of the Thermal Rearrangement of 4-(2-Fluoroallyl)-4-phenyloxazol-5(4H)-ones 5
Entry
Oxazol-5(4H)-one R1
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R3
Pyridine
11e
Yield (%)
1
2
3
4
5
6
7
8
5e
5f
5g
5h
5i
H
Ph
39
30
32
24
46
55
21
40
n-Pr
Ph
11f
n-C7H15
n-C13H27
n-C7H15
n-C7H15
n-C7H15
n-C7H15
Ph
11g
11h
11i
Ph
4-ClC6H4
4-O2NC6H4
4-F3CC6H4
4-MeOC6H4
5j
5k
5l
11j
11k
11l
Melting points are uncorrected. NMR spectra were recorded at 300
MHz (1H), at 75 MHz (13C) and 282 MHz (19F) and are reported in
ppm downfield from TMS (1H and 13C, CDCl3 as internal standard,
d = 77.0), or CFCl3 (19F) unless otherwise noted. Mass spectra were
recorded by GC-MS-EI (GC-TOF, Micromass, Manchester, UK),
EI-direct inlet (Finnigan-MAT 8230, Bremen, Ger.), nanospray-ES
(Quattro LCZ, Waters Micromass, Manchester, UK) or ES-exact
mass (EM) determination (Micro-TOF, Bruker Daltonics, Bremen,
Ger.). Elemental analyses: C,H,N 0.4 for: 3a–l, 5e,f,i–l, 6c–g,i–l.
Hz), 127.0, 128.4, 131.6, 133.9, 160.3–164.0 (2 d, J = 261.9 Hz,
J = 260.7 Hz), 166.8, 166.9, 172.2, 172.3.
19F NMR: d = –111.5.
MS: m/z (%) = 293 (1) [M+], 148 (31) [C9H10NO+], 118 (1)
+
+
[C6H11OF+], 105 (100) [C7H5O+], 77 (37) [C6H5 ], 51 (10) [C4H3 ],
41 (5) [C3H3 ].
+
2-Fluoro-1-heptylprop-2-enyl 2-(Benzoylamino)propanoate
(3c)
White solid; yield: 503 mg (72%); mp 63 °C.
Aroylamino Acid Esters 3a–d; General Procedure
1H NMR: d = 0.88 (t, J = 6.9 Hz, 3 H, 10-CH3), 1.27 (m, 10 H, 5-,
6-, 7-, 8-, 9-CH2), 1.53–1.54 (2 d, J = 7.2 Hz, 3 H, 13-CH3), 1.79 (m,
2 H, 4-CH2), 4.48–4.68 (2 dd, J = 3.3 Hz, J = 48.2 Hz, 1 H, 1-CH2),
4.71–4.73 (ddd, J = 3.3 Hz, J = 16.7 Hz, J = 1.0 Hz, 1 H, 1-CH2),
4.81–4.83 (m, 1 H, 12-CH), 5.33 (dt, J = 6.9 Hz, J = 15.3 Hz, 1 H,
3-CH), 6.75 (br s, 1 H, NH), 7.37–7.46 (m, 2 H, 17-CH), 7.46–7.54
(m, 1 H, 18-CH), 7.79 (d, J = 7.9 Hz, 2 H, 16-CH).
13C NMR: d = 14.0, 18.4, 18.6, 22.5, 24.8, 29.0, 29.1 (J = 2.5 Hz),
31.0, 31.6, 48.5, 48.7, 72.5 (J = 31.8 Hz), 72.7 (J = 30.5 Hz), 92.8
(J = 17.8 Hz), 93.0 (J = 16.5 Hz), 127.0, 128.5, 131.7, 134.0,
160.4–164.0 (2 d, J = 260.7 Hz; J = 262.0 Hz), 166.8, 172.3.
Method A: To a soln of the allylic alcohol 1a–d (2 mmol) and DCC
(2.2 mmol) in dry CH2Cl2 (10 mL) was added N-benzoylalanine
(2a, 483 mg, 2.5 mmol), resulting in a white precipitate. A catalytic
amount of DMAP was added and stirred overnight at r.t. The sus-
pension was diluted with pentane (100 mL) and filtered. The filtrate
was washed with H2O, 5% AcOH and, again, H2O (each 3 × 50 mL)
and dried (MgSO4). After evaporation of the solvent the crude prod-
uct was purified by column chromatography (cyclohexane–EtOAc,
4:1 to 6:1). All products are 1:1 mixtures of diastereomers.
2-Fluoroprop-2-enyl 2-(Benzoylamino)propanoate (3a)
White solid; yield: 255 mg (51%); mp 63 °C.
19F NMR: d = –111.5 and –111.6 (2 ddd, J = 15.3 Hz, J = 17.2 Hz,
J = 47.7 Hz).
1H NMR: d = 1.53 (d, J = 7.2 Hz, 3 H, 6-CH3), 4.55–4.88 (m, 5 H,
1-CH2, 3-CH2, 5-CH), 6.84 (br s, 1 H, NH), 7.40 (m, 2 H, 10-CH),
7.48 (m, 1 H, 11-CH), 7.78 (d, 2 H, 9-CH).
13C NMR: d = 18.2, 48.5, 61.9 (J = 34.3 Hz), 94.6 (J = 16.5 Hz),
127.0, 128.4, 131.7, 133.8, 159.6 (J = 258.1 Hz), 166.9, 172.4.
MS: m/z (%) = 349 (1) [M+], 306 (1) [M+ – C3H7], 292 (1), 265 (1),
228 (1), 208 (1), 194 (1), 176 (5) [C10H10O2N+], 148 (52)
+
[C9H10ON+], 105 (100) [C6H5CO+], 77 (36) [C6H5 ], 57 (8), 43 (17)
+
+
[C3H7 ], 41 (15) [C3H5 ].
19F NMR: d = –106.3 (J = 15.3 Hz, J = 47.7 Hz).
MS: m/z (%) = 251 (1) [M+], 148 (24) [C9H10NO+], 105 (100)
2-Fluoro-1-tridecylprop-2-enyl 2-(Benzoylamino)propanoate
(3d)
White solid; yield: 624 mg (72%); mp 75 °C.
+
+
[C7H5O+], 77 (46) [C6H5 ], 59 (5) [C3H4F+], 51 (18) [C4H3 ], 39 (4)
+
[C3H3 ].
1H NMR: d = 0.88 (t, J = 6.5 Hz, 3 H, 16-CH3), 1.17–1.37 (m, 22 H,
5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-CH2), 1.53–1.54 (2 d,
J = 7.2 Hz, 3 H, 19-CH3), 1.78 (m, 2 H, 4-CH2), 4.57–4.59 (2 dd,
J = 3.3 Hz, J = 48.2 Hz, 1 H, 1-CH2), 4.75 (dd, J = 3.3 Hz, J = 16.7
Hz, 1 H, 1-CH2), 4.82 (2 q, J = 7.2 Hz, 1 H, 18-CH), 5.33 (dt, J = 6.9
Hz, J = 15.3 Hz, 1 H, 3-CH), 6.74 and 6.76 (2 br s, 1 H, NH), 7.42
(m, 2 H, 22-CH), 7.50 (m, 1 H, 24-CH), 7.79 (m, 2 H, 23-CH).
13C NMR: d = 14.0, 18.4, 18.9, 22.6, 24.9, 29.1, 29.3, 29.4, 29.5,
29.6, 31.0, 31.9, 48.5, 48.7, 72.6 (J = 30.5 Hz), 72.7 (J = 31.8 Hz),
92.9 (J = 17.8 Hz), 93.0 (J = 17.8 Hz), 127.0, 128.5, 128.5, 131.7,
134.0, 160.4–164.0 (2 d, J = 260.7 Hz), 166.8, 172.2.
2-Fluoro-1-propylprop-2-enyl 2-(Benzoylamino)propanoate
(3b)
White solid; yield: 205 mg (33%); mp 61 °C.
1H NMR: d = 0.94 (t, J = 7.2 Hz, 3 H, 6-CH3), 1.39 (m, 2 H, 5-CH2),
1.53 (2 d, J = 7.2 Hz, J = 7.2 Hz, 3 H, 9-CH3), 1.86 (m, 2 H, 4-CH2),
4.46–4.69 (2 dd, J = 3.1 Hz, J = 48.4 Hz; J = 3.1 Hz, J = 48.2 Hz, 1
H, 1-CH2), 4.74 (dd, J = 3.1 Hz, J = 16.7 Hz, 1 H, 1-CH2), 4.78–
4.86 (2 d, J = 7.2 Hz, 1 H, 8-CH), 5.35 (m, 1 H, 3-CH), 6.84 (br s,
1 H, NH), 7.41 (m, 2 H, 13-CH), 7.49 (m, 1 H, 14-CH), 7.78 (m, 2
H, 12-CH).
13C NMR: d = 13.5, 18.1, 18.2, 18.4, 33.0, 48.5, 48.6, 72.0–72.5 (2
dd, J = 30.5 Hz; J = 31.8 Hz), 92.6–93.0 (2 dt, J = 17.8 Hz, J = 17.8
19F NMR: d = –111.6 (J = 15.3 Hz, J = 17.2 Hz, J = 47.7 Hz),
–111.5 (J = 15.3 Hz, J = 15.3 Hz, J = 47.8 Hz).
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Fluoropyridines from 2-Fluoroallylic Alcohols
2089
MS (direct inlet): m/z (%) = 434 (3) [M+ + H], 433 (10) [M+], 376
H, 12-CH), 7.16 (br dd, J = 6.9 Hz, J = 11.0 Hz, 1 H, NH) 7.31–
7.50 (m, 8 H, 14-, 15-, 16-, 20-, 21-CH), 7.81 (m, 2 H, 19-CH).
(1), 363 (1), 312 (1), 292 (1), 265 (1), 241 (1), 194 (21) [M+ + H –
C16H30F], 176 (25) [C10H10NO2 ], 148 (91), [C9H10NO+], 105 (100)
+
13C NMR: d = 14.0, 22.5, 24.4, 24.8, 28.8, 29.0, 29.1, 30.9, 31.2,
31.5, 31.6, 56.8, 57.0, 72.6 (J = 33.0 Hz), 72.7 (J = 31.8 Hz), 92.1
(J = 16.5 Hz), 92.8 (J = 17.8 Hz), 127.1, 127.3, 127.3, 128.6, 128.6,
128.9, 131.8, 133.6, 136.1, 136.5, 161.9 a. 162.0 (J = 260.7 Hz),
166.5, 166.6, 170.0, 170.2.
19F NMR: d = –111.2 (J = 15.3 Hz, J = 15.3 Hz, J = 50.4 Hz),
–110.5 (J = 11.6 Hz, J = 15.2 Hz, J = 47.7 Hz).
+
[C7H5O+], 77 (46) [C6H5 ].
Aroylamino Acid Esters 3e–l; General Procedure
Method B: To a soln/suspension of the allylic alcohol 1a–d (2.0
mmol) and the N-protected amino acid 2b–f (2.5 mmol) in toluene
(25 mL) was added PTSA (20 mg) and refluxed connected to a
Dean–Stark apparatus for 3 d. After cooling to r.t., the mostly clear
brown soln was washed with sat. aq. NaHCO3 (2 × 25 mL) and H2O
(25 mL) and dried (MgSO4). The crude product was purified by col-
umn chromatography (cyclohexane–EtOAc, 4:1 to 20:1). All prod-
ucts were isolated as 1:1 mixtures of diastereomers.
MS: m/z (%) = 411 (0) [M+], 306 (1) [M+ – C7H5O], 254 (2) [M+ –
+
C10H18F], 237 (1) [C15H11NO2 ], 210 (34) [C14H12NO+], 193 (8),
+
+
150 (1), 105 (100) [C7H5O+], 77 (33) [C6H5 ], 51 (4) [C4H3 ].
2-Fluoro-1-tridecylprop-2-enyl (Benzoylamino)(phenyl)ace-
tate (3h)
Starting from 2-fluorohexadec-1-en-3-ol (1d, 348 mg, 1.36 mmol),
2-Fluoroprop-2-enyl (Benzoylamino)(phenyl)acetate (3e)
Starting from 2-fluoroprop-2-en-1-ol (1a, 2.28 g, 30.0 mmol), 3e
was obtained as a light yellow solid; yield: 6.27 g (67%); mp 93 °C.
3h was obtained as a white solid; yield: 646 mg (96%); mp 88 °C.
1H NMR: d = 4.49 (ddt, J = 3.3 Hz, J = 47.5 Hz, J = 0.7 Hz, 1 H,
trans-3-CH2), 4.67 (dd, J = 12.9 Hz, J = 0.7 Hz, 2 H, 1-CH2), 4.74
(dd, J = 3.3 Hz, J = 16.0 Hz, 1 H, cis-3-CH2), 5.82 (d, J = 6.9 Hz,
1 H, 5-CH), 7.14 (br d, J = 6.9 Hz, 1 H, NH), 7.31–7.50 (m, 8 H, 7-,
8-, 9-, 13-, 14-CH), 7.80 (dt, J = 1.4 Hz, J = 6.9 Hz, 2 H, 12-CH).
13C NMR: d = 56.9, 62.1 (J = 35.6 Hz), 94.4 (J = 16.5 Hz), 127.1,
127.3, 128.6, 128.7, 129.0, 131.8, 133.6, 136.0, 159.8 (J = 258.1
Hz), 166.6, 170.3.
1H NMR: d = 0.89 (t, J = 6.5 Hz, 3 H, 16-CH3), 1.26 (m, 22 H, 5-,
6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-CH2), 1.62 and 1.77 (m, 2 H,
4-CH2), 4.13 (dd, J = 3.3 Hz, J = 48.6 Hz, 0.5 H, trans-1-CH2),
4.52 (dd, J = 3.3 Hz, J = 17.2 Hz, 0.5 H, cis-1-CH2), 4.61 (dd,
J = 3.3 Hz, J = 51.8 Hz, 0.5 H, trans-1-CH2), 4.75 (dd, J = 3.3 Hz,
J = 16.9 Hz, 0.5 H, cis-1-CH2), 5.33 (m, 1 H, 3-CH), 5.81 (m, 1 H,
18-CH), 7.15 (br m, 1 H, NH), 7.30–7.52 (m, 8 H, 20-, 21-, 22-, 26-,
27-CH), 7.81 (m, 2 H, 15-CH).
13C NMR: d = 14.0, 22.6, 24.4, 24.8, 28.9, 29.1, 29.2, 29.3, 29.4,
29.6, 30.9, 31.2, 31.9, 56.8, 57.0, 72.8 (J = 31.8 Hz), 92.1 (J = 16.5
Hz), 92.9 (J = 17.8 Hz), 127.1, 127.3, 127.4, 128.6, 128.6, 128.9,
131.8, 133.7, 136.2, 136.5, 161.9 a. 162.0 (J = 260.7 Hz), 166.5,
166.6, 170.0.
19F NMR: d = –106.3.
MS: m/z (%) = 313 (2) [M+], 254 (1) [C15H12NO3 ], 237 (6)
+
+
[C15H11NO2 ], 210 (22) [254 – CO2], 193 (6), 105 (100) [C7H5O+],
+
+
77 (42) [C6H5 ], 51 (4) [C4H3 ], 44 (2) [CO2].
19F NMR: d = –111.3 (J = 15.3 Hz, J = 15.3 Hz, J = 47.7 Hz),
–110.5 (J = 13.4 Hz, J = 17.2 Hz, J = 47.7 Hz).
2-Fluoro-1-propylprop-2-enyl (Benzoylamino)(phenyl)acetate
(3f)
Starting from 2-fluorohex-1-en-3-ol (1b, 1.3 g, 11.0 mmol), 3f was
MS: m/z (%) = 495 (0) [M+], 390 (1), 340 (1), 254 (5)
+
obtained as a white solid; yield: 2.18 g (56%); mp 116 °C.
[C15H12NO3 ], 210 (59) [254 – CO2], 193 (4), 150 (2), 133 (1), 105
+
+
(100) [C7H5O+], 77 (16) [C6H5 ], 51 (3) [C4H3 ].
1H NMR: d = 0.75 and 0.94 (2 t, J = 7.4 Hz, 3 H, 6-CH3), 1.06 and
1.42 (m, 2 H, 5-CH2), 1.61 and 1.77 (m, 2 H, 4-CH2), 4.11 (dd,
J = 3.3 Hz, J = 48.6 Hz, 0.5 H, trans-1-CH2), 4.53 (dd, J = 3.3 Hz,
J = 16.7 Hz, 0.5 H, cis-1-CH2), 4.70 (dd, J = 3.3 Hz, J = 46.1 Hz,
0.5 H, trans-1-CH2), 4.76 (dd, J = 3.3 Hz, J = 16.9 Hz, 0.5 H, cis-
1-CH2), 5.33 (m, 1 H, 3-CH), 5.80 (t, J = 7.5 Hz, 1 H, 8-CH), 7.02–
7.60 (m, 8 H, 10-, 11-,12-, 16-, 17-CH), 7.81 (m, 2 H, 15-CH).
13C NMR: d = 13.3, 13.6, 17.7, 18.0, 32.8, 33.2, 56.9, 57.0, 72.4
(J = 34.3 Hz), 72.6 (J = 33.1 Hz), 92.0 (J = 16.5 Hz), 93.0 (J = 16.5
Hz), 127.1, 127.3, 127.4, 128.6, 128.6, 128.9, 131.1, 133.6, 136.2,
136.5, 161.9 and 162.0 (J = 260.7 Hz), 166.5, 166.6, 170.0, 170.2.
2-Fluoro-1-heptylprop-2-enyl [(4-Chlorobenzoyl)amino](phen-
yl)acetate (3i)
Starting from 2-fluorodec-1-en-3-ol (1c, 0.87 g, 5.0 mmol), 3i was
obtained as a white solid; yield: 1.53 g (69%); mp 123 °C.
1H NMR: d = 0.86 (t, J = 7.2 Hz, 3 H, 10-CH3), 1.11 (m, 4 H, 5-, 6-
CH2), 1.27 (m, 6 H, 7-, 8-, 9-CH2), 1.61 and 1.75 (2 m, 2 H, 4-CH2),
4.12 (dd, J = 3.4 Hz, J = 48.6 Hz, 0.5 H, trans-1-CH2), 4.53 (dd,
J = 3.5 Hz, J = 16.8 Hz, 0.5 H, cis-1-CH2), 4.61 (dd, J = 3.3 Hz,
J = 48.2 Hz, 0.5 H, trans-1-CH2), 4.75 (dd, J = 2.9 Hz, J = 16.0 Hz,
0.5 H, cis-1-CH2), 5.32 (m, 1 H, 3-CH), 5.74 (d, J = 6.9 Hz, 0.5 H,
12-CH), 5.78 (d, J = 7.0 Hz, 0.5 H, 12-CH), 7.13 (br dd, J = 7.4 Hz,
J = 7.5 Hz, 1 H, NH), 7.34–7.42 (m, 7 H, 14-, 15-, 16-, 19-CH),
7.74 (m, 2 H, 20-CH).
13C NMR: d = 14.0, 22.5, 24.4, 24.8, 28.9, 29.0, 29.1, 30.9, 31.2,
31.5, 31.7, 56.9, 57.1, 72.8 (J = 33.6 Hz), 72.9 (J = 33.2 Hz), 92.1
(J = 17.2 Hz), 92.9 (J = 18.0 Hz), 127.3, 127.4, 128.0, 128.6,
128.7, 128.8, 129.0, 129.9, 132.0, 136.0, 136.3, 138.2, 161.8
(J = 258.9 Hz), 162.0 (J = 261.2 Hz), 165.4, 165.5, 169.9, 170.1.
19F NMR: d = –111.3 (J = 15.3 Hz, J = 15.3 Hz, J = 49.6 Hz),
–110.4 (J = 13.4 Hz, J = 17.2 Hz, J = 49.6 Hz).
MS: m/z (%) = 355 (1) [M+], 254 (6) [M+ – C6H10F], 237 (2) [M+ –
C6H11OF], 210 (62) [C14H12NO+], 193 (4), 150 (2), 105 (100)
[C7H5O+], 77 (28) [C6H5 ], 51 (3) [C4H3 ].
+
+
2-Fluoro-1-heptylprop-2-enyl (Benzoylamino)(phenyl)acetate
(3g)
Starting from 2-fluorodec-1-en-3-ol (1c, 1.74 g, 10.0 mmol), 3g was
19F NMR: d = –111.2 (J = 15.3 Hz, J = 15.5 Hz, J = 46.8 Hz),
–110.6 (J = 13.0 Hz, J = 16.9 Hz, J = 45.9 Hz).
obtained as a white solid; yield: 3.50 g (85%); mp 81 °C.
1H NMR: d = 0.88 (t, J = 7.2 Hz, 3 H, 10-CH3), 1.27 (m, 10 H, 5-,
6-, 7-, 8-, 9-CH2), 1.62 and 1.78 (2 m, 2 H, 4-CH2), 4.12 (dd, J = 3.3
Hz, J = 48.6 Hz, 0.5 H, trans-1-CH2), 4.52 (dd, J = 3.3 Hz, J = 16.9
Hz, 0.5 H, cis-1-CH2), 4.62 (dd, J = 3.3 Hz, J = 48.2 Hz, 0.5 H,
trans-1-CH2), 4.76 (dd, J = 3.3 Hz, J = 16.7 Hz, 0.5 H, cis-1-CH2),
5.32 (m, 1 H, 3-CH), 5.79 and 5.81 (2 d, J = 6.9 Hz, J = 11.0 Hz, 1
MS: m/z (%) = 447/445 (0/1) [M+], 308/306 (1/2) [M+ – C7H7Cl],
290/288 (4/7) [M+ – C10H18F], 273/271 (1/4) [290/288 – OH], 246/
244 (31/88) [290/288 – CO2], 227 (2), 150 (3), 141/139 (52/100)
[C7H7Cl+], 113/111 (6/18) [141/139 – CO], 104 (12) [141/139 – Cl],
+
77 (5) [C6H5 ], 55 (4).
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

2090
U. Wittmann et al.
PAPER
2-Fluoro-1-heptylprop-2-enyl [(4-Nitrobenzoyl)amino](phen-
yl)acetate (3j)
Starting from 2-fluorodec-1-en-3-ol (1c, 0.87 g, 5.0 mmol), 3j was
obtained as a white solid; yield: 930 mg (41%); mp 107 °C.
CH), 5.77 (d, J = 6.9 Hz, 0.5 H, 12-CH), 5.81 (d, J = 7.0 Hz, 0.5 H,
12-CH), 7.79 (d, J = 9.1 Hz, 2 H, 20-CH), 7.03 (d, J = 7.2 Hz, 0.5
H, NH), 7.07 (d, J = 6.9 Hz, 0.5 H, NH), 7.30–7.39 (m, 3 H, 15-, 16-
CH), 7.41–7.47 (m, 2 H, 14-CH), 7.79 (d, J = 9.0 Hz, 2 H, 19-CH).
1H NMR: d = 0.86 (t, J = 7.2 Hz, 3 H, 10-CH3), 1.04–1.20 (m, 4 H,
5-, 6-CH2), 1.21–1.40 (m, 6 H, 7-, 8-, 9-CH2), 1.62 and 1.77 (2 m, 2
H, 4-CH2), 4.14 (dd, J = 3.5 Hz, J = 48.5 Hz, 0.5 H, trans-1-CH2),
4.54 (dd, J = 3.4 Hz, J = 17.1 Hz, 0.5 H, cis-1-CH2), 4.62 (dd,
J = 3.3 Hz, J = 52.0 Hz, 0.5 H, trans-1-CH2), 4.77 (dd, J = 3.3 Hz,
J = 16.5 Hz, 0.5 H, cis-1-CH2), 5.32 (m, 1 H, 3-CH), 5.76 (d, J = 6.8
Hz, 0.5 H, 12-CH), 5.79 (d, J = 6.9 Hz, 0.5 H, 12-CH), 7.28–7.46
(m, 6 H, 14-, 15-, 16-CH, NH), 7.97 (m, 2 H, 20-CH), 8.26 (m, 2 H,
19-CH).
13C NMR: d = 14.0, 22.5, 22.6, 24.1, 24.8, 28.8, 28.9, 29.0, 29.1,
30.8, 31.1, 31.5, 31.6, 57.1, 57.3, 73.0 (J = 32.8 Hz), 73.1 (J = 32.3
Hz), 92.3 (J = 17.2 Hz), 93.1 (J = 16.2 Hz), 123.8, 127.3, 127.4,
128.4, 128.9, 129.1, 135.5, 135.9, 139.1, 149.8, 161.7 (J = 260.7
Hz), 161.9 (J = 261.0 Hz), 164.5, 164.6, 169.7, 169.9.
13C NMR: d = 14.0, 22.5, 22.6, 24.4, 24.8, 28.9, 29.0, 29.1, 30.9,
31.2, 31.5, 31.7, 55.4, 56.8, 57.0, 72.6 (J = 32.4 Hz), 72.7 (J = 34.4
Hz), 92.0 (J = 17.0 Hz), 92.8 (J = 19.0 Hz), 113.8, 125.9, 127.3,
127.4, 128.6, 128.9, 129.0, 136.3, 136.7, 161.9 (J = 259.1 Hz),
162.1 (J = 260.5 Hz), 162.5, 166.0, 166.1, 170.1, 170.3.
19F NMR: d = –111.2 (J = 15.0 Hz, J = 15.0 Hz, J = 53.0 Hz),
–110.5 (ddd, J = 11.9 Hz, J = 17.4 Hz, J = 47.6 Hz).
MS: m/z (%) = 441 (1) [M+], 306 (1) [M+ – C8H7O2], 268 (1) [M+ –
C10H18FO], 267 (4) [M+ – C10H19FO], 240 (28) [268 – CO], 135
(100) [C8H7O2 ], 107 (7) [C7H7O+], 105 (8) [C7H7N+], 104 (3)
+
[C7H4O+], 77 (12) [C6H5 ], 72 (3) [C4H5F+], 51 (4) [C4H3 ].
+
+
Oxazol-5(4H)-ones 5a–l; General Procedure
To a soln/suspension of the ester 3a–l (1.0 mmol) in MeCN (1.5
mL) were added CCl4 (0.34 mL, 542 mg, 3.52 mmol), Et3N (0.38
mL, 274 mg, 2.72 mmol) and Ph3P (524 mg, 2.0 mmol). After stir-
ring at r.t. overnight, the mixture was purified by column filtration
(silica gel; cyclohexane–EtOAc, 4:1 to 20:1). The products were
stored under argon or used directly for further reactions.
19F NMR: d = –111.3 (J = 15.1 Hz, J = 15.1 Hz, J = 47.6 Hz),
–110.6 (J = 12.9 Hz, J = 16.7 Hz, J = 49.5 Hz).
MS: m/z (%) = 456 (0) [M+], 341 (1), 325 (1) [M+ – C6H13NO2], 256
(16) [M+ – C11H17FO2], 255 (55) [M+ – C11H18FO2], 206 (1)
+
+
[C12H11FO2 ], 156 (10) [C10H18F+], 150 (100) [C7H4NO3 ] 136 (4)
[156 – HF], 134 (14) [C8H8NO+], 120 (19) [C7H6NO+], 105 (26)
4-(2-Fluoroprop-2-enyl)-4-methyl-2-phenyloxazol-5(4H)-one
(5a)
[C7H7N+], 104 (52) [C7H4O+], 72 (88) [C4H5F+], 55 (91) [C4H7 ].
+
Starting from 3a (126 mg, 0.50 mmol), 5a was obtained as a light
yellow oil; yield: 117 mg (100%).
1H NMR: d = 1.48 (s, 3 H, 6-CH3), 2.72 (m, 2 H, 3-CH2), 4.28 (dd,
J = 3.0 Hz, J = 48.9 Hz, 1 H, 5-CH2), 4.52 (dd, J = 3.0 Hz, J = 17.0
Hz, 1 H, 5-CH2), 7.38 (m, 2 H, 10-CH), 7.48 (m, 1 H, 11-CH), 7.90
(m, 2 H, 9-CH).
13C NMR: d = 23.7, 40.8 (J = 26.7 Hz), 67.8 (J = 2.5 Hz), 94.1
(J = 17.8 Hz), 125.8, 128.0, 128.7, 132.7, 160.5, 161.0 (J = 256.9
Hz), 179.5.
19F NMR: d = –93.7 (J = 15.3 Hz, J = 24.8 Hz, J = 49.6 Hz).
2-Fluoro-1-heptylprop-2-enyl (Phenyl){[4-(trifluoromethyl)-
benzoyl]amino}acetate (3k)
Starting from 2-fluorodec-1-en-3-ol (1c, 0.87 g, 5.0 mmol), 3k was
obtained as a white solid; yield: 1.67 g (70%); mp 115 °C.
1H NMR: d = 0.86 (t, J = 7.2 Hz, 3 H, 10-CH3), 1.05–1.15 (m, 4 H,
5-, 6-CH2), 1.20–1.35 (m, 6 H, 7-, 8-, 9-CH2), 1.62 and 1.76 (2 m, 2
H, 4-CH2), 4.12 (dd, J = 3.4 Hz, J = 48.5 Hz, 0.5 H, trans-1-CH2),
4.54 (dd, J = 3.4 Hz, J = 17.1 Hz, 0.5 H, cis-1-CH2), 4.63 (dd,
J = 3.3 Hz, J = 48.2 Hz, 0.5 H, trans-1-CH2), 4.77 (dd, J = 3.3 Hz,
J = 16.8 Hz, 0.5 H, cis-1-CH2), 5.32 (m, 1 H, 3-CH), 5.76 (d, J = 6.7
Hz, 0.5 H, 12-CH), 5.80 (d, J = 6.9 Hz, 0.5 H, 12-CH), 7.21 (d,
J = 6.3 Hz, 0.5 H, NH), 7.26 (d, J = 7.1 Hz, 0.5 H, NH), 7.34–7.47
(m, 5 H, 14-, 15-, 16-CH), 7.69 (d, J = 8.1 Hz, 2 H, 19-CH), 8.26 (d,
J = 8.0 Hz, 2 H, 20-CH).
MS: m/z (%) = 233 (4) [M+], 188 (1) [M+ – C2H2F], 174 (21) [M+ –
+
C3H4F], 147 (3) [C8H5O2N+], 105 (100) [C7H5O+], 77 (38) [C6H5 ],
+
+
59 (1), 51 (16) [C4H3 ], 39 (6) [C3H3 ].
13C NMR: d = 14.0, 22.6, 22.6, 24.4, 24.8, 28.8, 28.9, 29.0, 29.1,
30.8, 31.1, 31.6, 31.7, 57.0, 57.1, 72.9 (J = 32.6 Hz), 73.0 (J = 31.4
Hz), 92.2 (J = 15.9 Hz), 93.2 (J = 17.5 Hz), 123.6 (J = 273.1 Hz),
125.6, 125.7, 127.3, 127.4, 127.6, 128.0, 128.8, 129.1, 133.5
(J = 33.1 Hz), 135.8, 136.1, 136.8, 161.7 (J = 260.5 Hz), 161.8
(J = 261.0 Hz), 165.2, 165.3, 169.9, 170.0.
4-[(2Z)-2-Fluorohex-2-enyl]-4-methyl-2-phenyloxazol-5(4H)-
one (5b)
Starting from 3b (156 mg, 0.53 mmol), 5b was obtained as a light
yellow oil; yield: 146 mg (100%).
1H NMR: d = 0.75 (t, J = 7.4 Hz, 3 H, 8-CH3), 1.24 (ps sext, J = 7.4
Hz, 2 H, 7-CH2), 1.55 (s, 3 H, 9-CH3), 1.94 (m, 2 H, 6-CH2), 2.71
(m, 2 H, 3-CH2), 4.64 (dt, J = 7.6 Hz, J = 37.0 Hz, 1 H, 5-CH), 7.44
(m, 2 H, 13-CH), 7.56 (m, 1 H, 14-CH), 7.98 (m, 2 H, 12-CH).
13C NMR: d = 13.3, 22.3, 23.6, 25.4 (J = 3.8 Hz), 41.3 (J = 28.0
Hz), 68.2 (J = 2.6 Hz), 110.0 (J = 14.0 Hz), 126.0, 127.9, 128.7,
132.6, 154.2 (J = 251.8 Hz), 167.0, 179.8.
19F NMR: d = –111.4 (J = 15.9 Hz, J = 16.2 Hz, J = 47.7 Hz),
–110.7 (J = 13.6 Hz, J = 18.1 Hz, J = 48.0 Hz), –63.5.
MS: m/z (%) = 480 (1) [M+], 460 (1) [M+ – HF], 374 (2) [460 –
C6H13], 306 (1) [M+ – C10H18FO and M+ – C8H4F3O], 278 (26)
[306 – CO], 173 (100) [C10H19FO+ and C8H4F3O], 145 (57)
[C7H4F3 ], 105 (8) [C7H5O+], 104 (30) [C7H4O+], 77 (33) [C6H5 ],
+
+
19F NMR: d = –108.6 (J = 15.3 Hz, J = 24.8 Hz, J = 38.2 Hz).
72 (18) [C4H5F+], 51 (4) [C4H3 ].
+
MS: m/z (%) = 275 (1) [M+], 188 (1) [M+ – C5H8F], 175 (24) [M+ +
H – C6H10F], 174 (25) [M+ – C6H10F], 105 (100) [C7H5O+], 77 (37)
2-Fluoro-1-heptylprop-2-enyl [4-Methoxybenzoyl)amino]-
(phenyl)acetate (3l)
Starting from 2-fluorodec-1-en-3-ol (1c, 0.87 g, 5.0 mmol), 3l was
+
[C6H5 ], 59 (5), 51 (7), 42 (4).
obtained as a white solid; yield: 1.72 g (78%); mp 93 °C.
4-[(2Z)-2-Fluorodec-2-enyl]-4-methyl-2-phenyloxazol-5(4H)-
one (5c)
Starting from 3c (175 mg, 0.50 mmol), 5c was obtained as a light
1H NMR: d = 0.86 (t, J = 7.2 Hz, 3 H, 10-CH3), 1.04–1.18 (m, 4 H,
5-, 6-CH2), 1.21–1.40 (m, 6 H, 7-, 8-, 9-CH2), 1.62 and 1.77 (2 m, 2
H, 4-CH2), 3.83 (s, 3 H, 22-CH3), 4.12 (dd, J = 3.5 Hz, J = 48.4 Hz,
0.5 H, trans-1-CH2), 4.52 (dd, J = 3.5 Hz, J = 17.1 Hz, 0.5 H, cis-1-
CH2), 4.61 (dd, J = 3.3 Hz, J = 48.0 Hz, 0.5 H, trans-1-CH2), 4.75
(dd, J = 3.4 Hz, J = 16.6 Hz, 0.5 H, cis-1-CH2), 5.31 (m, 1 H, 3-
yellow oil; yield: 164 mg (100%).
1H NMR: d = 0.84 (t, J = 7.2 Hz, 3 H, 12-CH3), 1.08–1.27 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.55 (s, 3 H, 13-CH3), 1.95 (m, 2 H, 6-CH2),
2.60–2.90 (m, 2 H, 3-CH2), 4.62 (dt, J = 7.6 Hz, J = 37.2 Hz, 1 H,
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Fluoropyridines from 2-Fluoroallylic Alcohols
2091
5-CH), 7.50 (m, 2 H, 17-CH), 7.58 (m, 1 H, 18-CH), 7.99 (m, 2 H,
16-CH).
4-[(2Z)-2-Fluorodec-2-enyl]-2,4-diphenyloxazol-5(4H)-one (5g)
Starting from 3g (822 mg, 2.00 mmol), 5g was obtained as a light
yellow oil; yield: 778 mg (99%).
13C NMR: d = 14.0, 22.6, 23.4 (J = 3.8 Hz), 23.6, 28.8, 28.9, 29.1,
31.6, 41.3 (J = 26.7 Hz), 68.2 (J = 2.6 Hz), 110.3 (J = 15.3 Hz),
126.0, 128.0, 128.7, 132.6, 154.0 (J = 253.0 Hz), 160.4, 179.7.
19F NMR: d = –108.7 (J = 15.3 Hz, J = 24.8 Hz, J = 38.2 Hz).
1H NMR: d = 0.84 (t, J = 7.2 Hz, 3 H, 12-CH3), 1.00–1.39 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.94 (m, 2 H, 6-CH2), 2.98 (dd, J = 14.5 Hz,
J = 22.3 Hz, 1 H, 3-CH2), 3.21 (dd, J = 14.5 Hz, J = 14.5 Hz, 1 H,
3-CH2), 4.68 (dt, J = 7.6 Hz, J = 37.2 Hz, 1 H, 5-CH2), 7.44–7.62
(m, 6 H, 20-, 21-, 15-, 16-CH), 7.71 (m, 2 H, 14-CH), 8.08 (m, 2 H,
19-CH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 3.8 Hz), 28.8, 28.9, 29.1, 31.6,
44.1 (J = 28.0 Hz), 73.0, 92.6 (J = 19.1 Hz), 125.6, 128.2, 128.4,
128.7, 132.8, 137.7, 153.7 (J = 253.0 Hz), 177.3, 177.9.
MS: m/z (%) = 331 (0) [M+], 175 (17) [M+ + H – C10H18F], 174 (11)
[M+ – C10H18F], 147 (5), 131 (2), 105 (100) [C7H5O+], 77 (27)
+
+
+
[C6H5 ], 51 (7) [C4H3 ], 41 (3) [C3H5 ].
4-[(2Z)-2-Fluorohexadec-2-enyl]-4-methyl-2-phenyloxazol-
5(4H)-one (5d)
Starting from 3d (250 mg, 0.58 mmol), 5d was obtained as a light
19F NMR: d = –108.8 (J = 13.4 Hz, J = 24.8 Hz, J = 38.2 Hz).
yellow oil; yield: 233 mg (98%).
MS (direct inlet): m/z (%) = 393 (2.5) [M+], 365 (0.2) [M+ – CO],
1H NMR: d = 0.88 (t, J = 6.6 Hz, 3 H, 18-CH3), 1.08–1.36 (m, 22 H,
7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-CH2), 1.55 (s, 3 H, 19-
CH3), 1.84–2.01 (m, 2 H, 6-CH2), 2.64–2.86 (m, 2 H, 3-CH2), 4.64
(dt, J = 7.6 Hz, J = 37.2 Hz, 1 H, 5-CH), 7.45 (m, 2 H, 23-CH), 7.56
(m, 1 H, 24-CH), 7.99 (m, 2 H, 22-CH).
350 (0.1) [M+ + H-CO2], 349 (0.3) [M+ – CO2], 329 (0.1) [M+ – HF
+
– CO2], 289 (0.1), 250 (1), 237 (26) [C15H11NO2 ], 236 (78)
+
[C15H10NO2 ], 209 (4) [M+ – CO2 – C10H17F], 165 (1), 127 (3), 105
(100) [C7H5O+], 77 (36) [C6H5 ].
+
4-[(2Z)-2-Fluorohexadec-2-enyl]-2,4-diphenyloxazol-5(4H)-one
(5h)
Starting from 3h (206 mg, 0.42 mmol), 5h was obtained as a light
13C NMR: d = 14.1, 22.7, 23.5 (J = 3.8 Hz), 23.7, 28.9–29.7, 31.9,
41.3 (J = 26.7 Hz), 68.2 (J = 2.5 Hz), 110.3 (J = 14.0 Hz), 126.0,
128.0, 128.7, 132.7, 152.5 (J = 251.8 Hz), 160.4, 179.8.
19F NMR: d = –108.8 (J = 15.3 Hz, J = 24.8 Hz, J = 38.2 Hz).
yellow oil; yield: 199 mg (100%).
1H NMR: d = 0.88 (t, J = 6.9 Hz, 3 H, 18-CH3), 1.03–1.37 (m, 22 H,
7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-CH2), 1.94 (m, 2 H, 6-
CH2), 2.98 (dd, J = 14.8 Hz, J = 25.3 Hz, 1 H, 3-CH2), 3.20 (dd,
J = 14.6 Hz, J = 14.6 Hz, 1 H, 3-CH2), 4.66 (dt, J = 14.6 Hz,
J = 37.2 Hz, 1 H, 5-CH2), 7.28–7.41 (m, 3 H, 21-, 22-CH), 7.48 (m,
2 H, 26-CH), 7.56 (m, 1 H, 27-CH), 7.70 (m, 2 H, 20-CH), 8.08 (m,
2 H, 25-CH).
13C NMR: d = 14.1, 22.7, 23.5 (J = 3.8 Hz), 26.9, 28.9, 29.1, 29.3,
29.3, 29.4, 29.7, 29.7, 31.9, 44.1 (J = 26.7 Hz), 72.9 (J = 3.8 Hz),
110.8 (J = 15.3 Hz), 125.6, 125.9, 128.2, 128.6, 128.4, 132.8, 137.7,
153.7 (J = 253.0 Hz), 160.7, 177.7.
MS: m/z (%) = 415 (1) [M+], 371 (1) [M+ – CO2], 351 (11) [371 –
HF], 324 (1), 310 (1) [M+ – COC6H5], 282 (2) [M+ – CO – C7H5O],
224 (2), 198 (19), 196 (31), 175 (36), 105 (100) [C7H5O+], 77 (24)
+
+
[C6H5 ], 43 (15) [C3H7 ].
4-(2-Fluoroprop-2-enyl)-2,4-diphenyloxazol-5(4H)-one (5e)
Starting from 3e (157 mg, 0.50 mmol), 5e was obtained as a light
yellow oil; yield: 144 mg (98%).
1H NMR: d = 3.06 (dd, J = 14.8 Hz, J = 24.6 Hz, 1 H, 3-CH2), 3.23
(dd, J = 14.3 Hz, J = 13.8 Hz, 1 H, 3-CH2), 4.37 (dd, J = 3.0 Hz,
J = 51.1 Hz, 1 H, 5-CH2), 4.61 (dd, J = 3.0 Hz, J = 16.9 Hz, 1 H, 5-
CH2), 7.25–7.42 (m, 3 H, 8-, 9-CH), 7.43–7.63 (m, 3 H, 13-, 14-
CH), 7.70 (m, 2 H, 7-CH), 8.09 (m, 2 H, 12-CH).
13C NMR: d = 44.0 (J = 26.7 Hz), 72.9, 95.0 (J = 19.1 Hz), 126.1,
126.0, 128.6, 129.3, 129.4, 133.4, 137.9, 161.2 (J = 258.1 Hz),
161.4, 178.0.
19F NMR: d = –93.9.
19F NMR: d = –108.8 (J = 13.4 Hz, J = 24.8 Hz, J = 38.2 Hz).
MS (direct inlet): m/z (%) = 478 (0.1) [M+ + H], 477 (0.3) [M+], 413
+
(5.4) [M+ – HF – CO2], 258 (4.6), 236 (58) [C15H10NO2 ], 105 (100)
+
[C7H5O+], 77 (34) [C6H5 ].
2-(4-Chlorophenyl)-4-[(2Z)-2-fluorodec-2-enyl]-4-phenylox-
azol-5(4H)-one (5i)
Starting from 3i (669 mg, 1.50 mmol), 5i was obtained as a light yel-
low oil; yield: 635 mg (99%).
ESI-MS (MeOH–CHCl3): m/z (%) = 318 (100) [M + Na+], 296 (54)
[M + H+].
1H NMR: d = 0.85 (t, J = 7.1 Hz, 3 H, 12-CH3), 1.07–1.35 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.94 (m, 2 H, 6-CH2), 2.97 (dd, J = 14.6 Hz,
J = 25.5 Hz, 1 H, 3-CH2), 3.20 (dd, J = 14.5 Hz, J = 14.5 Hz, 1 H,
3-CH2), 4.65 (dt, J = 7.6 Hz, J = 37.4 Hz, 1 H, 5-CH2), 7.30–7.42
(m, 3 H, 15-, 16-CH), 7.45–7.50 (2 dt, J = 2.2 Hz, J = 9.0 Hz, 2 H,
20-CH), 7.69 (m, 2 H, 14-CH), 8.02 (2 dt, J = 2.2 Hz, J = 9.0 Hz, 2
H, 19-CH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 3.7 Hz), 28.4, 28.5, 28.8, 29.0,
29.1, 31.7, 44.2 (J = 27.2 Hz), 73.0 (J = 2.5 Hz), 110.9 (J = 15.9
Hz), 124.4, 125.5, 128.5, 128.8, 129.2, 129.4, 137.5, 139.3, 153.6
(J = 252.3 Hz), 159.9, 177.4.
4-[(2Z)-2-Fluorohex-2-enyl]-2,4-diphenyloxazol-5(4H)-one (5f)
Starting from 3f (178 mg, 0.50 mmol), 5f was obtained as a light
yellow oil; yield: 169 mg (100%).
1H NMR: d = 0.73 (t, J = 7.4 Hz, 3 H, 8-CH3), 1.19 (m, 2 H, 7-CH2),
1.93 (m, 2 H, 6-CH2), 2.99 (dd, J = 14.8 Hz, J = 25.5 Hz, 1 H, 3-
CH2), 3.21 (dd, J = 14.5 Hz, J = 14.5 Hz, J = 0.7 Hz, 1 H, 3-CH2),
4.66 (dt, J = 7.6 Hz, J = 37.2 Hz, 1 H, 5-CH2), 7.23–7.40 (m, 3 H,
11-, 12-CH), 7.40–7.50 (m, 2 H, 16-CH), 7.56 (m, 1 H, 17-CH),
7.69 (m, 2 H, 10-CH), 8.07 (m, 2 H, 15-CH).
13C NMR: d = 13.3, 22.2, 25.4 (J = 3.8 Hz), 44.0 (J = 26.7 Hz),
72.9 (J = 2.5 Hz), 110.5 (J = 14.0 Hz), 125.5, 125.9, 128.1, 128.4,
129.7, 132.8, 137.7, 153.9 (J = 254.3 Hz), 160.7, 177.7.
19F NMR: d = –109.0 (J = 14.5 Hz, J = 25.5 Hz, J = 38.5 Hz).
MS (direct inlet): m/z (%) = 429/427 (0.4/1.2) [M+], 342/340 (0.2/
19F NMR: d = –108.7 (J = 13.3 Hz, J = 24.8 Hz, J = 38.1 Hz).
MS (direct inlet): m/z (%) = 337 (1.7) [M+], 311 (0.8) [M+ – CO],
0.3) [M+ – CO2C3H7], 312/310 (0.3/0.5), 272/270 (18/46)
+
[C15H9ClNO2 ], 213 (4), 188 (1) [C11H7FNO+], 141/139 (39/100)
[C7H4ClO+], 127 (22), 113/111 (8/10) [141/139 – CO], 105 (25)
+
250 (1) [M+ – C5H8F], 236 (72) [C15H10NO2 ], 209 (3) [M+ – CO2 –
+
+
[C7H5O+], 77 (3) [C6H5 ], 57 (11) [C4H9 ].
C10H17F], 159 (2) [M+ – C16H22F], 191 (1), 146 (4), 115 (2), 105
+
(100) [C7H5O+], 77 (34) [C6H5 ].
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

2092
U. Wittmann et al.
PAPER
4-[(2Z)-2-Fluorodec-2-enyl]-2-(4-nitrophenyl)-4-phenyloxazol-
5(4H)-one (5j)
Starting from 3j (456 mg, 1.00 mmol), 5j was obtained as a light
yellow oil; yield: 433 mg (99%).
N-Protected Amino Acids 6a–l; General Procedure
To a soln of the oxazol-5(4H)-ones 5a–l (1.0 mmol) in THF (10
mL) was added aq 2 M HCl (20 mL). After stirring at r.t. overnight,
the mixture was quenched with H2O (30 mL) and extracted with
Et2O (3 × 40 mL). The organic layer was washed with brine (40 mL)
and dried (MgSO4). After evaporation of the solvent the products
were isolated as solids.
1H NMR: d = 0.84 (t, J = 7.1 Hz, 3 H, 12-CH3), 1.05–1.31 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.94 (m, 2 H, 6-CH2), 3.02 (dd, J = 14.6 Hz,
J = 25.3 Hz, 1 H, 3-CH2), 3.21 (dd, J = 14.6 Hz, J = 14.6 Hz, 1 H,
3-CH2), 4.67 (dt, J = 7.6 Hz, J = 37.2 Hz, 1 H, 5-CH2), 7.32–7.44
(m, 3 H, 15-, 16-CH), 7.66–7.72 (m, 2 H, 14-CH), 8.27 (m, 2 H, 20-
CH), 8.36 (m, 2 H, 19-CH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 3.6 Hz), 28.8, 28.9, 29.1, 31.7,
44.4 (J = 27.2 Hz), 73.4 (J = 2.0 Hz), 111.2 (J = 14.5 Hz), 123.9,
125.5, 128.7, 128.9, 129.2, 131.4, 137.0, 150.5, 153.4 (J = 253.4
Hz), 159.1, 176.8.
(4Z)-2-(Benzoylamino)-4-fluoro-2-methylpent-4-enoic Acid
(6a)
Starting from 5a (104 mg, 0.45 mmol), 6a was obtained as a white
solid; yield: 109 mg (96%); mp 152 °C (dec).
1H NMR (CD3OD): d = 1.65 (s, 3 H, 6-CH3), 2.97 (dd, J = 14.6 Hz,
J = 22.2 Hz, 1 H, 3-CH2), 3.34 (dd, J = 14.5 Hz, J = 21.2 Hz, 1 H,
3-CH2), 4.33 (dd, J = 2.6 Hz, J = 49.4 Hz, 1 H, 5-CH2), 4.61 (dd,
J = 2.6 Hz, J = 16.9 Hz, 1 H, 5-CH2), 7.43 (m, 2 H, 10-CH), 7.50
(m, 1 H, 11-CH), 7.77 (m, 2 H, 9-CH).
13C NMR (CD3OD): d = 23.9, 39.0 (J = 25.4 Hz), 59.8 (J = 2.5 Hz),
94.6 (J = 19.1 Hz), 128.5, 129.8, 133.0, 136.1, 165.0 (J = 256.9
Hz), 170.2, 177.0.
19F NMR: d = –109.3 (J = 13.5 Hz, J = 24.0 Hz, J = 37.4 Hz).
MS (direct inlet): m/z (%) = 438 (2) [M+], 418 (0.2) [M+ – HF], 341
(0.2), 282 (81) [M+ – C10H17F], 254 (13) [282 – CO], 237 (2) [254
– OH], 199 (1), 157 (17) [C10H18F+], 150 (100) [C7H4NO3 ], 104
+
(24) [C7H4O+], 81 (18).
19F NMR (CD3OD): d = –91.0.
4-[(2Z)-2-Fluorodec-2-enyl]-4-phenyl-2-[4-(trifluoromethyl)-
phenyl]oxazol-5(4H)-one (5k)
Starting from 3k (479 mg, 1.00 mmol), 5k was obtained as a light
yellow oil; yield: 460 mg (100%).
ESI-MS (MeOH–CHCl3): m/z (%) = 274 (100) [M + Na+], 252 (10)
[M + H+].
MS-ES-EM: m/z [M+ + Na] calcd for C13H14FNO3Na: 274.0850;
1H NMR: d = 0.84 (t, J = 7.1 Hz, 3 H, 12-CH3), 1.06–1.26 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.94 (m, 2 H, 6-CH2), 3.00 (dd, J = 14.6 Hz,
J = 25.8 Hz, 1 H, 3-CH2), 3.23 (dd, J = 14.5 Hz, J = 14.2 Hz, 1 H,
3-CH2), 4.67 (dt, J = 7.6 Hz, J = 37.1 Hz, 1 H, 5-CH2), 7.31–7.44
(m, 3 H, 15-, 16-CH), 7.66–7.70 (m, 2 H, 14-CH), 7.77 (dm, J = 8.1
Hz, 2 H, 19-CH), 8.22 (dm, J = 8.1 Hz, 2 H, 20-CH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 3.0 Hz), 26.9, 28.8, 28.9, 29.1,
31.6, 44.2 (J = 26.4 Hz), 73.1 (J = 2.2 Hz), 111.0 (J = 14.8 Hz),
123.5 (J = 273.8 Hz), 125.5, 125.8 (J = 4.2 Hz), 128.5, 128.6,
128.9, 129.1, 134.4 (J = 33.6 Hz), 131.4, 137.2, 153.5 (J = 254.1
Hz), 159.7, 177.2.
found: 274.0848.
(4Z)-2-(Benzoylamino)-4-fluoro-2-methyloct-4-enoic Acid (6b)
Starting from 5b (116 mg, 0.42 mmol), 6b was obtained as a white
solid; yield: 121 mg (98%).
1H NMR (CD3OD): d = 0.81 (t, J = 7.6 Hz, 3 H, 8-CH3), 1.28 (m, 2
H, 7-CH2), 1.35 (s, 3 H, 9-CH3), 1.98 (m, 2 H, 6-CH2), 2.93 (dd,
J = 14.8 Hz, J = 22.9 Hz, 1 H, 3-CH2), 3.14 (dd, J = 14.5 Hz,
J = 21.7 Hz, 1 H, 3-CH2), 4.62 (dt, J = 7.6 Hz, J = 37.2 Hz, 1 H, 5-
CH), 7.43 (m, 2 H, 13-CH), 7.53 (m, 1 H, 14-CH), 7.78 (m, 2 H, 12-
CH).
19F NMR: d = –109.5 (J = 14.1 Hz, J = 25.1 Hz, J = 37.2 Hz),
13C NMR (CD3OD): d = 14.2, 23.8, 23.9, 26.9 (J = 5.1 Hz), 39.4
(J = 25.4 Hz), 60.1 (J = 3.8 Hz), 110.9 (J = 15.3 Hz), 128.5, 129.8,
132.9, 136.2, 157.7 (J = 253.0 Hz), 170.0, 177.2.
19F NMR: d = –104.9 (J = 21.0 Hz, J = 22.9 Hz, J = 36.3 Hz).
–63.7.
MS (direct inlet): m/z (%) = 461 (3) [M+], 417 (0.2) [M+ – CO2], 348
(0.1) [417 – CF3], 305 (45) [348 – C3H7], 277 (10) [348 – C5H11],
+
231 (0.5), 213 (1), 173 (100) [C10H17NO2 ], 157 (12) [173 – O], 104
ESI-MS (MeOH–CHCl3): m/z (%) = 316 (34) [M + Na+], 294 (100)
(8) [C7H4O+], 81 (7).
[M + H+].
4-[(2Z)-2-Fluorodec-2-enyl]-2-(4-methoxyphenyl)-4-phenylox-
azol-5(4H)-one (5l)
Starting from 3l (441 mg, 1.00 mmol), 5l was obtained as a light yel-
(4Z)-2-(Benzoylamino)-4-fluoro-2-methyldodec-4-enoic Acid
(6c)
Starting from 5c (166 mg, 0.50 mmol) 6c was obtained as a white
solid; yield: 174 mg (100%); white solid; mp 99 °C.
low oil; yield: 423 mg (100%).
1H NMR: d = 0.84 (t, J = 7.3 Hz, 3 H, 12-CH3), 1.04–1.29 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.95 (m, 2 H, 6-CH2), 2.97 (dd, J = 14.6 Hz,
J = 25.7 Hz, 1 H, 3-CH2), 3.20 (dd, J = 14.6 Hz, J = 14.3 Hz, 1 H,
3-CH2), 3.88 (s, 3 H, 22-CH3), 4.67 (dt, J = 7.7 Hz, J = 37.2 Hz, 1
H, 5-CH2), 6.99 (d, J = 9.1 Hz, 2 H, 20-CH), 7.28–7.42 (m, 3 H, 15-,
16-CH), 7.70 (d, J = 6.9 Hz, 2 H, 14-CH), 8.04 (d, J = 8.6 Hz, 2 H,
19-CH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 4.6 Hz), 26.9, 28.8, 29.0, 29.1,
31.7, 44.0 (J = 28.0 Hz), 55.5, 72.7 (J = 3.2 Hz), 110.8 (J = 14.6
Hz), 118.1, 125.6, 128.4, 128.7, 130.1, 137.9, 153.8 (J = 252.9 Hz),
160.6, 163.5, 177.8.
1H NMR: d = 0.84 (t, J = 6.9 Hz, 3 H, 12-CH3), 1.32 (m, 10 H, 7-,
8-, 9-, 10-, 11-CH2), 1.78 (s, 3 H, 13-CH3), 1.98 (m, 2 H, 6-CH2),
3.13 (m, 2 H, 3-CH2), 4.66 (dt, J = 7.4 Hz, J = 37.9 Hz, 1 H, 5-CH),
7.17 (s, 1 H, NH), 7.44 (m, 3 H, 17-, 18-CH), 7.76 (m, 2 H, 16-CH),
10.15 (br s, 1 H, COOH).
13C NMR: d = 14.0, 22.6, 23.0, 23.5 (J = 5.1 Hz), 29.0, 29.0, 29.2,
31.7, 38.7 (J = 25.4 Hz), 59.3, 110.5 (J = 14.0 Hz), 127.0, 128.6,
131.8, 134.3, 155.1 (J = 251.8 Hz), 167.6, 177.7.
19F NMR: d = –109.9.
ESI-MS (MeOH): m/z (%) = 372 (100) [M + Na+].
19F NMR: d = –108.9 (J = 11.9 Hz, J = 23.2 Hz, J = 37.2 Hz).
(4Z)-2-(Benzoylamino)-4-fluoro-2-methyloctadec-4-enoic Acid
(6d)
Starting from 5d (149 mg, 0.34 mmol), 6d was obtained as a white
MS (direct inlet): m/z (%) = 423 (0.22) [M+], 341 (0.29), 305 (0.45)
[M+ – HF – C7H14], 294 (0.61), 277 (1) [C19H16FN+], 267 (18)
+
+
[C16H13NO3 ], 266 (76) [C16H12NO3 ], 213 (1), 201 (1)
solid; yield: 149 mg (100%); mp 91 °C.
+
+
[C12H8NO2 ], 173 (1) [201 – CO], 135 (100) [C8H7O2 ], 107 (4)
[C7H7O+], 77 (3) [C6H5 ].
+
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Fluoropyridines from 2-Fluoroallylic Alcohols
2093
1H NMR (CD3OD): d = 0.89 (t, J = 6.7 Hz, 3 H, 18-CH3), 1.10–1.40
(m, 22 H, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-CH2), 1.65
(s, 3 H, 19-CH3), 1.99 (m, 2 H, 6-CH2), 2.94 (dd, J = 14.8 Hz,
J = 23.1 Hz, 1 H, 3-CH2), 3.14 (dd, J = 14.8 Hz, J = 21.5 Hz, 1 H,
3-CH2), 4.61 (dt, J = 7.4 Hz, J = 37.2 Hz, 1 H, 5-CH), 7.43 (m, 2 H,
23-CH), 7.49 (m, 1 H, 24-CH), 7.78 (m, 2 H, 22-CH).
128.7, 128.7, 132.2, 133.7, 137.8, 154.6 (J = 251.5 Hz), 167.5,
174.6.
19F NMR: d = –110.7 (J = 12.5 Hz, J = 30.6 Hz, J = 39.9 Hz).
ESI-MS (MeOH): m/z = (%) 450 (68) [M + K+], 434 (100) [M +
Na+], 411 (39) [M + H+].
13C NMR (CD3OD): d = 14.7, 24.0, 24.0, 24.8 (J = 5.1 Hz), 30.4,
30.7, 30.8, 30.9, 31.0, 33.3, 39.4 (J = 25.4 Hz), 60.1 (J = 3.8 Hz),
111.1 (J = 15.3 Hz), 128.5, 129.8, 132.9, 136.2, 157.6 (J = 253.0
Hz), 169.9, 177.2.
19F NMR (CD3OD): d = –106.8 (J = 21.0 Hz, J = 22.9 Hz, J = 38.2
Hz).
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenyloctadec-4-enoic Acid
(6h)
Starting from 5h (158 mg, 0.33 mmol), 6h was obtained as a white
solid; yield: 159 mg (97%); mp 136 °C.
1H NMR: d = 0.88 (t, J = 6.9 Hz, 3 H, 18-CH3), 1.08–1.38 (m, 22
H, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-CH2), 1.94 (m, 2 H,
6-CH2), 3.55 (dd, J = 14.3 Hz, J = 10.5 Hz, 1 H, 3-CH2), 3.68 (dd,
J = 14.5 Hz, J = 31.5 Hz, 1 H, 3-CH2), 4.62 (dt, J = 7.6 Hz, J = 38.6
Hz, 1 H, 5-CH), 7.31 (m, 5 H, 20-, 21-, 22-CH), 7.43 (m, 2 H, 26-
CH), 7.50 (m, 1 H, 27-CH), 7.80 (m, 2 H, 25-H), 9.64 (br s, 1 H,
COOH).
13C NMR: d = 14.0, 22.6, 23.6 (J = 3.8 Hz), 29.1, 29.2, 29.4, 29.5,
29.6, 31.9, 37.7 (J = 24.2 Hz), 64.6, 111.0 (J = 14.0 Hz), 125.7,
127.1, 128.0, 128.6, 131.9, 134.0, 138.2, 154.7 (J = 250.5 Hz),
167.1, 174.7.
19F NMR: d = –111.1.
ESI-MS (MeOH): m/z (%) = 518 (100) [M + Na+].
MS-ES-EM: m/z [M+ + H] calcd for C31H41FNO3: 494.3070; found:
494.3076.
ESI-MS (MeOH): m/z (%) = 456 (100) [M + Na+], 434 (9) [M +
H+].
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenylpent-4-enoic Acid (6e)
Starting from 5e (590 mg, 2.00 mmol), 6e was obtained by crystal-
lization (EtOAc) as a white solid; yield: 576 mg (92%); mp 199 °C
(dec).
1H NMR: d = 3.68 (dd, J = 10.4 Hz, J = 14.2 Hz, 1 H, 3-CH2), 3.91
(dd, J = 29.7 Hz, J = 14.2 Hz, 1 H, 3-CH2), 4.40 (dd, J = 49.8 Hz,
J = 2.7 Hz, 1 H, 5-CH2), 4.63 (dd, J = 17.4 Hz, J = 2.7 Hz, 1 H, 5-
CH2), 7.26–7.38 (m, 3 H, 8-, 9-CH), 7.42–7.56 (m, 5 H, 7-, 13-, 14-
CH), 7.77–7.81 (m, 2 H, 12-CH).
13C NMR: d = 36.1 (J = 24.5 Hz), 63.4 (J = 2.5 Hz), 93.8 (J = 19.3
Hz), 125.3, 126.5, 127.6, 128.2, 128.3, 131.5, 134.2, 138.8, 162.3
(J = 257.0 Hz), 166.6, 173.4.
19F NMR: d = –96.0 (J = 12.3 Hz, J = 17.1 Hz, J = 29.5 Hz,
J = 48.1 Hz).
(4Z)-2-[(4-Chlorobenzoyl)amino]-4-fluoro-2-phenyldodec-4-
enoic Acid (6i)
Starting from 5i (420 mg, 0.98 mmol), 6i was obtained as a white
ESI-MS (MeOH): m/z (%) = 336 (100) [M + Na+], 314 (64) [M +
solid; yield: 421 mg (96%); mp 155 °C.
H+].
1H NMR: d = 0.85 (t, J = 7.1 Hz, 3 H, 12-CH3), 1.04–1.29 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.93 (m, 2 H, 6-CH2), 3.53 (dd, J = 14.4 Hz,
J = 9.0 Hz, 1 H, 3-CH2), 3.72 (dd, J = 14.4 Hz, J = 33.0 Hz, 1 H, 3-
CH2), 4.62 (dt, J = 7.5 Hz, J = 37.5 Hz, 1 H, 5-CH), 7.23–7.33 (m,
3 H, 15-, 16-CH), 7.34–7.40 (d, J = 8.4 Hz, 2 H, 20-CH and 2 H, 14-
CH), 7.68 (d, J = 8.4 Hz, 2 H, 19-CH), 7.84 (s, 1 H, NH), 10.24 (br
s, 1 H, COOH).
13C NMR: d = 14.1, 22.6, 23.5 (J = 5.4 Hz), 29.0, 29.2, 31.7, 37.1
(J = 25.9 Hz), 64.2 (J = 2.3 Hz), 110.9 (J = 15.7 Hz), 125.6, 128.2,
128.5, 128.6, 128.9, 132.2, 137.9, 138.3, 154.5 (J = 251.2 Hz),
165.8, 175.1.
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenyloct-4-enoic Acid (6f)
Starting from 5f (153 mg, 0.45 mmol), 6f was obtained as a white
solid; yield: 160 mg (100%); mp 183 °C (dec).
1H NMR: d = 0.74 (t, J = 7.4 Hz, 3 H, 8-CH3), 1.20 (qt, J = 7.5 Hz,
J = 7.4 Hz, 2 H, 7-CH2), 1.91 (dt, J = 7.4 Hz, J = 7.6 Hz, 2 H, 6-
CH2), 3.63 (ddd, J = 10.4 Hz, J = 14.3 Hz, J = 0.6 Hz, 1 H, 3-CH2),
3.81 (dd, J = 31.1 Hz, J = 14.4 Hz, 1 H, 3-CH2), 4.67 (dt, J = 37.9
Hz, J = 7.6 Hz, 1 H, 5-CH2), 7.26–7.37 (m, 3 H, 11-, 12-CH), 7.43–
7.56 (m, 5 H, 10-, 16-, 17-CH), 7.77–7.81 (m, 2 H, 15-CH).
13C NMR: d = 13.1, 22.1, 27.2 (J = 6.0 Hz), 36.5 (J = 25.8 Hz), 63.7
(J = 2.8 Hz), 109.9 (J = 16.2 Hz), 125.5, 126.7, 127.6, 128.2, 128.4,
131.5, 134.3, 139.1, 155.1 (J = 252.3 Hz), 166.4, 173.8.
19F NMR: d = –111.5 (J = 10.2 Hz, J = 30.8 Hz, J = 39.1 Hz).
19F NMR: d = –112.0.
ESI-MS (MeOH): m/z (%) = 470/468 (33/100) [M + Na+], 448/446
(2/6) [M + H+].
ESI-MS (MeOH): m/z (%) = 378 (24) [M + Na+], 356 (100) [M +
(4Z)-4-Fluoro-2-[(4-nitrobenzoyl)amino]-2-phenyldodec-4-
enoic Acid (6j)
H+].
Starting from 5j (400 mg, 0.91 mmol), 6j was obtained as a white
solid; yield: 380 mg (91%); mp 150 °C.
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenyldodec-4-enoic Acid
(6g)
Starting from 5g (786 mg, 2.00 mmol), 6g was obtained as a white
solid; yield: 740 mg (90%); mp 149 °C.
1H NMR: d = 0.85 (t, J = 7.0 Hz, 3 H, 12-CH3), 1.12 (m, 8 H, 8-, 9-,
10-, 11-CH2), 1.21 (m, 2 H, 7-CH2), 1.95 (m, 2 H, 6-CH2), 3.50 (dd,
J = 11.8 Hz, J = 14.5 Hz, 1 H, 3-CH2), 3.61 (dd, J = 30.6 Hz,
J = 14.7 Hz, 1 H, 3-CH2), 4.60 (dt, J = 38.7 Hz, J = 7.6 Hz, 1 H, 5-
CH2), 7.25–7.35 (m, 3 H, 15-, 16-CH), 7.37–7.47 (m, 4 H, 14-, 21-
CH), 7.51–7.57 (m, 1 H, 22-CH), 7.75–7.82 (m, 2 H, 20-CH), 8.25
(br s, 1 H, NH).
1H NMR: d = 0.86 (t, J = 7.0 Hz, 3 H, 12-CH3), 1.08–1.27 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.95 (m, 2 H, 6-CH2), 3.58 (dd, J = 14.4 Hz,
J = 9.4 Hz, 1 H, 3-CH2), 3.78 (dd, J = 14.4 Hz, J = 31.7 Hz, 1 H, 3-
CH2), 4.66 (dt, J = 7.6 Hz, J = 38.2 Hz, 1 H, 5-CH), 7.28–7.46 (m,
5 H, 14-, 15-, 16-CH), 7.87 (s, 1 H, NH), 7.91 (dm, J = 9.0 Hz, 2 H,
20-CH), 8.26 (dm, J = 8.9 Hz, 2 H, 19-CH), 9.13 (br s, 1 H, COOH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 5.8 Hz), 29.0, 29.2, 31.7, 36.9
(J = 23.4 Hz), 64.4 (J = 3.8 Hz), 111.1 (J = 14.6 Hz), 123.9, 125.6,
128.2, 128.4, 128.8, 137.6, 139.6, 149.9, 154.5 (J = 254.4 Hz),
164.6, 175.1.
13C NMR: d = 14.0, 22.6, 23.6 (J = 3.4 Hz), 29.0, 29.0, 29.1, 31.7,
38.5 (J = 24.7 Hz), 65.1, 111.3 (J = 15.2 Hz), 125.7, 127.1, 128.2,
19F NMR: d = –111.9 (J = 9.7 Hz, J = 32.5 Hz, J = 38.7 Hz).
ESI-MS (MeOH): m/z (%) = 479 (100) [M + Na+].
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

2094
U. Wittmann et al.
PAPER
(4Z)-4-Fluoro-2-phenyl-2-{[4-(trifluoromethyl)benzoyl]amino}-
dodec-4-enoic Acid (6k)
Starting from 5k (461 mg, 1.00 mmol), 6k was obtained as a white
solid; yield: 451 mg (94%); mp 141 °C.
1H NMR: d = 0.87 (t, J = 7.3 Hz, 3 H, 8-CH3), 1.56 (m, 2 H, 7-CH2),
2.67 (m, 2 H, 6-CH2), 7.38–7.49 (m, 7 H, 4-, 11-, 12-, 15-, 16-CH),
7.52–7.62 (m, 2 H, 10-CH), 8.02 (m, 2 H, 14-CH).
13C NMR: d = 14.0, 23.3, 27.6 (J = 2.5 Hz), 106.2 (J = 20.3 Hz),
122.3 (J = 12.7 Hz), 126.9, 128.1, 128.2, 128.7, 129.0, 129.2, 138.4
(J = 2.5 Hz), 140.1 (J = 3.8 Hz), 156.6 (J = 8.9 Hz), 161.4 (J = 6.4
Hz), 168.7 (J = 258.1 Hz).
1H NMR: d = 0.84 (t, J = 7.0 Hz, 3 H, 12-CH3), 1.06–1.28 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.94 (m, 2 H, 6-CH2), 3.56 (dd, J = 14.5 Hz,
J = 8.5 Hz, 1 H, 3-CH2), 3.77 (dd, J = 14.5 Hz, J = 33.0 Hz, 1 H, 3-
CH2), 4.65 (dt, J = 7.6 Hz, J = 38.3 Hz, 1 H, 5-CH), 7.24–7.45 (m,
5 H, 14-, 15-, 16-CH), 7.68 (d, J = 8.1 Hz, 2 H, 19-CH), 7.86 (d,
J = 8.1 Hz, 2 H, 20-CH), 7.91 (s, 1 H, NH), 10.15 (br s, 1 H,
COOH).
13C NMR: d = 14.0, 22.6, 23.6 (J = 4.8 Hz), 29.0, 29.2, 31.7, 36.9
(J = 24.1 Hz), 64.2 (J = 3.4 Hz), 111.0 (J = 14.7 Hz,), 123.6
(J = 272.3 Hz), 125.6, 125.7, 127.5, 128.3, 128.7, 129.0, 133.7
(J = 33.0 Hz), 137.2, 137.9, 154.5 (J = 250.9 Hz), 165.4, 175.3.
19F NMR: d = –107.6 (J = 9.5 Hz).
MS: m/z (%) = 292 (11) [M+ + H], 291 (77) [M+], 290 (92) [M+ –
H], 277 (18) [292 – CH3], 276 (100) [M+ – CH3], 263 (16) [292 –
C2H5], 262 (90) [M+ – C2H5], 261 (35) [290 – C2H5] 248 (4) [M+ –
C3H7], 228 (1) [M+ – HF], 215 (5) [292 – C6H5] 184 (9), 157 (8),
+
133 (10), 77 (5) [C6H5 ].
MS-ES-EM: m/z [M+] calcd for C20H18FN: 291.1423; found:
291.1383.
19F NMR d = –112.1 (J = 6.8 Hz, J = 31.4 Hz, J = 37.9 Hz), –63.5.
ESI-MS (MeOH): m/z (%) = 502 (100) [M + Na+], 480 (2) [M + H+].
4-Fluoro-3-heptyl-2,6-diphenylpyridine (11g)
Starting from 5g (778 mg, 1.98 mmol), 11g was obtained as a
colorless liquid; yield: 220 mg (32%).
1H NMR: d = 0.85 (t, J = 7.2 Hz, 3 H, 12-CH3), 1.20 (m, 8 H, 8-, 9-,
10-, 11-CH2), 1.46–1.57 (m, 2 H, 7-CH2), 2.67 (dt, J = 7.6 Hz,
J = 1.2 Hz, 2 H, 6-CH2), 7.35–7.46 (m, 7 H, 4-, 15-, 16-, 19-, 20-
CH), 7.54 (m, 2 H, 14-CH), 8.02 (m, 2 H, 18-CH).
13C NMR: d = 14.0, 22.5, 25.5 (J = 2.5 Hz), 28.7, 29.4, 29.9, 31.6,
106.1 (J = 20.3 Hz), 122.5 (J = 12.8 Hz), 126.8, 128.1, 128.1,
128.6, 129.0, 129.1, 138.4 (J = 3.8 Hz), 140.2 (J = 2.6 Hz), 156.5
(J = 7.6 Hz), 161.3 (J = 6.3 Hz), 168.6 (J = 258.1 Hz).
(4Z)-4-Fluoro-2-[(4-methoxybenzoyl)amino]-2-phenyldodec-4-
enoic Acid (6l)
Starting from 5l (423 mg, 1.00 mmol), 6l was obtained as a white
solid; yield: 438 mg (99%); mp 148 °C.
1H NMR: d = 0.85 (t, J = 7.2 Hz, 3 H, 12-CH3), 1.05–1.27 (m, 10 H,
7-, 8-, 9-, 10-, 11-CH2), 1.94 (m, 2 H, 6-CH2), 3.43–3.58 (m, 2 H,
3-CH2), 3.85 (s, 3 H, 22-CH3), 4.56 (dt, J = 7.6 Hz, J = 39.0 Hz, 1
H, 5-CH), 6.93 (d, J = 8.8 Hz, 2 H, 20-CH), 7.24–7.40 (m, 5 H, 14-,
15-, 16-CH), 7.67 (d, J = 2.1 Hz, 1 H, NH), 7.77 (d, J = 8.8 Hz, 2 H,
19-CH), 9.33 (br s, 1 H, COOH).
13C NMR: d = 14.0, 22.6, 23.5 (J = 3.2 Hz), 29.0, 29.0, 29.1, 31.7,
39.0 (J = 14.5 Hz), 55.4, 64.4, 111.4 (J = 13.1 Hz), 113.9, 125.6,
128.1, 128.5, 129.1, 137.8, 154.5 (J = 249.0 Hz), 162.8, 167.4,
174.2.
19F NMR: d = –107.9 (J = 11.5 Hz).
MS: m/z (%) = 348 (11) [M+ + H], 347 (36) [M+], 346 (22) [M+ –
H], 332 (3) [M+ – CH3], 318 (5) [M+ – C2H5], 304 (2) [M+ – C3H7],
290 (12) [M+ – C4H9], 277 (18) [348 – C5H11], 276 (100) [M+ –
C5H11], 263 (29) [348 – C6H13], 262 (91) [M+ – C6H13], 248 (1)
[M+ – C7H15], 228 (4) [248 – HF], 213 (4), 184 (4), 157 (2), 133 (4),
19F NMR: d = –110.4.
ESI-MS (MeOH): m/z (%) = 464 (100) [M + Na+], 442 (4) [M + H+].
+
+
+
118 (1), 77 (4) [C6H5 ], 43 (3) [C3H7 ], 41 (4) [C3H5 ].
MS-ES-EM: m/z [M+] calcd for C24H26FN: 347.2049; found:
347.2029.
4-Fluoropyridines 11e–l; General Procedure
In an open Schlenk-flask the oxazolone 5e–l (1 mmol) was heated
in decahydronaphthalene (5 mL) to 160 °C for 20 h. After cooling
to r.t. the mixture was filtered over silica gel (cyclohexane–EtOAc,
4:1). Then, the solvent and decahydronaphthalene were removed at
30–40 °C under vacuum. The crude product was purified by column
chromatography (silica gel, cyclohexane– EtOAc, 20:1).
4-Fluoro-2,6-diphenyl-3-tridecylpyridine (11h)
Starting from 5h (463 mg, 0.97 mmol), 11h was obtained as a col-
orless liquid; yield: 102 mg (24%).
1H NMR: d = 0.88 (t, J = 7.2 Hz, 3 H, 18-CH3), 1.26 (m, 20 H, 8-,
9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-CH2), 1.49–1.79 (m, 2 H, 7-
CH2), 2.67 (t, J = 7.9 Hz, 2 H, 6-CH2), 7.38–7.47 (m, 7 H, 4-, 21-,
22-, 25-, 26-CH), 7.81 (m, 2 H, 20-CH), 8.02 (m, 2 H, 24-CH).
4-Fluoro-2,6-diphenylpyridine (11e)
Starting from 5e (295 mg, 1.00 mmol), 11e was obtained as a white
13C NMR: d = 14.1, 22.7, 25.6 (J = 2.4 Hz), 29.1, 29.3, 29.4, 29.6,
29.6, 29.9, 31.9, 33.7, 106.3 (J = 20.5 Hz), 122.6 (J = 13.3 Hz),
126.9, 128.1, 128.2, 128.2, 128.7, 129.0, 129.2, 129.5, 132.6, 138.4
(J = 3.2 Hz), 140.1, 156.5 (J = 8.8 Hz), 161.3 (J = 6.0 Hz), 168.7
(J = 258.2 Hz).
solid; yield: 97 mg (39%); mp 98-100 °C.
1H NMR: d = 7.39 (t, J = 10.0 Hz, 2 H, 2-CH), 7.43–7.52 (m, 6 H,
6-, 7-CH), 8.12 (m, 4 H, 5-CH).
13C NMR: d = 106.1 (J = 17.8 Hz), 127.0, 128.7, 129.6, 138.4,
159.8, 161.3 (J = 6.0 Hz), 168.7 (J = 258.2 Hz).
19F NMR: d = –107.6 (d, J = 10.5 Hz).
19F NMR: d = –107.6 (J = 11.0 Hz).
MS: m/z (%) = 432 (11) [M+ + H], 431 (37) [M+], 430 (29) [M+ –
H], 416 (4) [M+ – CH3], 402 (6) [M+ – C2H5], 388 (8) [M+ – C3H7],
374 (7) [M+ – C4H9], 360 (5) [M+ – C5H11], 346 (6) [M+ – C6H13],
332 (12) [M+ – C7H15], 318 (8) [M+ – C8H17], 304 (2) [M+ – C9H19],
290 (11) [M+ – C10H21], 277 (24) [432 – C11H23], 276 (98) [M+ –
C11H23], 263 (57) [432 – C12H25], 262 (100) [M+ – C12H25], 248 (2)
[M+ – C13H27], 228 (2) [248 – HF], 184 (4) [C13H28+], 158 (1), 131
MS: m/z (%) = 250 (16) [M + H+], 249 (100) [M+], 248 (68) [M –
H+], 228 (2), 227 (2), 220 (3), 201 (2), 172 (4) [M – C6H5 ], 145 (6),
+
+
+
+
125 (12), 102 (6), 77 (8) [C6H5 ], 51 (4) [C4H3 ], 39 (1) [C3H3 ].
MS-ES-EM: m/z [M+] calcd for C17H12FN: 249.0954; found:
249.0944.
+
4-Fluoro-2,6-diphenyl-3-propylpyridine (11f)
Starting from 5f (324 mg, 0.96 mmol), 11f was obtained as a white
solid; yield: 84 mg (30%); mp 59–60 °C.
(2), 118 (1), 77 (1) [C6H5 ].
MS-ES-EM: m/z [M+ + H] calcd for C30H39FN: 432.3061; found:
432.3049.
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Fluoropyridines from 2-Fluoroallylic Alcohols
2095
2-(4-Chlorophenyl)-4-fluoro-3-heptyl-6-phenylpyridine (11i)
Starting from 5i (635 mg, 1.48 mmol), 11i was obtained as a light
yellow liquid; yield: 259 mg (46%).
1H NMR: d = 0.86 (t, J = 6.9 Hz, 3 H, 16-CH3), 1.19–1.31 (m, 8 H,
12-, 13-, 14-, 15-CH2), 1.52 (m, 2 H, 11-CH2), 2.67 (m, 2 H, 10-
CH2), 7.37–7.52 (m, 8 H, 4-, 7-, 8-, 19-, 20-CH), 7.45–7.50 (m, 2 H,
18-CH).
[M+ – C3H7], 358 (4) [M+ – C4H9], 344 (28) [M+ – C5H11], 331 (14)
[416 – C6H13], 330 (100) [M+ – C6H13], 310 (5) [330 – HF], 283 (1),
261 (9) [310 – CF3], 240 (1), 228 (2), 195 (1), 133 (3), 130 (1), 115
(1), 102 (1), 77 (2), 55 (2), 43 (5).
MS-ES-EM: m/z [M+ + H] calcd for C25H26F4N: 416.1996; found:
416.1997.
4-Fluoro-3-heptyl-2-(4-methoxyphenyl)-6-phenylpyridine (11l)
Starting from 5l (393 mg, 0.93 mmol), 11l was obtained as a white
solid; yield: 153 mg (40%); mp 49 °C.
1H NMR: d = 0.86 (t, J = 6.7 Hz, 3 H, 17-CH3), 1.22 (m, 8 H, 13-,
14-, 15-, 16-CH2), 1.55 (m, 2 H, 13-CH2), 2.70 (dt, J = 8.0 Hz,
J = 0.9 Hz, 2 H, 11-CH2), 3.84 (s, 3 H, 10-CH3), 6.98 (d, J = 8.8 Hz,
2 H, 8-CH), 7.36 (d, J = 11.2 Hz, 1 H, 4-CH), 7.36–7.45 (m, 3 H,
20-, 21-CH), 7.51 (d, J = 8.8 Hz, 2 H, 7-CH), 8.01 (dd, J = 8.5 Hz,
J = 1.7 Hz, 2 H, 19-CH).
13C NMR: d = 14.0, 22.6, 25.6 (J = 3.0 Hz), 28.8, 29.4, 29.9, 31.6,
55.2, 105.8 (J = 20.2 Hz), 113.5, 122.3 (J = 12.4 Hz), 126.7, 128.6,
129.0, 130.3, 132.8 (J = 4.0 Hz), 138.5 (J = 3.0 Hz), 156.4 (J = 8.7
Hz), 159.6, 160.9 (J = 4.7 Hz), 168.7 (J = 257.8 Hz).
13C NMR: d = 14.0, 22.6, 25.6 (J = 3.1 Hz), 28.8, 29.4, 30.0, 31.7,
106.4 (J = 20.5 Hz), 122.6 (J = 15.0 Hz), 126.8, 128.4, 128.7,
129.3, 130.3, 134.3, 138.3 (J = 3.0 Hz), 138.6 (J = 3.2 Hz), 156.8
(J = 9.4 Hz), 160.0 (J = 4.4 Hz), 168.7 (J = 258.1 Hz).
19F NMR: d = –107.5 (J = 10.9 Hz).
MS: m/z (%) = 384/382 (5/15) [M+ + H], 383/381 (13/49) [M+],
382/380 (15/29) [M+ – H], 368/366 (1/3) [M+ – CH3], 354/352 (2/6)
[M+ – C2H5], 340/338 (1/2) [M+ – C3H7], 326/324 (4/12) [M+ –
C4H9], 313/311 (9/22) [384/382 – C5H11], 312/310 (32/100) [M+ –
C5H11], 299/297 (11/33) [384/382 – C6H13], 298/296 (31/86) [M+ –
C6H13], 284 (3), 274 (6), 261 (70) [298/296 – Cl], 240 (3), 183 (4),
157 (3 129 (4), 43 (5), 41 (3).
MS-ES-EM: m/z [M+ + H] calcd for C24H26ClFN: 382.1738; found:
382.1732.
19F NMR: d = –108.0 (J = 10.8 Hz).
MS: m/z (%) = 378 (12) [M+ + H], 377 (38) [M+], 376 (27) [M+ –
H], 362 (6) [M+ – CH3], 348 (7) [M+ – C2H5], 334 (3) [M+ – C3H7],
321 (3) [378 – C4H9], 320 (12) [M+ – C4H9], 307 (17) [378 – C5H11],
306 (100) [M+ – C5H11], 293 (17) [378 – C6H13], 292 (56) [M+ –
C6H13], 278 (4) (7) [M+ – C7H15], 277 (18) [292 – CH3], 263 (9)
[278 – CH3], 262 (9) [292 – OCH2], 261 (6) [292 – OCH3], 249 (16),
248 (29) [278 – OCH2], 228 (3), 222 (1), 184 (2), 170 (3), 139 (3),
4-Fluoro-3-heptyl-2-(4-nitrophenyl)-6-phenylpyridine (11j)
Starting from 5j (418 mg, 0.95 mmol), 11j was obtained as a light
yellow solid; yield: 205 mg (55%); mp 80 °C.
1H NMR: d = 0.85 (t, J = 6.8 Hz, 3 H, 16-CH3), 1.19–1.31 (m, 8 H,
12-, 13-, 14-, 15-CH2), 1.53 (m, 2 H, 11-CH2), 2.67 (m, 2 H, 10-
CH2), 7.35–7.48 (m, 4 H, 4-, 19-, 20-CH), 7.73 (dm, J = 8.4 Hz, 2
H, 7-CH), 7.99 (dd, J = 8.2 Hz, J = 1.6 Hz, 2 H, 18-CH), 8.32 (dm,
J = 8.6 Hz, 2 H, 8-CH).
+
+
125 (2), 55 (5) [C4H7 ], 43 (7) [C3H7 ].
MS-ES-EM: m/z [M+ + H] calcd for C25H29FNO: 378.2228; found:
378.2221.
13C NMR: d = 14.0, 22.5, 25.6 (J = 2.9 Hz), 28.8, 29.4, 30.0, 31.6,
107.1 (J = 20.7 Hz), 122.9 (J = 13.7 Hz), 123.4, 126.8, 128.8,
129.6, 130.1, 137.9 (J = 3.3 Hz), 146.4 (J = 3.6 Hz), 147.7, 157.2
(J = 8.9 Hz), 158.7 (J = 6.5 Hz), 168.7 (J = 259.2 Hz).
X-ray Structures
Data sets were collected with Enraf-Nonius CAD4 and Nonius Kap-
paCCD diffractometers. Programs used: data collection EXPRESS
(Nonius B.V., 1994) and COLLECT (Nonius B.V., 1998), data re-
duction MolEN (Fair, K., Enraf-Nonius B.V., 1990) and Denzo-
SMN,18 absorption correction for CCD data SORTAV,19 structure
solution SHELXS-97,20 structure refinement SHELXL-97,21 and
graphics SCHAKAL.22
19F NMR: d = –106.6 (J = 11.5 Hz).
MS: m/z (%) = 393 (14) [M+ + H], 392 (38) [M+], 391 (11) [M+ –
H], 375 (8), 363 (5) [M+ – C2H5], 362 (7) [M+ – C2H4], 349 (2)
[M+ – C3H7] 346 (2) [M+ – NO2], 335 (7) [M+ – C4H9], 322 (11)
[393 – C5H11], 321 (49) [M+ – C5H11], 308 (15) [393 – C6H13], 307
(17) [M+ – C6H13], 291 (20) [307 – O], 277 (11) [M+ – C7H15O], 275
(14) [321 – NO2], 262 (19) [308 – NO2], 261 (100) [307 – NO2], 260
(34) [C18H11FN+], 241 (3) [261 – HF], 240 (4) [260 – HF], 209 (2),
208 (3), 183 (4), 129 (4), 43 (12).
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenylpent-4-enoic Acid (6e)
Formula C18H16FNO3, M = 313.32, colorless crystal 0.40 × 0.30 ×
0.20 mm, a = 9.162(1), b = 11.562(1), c = 14.992(1) Å,
b = 92.58(1)°, V = 1586.5(2) Å3, rcalcd = 1.312 g·cm–3, m = 0.810
mm–1, empirical absorption correction (0.738 £ T £ 0.855), Z = 4,
monoclinic, space group P21/c (no. 14), l = 1.54178 Å, T = 223 K,
w and j scans, 9618 reflections collected ( h, k, l), [(sin q)/
l] = 0.59Å–1, 2645 independent (Rint = 0.034) and 1833 observed
reflections [I ≥ 2 s(I)], 212 refined parameters, R = 0.041,
wR2 = 0.101, max. residual electron density 0.15 (–0.12) e·Å–3, hy-
drogen atom at N1 from difference Fourier maps, other calculated
and refined as riding atoms.
MS-ES-EM: m/z [M+ + Na] calcd for C24H25FN2NaO2: 415.1798,
found: 415.1792.
4-Fluoro-3-heptyl-6-phenyl-2-[4-(trifluoromethyl)phenyl]pyri-
dine (11k)
Starting from 5k (460 mg, 1.00 mmol), 11k was obtained as a col-
orless liquid; yield: 87 mg (21%).
1H NMR: d = 0.85 (t, J = 6.7 Hz, 3 H, 17-CH3), 1.22 (m, 8 H, 13-,
14-, 15-, 16-CH2), 1.51 (m, 2 H, 13-CH2), 2.70 (m, 2 H, 11-CH2),
7.30–7.49 (m, 4 H, 4-, 20-, 21-CH), 7.60–7.78 (m, 4 H, 7-, 19-CH),
7.94–8.02 (m, 2 H, 8-CH).
13C NMR: d = 14.0, 22.6, 25.5 (J = 3.3 Hz), 28.8, 29.4, 30.0, 31.6,
106.7 (J = 19.8 Hz), 122.8 (J = 12.3 Hz), 124.2 (J = 259.2 Hz),
125.1 (J = 3.7 Hz), 126.8, 126.8, 127.3, 128.8, 129.3, 129.4. 129.4,
130.3 (J = 31.7 Hz), 138.1 (J = 3.3 Hz), 143.6 (J = 3.4 Hz), 156.9
(J = 7.9 Hz), 159.7 (J = 5.3 Hz), 168.7 (J = 258.1 Hz).
(4Z)-2-(Benzoylamino)-4-fluoro-2-phenyloct-4-enoic Acid (6f)
Formula C21H22FNO3, M = 355.40, colorless crystal 0.50 × 0.50 ×
0.10 mm, a = 10.721(1), b = 12.055(1), c = 15.113(1) Å,
b = 105.88(1)°, V = 1878.7(3) Å3, rcalc = 1.257 g·cm–3, m = 0.742
mm–1, empirical absorption correction (0.708 £ T £ 0.930), Z = 4,
monoclinic, space group P21/c (no. 14), l = 1.54178 Å, T = 223 K,
q/2q scans, 4024 reflections collected (–h,+k, l), [(sin q)/
l] = 0.62Å–1, 3817 independent (Rint = 0.019) and 3426 observed
reflections [I ≥ 2 s(I)], 241 refined parameters, R = 0.044,
wR2 = 0.129, max. residual electron density 0.27 (–0.23) e·Å–3, hy-
19F NMR: d = –107.2 (J = 11.3 Hz), –63.1.
MS: m/z (%) = 416 (5) [M+ + H], 415 (16) [M+], 414 (11) [M+ – H],
400 (2) [M+ – CH3], 396 (3) [M+ – F], 386 (1) [M+ – C2H5], 372 (1)
Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York

2096
U. Wittmann et al.
PAPER
W.; Henschler, D.; Rummel, W.; Starke, K., Eds.; BI
drogen atom at N1 from difference Fourier maps, other calculated
and refined as riding atoms.
Wissenschaftsverlag: Mannheim-Leipzig-Wien-Zürich,
1992.
(4Z)-2-[(4-Chlorobenzoyl)amino]-4-fluoro-2-phenyldodec-4-
enoic Acid (6i)
(6) Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107.
(7) (a) See reference 1g, pages 155-172 (b) Essers, M.; Mück-
Lichtenfeld, C.; Haufe, G. J. Org. Chem. 2002, 67, 4715.
(c) Ernet, T.; Maulitz, A. H.; Würthwein, E.-U.; Haufe, G. J.
Chem. Soc., Perkin Trans. 1 2001, 1929. (d) Meyer, O. G.
J.; Fröhlich, R.; Haufe, G. Synthesis 2000, 1479. (e) Haufe,
G.; Meyer, O. G. J.; Mück-Lichtenfeld, C. Collect. Czech.
Chem. Commun. 2002, 67, 1493. (f) Marhold, M.; Buer, A.;
Hiemstra, H.; van Maarseveen, J. H.; Haufe, G. Tetrahedron
Lett. 2004, 45, 57. (g) Shendage, D. M.; Fröhlich, R.;
Bergander, K.; Haufe, G. Eur. J. Org. Chem. 2005, 719.
(8) Tranel, F.; Fröhlich, R.; Haufe, G. J. Fluorine Chem. 2005,
126, 557.
Formula C25H29ClFNO3, M = 445.94, colorless crystal 0.30 × 0.30
× 0.30 mm, a = 13.309(1), b = 12.177(1), c = 14.951(1) Å,
b = 99.05(1)°, V = 2392.9(3) Å3, rcalc = 1.238 g·cm–3, m = 1.687
mm–1, empirical absorption correction (0.632 £ T £ 0.632), Z = 4,
monoclinic, space group P21/c (no. 14), l = 1.54178 Å, T = 223 K,
w and j scans, 22099 reflections collected ( h, k, l), [(sin q)/
l] = 0.60Å–1, 4251 independent (Rint = 0.034) and 4101 observed
reflections [I ≥ 2 s(I)], 289 refined parameters, R = 0.046,
wR2 = 0.130, max. residual electron density 0.61 (–0.33) e·Å–3, hy-
drogen atoms at O2 and N1 from difference Fourier maps, other cal-
culated and refined as riding atoms.
(9) (a) Aksenov, V. V.; Vlasov, V. M.; Moryakina, I. M.;
Rodionov, P. P.; Fadeeva, V. P.; Chertok, V. S.; Yakobson,
G. G. J. Fluorine Chem. 1985, 28, 73. (b) Bobbio, C.;
Rausis, T.; Schlosser, M. Chem. Eur. J. 2005, 11, 1903.
(10) (a) Lyle, J. L.; Taft, R. W. J. Heterocycl. Chem. 1972, 9,
745. (b) Marsais, F.; Trecourt, F.; Breant, P.; Queguiner, G.
J. Heterocycl. Chem. 1988, 25, 81.
(11) Laue, K. W.; Haufe, G. Synthesis 1998, 1453.
(12) (a) Alvernhe, G.; Laurent, A.; Haufe, G. Synthesis 1987,
561. (b) Haufe, G.; Alvernhe, G.; Laurent, E.; Ernet, T.; Goj,
O.; Kröger, S.; Sattler, A. Org. Synth. Coll. Vol. X; John
Wiley & Sons: London, 2004, 128. (c) Ernet, T.; Haufe, G.
Synthesis 1997, 953. (d) Tranel, F.; Haufe, G. J. Fluorine
Chem. 2004, 125, 1593.
Crystallographic data (excluding structure factors) for the reported
structures have been deposited with the Cambridge Crystallograph-
ic Data Centre as supplementary publication no. CCDC 601296-
601298. Copies of the data can be obtained free of charge on appli-
cation to The Director CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [Fax: +44(1223)336-033, E-mail: deposit@ccdc.cam.ac.uk]
or at www.ccdc.cam.ac.uk/conts/retrieving.html.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft (Gra-
duiertenkolleg 71, and Sonderforschungsbereich 424) is gratefully
acknowledged.
(13) (a) Engel, N.; Kübel, B.; Steglich, W. Angew. Chem., Int. Ed.
Engl. 1977, 16, 394; Angew. Chem. 1977, 89, 408.
(b) Kübel, B.; Höfle, G.; Steglich, W. Angew. Chem., Int. Ed.
Engl. 1975, 14, 58; Angew. Chem. 1975, 87, 64.
(14) Fischer, J.; Kilpert, C.; Klein, U.; Steglich, W. Tetrahedron
1986, 42, 2063.
(15) (a) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33,
998; Angew. Chem. 1994, 106, 1046. (b) Kazmaier, U.;
Krebs, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 2012;
Angew. Chem. 1995, 107, 2213. (c) Kazmaier, U. Liebigs
Ann./Recl. 1997, 285. (d) Kazmaier, U.; Maier, S.
Tetrahedron 1996, 52, 941.
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Synthesis 2006, No. 13, 2085–2096 © Thieme Stuttgart · New York