α-Fluoroacrylonitriles: Horner-Wittig synthesis and conversion into 2-fluoroallylamines and C-(1-fluorovinyl)nitrones

Article abstract of DOI:10.1016/j.jfluchem.2003.11.001

α-Fluoroacrylonitriles 2 were synthesized in moderate to good yields by Horner-Wittig (HW) reaction of aldehydes and ketones with (diphenylphosphinoyl)fluoroacetonitrile (1), prepared in situ from commercially available fluoroacetonitrile and diphenylphosphinyl chloride. New synthetic applications of 2 are presented with the one-pot conversion into 2-fluoroallylamines 6 and C-(1-fluorovinyl)nitrones 8 through a diisobutylaluminum hydride (DIBALH)-reduction transimination protocol. The scope and limitations of this procedure are discussed.

Full text of DOI:10.1016/j.jfluchem.2003.11.001

Journal of Fluorine Chemistry 125 (2004) 107–117
a-Fluoroacrylonitriles: Horner–Wittig synthesis and conversion
into 2-fluoroallylamines and C-(1-fluorovinyl)nitrones
Jan Hein van Steenis, Adrianus M.C.H. van den Nieuwendijk, Arne van der Gen*
Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, NL-2300 RA Leiden, The Netherlands
Received 6 August 2003; received in revised form 31 October 2003; accepted 3 November 2003
Abstract
a-Fluoroacrylonitriles 2 were synthesized in moderate to good yields by Horner–Wittig (HW) reaction of aldehydes and ketones with
(diphenylphosphinoyl)fluoroacetonitrile (1), prepared in situ from commercially available fluoroacetonitrile and diphenylphosphinyl
chloride. New synthetic applications of 2 are presented with the one-pot conversion into 2-fluoroallylamines 6 and C-(1-fluorovinyl)nitrones
8 through a diisobutylaluminum hydride (DIBALH)-reduction transimination protocol. The scope and limitations of this procedure are
discussed.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Horner–Wittig; Phosphine oxide; Fluorine; Nitrile; Transimination; Amine; Nitrone
1. Introduction
addition of the reagents [8]. Pure diethyl cyanofluoromethyl-
phosphonate was obtained by electrophilic fluorination of
diethyl cyanomethylphosphonate with commercially una-
vailable N-fluoro[bis(trifluoromethyl)]sulfonimide [12]. As
it was found to be extremely sensitive to hydrolysis, it was
best used immediately in the HWE reaction with aldehydes
or ketones to prepare a-fluoroacrylonitriles in moderate
yields, and with low (E)/(Z) selectivities [12].
The corresponding phosphine oxide was patented [13],
but its application in the Horner–Wittig (HW) reaction has
not been reported. In line with our research towards new
a-fluorinated phosphine oxides [14,15], we were interested
in its synthesis and properties.
The concept of using fluorinated analogues of natural
compounds has received much attention [1–3]. A class of
compounds which can act as fluorinated building blocks are
the a-fluoroacrylonitriles. On the one hand, the electron-
poor double bond provides the possibility of applying both
the Michael addition [4], and the Diels–Alder reaction [5].
On the other hand, the nitrile function can be converted into
an ester through the Pinner reaction [6], or into an aldehyde
by reduction with diisobutylaluminum hydride (DIBALH)
and hydrolysis [7,8]. The resulting aldehydes were con-
verted into mono-fluorinated dienes by Wittig reactions.
However, applications have been hampered by the limited
availability of a-fluoroacrylonitriles.
Various synthetic schemes have been designed for specific
a-fluoroacrylonitriles [4,9–11]. The most general route is
based on the Horner–Wadsworth–Emmons (HWE) reaction
of a cyanofluoromethyl-substituted phosphonate with car-
bonyl compounds [7,8,12]. Reaction of fluoroacetonitrile
with diethyl chlorophosphate in the presence of 2 eq. of
base, followed by addition of aromatic aldehydes, yielded a-
fluorocinnamonitrile derivatives with little stereoselectivity
[8]. The likely intermediary phosphonate could not be
identified [8]. The reaction failed for enolizable aldehydes,
possibly caused by an unfortunate choice for the order of
2. Results and discussion
2.1. Synthesis of a-fluoroacrylonitriles
From a solution of fluoroacetonitrile and diphenylphos-
phinoyl chloride in THF, the anion of phosphine oxide 1
could be obtained as a clear, yellow or light-brown solution,
by addition of 2 eq. of LDA or LiHMDS at ꢀ78 8C.1
Reproducibility was better with LiHMDS. Reactions
using LDA as the base were carried out on a 2 mmol scale,
unless indicated otherwise; reactions using LiHMDS were
* Corresponding author. Fax: þ31-71-5274537.
1 Formation of a dark solution resulted in lower yields, as well as in
changes of stereoselectivity.
E-mail address: a.gen@chem.leidenuniv.nl (A. van der Gen).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.11.001

108
J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
FCH2CN + Ph2P(O)Cl
Yields of the HW reaction are comparable to those of the
HWE reaction. The higher basicity of the phosphine oxide
anion may explain the slightly lower yields found in some
cases. Phenylacetaldehyde gave a very low yield of 2r. In the
major product, 2-fluoro-4-phenylbut-3-enenitrile (4), the
double bond had shifted into conjugation with the phenyl
group. A similar rearrangement has been noted for the
reaction of the non-fluorinated analogue with 2-phenylpro-
panal [16]. Best yields were found for 2d (73%) and 2l
(76%). In these cases, precipitation of phosphinate 3 showed
the reaction to occur at relatively low temperatures, which
obviously is advantageous. Possibly, anion 1ꢀ is unstable at
temperatures over 0 8C.
The applicability of commercially available fluoroaceto-
nitrile as a starting compound is considerably expanded by
the HW approach described here, since in the HWE reaction
it could only be successfully applied in the case of aromatic
aldehydes [8]. Furthermore, diphenylphosphinoyl chloride
is considerably less toxic than the acetylcholinesterase
inhibitor diethyl chlorophosphate [17].
Stereoselectivity of the HW reactions is low, although
sometimes clearly different from that of the HWE reaction.
Benzaldehyde derivatives 2a–c, and aliphatic aldehyde
derivatives 2f–h were formed with some preference for
the (Z)-isomers, while with phosphonates, the outcome
varied. Surprisingly, (E) selectivity was found for benzy-
loxyacetaldehyde derivative 2i. With the remaining sub-
strates, little or no stereoselectivity was found. The
generally low and unpredictable stereoselectivities found
base (2 equiv.)
THF, –78 ºC
O
R1R2CO
R1
R2
CN
F
+ Ph2PO2- Li+
Ph2P
CN
–78 ºC to r.t.
F
1–
3
2
Scheme 1.
performed on a 6 mmol scale. After addition of the carbonyl
compound R1R2C¼O, the temperature was allowed to rise to
room temperature. Gradually a suspension developed, sig-
nifying formation of a-fluoroacrylonitriles 2 and (poorly
soluble) lithium diphenylphosphinate (3). This usually
occurred between 0 and 10 8C, but at lower temperatures
for 2d (ꢀ5 8C), and 2l (ꢀ40 8C). In contrast to the HWE
synthesis, no heating is needed to obtain a-fluoroacryloni-
triles 2 [8,12]. The general procedure is illustrated in
Scheme 1. An attempt to isolate phosphine oxide 1 by
quenching the reaction with acetic acid gave only impure
compound in low yield.
After work-up, the crude mixture was analyzed by 1H and
19F NMR in order to determine the (E)/(Z) ratio of a-
fluorinated a,b-unsaturated nitriles 2 formed. Subsequently,
the compounds were purified by column chromatography.
Results are listed in Table 1. For known compounds, litera-
ture data of the analogous HWE reactions are presented.
Table 1
Synthesis of a-fluoroacrylonitriles 2
Entry
Substrate (R1R2C¼O)
Basea
Yield (%)b
Yield HWE (%)b
a
b
c
Benzaldehyde
p-Methoxybenzaldehyde
p-Tolualdehyde
LDAc
LDA
53 (21:79)
50 (32:68)
46 (28:72)
73 (53:47)
45 (44:56)
50 (26:74)
48 (26:74)
51 (26:74)
42 (19:81)
40 (79:21)
42d
54 (2:1) [12]
52 (1:1) [8]
51 (1:3) [8]
53 (3:2) [12]
38 (3:2) [12]
30 (1:1) [12]
LDA
d
e
2-Pyridinecarboxaldehyde
(E)-Cinnamaldehyde
n-Heptanal
LDA
LDA
LDA
f
g
g
h
i
3-Phenylpropanal
LDA
3-Phenylpropanal
LiHDMS
LDA
Cyclohexanecarboxaldehyde
Benzyloxyacetaldehyde
Phenylacetaldehyde
tert-Butylcyclohexanone
1,4-Dioxaspiro[4,5]cyclodecan-8-onee
Cyclododecanone
LiHDMS
LDA
j
50 (2:3) [12]
k
l
LiHDMS
LiHDMS
LiHDMS
LiHDMS
LDA
56
76
m
n
o
p
q
rc
62
Adamantanone
31
Acetophenone
b-Ionone
(R)-Carvone
44 (61:39)
41 (41:59)
50 (68:32)f
45g (50:50)
58 (1:1) [12]
46 (2:1) [12]
LDA
LiHDMS
LiHDMS
a,a,a-Trifluoroacetophenone
a Reactions with LDA carried out on 2 mmol scale, with LiHMDS on 6 mmol scale.
b Yield of combined isomers, after column chromatography; (E)/(Z) ratio (determined from 19F NMR of the crude product) given in parentheses.
c Reaction carried out on 1 mmol scale.
d Including rearranged product 4; E-1j:Z-1j:4 ¼ 22:22:56: original (E)/(Z) ratio unknown.
e 1,4-Cyclohexanedione mono-ethylene ketal.
f Stereochemistry determined on the basis of d (H-3) and d (F).
g Product could not be separated from starting ketone.

J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
109
Table 2
Synthesis of 2-fluoroallylcarbamates 7 from a-fluoroacrylonitriles 2
Entry
Substrate
Substrate (R1R2C¼O) of 2a
R3
R4
Yield (%)b
a
b
c
d
e
f
2g
2i
3-Phenylpropanal (26:74)
Benzyloxyacetaldehyde (79:21)
tert-Butylcyclohexanone
tert-Butylcyclohexanone
tert-Butylcyclohexanone
1,4-Dioxaspiro[4,5]cyclodecan-8-one
Cyclododecanone
PMB
Me
Me
Bn
64 (28:72)
35 (76:24)
53
t-Bu
t-Bu
Bn
2k
2k
2k
2l
Bn
60c
PMB
PMB
Me
Bn
81d
Bn
70e
g
h
i
2m
2m
2m
2q
2r
t-Bu
t-Bu
Bn
72f
Cyclododecanone
Bn
n.d.g
Cyclododecanone
(R)-Carvone (68:32)
PMB
PMB
Bn
65h
j
Bn
77 (84:16)
50 (50:50)
k
a,a,a-Trifluoroacetophenone (50:50)
Bn
a (E)/(Z) ratio in parentheses.
b Yield of combined isomers, after column chromatography; (E)/(Z) ratio, determined by NMR-analysis of the crude product, in parentheses.
c Not obtained in pure form.
d Contained 10% of amine 6e.
e Contained 13% of amine 6f.
f Possibly contained some BOC2O.
g Could not be separated from BOC2O.
h Contained 13% of amine 6i.
for a-fluoroacrylonitriles 2 contrast the high, consistent
selectivities found for a-fluorinated acrylates [18], and
vinyl sulfoxides [15]. Notably, the non-fluorinated diethyl
phosphonate analogue, which was expected to be a good
indicator for the stereochemistry of 1 [18], did not show
much (E)/(Z)-selectivity either [16].
imino group with sodium borohydride gave 2-fluoroallyla-
mines 6. Such amines have received attention from indus-
trial research groups [24]. The corresponding carbamates
were tested as peptide isosteres [25–27].
To facilitate work-up, crude amines 6 were converted
directly into the tert-butoxycarbonyl (BOC, R4: t-Bu) or
benzyloxycarbonyl (Cbz, R4: Bn) derivatives 7, which were
isolated as oils. Results are presented in Table 2.
2.2. Transimination reactions with a-fluoroacrylonitriles
The (E)/(Z) ratios of starting compounds 2 seemed not to
be affected by transimination with primary amines, except
for carvone derivative 2q. Probably, in this case the inter-
mediate imine underwent (Z) ! (E) isomerization. Highest
yields were obtained when transimination was performed
with p-methoxybenzylamine (R3: PMB), which also pro-
vides a convenient protecting group [28], and when benzyl
chloroformate (R4: Bn) was used to protect the amino
function. In addition, pure products could be obtained more
easily by column chromatography. Though yields were not
as high as found for O-protected cyanohydrins [19–23], the
reactions show that a-fluoroacrylonitriles 2 can be conve-
niently derivatized through the transimination procedure.2
Reaction of primary imines 5 with N-benzylhydroxyla-
DIBALH reduction of 2 [7,8] presents an entry into a wide
variety of products, using the DIBALH-reduction transimi-
nation protocol. This one-pot, multi-step method was devel-
oped in our laboratories for the derivatization of protected
cyanohydrins [19–23].
The protocol is outlined in Scheme 2. Hydroalumination
of the cyanide function in 2 afforded metallo-imines [7,8].
After addition of methanol, to destroy the excess of
DIBALH and liberate the free primary imines 5, addition
of a primary amine R3NH2 (R3: methyl, benzyl, p-methox-
ybenzyl (PMB)) led to transimination to the more stable
secondary imine, under loss of NH3. Finally, reduction of the
R1
R2
CN
F
R1
R2
mine [29] yielded novel C-(1-fluorovinyl)nitrones
8
NH
1. DIBALH
2. MeOH
(Scheme 3). They were obtained, usually in high yields,
as colorless solids. Results are listed in Table 3.
F
2
5
From aldehyde derivatives 2g and i, nitrones 8 were
formed as single isomers, with the carbon–carbon double
bond in the (Z) configuration. This is probably due to failure
of the (E)-isomers to react with benzylhydroxylamine. The
yields can readily be explained by presuming a complete
3. R3NH2
4. NaBH4
R3
H
R3
N
R1
R2
N
R1
R2
BOC2O
Cbz-Cl
OR4
F
F
O
2 Imines can also be obtained by reaction of the nitrile with Grignard
reagents (cf. [20,22,23]), but this procedure has not been investigated in
the study presented here.
7
6
Scheme 2.

110
J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
Table 3
Synthesis of C-(1-fluorovinyl)nitrones 8 from aꢀfluoroacrylonitriles 2
Entry
Substratea
Substrate (R1R2C¼O) of 2
Yield (%)b
(E)/(Z) (C¼N)c
a
b
c
d
e
f
2g (26:74)
2i (79:21)
3-Phenylpropanal
79 (< 2:98)
< 2:98
Benzyloxyacetaldehyde
tert-Butylcyclohexanone
1,4-Dioxaspiro[4,5]cyclodecan-8-one
Cyclododecanone
18 (< 2:98)
< 2:98
10:90
2k
2l
81
93
98
67
10:90
2m
2n
< 5:95 (20:80)
2:98 (4:96)
Adamantanone
a (E)/(Z) ratio in parentheses.
b Yield of combined isomers, after column chromatography; (E)/(Z) ratio of C¼C bond in parentheses (determined by 1H NMR).
c For crude compound; for isolated compound in parentheses (if different) (determined by NMR).
Bn
as the solvent. Chemical shifts are given relative to TMS
(1H, 13C), CFCl3 (19F, external reference) or 85% phospho-
ric acid (31P, external reference). Mass spectra were
recorded on a Finnigan MAT 900 equipped with an electro-
spray interface (ESI), or with a Finnigan MAT TSQ70 triple
quadrupole mass spectrometer equipped with a custom-
made ESI. Exact masses were obtained on a Finnigan
TSQ Quantum AM. GC/MS spectra were recorded on a
Finnigan MAT ITD 700, coupled with a Packard 438A GC.
Fluoroacetonitrile was obtained from Aldrich, and used
without purification. Ph2P(O)Cl, obtained from Acros Chi-
mica, was used without purification; old batches were dis-
tilled before use. THF was distilled from LiAlH4. Aldehydes
were freshly distilled. Cyclododecanone was purified by
column chromatography. LDA was prepared from n-BuLi
(2.8 ml, 1.6 M in hexanes) and diisopropylamine (0.67 ml) in
THF (5 ml) at 0 8C. Petroleum ether signifies the fraction
boiling at 40–60 8C. CAUTION: Fluoroacetonitrile is
highly toxic!
1. DIBALH
2. MeOH
R1
R2
CN
F
R1
R2
N+
O-
3. BnNHOH
F
2
8
Scheme 3.
conversion of the (Z)-isomers. Ketone derivatives 2k–n
reacted well, except a,a,a-trifluoroacetophenone derivative
2r, which resisted transimination.
Nitrones 8e, and to a lesser extent 8f, which were formed
as single isomers, showed some silica-induced (Z) ! (E)
isomerization.
Like their saturated analogues [30,31], the novel unsatu-
rated a-fluorovinyl nitrones 8 are expected to engage in 1,3-
dipolar cycloaddition reactions.
3. Conclusions
4.2. (Diphenylphosphinoyl)fluoroacetonitrile (1)
Horner–Wittig reaction of (diphenylphosphinoyl)fluoroa-
cetonitrile (2), prepared in situ from commercially available
compounds, with a wide range of carbonyl compounds
yielded a-fluoroacrylonitriles 2 in moderate to good yields.
No heating was required to complete the reaction. As in
related Wittig-type syntheses, stereoselectivity was gener-
ally low. a-Fluoroacrylonitriles could be applied in one-pot
transimination reactions to form 2-fluoroallylamines 6 and
C-(1-fluorovinyl)nitrones 8, usually in good yields. Straight-
forward conversion of a,b-unsaturated nitriles into asym-
metric allylic amines is unprecedented.
Fluoroacetonitrile (0.11 ml, 2.0 mmol) and Ph2P(O)Cl
(0.29 ml, 2.0 mmol) were dissolved in THF (25 ml) in an
inert atmosphere. At ꢀ78 8C, LDA (2 eq.) or LiHMDS
(4.0 ml, 1.0 M in THF) were added, leading to a yellow or
light-brown solution of phosphine oxide anion 1ꢀ. After
stirring for 15 min at ꢀ78 8C, the reaction was quenched
with HOAc (4 mmol) in Et2O (10 ml). The temperature was
raised to room temperature, and solvents were removed
under reduced pressure. Column chromatography (eluent:
EtOAc) yielded impure phosphine oxide 1. During further
attempts to purify the compound by column chromatogra-
phy, it decayed.
4. Experimental
1H NMR: d 5.67 (dd, 1H, JFH ¼ 46:8, JHP ¼ 8:0, H-2),
7.54–7.73 (m, 6H, H-arom.), 7.85–7.99 (m, 4H, H-arom.);
19F NMR: d ꢀ207.3; 31P NMR: d 25.7 (d, JPF ¼ 52:5).
4.1. General procedures
Column chromatography was performed on Baker Silica
Gel (0.063–0.200 mm). For TLC-analyses, Schleicher and
Schuell F1500/LS 254 silica plates were used, visualized
with ultraviolet light or KMnO4. 1H (200 MHz), 13C
(50 MHz), 31P (80 MHz), and 19F NMR (188 MHz) spectra
were recorded on a Bruker AC-200 instrument, with CDCl3
4.3. Synthesis of a-fluoroacrylonitriles 2, typical procedure
Anion 1ꢀ was prepared as described before. After stirring
for 15 min at ꢀ78 8C, the carbonyl substrate (1.1 eq.) was
added in portions (solids) or as a THF solution (ca. 5 ml), and

J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
111
the temperature was allowed to rise to room temperature.
After 1 h, saturated brine (15 ml) was added to the reaction
mixture, and the aqueous layer was extracted with Et2O (2Â
10 ml). The combined organic layers were dried with MgSO4.
After filtration and evaporation of the solvents, the crude
E), 130.0 (d, JFC ¼ 7:6, CH, Tol, Z), 136.8 (d, JFC ¼ 415:0,
CF, E), 137.0 (d, JFC ¼ 408:9, CF, Z), 141.2 (Cp, Z), 142.7
(Cp, E); 19F NMR: d ꢀ124.7 (E), ꢀ123.7 (Z).
4.7. 2-Fluoro-3-(2-pyridyl)acrylonitrile (2d) [12]
1
product was analyzed by H and 19F NMR. Column chro-
matography (eluent: petroleum ether/Et2O, 10/1; or n-pen-
tane/Et2O 20/1; for 2d: petroleum ether/Et2O/Et3N, 100/10/1;
for 2l: n-pentane/Et2O, 20/1 ! 4/1) yielded the pure a-
fluoroacrylonitrilesas(usuallycolorless) mixtures ofisomers,
with yields and (E)/(Z) ratios as listed in Table 1. a-Fluor-
oacrylonitriles 2 were difficult to analyze through LC/MS,
causing exact mass analysis of new compounds 2i, k, m, q,
and r to fail. For all of these consecutive reactions (to
carbamates 7 or nitrones 8) led to products with an acceptable
exact mass, indirectly proving the assumed structures.
Solid; 1H NMR: d 6.71 (d, 0.4H, JFH ¼ 34:4, H-3, Z), 7.06
(d, 0.6H, JFH ¼ 16:1, H-3, E), 7.30–7.35 (m, 1H), 7.43 (d,
0.6H, J ¼ 8:0, H-30, E), 7.71–7.79 (m, 1.4H), 8.67–8.71 (m,
1H, H-60); 13C NMR: d 111.9 (CBN, Z), 112.8 (CBN, E),
123.9, 124.0, 124.1, 124.2, 124.4, 124.6 (CH, Pyr/CH-3, 1
isomer), 125.8 (d, JFC ¼ 12:2, CH-3, 1 isomer), 132.6 (d,
JFC ¼ 257:9, CF, Z), 133.5 (d, JFC ¼ 252:6, CF, E), 136.6
(CH, Pyr, 1 isomer), 136.7 (CH, Pyr, 1 isomer), 147.9 (d,
JFC ¼ 10:7, Ci, E), 149.1 (d, JFC ¼ 7:6, Ci, Z), 149.7 (CH-60,
E), 149.9 (CH-60, Z); 19F NMR: d ꢀ119.1 (E), ꢀ117.6 (Z).
4.4. 2-Fluoro-3-phenylacrylonitrile (2a) [12]
4.8. 2-Fluoro-5-phenylpenta-2,4-dienenitrile (2e) [12]
Oil; 1H NMR: d 6.46 (d, 0.8H, JFH ¼ 34:3, H-3, Z),3 7.07
(d, 0.2H, JFH ¼ 16:8, H-3, E), 7.36–7.44 (m, 3H, Hm, p), 7.52–
7.59 (m, 2H, Ho); 13C NMR: d 112.9 (d, J ¼ 51:3, CBN, E),
113.1 (d, J ¼ 47:3, CBN, Z), 123.5 (d, JFC ¼ 7:6, CH-3, Z),
125.9 (d, JFC ¼ 24:4, CH-3, E), 128.3 (d, JFC ¼ 3:0, CH, E),
129.0 (CHp, Z), 129.1 (CHp, E), 130.1 (d, JFC ¼ 7:6, CH, Z),
130.4 (d, JFC ¼ 14:4, CH, E), 130.6 (d, JFC ¼ 3:0, CH, Z),
133.4 (Ci, E), 133.6 (Ci, Z); d (CF, both isomers) not eluci-
dated; 19F NMR: d ꢀ122.7 (E), ꢀ122.0 (Z).
Yellow oil; 1H NMR: d 6.39 (dd, 0.5H, JFH ¼ 30:7,
J ¼ 9:0, H-3, Z), 6.77–6.91 (m, 2H, H-4,5), 7.04 (dd,
0.5H, JFH ¼ 16:1, J ¼ 11:0, H-3, E), 7.35–7.40 (m, 3H,
H
m, p), 7.49 (m, 2H, Ho); 13C NMR: d 110.4 (d, JFC ¼ 45:8,
CBN, E), 113.0 (d, JFC ¼ 45:8, CBN, Z), 117.0 (CH-5, Z),
117.9 (d, JFC ¼ 3:0, CH-5, E), 124.4 (d, JFC ¼ 10:7, CH-3,
Z), 126.6 (d, JFC ¼ 36:9, CH-3, E), 127.1 (CH, Ph, E), 127.4
(CH, Ph, Z), 128.8 (CHp, Ph), 129.4 (CH, Ph, E), 129.6 (CH,
Ph, Z), 130.3 (d, JFC ¼ 248:7, CF), 132.7 (d, JFC ¼ 242:6,
CF), 135.1 (Ci), 139.8 (d, JFC ¼ 4:6, CH-4, Z), 140.8 (d,
JFC ¼ 10:7, CH-4, E); 19F NMR: d ꢀ127.8 (E), ꢀ126.9 (Z);
GC/MS: m=z ¼ 173 [Mþ].
4.5. 2-Fluoro-3-(4-methoxyphenyl)acrylonitrile (2b) [8]
Solid; 1H NMR: d 3.85 (s, 3H, Me), 6.39 (d, 0.7H,
JFH ¼ 35:2, H-3, Z), 6.93 (d, 1.4H, J ¼ 8:9, Hm, Z), 6.94
(d, 0.6H, J ¼ 8:9, Hm, E), 7.01 (d, 0.3H, JFH ¼ 17:0, H-3,
E), 7.51 (d, 1.4H, J ¼ 8:9, Ho, Z), 7.55 (d, 0.6H, J ¼ 8:7, Ho,
E); 13C NMR: d 55.2 (OMe), 112.9 (d, JFC ¼ 45:8, CBN, E),
113.4 (d, JFC ¼ 45:8, CBN, Z), 114.3 (CHm, Z), 114.4 (CHm,
E), 120.1 (d, JFC ¼ 5:9, Ci, E), 122.6 (d, JFC ¼ 6:1, Ci, Z),
123.1 (d, JFC ¼ 6:1, CH-3, Z), 125.7 (d, JFC ¼ 24:4, CH-3,
E), 129.9 (d, JFC ¼ 3:0, CHo, E), 131.8 (d, JFC ¼ 9:2, CHo,
Z), 161.2 (Cp); d (CF, both isomers) not elucidated; 19F
NMR: d ꢀ127.3 (E), ꢀ126.5 (Z).
4.9. 2-Fluoronon-2-enenitrile (2f) [12]
1
Oil; H NMR: d 0.86–0.92 (m, 3H, CH3), 1.29–1.55 (m,
8H, CH2-5 to CH2-8), 2.19–2.29 (m, 2H, CH2-4), 5.78 (dt,
0.8H, JFH ¼ 32:9, J ¼ 8:0, H-3, Z), 6.12 (dt, 0.2H,
JFH ¼ 13:9, J ¼ 8:8, H-3, E); 13C NMR: d 13.8 (CH3),
22.4 (CH2-8), 26.2 (CH2-7, E), 27.8 (CH2-6, Z), 28.4
(CH2-5, E), 28.6 (CH2-5, Z), 31.2 (CH2-4), 110.9 (d,
JFC ¼ 48:8, CBN, E), 112.2 (d, JFC ¼ 48:8, CBN, Z),
126.7 (d, JFC ¼ 15:3, CH-3, E), 127.1 (d, JFC ¼ 13:7,
CH-3, Z), 132.0 (d, JFC ¼ 244:2, CF, Z), 132.5 (d,
JFC ¼ 229:6, CF, E); 19F NMR: d ꢀ125.9 (Z), ꢀ124.0 (E).
4.6. 2-Fluoro-3-(p-tolyl)acrylonitrile (2c) [8]
1
Oil; H NMR: d 2.39 (s, Me, Z), 2.41 (s, Me, E) {comb.
4.10. 2-Fluoro-5-phenylpent-2-enenitrile (2g)
3H}, 6.42 (d, 0.7H, JFH ¼ 35:1, H-3, Z), 7.03 (d, 0.3H,
JFH ¼ 16:8, H-3, E), 7.22 (d, 2H, J ¼ 8:0, Hm), 7.45 (d,
1.3H, J ¼ 8:0, Ho, Z), 7.48 (d, 0.7H, J ¼ 8:0, Ho, E); 13C
NMR: d 21.3 (Me, E), 21.6 (Me, Z), 112.6 (d, JFC ¼ 47:3,
CBN, E), 113.2 (d, JFC ¼ 45:8, CBN, Z), 123.4 (d, JFC ¼ 6:1,
CH-3, Z), 125.4 (d, JFC ¼ 24:4, CH-3, E), 125.1 (d,
JFC ¼ 6:1, Ci, E), 127.1 (d, JFC ¼ 6:1, Ci, Z), 128.2 (d,
JFC ¼ 3:0, CH, Tol, E), 129.6 (CH, Tol, Z), 129.7 (CH, Tol,
Oil; 1H NMR: d 2.54–2.65 (m, 2H, CH2-4), 2.72–2.83 (m,
2H, CH2-5), 5.75 (dt, 0.7H, JFH ¼ 32:5, J ¼ 7:7, H-3, Z),
6.10 (dt, 0.3H, JFH ¼ 14:2, J ¼ 8:4, H-3, E), 7.15–7.36 (m,
5H, Ph); 13C NMR: d 26.0 (CH2-5, Z), 27.8 (CH2-5, E), 33.7
(CH2-4, Z), 34.4 (d, JFC ¼ 3:1, CH2-4, E), 110.7 (d,
JFC ¼ 48:8, CBN, E), 112.1 (d, JFC ¼ 47:3, CBN, Z),
125.5 (d, JFC ¼ 15:3, CH-3, E), 125.8 (d, JFC ¼ 12:2,
CH-3, Z), 126.4 (CHp), 128.1 (CHo, Z), 128.2 (CHo, E),
128.5 (CHm), 132.1 (d, JFC ¼ 244:1, CF, Z), 132.7 (d,
3 The coupling constant reported in literature is erroneous: cf. [12].

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J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
JFC ¼ 241:1, CF, E), 139.2 (Ci, E), 139.5 (Ci, Z); 19F NMR: d
ꢀ122.8 (E), ꢀ124.5 (Z); GC/MS: m=z ¼ 176 [Mþ þ H],
154 [Mþ ꢀ F], 91 [C7H7þ]. HRMS calcd. for C11H11FN
([M þ H]þ): 176.0876, found: 176.0890.
25.9 (CH2), 26.9 (CH2), 27.0 (Me, t-Bu), 27.6 (CH2), 29.0
(CH2), 32.0 (C, t-Bu), 47.0 (CH), 111.4 (d, JFC ¼ 47:3,
CBN), 125.5 (d, JFC ¼ 232:0, CF), 139.2 (d, JFC ¼ 12:2, C-
1); 19F NMR: d ꢀ135.2 (d, JFH ¼ 2:9); GC/MS: m=z ¼ 196
[Mþ þ H], 57 [C4H9þ].
4.11. 3-Cyclohexyl-2-fluoroacrylonitrile (2h)
4.15. (1,4-Dioxaspiro[4,5]dec-8-ylidene)fluoroacetonitrile
(2l)
1
Oil; H NMR: d 0.83–0.91 (m, 0.4H, CH2-40, E), 1.06–
1.43 (m, 5.6H, CH2-30,50; CH2-40, Z), 1.71–1.80 (m, 4H,
CH2-20,60), 2.22–2.36 (m, 0.2H, H-10, E), 2.52–2.69 (m,
0.8H, H-10, Z), 5.63 (dd, 0.8H, JFH ¼ 33:6, J ¼ 9:9, H-3, Z),
5.99 (dd, 0.2H, JFH ¼ 14:4, J ¼ 10:8, H-3, E); 13C NMR: d
25.0 (CH2-30,50, Z), 25.2 (CH2-40, E), 25.3 (CH2-40, Z), 29.5
(CH2-30,50, E), 31.4 (CH2-20,60, Z), 32.2 (CH2-20,60, E), 34.3
(CH-10, Z), 36.0 (CH-10, E), 110.9 (d, JFC ¼ 47:3, CBN, E),
112.2 (d, JFC ¼ 48:8, CBN, Z), 130.7 (d, JFC ¼ 242:6, CF,
Z), 131.3 (d, JFC ¼ 241:1, CF, E), 131.4 (d, JFC ¼ 13:7, CH-
3, E), 131.6 (d, JFC ¼ 12:2, CH-3, Z); 19F NMR: d ꢀ126.3
(Z), ꢀ126.2 (E); GC/MS: m=z ¼ 154 [Mþ þ H], 82
[C6H10þ], 67 [C5H7þ]. HRMS calcd. for C9H13FN
([M þ H]þ): 154.1032, found: 154.1030.
Oil; 1H NMR: d 1.71–1.82 (m, 4H, CH2-6,10), 2.47–2.58
(m, 4H, CH2-7,9), 3.98 (s, 4H, CH2-2,3); 13C NMR: d 23.0
(CH2-9), 26.1 (CH2-7), 33.5 (CH2-10), 34.1 (CH2-6), 64.2
(CH2-2,3), 106.9 (C-5), 111.2 (d, JFC ¼ 47:3, CBN), 126.1
(d, JFC ¼ 235:0, CF), 136.9 (d, JFC ¼ 12:2, C-8); 19F NMR:
d ꢀ132.5; GC/MS: m=z ¼ 197 [Mþ], 182 [Mþ ꢀ Me], 168
[Mþ ꢀ CHO]. HRMS calcd. for C10H13FNO2 ([M þ H]þ):
198.0930, found: 198.0979.
4.16. Cyclododecylidenefluoroacetonitrile (2m)
1
Oil; H NMR: d 1.35 (broad, 14H, CH2-4 to CH2–10),
1.52–1.64 (m, 4H, CH2-3,11), 2.26–2.35 (m, 4H, CH2-2,12);
13C NMR: d 22.2, 23.0, 23.3, 23.6, 23.8, 24.1, 24.6, 26.0,
29.4 (each CH2), 111.7 (d. JFC ¼ 47:3, CBN), 129.4 (d,
JFC ¼ 235:0, CF), 139.2 (d, JFC ¼ 9:2, C-1); 19F NMR: d
ꢀ127.8; GC/MS: m=z ¼ 224 [Mþ þ H].
4.12. 4-Benzyloxy-2-fluorobut-2-enenitrile (2i)
Oil; 1H NMR: d 4.23 (dd, JFH ¼ 2:6, J ¼ 7:3, CH2-4, E),
4.26 (dd, JFH ¼ 2:9, J ¼ 6:6, CH2-4, Z) {comb. 2H}, 4.52 (s,
PhCH2, Z), 4.56 (s, PhCH2, E) {comb. 2H}, 5.95 (dt, 0.2H,
JFH ¼ 32:9, J ¼ 6:6, H-3, Z), 6.26 (dt, 0.8H, JFH ¼ 13:5,
J ¼ 7:3, H-3, E), 7.35 (b, 5H, Ph); 13C NMR: d 61.6 (CH2-
4, Z), 63.5 (d, JFC ¼ 7:6, CH2, E), 72.6 (CH2Ph), 110.1 (d,
JFC ¼ 47:3, CBN), 122.4 (d, JFC ¼ 16:8, CH-3, E), 123.1 (d,
JFC ¼ 10:7,CH-3,Z),127.5(CHo,Ph),127.7(CHp,Ph),128.2
(CHm, Ph), 133.7 (d, JFC ¼ 245:7, CF, E), 136.8 (Ci, Ph); d
(CBN, CF, Z)notdetermined;19F NMR:dꢀ119.9(Z), ꢀ118.6
(E); GC/MS: m=z ¼ 192 [Mþ þ H], 114 [Mþ ꢀ C6H5].
4.17. Adamant-2-ylideneacetonitrile (2n)
1
Oil; H NMR: d 1.56–1.87 (m, 6H), 1.92–1.94 (m, 2H),
2.00–2.05 (m, 4H), 2.80 (b, 1H, CH), 3.16 (broad, 1H, CH);
13C NMR: d 27.4, 30.0, 33.0 (each CH), 36.1 (CH2), 37.9
(2CH2), 38.7 (2CH2), 111.8 (d, JFC ¼ 48:8, CBN), 122.7 (d,
JFC ¼ 231:9, CF), 147.5 (d, JFC ¼ 10:7, C-2); 19F NMR: d
ꢀ140.9; GC/MS: m=z ¼ 191 [Mþ]. HRMS calcd. for
C12H15FN ([M þ H]þ): 192.1189, found: 192.1186.
4.13. 2-Fluoro-4-phenylbut-2-enenitrile (2j) [12]
4.18. 2-Fluoro-3-phenylbut-2-enenitrile (2o) [12]
1
First fraction after chromatography, oil (yield: 18%); H
NMR: d 3.56–3.63 (m, 2H, CH2), 5.95 (dt, 0.5H, JFH ¼ 31:8,
J ¼ 7:9, H-3, Z), 6.29 (dt, 0.5H, JFH ¼ 13:5, J ¼ 8:6, H-3, E),
7.16–7.39 (m, 5H, Ph); 19F NMR: d ꢀ125.7 (Z), ꢀ123.1 (E);
GC/MS: m=z ¼ 161 [Mþ], 133 [Mþ ꢀ HCN ꢀ H], 115
[Mþ ꢀ F ꢀ HCN]. The second fraction consisted of main
product (E)-2-fluoro-4-phenylbut-3-enenitrile (4): oil (yield:
24%); 1H NMR: d 5.69 (dd, 1H, JFH ¼ 46:5, J ¼ 7:3, CH-2),
6.31 (ddd, 1H, JFH ¼ 8:0, J ¼ 16:1, 7.3, H-3), 7.01 (dd, 1H,
JFH ¼ 5:5, J ¼ 16:1, H-4), 7.34–7.46 (m, 5H, Ph); 19F NMR:
d ꢀ172.0; GC/MS: m=z ¼ 161 [Mþ], 142 [Mþ ꢀ F], 135
[Mþ ꢀ CN], 115 [Mþ ꢀ F ꢀ HCN]. HRMS calcd. for
C10H9FN ([M þ H]þ): 162.0719, found: 162.0768.
Oil; 1H NMR: d 2.22 (d, 0.6H, JFH ¼ 4:4, CH3, E), 2.30
(d, 0.4H, JFH ¼ 4:4, CH3, Z), 7.42 (m, 5H, Ph); 13C NMR: d
16.3 (d, JFC ¼ 3:0, CH3, Z), 17.8 (CH3, E), 112.4 (d,
JFC ¼ 45:8, CBN), 127.4 (CHo, E), 127.8 (d, JFC ¼ 4:6,
CHo, Z), 128.4 (CHm, E), 128.7 (CHm, Z), 128.7 (d,
JFC ¼ 242:6, CF, E), 129.3 (d, JFC ¼ 238:0, CF, Z), 129.5
(CHp), 132.8 (d, JFC ¼ 9:2, C-3, E), 133.3 (d, JFC ¼ 3:0, Ci,
E), 134.1 (d, JFC ¼ 3:0, Ci, Z), 136.4 (d, JFC ¼ 15:3, C-3, Z);
19F NMR: d ꢀ127.9 (E), ꢀ124.6 (Z).
4.19. 3-Methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2(E/
Z),4(E)-pentadienenitrile (2p) [12]
Yellow oil; 1H NMR: d 1.02 (2 Â CH3, Z), 1.03 (2 Â CH3,
E) {comb. 6H}, 1.43–1.50 (m, 2H, CH2), 1.56–1.67 (m, 2H,
CH2), 1.72 (b, 3H, CH3-20), 2.01 (d, 2H, JFH ¼ 3:6, CH3-3,
Z), 2.05 (d, 1H, JFH ¼ 3:6, CH3-3, E), 6.31 (dd, 0.6H,
4.14. (4-tert-Butylcyclohexylidene)fluoroacetonitrile (2k)
Oil; 1H NMR: d 0.87 (s, 9H, CMe3), 0.98–1.29 (m, 3H),
1.75–2.17 (m, 4H), 2.64 (m, 1H), 2.97 (m, 1H); 13C NMR: d

J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
113
J ¼ 16:1, JFH ¼ 2:2, H-4, Z), 6.52 (m, 0.8H, H-4,5, E), 6.56
(m, 0.6H, H-5, Z); 13C NMR: d 10.3 (d, JFC ¼ 3:0, CH3-3,
Z), 13.1 (CH3-3, E), 18.9 (CH2-40), 21.5 (CH3-20), 28.7 (2 Â
CH3), 33.0 (CH2-30, Z), 33.1 (CH2-30, E), 34.0 (C-60), 39.3
(CH2-50, Z), 39.4 (CH2-50, E), 111.9 (d, JFC ¼ 38:2, CBN, E),
112.8 (d, JFC ¼ 36:6, CBN, Z), 123.5 (d, JFC ¼ 3:0, CH-5,
E), 125.6 (CH-5, Z), 131.2 (d, JFC ¼ 7:6, C-3, E), 132.2 (C,
E), 133.0 (C, Z), 129.3 (d, JFC ¼ 300:6, CF, E), 133.8 (d,
JFC ¼ 15:3, C-3, Z), 135.5 (d, JFC ¼ 4:6, CH-4, E), 135.6 (d,
JFC ¼ 10:7, CH-4, Z), 136.6 (C, Z), 136.7 (C, E); d (CF, Z)
not elucidated; 19F NMR: d ꢀ133.1 (E), ꢀ132.3 (Z).
saturated brine, and drying with MgSO4, crude amine 6 was
obtained after filtration and evaporation of the solvents.
Amines 6 were immediately converted into the corresponding
carbamates 7. BOC-protection: tert-Butyl carbamates were
prepared by dissolving crude amine 6 (ca. 1.0 mmol) in
CH2Cl2 (10 ml), with Et3N (1.0 ml) and excess di-tert-butyl
dicarbonate (BOC2O), and stirring overnight. Solvents
were removed under reduced pressure; removal of remaining
BOC2O under high vacuum may be advantageous. Cbz-
protection: Benzyl carbamates were prepared by overnight
stirring of amine 6 in a biphasic system of CH2Cl2
and saturated aqueous NaHCO3 (1/2, (v/v)) with excess
benzyl chloroformate. Separation of the layers, and extraction
of the aqueous layer with CH2Cl2, was followed by drying
the organic layers with MgSO4. Evaporation of the solvents
gave crude carbamates 7, which were purified by column
chromatography (Et2O/EtOAc, 95/5), and obtained as
colorless oils, with yields and (E)/(Z) ratios as provided in
Table 2.
4.20. (R)-Fluoro-(5-isopropenyl-2-methylcyclohex-2-
enylidene)acetonitrile (2q)
Oil; 1H NMR: d 1.75 (s, 3H, CH3-300), 1.99–2.03 (m, 3H,
CH3-2), 2.11 (s, 2H, CH2), 2.16–2.24 (m, 2H, CH2), 2.27–
2.38 (m, 2H, CH2), 2.61–2.71 (m, H-50, E), 2.88–2.98 (m, H-
50, Z) {comb. 1H}, 4.76 (s, 1H, CH2-100), 4.82 (q, 1H,
J ¼ 1:5, CH2-100), 5.92 (m, H-3, E), 6.02 (m, H-3, Z) {comb.
1H}; 13C NMR: d 20.0 (CH3-300, E), 20.5 (CH3-300, Z), 21.5
(d, JFC ¼ 9:2, CH3-20), 28.3 (d, JFC ¼ 6:1, CH2-60, Z), 30.9
(CH2-40, Z) 31.3 (E), 31.5 (E), 39.3 (CH-50, Z), 40.2 (CH-50,
E), 110.1 (CH2-100), 112.5 (d, JFC ¼ 47:3, CBN), 124.9–
130.0 (C’s), 136.0 (CH-30, E), 137.1 (CH-30, Z), 146.4 (C-200,
E), 146.6 (C-200, Z); 19F NMR: d ꢀ128.6 (E), ꢀ126.7 (Z);
GC/MS: m=z ¼ 192 [Mþ þ H], 176 [Mþ ꢀ Me], 150
[Mþ ꢀ Me ꢀ CN], 136 [Mþ ꢀ C2H5 ꢀ CN].
4.23. Benzyl (E/Z)-(2-fluoro-5-phenylpent-2-enyl)-p-
methoxybenzylcarbamate (7a)
1H NMR: d 2.22–2.30 (bm, 0.6H, CH2-4, E), 2.35–2.45
(bm, 1.4H, CH2-4, E), 2.66 (b, 2H, CH2-5), 3.78 (s, 3H,
OCH3), 3.71–3.98 (bm, 2H, CH2-1), 4.32–4.42 (bm, 2H,
CH2, PMB), 4.50–4.80 (bm, H-3), 5.18 (s, 2H, CH2O), 6.80
(bd, 2H, J ¼ 8:0, Hm, PMB), 7.00–7.32 (m, 7H, H-arom.);
13C NMR: d 24.8 (CH2, E), 26.7 (b, CH2, Z), 35.0 (CH2, E),
35.7 (CH2, Z), 41.4 (d, JFH ¼ 29:0, CH2-1, 1 rotamer, Z),
41.9 (d, JFH ¼ 24:3, CH2-1, 1 rotamer, Z), 45.5 (d,
JFH ¼ 32:0, CH2-1, 1 rotamer, E), 46.1 (d, JFH ¼ 30:5,
CH2-1, 1 rotamer, E), 48.4–48.7 (b, CH2, PMB), 54.9
(OCH3), 67.2 (CH2O), 107.5 (d, JFH ¼ 12:2, CH-3, 1 rota-
mer, E), 108.0 (d, JFH ¼ 13:2, CH-3, 1 rotamer, E), 108.3–
108.9 (m, CH-3, both rotamers, Z), 113.7 (CHm, PMB),
125.8, 127.8–129.2 (CH, arom.), 136.4 (C), 140.6 (C, Z),
141.0 (C, E), 154.5, (d, JFC ¼ 255:4, CF), 156.0 (b, C¼O),
158.8 (Cp, PMB); 19F NMR: d ꢀ116.2 (72%, Z), ꢀ109.8
(14%, E, 1 rotamer), ꢀ108.9 (14%, E, 1 rotamer); MS (ESI):
m=z ¼ 456 [Mþ þ Na], 434 [Mþ þ H]. HRMS calcd. for
C27H29FNO3 ([M þ H]þ): 434.2131, found: 434.2142.
4.21. 2,4,4,4-Tetrafluoro-3-phenylbut-2-enenitrile (2r)
Not separated from remaining a,a,a-trifluoroacetophe-
1
none; H NMR: d 7.33–7.56 (m, 5H, Ph); 13C NMR: d
109.3 (d, JFC ¼ 44:2, CBN), 110.0 (d, JFC ¼ 44:3, CBN),
125.4 (C), 125.6 (C), 128.7, 128.8, 129.1, 129.4, 129.5,
130.7, 131.1 (each CH), 131.7 (C), 132.1 (C), 136.5 (m, C-
3), 137.6 (C-3); 19F NMR: d ꢀ111.5 (q, 1F, JFF ¼ 14:1, F-2,
Z), ꢀ108.1 (q, 1F, JFF ¼ 24:4, F-2, E), ꢀ61.6 (d, 3F,
JFF ¼ 14:1, F-4, Z), ꢀ61.2 (d, 3F, JFF ¼ 24:4, F-4, E);
GC/MS: m=z ¼ 215 [Mþ].
4.22. Synthesis of 2-fluoroallylamines 6 and conversion
into the corresponding carbamates 7, typical procedures
4.24. tert-Butyl (4-benzyloxy-2-fluorobut-2-
enyl)methylcarbamate (7b)
To a solution of a-fluoroacrylonitrile 2 (1.0 mmol) in Et2O
(10 ml), DIBALH (1.0 M in hexanes, 1.6–2.0 eq.) was added
through a syringe at ꢀ80 8C. After allowing the temperature
to rise to 0 8C, themixturewas cooled to ꢀ100 8C, andMeOH
(1 ml)was added. The appropriate amine (methylamine: 8 eq.
(8.0N in ethanol); benzylamine: 5.5 eq. (neat); p-methoxy-
benzylamine: 3.2 eq. (neat)) was added after a few minutes,
and the temperature was allowed to rise to room temperature.
After 2.5 h, the mixture was cooled to ꢀ10 8C, NaBH4 (6 eq.)
was added, and stirring was continued for at least 3 h.
The reaction mixture was poured into water, and extracted
with Et2O (3Â). After washing the combined layers with
1H NMR: d 1.45 (s, 6.75H, CH3, t-Bu, E), 1.46 (s, 2.25H,
CH3, t-Bu, Z), 2.86 (s, 2.25H, NCH3, E), 2.88 (s, 0.75H,
NCH3, Z), 3.99–4.16 (m, 4H, CH2-1,4), 4.50 (s, 0.5H,
PhCH2, Z), 4.51 (s, 1.5H, PhCH2, E), 4.96 (dt, 0.25H,
JFH ¼ 35:8, J ¼ 7:7, H-3, Z), 5.46 (dt, 0.75H, JFH ¼ 20:5,
J ¼ 7:7, H-3, E), 7.33 (b, 5H, Ph); 13C NMR: d 28.2 (CH3, t-
Bu), 34.1 (NCH3), 45.1 (m, CH2-1), 62.3 (d, JFC ¼ 6:1,
CH2-4, Z), 72.2 (PhCH2), 79.9 (C, t-Bu), 104.4 (d,
JFC ¼ 12:2, CH-3), 106.1 (m, CH-3), 127.6, 128.3, 128.7
(each CH, Ph), 137.8 (Ci, Ph); 19F NMR: d ꢀ112.6 (24%, Z),

114
J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
ꢀ104.7 (38%, E, 1 rotamer), ꢀ103.8 (38%, E, 1 rotamer);
MS (ESI): m=z ¼ 332 [Mþ þ Na], 310 [Mþ þ H], 254
[Mþ þ H ꢀ C4H8], 210 [Mþ þ 2H ꢀ BOC]. HRMS calcd.
for C17H25FNO3 ([M þ H]þ): 310.1818, found: 310.1806.
CH2-1, 1 rotamer), 47.6 (CH-40), 48.6 (CH2, PMB, 1 rotamer),
49.0 (CH2, PMB, 1 rotamer), 54.8 (OCH3), 67.1 (PhCH2),
113.6 (CHm, PMB), 119.5 (d, JFC ¼ 13:7, C-10, 1 rotamer),
120.1 (d, JFC ¼ 13:8, C-10, 1 rotamer), 127.6 (CHo, PMB),
128.0, 128.1, 129.0 (each CH, Ph), 129.2 (Ci, PMB), 136.4 (C,
Ph), 146.8 (d, JFC ¼ 245:7, CF), 155.9 (C¼O, 1 rotamer),
156.1 (C¼O, 1 rotamer), 158.7 (Cp, PMB ); 19F NMR: d
ꢀ120.4 (52%), ꢀ119.3 (48%); MS (ESI): m=z ¼ 476
[Mþ þ Na], 454 [Mþ þ H], 320 [Mþ ꢀ Cbz þ 2H].
HRMS calcd. for C28H37FNO3 ([M þ H]þ): 454.2757,
found: 454.2766. Contained 10% of [2-(4-tert-butylcyclo-
hexylidene)-2-fluoroethyl]-p-methoxybenzylamine (6e): 19F
NMR: d ꢀ121.8; MS (ESI): m=z ¼ 320.
4.25. tert-Butyl [2-(4-tert-butylcyclohexylidene)-2-
fluoroethyl]methylcarbamate (7c)
1H NMR: d 0.84 (s, 9H, CH3, t-Bu-4), 0.92–1.38 (m, 2H),
1.46 ({s, 9H, CH3, t-BuO} þ m, 1H), 1.52–1.67 (m, 1H),
1.82–1.89 (m, 3H), 2.47 (b, 1H), 2.85 (s, 3H, NCH3), 2.77–
2.92 (m, 1H), 4.03 (d, 2H, J ¼ 21:9, CH2-1); 13C NMR: d
25.5 (CH2, c-Hex), 25.6 (CH2, c-Hex), 27.4 (CH3, t-Bu),
27.9 (CH2, c-Hex), 28.0 (CH2, c-Hex), 28.3 (CH3, t-BuO),
32.3 (C, t-Bu-4), 33.6 (NCH3), 44.3–45.6 (CH2-1), 47.8
(CH-40), 79.5 (C, t-BuO), 119.5 (b, C-10), 147.5 (d,
JFC ¼ 244:1, CF), 155.4 (C¼O); 19F NMR: d ꢀ119.8,
ꢀ119.3; MS (ESI): m=z ¼ 649 [ð2MÞþ þ Na], 336
[Mþ þ Na], 314 [Mþ þ H], 258 [Mþ þ H ꢀ C4H8],
238 [Mþ ꢀ F ꢀ C4H8]. HRMS calcd. for C18H33FNO2
([M þ H]þ): 314.2495, found: 314.2439.
4.28. Benzyl [2-(1,4-dioxaspiro[4,5]dec-8-ylidene)-2-
fluoroethyl]-p-methoxybenzylcarbamate (7f)
1H NMR: d 1.58–1.72 (m, 4H, CH2-60,100), 2.03–2.09
(bm, 50% of 2H, CH2-90, 1 rotamer), 2.20–2.28 (bm, 50% of
2H, CH2-90, 1 rotamer), 2.35–2.40 (bm, 2H, CH2-70), 3.79 (s,
3H, CH3), 4.02–4.13 (m, 2H, CH2-1), 4.48 (bs, 2H, CH2,
PMB), 5.19 (s, 2H, PhCH2), 6.81–6.85 (bm, 2H, Hm, PMB),
7.06–7.18 (m, 2H, Ho, PMB), 7.33 (b, 5H, Ph); 13C NMR: d
22.2 (d, JFC ¼ 7:6, CH2-90), 24.5 (CH2-70), 34.2, 34.8 (CH2-
60, CH2-100), 41.2–42.6 (m, CH2-1), 48.6 (CH2, PMB, 1
rotamer), 48.8 (CH2, PMB, 1 rotamer), 54.9 (CH3), 64.0
(CH2-20,30), 67.2 (PhCH2), 107.9 (C-50), 113.7 (CHm, PMB),
117.0–117.9 (m, C-80), 127.6, 127.7, 128.2, 128.3 (b), 128.8
(b) (each CH), 129.0 (Ci, PMB), 136.3 (C, Ph), 147.5 (bd,
JFC ¼ 245:7, CF), 155.9 (C¼O, 1 rotamer), 156.0 (C¼O, 1
rotamer), 158.7 (Cp, PMB); 19F NMR: d ꢀ118.4 (50%, 1
rotamer), ꢀ117.3 (50%, 1 rotamer); MS (ESI): m=z ¼ 495
[Mþ þ K], 479 [Mþ þ Na]. HRMS calcd. for C26H31FNO5
([M þ H]þ): 456.2186, found: 456.2160. Probably con-
tained 14% of [2-(1,4-dioxaspiro[4,5]dec-8-ylidene)-2-
4.26. Benzyl benzyl-[2-(4-tert-butylcyclohexylidene)-2-
fluoroethyl]carbamate (7d)
1H NMR: d 0.82 (s, 9H, CH3), 0.89–1.01 (m, 1H), 1.55–
1.84 (bm, 4H), 2.10–2.35 (bm, 1H), 1.81 (bd, J ¼ 11:7, 1H),
4.02 (bd, 1H, JFH ¼ 17:6, CH2-1, 1 rotamer), 4.12 (bd, 1H,
J ¼ 21:9, CH2-1, 1 rotamer), 4.55 (bm, 2H, PhCH2N), 5.18
(s, 1H, CH2O, 2 rotamers), 5.18 (d, 0.5H, J ¼ 14:2, CH2O, 1
rotamer), 5.22 (d, 0.5H, J ¼ 14:2, CH2O, 1 rotamer), 7.28–
7.78 (m, 10H, Ph); 13C NMR: d 25.1 (CH2, c-Hex), 25.2
(CH2, c-Hex), 27.1 (CH3), 27.5 (CH2, c-Hex), 27.7 (CH2, c-
Hex), 31.9 (C, t-Bu), 41.8 (d, JFC ¼ 30:5, CH2-1, 1 rotamer),
42.5 (d, JFC ¼ 30:5, CH2-1, 1 rotamer), 47.4 (CH-40), 49.1
(PhCH2N, 1 rotamer), 49.4 (PhCH2N, 1 rotamer), 67.0
(CH2O, 1 rotamer), 69.1 (CH2O, 1 rotamer), 119.2–120.1
(2d, C-10), 126.9–128.1 (CH-arom.), 136.3 (C, PhCH2O),
137.2 (C, PhCH2N), 146.5 (bd, J ¼ 244:9, CF), 155.8
(C¼O, 1 rotamer), 155.9 (C¼O, 1 rotamer); 19F NMR: d
ꢀ120.1, ꢀ119.0; MS (ESI): m=z ¼ 446 [Mþ þ Na], 424
[Mþ þ H]. HRMS calcd. for C27H35FNO2 ([M þ H]þ):
424.2652, found: 424.2675.
1
fluoroethyl]-p-methoxybenzylamine (6f): H NMR: d 3.81
(s, CH3), 3.96 (s, CH2-20,30), 6.90 (dd, J ¼ 8:6, 2.7, Hm); 13
C
NMR: d 24.9, 25.0, 34.4 (CH2-60,70,90,100), 50.2 (d,
JFC ¼ 30:5, CH2-1), 52.1 (CH2, PMB), 107.7 (C-50),
113.8 (CHm, PMB), 113.9 (CHm, PMB), 120.1 (d, JFH
13:7, C-80), 129.4 (CH), 130.8 (CH), 159.6 (Cp, PMB); 19
NMR: d ꢀ119.5 (d, JFH ¼ 20:7).
¼
F
4.29. tert-Butyl [2-(cyclododecylidene)-2-
fluoroethyl]methylcarbamate (7g)
4.27. Benzyl [2-(4-tert-butylcyclohexylidene)-2-
fluoroethyl]-p-methoxybenzylcarbamate (7e)
1H NMR: d 1.34 (b, 18H, c-Dod), 1.46 (s, 9H, CH3, t-Bu),
2.07–2.18 (m, 4 H, CH2-20,120, c-Dod), 2.85 (s, 3H, NCH3),
4.06 (bd, 2H, JFH ¼ 21:2, CH2); 13C NMR: d 22.3, 22.6,
23.2, 23.6, 23.9, 24.2, 24.7, 25.0 (each CH2, c-Dod), 28.2
(CH3, t-Bu), 33.4 (NCH3), 44.9 (d, JFC ¼ 30:5, CH2-1, 1
rotamer), 45.6 (d, JFC ¼ 30:5, CH2-1, 1 rotamer), 79.4 (C, t-
Bu), 119.3 (b, C-10), 151.3 (bd, JFC ¼ 250:2, CF), 155.3
(C¼O); 19F NMR: d ꢀ114.6 (50%), ꢀ113.2 (50%); MS
(ESI): m=z ¼ 706 [ð2MÞþ þ Na], 364 [Mþ þ Na], 342
[Mþ þ H], 327 [Mþ þ H ꢀ Me], 286 [Mþ þ H ꢀ C4H8],
1H NMR: d 0.84, 0.85 (2 Â s, 9H, CH3), 0.87–1.17 (bm,
1H), 1.46–1.85 (bm, 5H), 2.16–2.39 (bm, 1H), 2.88 (bd, 1H,
J ¼ 12:8), 3.79 (s, 3H, OCH3), 3.90–4.13 (2bm, 2H, CH2-1),
4.47 (bs, CH2, PMB), 5.18 (d, 1H, J ¼ 14:3, PhCH2), 5.21
(d, 1H, J ¼ 14:3, PhCH2), 6.82–6.85 (bm, 2H, Hm, PMB),
7.07–7.21 (bm, 2H, Ho, PMB), 7.33–7.36 (bm, 5H, Ph); 13
C
NMR: d 25.3 (CH2, c-Hex), 25.4 (CH2, c-Hex), 27.3 (CH3, t-
Bu), 27.7 (CH2, c-Hex), 27.9 (CH2, c-Hex), 32.1 (C, t-Bu),
41.7 (d, JFC ¼ 32:0, CH2-1, 1 rotamer), 42.3 (d, JFC ¼ 32:0,

J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
115
266 [Mþ ꢀ F ꢀ C4H8]. HRMS calcd. for C20H37FNO2
([M þ H]þ): 342.2808, found: 342.2759.
1H, H-30, E), 5.60 (b, 1H, H-30, Z), 6.82 (bd, J ¼ 8:0, Hm,
PMB, E), 6.90 (dd, J ¼ 8:8, 1.5, Hm, PMB, Z) {comb. 2H},
7.16–7.27 (m, 2H, Ho, PMB), 7.34–7.37 (m, 5H, Ph); 13C
NMR: d 20.2 (CH3, E), 20.4 (CH3, Z), 23.1 (d, JFC ¼ 12:2,
CH3, E), 23.6 (CH3, Z), 28.6 (d, JFC ¼ 12:2, CH2-60, Z), 29.5
(CH2-40, Z), 30.5 (d, JFC ¼ 4:6, CH2-60, E), 31.4 (CH2), 40.2
(CH-50, Z), 41.0 (CH-50), 43.0 (d, JFC ¼ 29:0, CH2-1, E, 1
rotamer), 43.6 (d, JFC ¼ 29:0, CH2-1, E, 1 rotamer), 44.4 (m,
CH2-1, Z), 48.6 (CH2, PMB, E, 1 rotamer), 49.1 (CH2, PMB,
E, 1 rotamer), 51.4 (d, JFC ¼ 12:2, CH2, PMB, Z, 1 rotamer),
52.0 (d, JFC ¼ 9:2, CH2, PMB, Z, 1 rotamer), 54.9 (OCH3),
65.3 (PhCH2, Z), 67.2 (PhCH2, E), 109.1 (CH2-100), 113.7
(CHm, PMB), 114.0 (CHm, PMB), 127.7–128.6 (CH), 130.1
(d, JFC ¼ 21:4, CH-30), 130.1 (Ci, PMB), 130.9 (d,
JFC ¼ 9:2, CH-30), 135.0 (C, Ph, Z), 136.4 (C, Ph, E),
144.7 (C-200, Z), 148.3 (C-200, E), 149.8 (d, JFC ¼ 259:4,
CF), 150.1 (d, JFC ¼ 245:7, CF), 156.0 (b, C¼O), 158.8 (Cp,
PMB); 19F NMR: d ꢀ112.6 (12%, probably unprotected
amine 6j), ꢀ110.6 (36%), ꢀ109.3 (36%), ꢀ108.7 (8%),
ꢀ107.2 (8%); MS (ESI): m=z ¼ 472 [Mþ þ Na], 450
[Mþ þ H]. HRMS calcd. for C28H33FNO3 ([M þ H]þ):
450.2444, found: 450.2493.
4.30. tert-Butyl benzyl-[2-(cyclododecylidene)-2-
fluoroethyl]carbamate (7h)
1H NMR: d 1.32 (b, 18H, c-Dod), 1.45 (bs, 9H, CH3), 1.92
(b, 2H), 2.11 (b, 2H), 3.98 (bd, JFH ¼ 21:2), 4.08 (bd,
JFH ¼ 21:2) {comb. 2H, CH2-1}, 4.46 (b, 2H, PhCH2),
7.20–7.30 (m, 5H, Ph); 13C NMR: d 22.2, 22.6, 23.2,
24.0, 24.9 (each CH2, c-Dod), 27.0 (CH3), 42.6 (d,
JFC ¼ 30:3, CH2-1), 49.1 (2b, PhCH2), 79.6 (C, t-Bu),
119.3 (2d, C-10), 126.8 (CH, Ph), 128.1 (CH, Ph), 137.9
(C, Ph), 153.2 (C¼O); d (CF) not determined; 19F NMR: d
ꢀ114.þ9 (45%), ꢀ113.2 (55%); MS (ESI): m=z ¼ 857
[ð2MÞ þ Na], 835 [ð2MÞþ þ H], 440 [Mþ þ Na], 418
[Mþ þ H], 362 [Mþ þ H ꢀ C4H8]. HRMS calcd. for
C26H41FNO2 ([M þ H]þ): 418.3121, found: 418.3108.
4.31. Benzyl [2-(cyclododecylidene)-2-fluoroethyl]-p-
methoxybenzylcarbamate (7i)
1H NMR: d 1.23–1.31 (b, 18H, c-Dod), 1.99–2.10 (bm,
4H, CH2-20,120), 3.80 (s, 3H, CH3), 4.04–4.15 (2d, 2H,
JFH ¼ 12:4, CH2-1), 4.48 (b, 2H, CH2, PMB), 5.19 (s,
2H, CH2O), 6.84 (bm, 2H, Hm, PMB), 7.09 (bd, 50% of
2H, Ho, PMB, 1 rotamer), 7.20 (bd, 50% of 2H, Ho, PMB, 1
rotamer), 7.33 (b, 5H, Ph); 13C NMR: d 22.0, 22.6, 23.0–
24.9, 26.4, 27.0 (CH2, c-Dod), 42.2 (d, JFC ¼ 29:0, CH2-1, 1
rotamer), 42.8 (d, JFC ¼ 33:1, CH2-1, 1 rotamer), 48.6 (CH2,
PMB, 1 rotamer), 49.1 (CH2, PMB, 1 rotamer), 54.7 (CH3),
67.1 (CH2O), 113.5 (CHm, PMB), 119.4 (d, JFC ¼ 12:2, C-
10, 1 rotamer), 119.8 (d, JFC ¼ 12:2, C-10, 1 rotamer), 127.6–
129.1 (CH, arom.), 130.8 (Ci, PMB), 136.3 (C, Ph), 150.5 (d,
JFC ¼ 245:7, CF, 1 rotamer), 150.8 (d, JFC ¼ 245:7, CF, 1
rotamer), 155.8 (C¼O, 1 rotamer), 156.0 (C¼O, 1 rotamer),
158.6 (Cp, PMB); 19F NMR: d ꢀ115.8 (t, 49%, JFH ¼ 21:3,
rotamer), ꢀ114.3 (t, 51%, JFH ¼ 18:3, rotamer); MS (ESI):
m=z ¼ 504 [Mþ þ Na], 482 [Mþ þ H]. HRMS calcd. for
C30H41FNO3 ([M þ H]þ): 482.3070, found: 482.3063. N-
protection incomplete, contained 13% of amine [2-(cyclo-
dodecylidene)-2-fluoroethyl]-p-methoxybenzylamine (6i):
Identified signals provided; 1H NMR: d 1.76 (b, 4H,
CH2-20,120), 3.82 (s, 3H, CH3); 13C NMR: d 51.0 (d,
JFC ¼ 29:0, CH2-1), 57.5 (CH3), 113.7 (CHm, PMB),
122.4 (d, JFC ¼ 12:2, C-10), 125.8 (CH), 159.5 (Cp,
PMB); 19F NMR: d ꢀ118.3 (t, JFH ¼ 18:3); MS could
not confirm the nature of the side products.
4.33. Benzyl benzyl-(2,4,4,4-tetrafluoro-3-phenylbut-2-
enyl)carbamate (7k)
1H NMR: d 3.87 (bd, 0.5H, JFH ¼ 14:7, CH2-1, 1 rotamer),
3.99 (bd, 0.5H, JFH ¼ 16:1, CH2-1, 1 rotamer), 4.36–4.44
(bm, 2.5H, PhCH2N; CH2-1, 1 rotamer), 4.60 (d, 0.5H,
JFH ¼ 5:8, 1 rotamer), 5.15–5.17 (b, 2H, CH2O), 6.99–7.45
(bm, 15H, H-arom.); 13C NMR: d 43.6–44.4 (CH2-1), 46.0–
48.1 (CH2-1), 48.2 (PhCH2N), 50.3–51.2 (CH2-1), 66.8–72.5
(CH2O), 126.2–130.0 (CH, Ph), 135.9–139.4 (Ci, C-3), 155.9,
156.2 (C¼O); 19F NMR (1H decoupled): d ꢀ102.1 (q, 55% of
1F, JFF ¼ 24:4, F-2, Z, 1 rotamer), ꢀ101.7 (q, 45% of 1F,
JFF ¼ 24:4, F-2, Z, 1 rotamer), ꢀ97.0 (55% of 1F, JFF ¼ 12:2,
F-2, E, 1 rotamer), ꢀ96.5 (45% of 1F, JFF ¼ 12:2 F-2, E, 1
rotamer), ꢀ59.7 (55% of 3F, JFF ¼ 24:4, F-4, Z, 1 rotamer),
ꢀ59.3 (45% of 3F, JFF ¼ 24:4, F-4, Z, 1 rotamer), ꢀ57.0
(55% of 3F, JFF ¼ 12:2 F-4, E, 1 rotamer), ꢀ56.7 (45%
of 3F, JFF ¼ 12:2, F-4, E, 1 rotamer); MS (ESI): m=z ¼
909 [ð2MÞþ þ Na], 466 [Mþ þ Na], 444 [Mþ þ H],
310 [Mþ þ H ꢀ Cbz], 306 [Mþ þ Na ꢀ CF3 ꢀ Bn], 284
[Mþ þ H ꢀ CF3 ꢀ Bn]. HRMS calcd. for C25H22F4NO2
([M þ H]þ): 444.1587, found: 444.1564.
4.34. Synthesis of C-(1-fluorovinyl)nitrones 8
With a solution of acrylonitrile 2 (1.0 mmol) in Et2O
(20 ml), reduction with DIBALH (2 eq.) was performed in
similar manner as for amines 6. After protonation with MeOH
(1.0 ml), N-benzylhydroxylammonium chloride (1.1 eq.) was
added, after which the mixture was allowed to reach room
temperature, at which it was stirred for 3 h. The mixture was
diluted with Et2O, washed with water (10 ml) and brine
(10 ml), and dried (MgSO4). Column chromatography
4.32. Benzyl (R)-[2-(5-isopropenyl-2-methylcyclohex-2-
enylidene)-2-fluoroethyl]-p-methoxybenzylcarbamate (7j)
1H NMR: d 1.65 (b, 3H, CH3-20), 1.98–2.01 (m, 3H, CH3-
300), 2.16–2.36 (bm, 6H), 2.80 (bd, 1H, J ¼ 16:0, H-50), 3.79
(OCH3, E), 3.81 (OCH3, Z) {comb. 3H}, 3.93–4.20 (m, 2H,
CH2), 4.36–4.76 (m, 4H, 2CH2), 5.20 (s, 2H, CH2O), 5.56 (b,

116
J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
(petroleum ether/Et2O, 3/1 ! 2/3) gave pure nitrones
8 as colorless solids, with yields and isomeric ratios as
listed in Table 3. Silica-induced isomerization was noted
for 8d and e.
(m, 2H, CH2-70), 3.95 (s, CH2-20,30), 3.97 (s, CH2-20,30)
{comb. 4H}, 4.95 (s, 1.8H, CH2N), 5.19 (s, 0.2H, CH2N, E),
7.04 (d, 0.9H, JFH ¼ 11:7, H-1), 7.34–7.48 (m, 5H, Ph), 7.55
(d, 0.1H, JFH ¼ 20:8, H-1, E); 13C NMR: d 23.1 (d,
JFC ¼ 6:1, CH2-90), 25.2 (d, JFC ¼ 3:0, CH2-70), 34.1,
34.4 (CH2-60, CH2-100), 64.1 (CH2-20,30), 70.8 (CH2N),
107.9 (C-50), 125.4 (d, JFC ¼ 32:0, CH-10), 125.6 (C-80),
128.3 (CH, Ph, E), 128.8 (2CH, Ph), 128.9 (CH, Ph), 132.6
(C, Ph), 142.2 (d, JFC ¼ 236:5, CF); 19F NMR: d ꢀ125.5
(90%,þ Z), ꢀ123.1 (10%,þ E); MS (ESI): m=z ¼ 633
[ð2MÞ þ Na], 611 [ð2MÞ þ H], 328 [Mþ þ Na], 306
[Mþ þ H]. HRMS calcd. for C17H21FNO3 ([M þ H]þ):
306.1505, found: 306.1496.
4.35. Benzyl-(2-fluoro-5-phenylpent-2-enylidene)amine
N-oxide (8a)
1H NMR: d 2.50–2.62 (m, 2H, CH2), 2.71–2.78 (m, 2H,
CH2), 4.93 (s, 2H, CH2N), 6.94 (d, 1H, JFH ¼ 8:0, H-1), 7.04
(t, 0.5H, J ¼ 7:7, H-3, other half eclipsed), 7.14–7.31 (m,
6.5H, H-arom., H-3, H-arom.), 7.40 (b, 4H, H-arom.); 13C
NMR: d 25.8 (d, JFC ¼ 4:6, CH2-4), 34.0 (CH2-5), 70.3
(CH2N), 116.0 (d, JFC ¼ 10:7, CH-3), 125.6 (CH, Ph), 126.5
(d, JFC ¼ 58:0, CH-1), 128.0 (CH, Ph), 128.6 (CH, Ph),
128.8 (CH, Ph), 128.9 (CH, Ph), 132.3 (C), 141.0 (C), 149.6
(d, JFC ¼ 318:9, CF); 19F NMR: d ꢀ121.6 (d, JFH ¼ 30:5;
MS (ESI): m=z ¼ 306 [Mþ þ Na], 284 [Mþ þ H]. HRMS
calcd. for C18H19FNO ([M þ H]þ): 284.1451, found:
284.1493.
4.39. Benzyl-[2-(cyclododecylidene)-2-
fluoroethylidene]amine N-oxide (8e)
Formed as a single isomer, isomerizing to a 4:1 mixture
1
during purification by column chromatography: H NMR:
d 1.17–1.44 (b, 16H, CH2), 1.52 (m, 1.6H, CH2, Z), 1.55
(m, 0.4H, CH2, E), 1.96 (dd, 1.6H, J ¼ 7:3, 5.8, CH2, Z),
2.10 (t, 0.4H, 7.0, CH2, E), 2.24 ({dt, 1.6H, J ¼ 7:3, 2.2,
CH2, Z} þ {m, 0.4H, CH2, E}), 4.94 (s, 1.6H, CH2Ph, Z),
5.20 (s, 0.4H, CH2Ph, E), 6.99 (d, 0.8H, JFH ¼ 14:6, H-1,
Z), 7.35–7.45 (m, 5H, Ph), 7.56 (d, 0.2H, JFH ¼ 21:2, H-1,
E); 13C NMR: d 22.3, 22.7, 23.3, 23.5, 23.8 (3Â), 24.8
(CH2-2 to CH2-11), 26.0 (d, JFC ¼ 4:6, CH2-12), 27.4
(CH2-1), 65.6 (d, JFC ¼ 12:2, CH2Ph, E), 70.6 (CH2Ph, Z),
125.6 (d, JFC ¼ 24:4, CH-1, Z), 127.4 (d, JFC ¼ 21:4, CH-
1, E), 128.2 (CH, Ph, E), 128.5 (CH, Ph), 128.6 (CH, Ph),
128.9 (CH, Ph), 132.6 (Ci, Ph, Z), 133.3 (C, Ph, E),
144.0 (d, JFC ¼ 238:0, CF, E), 145.8 (d, JFC ¼ 241:1,
CF, Z); 19F NMR: d ꢀ125.2 (Z), ꢀ121.9 (E); MS
(ESI): m=z ¼ 663 [ð2MÞþ þ H], 332 [Mþ þ H]. HRMS
calcd. for C21H31FNO ([M þ H]þ): 332.2390, found:
332.2372.
4.36. Benzyl-(2-fluoro-4-benzyloxybut-2-enylidene)amine
N-oxide (8b)
1H NMR: d 4.29 (dd, 2H, JFH ¼ 2:2, J ¼ 7:3, CH2-4),
4.52 (s, 2H, PhCH2O), 4.96 (s, 2H, CH2N), 6.98 (d, 1H,
JFH ¼ 7:3, H-1), 7.16 (t, 0.5H, J ¼ 7:3, H-3, other half
eclipsed), 7.26–7.39 (m, 6.5H, H-arom., H-3), 7.41 (b,
4H, H-arom.); 13C NMR: d 62.7 (d, JFC ¼ 7:6, CH2N),
71.2 (CH2-4), 72.2 (PhCH2O), 112.7 (d, JFC ¼ 11:2, CH-
3), 126.8 (d, JFC ¼ 58:0, CH-1), 127.6, 127.8, 128.3, 129.1,
129.4 (each CH, Ph), 132.0 (C), 137.9 (C); d (CF) not
elucidated; 19F NMR, HRMS not measured.
4.37. Benzyl-[2-(4-tert-butylcyclohexylidene)-2-
fluoroethylidene]amine N-oxide (8c)
1H NMR: d 0.83 (s, 8.1H, CH3), 0.85 (s, 0.9 H, CH3, E),
0.96–1.25 (m, 2H), 1.64–1.71 (bm), 1.84–1.88 (bm) {comb.
3H}, 2.20 (bd, 0.9H, J ¼ 13:2), 2.45 (bd, 0.1H, J ¼ 14:2, E),
2.97 (bd, 1H, J ¼ 14:2), 4.94 (s, 2H, CH2N), 7.03 (d, 0.9H,
JFH ¼ 12:4, H-1), 7.28–7.36 (m, 2H, Ph), 7.37–7.49 (m, 3H,
Ph), 7.57 (d, 0.1H, JFH ¼ 21:5, H-1, E); 13C NMR: d 26.0
(CH2), 26.2 (CH2), 27.2 (CH3), 27.6 (CH2), 28.3 (CH2), 32.1
(C, t-Bu), 47.4 (CH-40, c-Hex), 70.6 (CH2N), 125.8 (d,
JFC ¼ 27:5, CH-1), 127.2–128.9 (CH-arom.), 132.7 (C,
Ph); d (C-10, CF) not assigned; 19F NMR: d ꢀ128.6
(90%,þ Z), ꢀ126.0 (10%, E); MS (ESI): m=z ¼ 607
[ð2MÞ þ H], 326 [Mþ þ Na], 304 [Mþ þ H]. HRMS calcd.
for C19H27FNO ([M þ H]þ): 304.2077, found: 304.2062.
4.40. [2-(Adamant-2-ylidene)-2-
fluoroethylidene]benzylamine N-oxide (8f)
Formed as a single isomer, isomerizing slightly during
purification by chromatography; 1H NMR: d 1.76–1.94
(bm, 12H, Ada), 2.42 (b, 1H, CH), 2.67 (b, CH, E), 3.16
(b, 1H, CH), 4.94 (s, 2H, CH2N), 5.30 (s, CH2N, E), 7.04 (d,
1H, JFH ¼ 13:2, H-1), 7.34–7.49 (m, 5H, Ph), 7.55 (d,
JFH ¼ 21:9, H-1, E); 13C NMR: d 27.6 (CH, E), 27.7
(CH-30,50), 29.4 (d, JFC ¼ 6:1, CH-10), 31.9 (d, JFC ¼ 3:0,
CH-30), 36.5 (CH2-60), 38.2 (2CH2), 38.6 (2CH2), 70.8
(CH2N), 125.5 (d, JFC ¼ 27:5, CH-1), 127.0 (d,
JFC ¼ 23:6, CH-1, E), 128.3 (CH, Ph, E), 128.4, 128.8,
129.0 (CH, Ph), 132.8 (C), 137.0 (C-20), 139.4 (d,
JFC ¼ 228:9, CF); 19F NMR: d ꢀ133.4 (94%), ꢀ130.3
(6%); MS (ESI): m=z ¼ 599 [ð2MÞþ þ H], 300
[Mþ þ H]. HRMS calcd. for C19H23FNO ([M þ H]þ):
300.1764, found: 300.1781.
4.38. Benzyl-[2-(1,4-dioxaspiro[4,5]dec-8-ylidene)-2-
fluoroethylidene]amine N-oxide (8d)
1H NMR: d 1.67–1.74 (m, 4H, CH2-60,100), 2.15–2.20 (m,
1.8H, CH2-90), 2.28–2.35 (m, 0.2H, CH2-90, E), 2.46–2.52

J.H. van Steenis et al. / Journal of Fluorine Chemistry 125 (2004) 107–117
117
[16] G. Etemad-Moghadam, J. Seyden-Penne, Synth. Commun. 14 (1984)
565–573.
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