A ring-closing metathesis pathway to fluorovinyl-containing nitrogen heterocyles

Article abstract of DOI:10.1002/ejoc.200500826

The synthesis of highly functionalized fluorinated piperidines is described. The key step in this synthesis is a ring-closing metathesis reaction involving fluoride-substituted olefins, which leads to the corresponding cyclic vinyl fluorides. Several sequences to arrive at differently substituted piperidines have been evaluated. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500826

FULL PAPER
DOI: 10.1002/ejoc.200500826
A Ring-Closing Metathesis Pathway to Fluorovinyl-Containing
Nitrogen Heterocyles
Valeria De Matteis,[a] Floris L. van Delft,[a] Jörg Tiebes,[b] and Floris P. J. T. Rutjes*[a]
Keywords: Ring-closing metathesis / Cyclic amino acids / Vinyl fluoride / Fluorinated heterocycles / Fluoroacrylates
The synthesis of highly functionalized fluorinated piperi-
dines is described. The key step in this synthesis is a ring-
rides. Several sequences to arrive at differently substituted
piperidines have been evaluated.
closing metathesis reaction involving fluoride-substituted (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
olefins, which leads to the corresponding cyclic vinyl fluo-
Germany, 2006)
of the research focuses on the development of such method-
ologies. In this contribution recent progress in the area of
fluoride-substituted heterocycles will be detailed.
Introduction
During the past decades, the pharmaceutical and agro-
chemical industry have shown a growing interest in fluori-
nated organic compounds due to their specific chemical,
biological and physical properties.[1] For example, in the
medicinal chemistry field, 9 out of the 31 new chemical enti-
ties approved in 2002 contained at least one fluorine
atom.[2] The first successful fluorinated drugs were intro-
duced on the market as early as in the 1950s being anaes-
thetic and anti-inflammatory agents.[3] Subsequently, the
interest of the pharmaceutical industry in such a fluorina-
tion approach has grown substantially, and a variety of new
fluorine-containing products have become available in dif-
ferent areas.[4] Besides in the pharmaceutical industry, a
similar expansion in the use of fluorinated compounds was
encountered in the field of agrochemical research and devel-
opment. For example, recent market studies have shown
that the share of fluorine-containing ingredients for crop
protection has grown from 9% in 1988 to 17% in 1999.[5]
Today, there are successfully utilized fluorinated com-
pounds in all major areas of crop protection.[6]
The relevance of the latter class of compounds is exem-
plified in Scheme 1. As an example, betamethasone (1) is a
representative of a class of anti-inflammatory drugs, in
which useful modification of the biological activity was
achieved by the introduction of a carbon–fluoride instead
of a carbon–hydrogen bond.[8] Fluoroneplanocin A (2) acts
as an antiviral drug by inhibiting (S)-adenosylhomocysteine
hydrolase (SAN).[9] Finally, profluazol (3) is a herbicide that
inhibits protoporphyrinogen oxidase.[10]
Generally, the term ‘fluorinated’ refers to the presence
of either a fluoride or a trifluoromethyl substituent. More
particularly, most of the biologically active fluorinated
compounds up to date possess either a fluoride- or trifluor-
omethyl-substituted aromatic system because of the relative
facile access to these structural units. Such (hetero)aro-
matics are either commercially available or can be readily
prepared by well-established synthetic methodologies. In-
versely, until now the synthesis of fluorinated non-aromatic
(hetero)cycles is much less established.[7] In our group, part
Scheme 1.
Considering the general relevance of (partially) saturated
fluorinated heterocycles and the poor accessibility to such
structural units, we set out to explore new synthetic meth-
odology in order to gain access to these molecules. In con-
junction with a continuing program on ring-closing metath-
esis in our group,[11] we decided to study the possibility to
[a] Institute for Molecules and Materials, Radboud University
Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: +31-24-365-3393
E-mail: F.Rutjes@science.ru.nl
[b] Bayer CropScience GmbH,
65926 Frankfurt am Main, Germany
1166
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Highly Functionalized Fluorinated Piperidines
FULL PAPER
obtain the fluoride-containing heterocycles 4 through ring- alkylating reagents, which allow the introduction of the
closing metathesis of the vinyl fluorides 5, which in turn fluoroalkene moiety. In order to introduce a fluoroacrylate
should be readily accessible from allylglycine (6, Scheme 2). moiety, we initially relied on the acid fluoride 9, which has
Besides the study of this key reaction, we also aimed to been described previously in the literature (Scheme 3).[23]
develop suitable pathways to functionalize these scaffolds This sequence commences with 2,2,3,3-tetrafluoropropanol
with biologically relevant pharmacophores (Ar = 4- (7), which upon elimination of HF, followed by acid-medi-
MeC6H4, 2-Cl-5-MeOC6H3, Ar1 = Ph, 2,3-F2C6H3, 2- ated isomerization can be transformed into the desired acyl-
ClC6H4, 2-CF3-3-ClC6H3).
ating agent 9. Besides a reagent that can be used to intro-
duce a fluoracrylate moiety, we used commercially available
1-chloro-2-fluoro-2-propene to introduce the 2-fluoroallyl
substituent. A drawback of this latter reagent is that it is
rather expensive, which prompted us to search for pathways
to an alternative fluoroallylating reagent. Such a reagent
might be accessible by the reduction of 9 into 2-fluoro-2-
propenol. However, because direct reductive methods in our
hands failed to convert the acyl fluoride 9 into the 2-fluoro-
2-propenol, we envisioned that temporary masking of the
double bond might solve this problem. This approach was
chosen in analogy with our own synthesis of the corre-
sponding trifluoromethyl-substituted propenol, where such
a masking strategy was applied successfully.[19] Thus, esteri-
fication of 9, followed by Diels–Alder reaction with cyclo-
pentadiene provided the adduct 11 as a 2:1 mixture of endo-
and exo-products in 40% yield.[24] Again, however, re-
ductive methods failed to produce the intended product 14,
which was planned to undergo a retro-Diels–Alder reaction
using Flash Vacuum Thermolysis (FVT). This failure may
be due to intramolecular displacement of the fluoride with
the generated alkoxide to form an epoxide. Proof for such
a mechanism was obtained from the reaction of 11 with
NaBH4, where we were indeed able to isolate small amounts
of the epoxide 13. Whereas using the stronger reducing
agent LiAlH4, the same reaction may occur, followed by
nucleophilic opening of the epoxide to form the alcohol 12.
More definite proof for loss of the fluoride was obtained
by the tosylation of 11 (TsCl, pyridine, room temp.), fol-
lowed by FVT (oven temperature 600 °C, 0.04 mbar), which
only yielded the tosylated allyl alcohol. A series of other
reducing agents applied under a variety of conditions (e.g.
Scheme 2. RCM approach to fluorinated (hetero)cyclic systems.
Over the years, ring-closing olefin metathesis has become
a reliable approach for the construction of (hetero)cyclic
systems.[12] Initially, applications were restricted to terminal
olefins, but gradually – stimulated by the emergence of
more reactive Ru-carbene and Mo-catalysts – a wide variety
of different substituents located at one of the participating
olefins was reported to successfully undergo a ring-closing
metathesis process. Substituents other than alkyl include he-
teroatoms such as nitrogen,[11g,13] oxygen,[14] phosphorus,[15]
silicon,[16] and boron.[17] Until recently, however, there were
no examples in which halides were tolerated in this conver-
sion. Considering the generally low reactivity of vinyl fluo-
rides in transition-metal-mediated reactions, we reasoned
that such functionalities might well undergo a metathesis
process in the desired fashion. Although Grubbs had shown
previously that 1,1-difluoroethylene forms a stable complex
with ruthenium carbenes,[18] several other groups were
working along the same lines. In fact, during the course of
our work RCM of vinyl fluorides and trifluoromethylated
olefins,[19] the Weinreb group published the first successful
examples of vinyl chloride metathesis[20] and soon there-
after, the Brown group reported the first examples of vinyl
fluoride ring-closing metathesis.[21] More recently, the
Haufe group published examples of fluoroacrylate ring-
closing metathesis.[22] These examples once more emphasize
the versatility of the RCM technique, giving facile access to
potentially useful cyclic vinyl fluoride-containing hetero-
cycles.
In this contribution, we wish to provide a detailed ac-
count of recent research in this area from our group, includ-
ing studies towards the preparation of vinyl fluoride-con-
taining reagents, a series of successful metathesis examples
and elaboration of the resulting products into highly func-
tionalized biologically relevant heterocycles.
Results and Discussion
The synthesis of precursor molecules for vinyl fluoride
metathesis requires the availability of suitable acylating or Scheme 3.
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same reagents at lower temperatures, use of DIBALH at and aimed for new classes of heterocycles, that would allow
low temperatures) also failed to give the target compound straightforward variation of substituents at multiple posi-
14, and generally showed loss of the fluoride substituent. tions. In the new strategy, we intended to start from com-
Because we were not able to come up with alternative path- mercially available 2-amino-4-pentenoic acid, a so-called
ways, we decided to abandon these alternative pathways.
trifunctional amino acid,[25] which allows the use of the ni-
We set out to prepare the fluoroacrylates 15–17 since we trogen and ester substituent as an attachment point for the
had the desired reagents available (Table 1). The yields of introduction of new substituents in a later stage, and thus
15–17 refer to the acylation of the corresponding benzyl- generate series of potentially biologically active cyclic fluo-
amines with 1.0 equiv. of 2-fluoroacryloyl fluoride (9) at rinated amino acid derivatives.
–78 °C in diethyl ether. After stirring overnight at room
The first vinyl fluoride-containing metathesis precursor
temp., the acylated products were isolated in satisfactory 22 was obtained by standard protection of 2-amino-4-pen-
yields considering the volatility of acyl fluoride 9. Whereas tenoic acid (6, allylglycine) as the corresponding Boc-pro-
the first two benzylamines were readily available (Entries 1 tected methyl ester (21), followed by alkylation with 1-
and 2), the preparation of the third benzylamine required a chloro-2-fluoro-2-propene using NaH in DMF in 79%
few steps. This involved condensation of methyl 2-amino- overall yield (Scheme 4).
4-pentenoate with benzaldehyde and subsequent reduction
with NaBH4. The precursors 15–17 were treated with the
2nd generation Grubbs catalyst at 100 °C in toluene for the
indicated time. In all cases, the catalyst was added in small
portions during the reaction, because at these elevated tem-
peratures the catalyst decomposition would lead to incom-
plete conversions. The ring-closing metathesis process also
proceeded at lower temperatures (70 or 80 °C), but again
Scheme 4.
the catalyst had to be added in small portions due to de-
composition and the reaction rate was significantly lower.
Additionally, several experiments were conducted in a mi-
crowave without better results. Thus, the products 18–20
were obtained in good to excellent yields in these RCM re-
actions, giving rise to fluoro-substituted five- and six-mem-
bered α,β-unsaturated lactams. Interestingly, the corre-
sponding seven-membered ring precursor (not shown)
failed to give any cyclization product under these condi-
tions.
Other specifically functionalized metathesis precursors
were also synthesized (Table 2). This sequence also com-
menced with allylglycine (6), which was first transformed
into the sulfonamides 23–25 (TMSCl, CH2Cl2 reflux, then
sulfonyl chloride, Et3N) in good yields, followed by intro-
duction of differently substituted benzylamines at the car-
boxylic acid position (HOBt, EDCI, CH2Cl2, room temp.,
1 h, then benzylamine, room temp., 12 h) to give the amides
26–28. The amide formation also proceeded in very good to
excellent yields. Finally, the 2-fluoro-2-propenyl substituent
was introduced at the sulfonamide nitrogen. As can be seen
from Table 2, this resulted in rather disappointing yields of
the target products 29 and 30 (Entries 1 and 2). A different
solvent (THF) or base (NaHMDS) and variable amounts
of 3-chloro-2-fluoropropene (up to 2 equiv.) did not give
better results. The addition of NaI also did not improve the
reaction, but only the raise of the temperature to 50 °C gave
a significant increase in the yield to 30% for product 31
(Entry 3). The lower alkylation yields compared to 22 might
be explained by the lower nucleophilicity of the sulfon-
amides, but these problems could also be due to the pres-
ence of the amide nitrogen, which may give rise to side
products.
Table 1. RCM of vinyl fluorides.
Gratifyingly, all four precursors 21 and 29–31 underwent
facile cyclization under the previously optimized conditions
(2nd generation Grubbs catalyst, added in portions during
the reaction, toluene, 100 °C, Table 3). Compound 21 gave
a somewhat faster cyclization reaction, with a lower amount
of catalyst. This may have to do with the nature of the side
chain, where the methyl ester interferes less with the cycliza-
tion than the amide substituents in the precursors 29–31. A
variety of other conditions [lower temperatures, lower and
higher catalyst loading (added both in portions and at
At this point, because we had realized successful exam- once), different solvents] was also screened. However, no
ples of fluoroacrylate metathesis, we adjusted our strategy clear difference in yields was observed, the cyclizations pro-
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Highly Functionalized Fluorinated Piperidines
Table 2. Synthesis of RCM precursors.[a]
FULL PAPER
Table 3. RCM to functionalized cyclic amino acid derivatives.
[a] Reagents and conditions. (a) i) Me3SiCl, CH2Cl2, reflux, 2 h, ii)
ArSO2Cl, Et3N, CH2Cl2, room temp., 1 h; (b) HOBt, EDCI,
CH2Cl2, room temp., 1 h, then benzylamine, room temp., 12 h;
(c) NaH, DMF, 3-chloro-2-fluoropropene (1 equiv.), room temp. or
50 °C, 12 h.
ceeded smoothly in very good to excellent yields. The cycli-
zation of 29 (Entry 2) was also carried out in a microwave
(toluene, 100 °C, 300 W, 5 mol-% catalyst, 50 min) to see if
this would lead to a faster reaction and/or a higher yield of
the reaction. However, this did not really lead to an increase
of the yield. In conclusion, a series of functionalized cyclic
vinyl fluoride-containing amino acids was obtained in a
straightforward manner.
[a] The reaction was carried out in a microwave oven: toluene,
100 °C, 300 W, 5 mol-% 2nd generation Grubbs catalyst, 50 min.
Clearly, the previously detailed sequence contains one
low-yielding step, which makes the pathway less suitable for
the production of large libraries of compounds. Therefore,
we investigated whether building block 32 – readily access-
ible in good yields – could be used as a useful starting point
for further functionalization. Initially, we focused on a
pathway consisting of Boc-deprotection/functionalization,
followed by ester hydrolysis/amide formation, which is out-
lined in Scheme 5. TFA-mediated Boc-deprotection pro-
ceeded in excellent yield, but sulfonylation of the nitrogen
(Hünig’s base, sulfonyl chloride, CH2Cl2) gave a rather dis-
appointing 23% yield of the sulfonamide 37. Then, ester
hydrolysis (LiOH, THF/H2O) followed by amide formation
resulted in the target compound 39. However, the low yield
in the amide formation, combined with the poor sulfo-
nylation reaction prompted us to reverse the order of
events.
Thus, ester hydrolysis under similar conditions was again
followed by amide formation with appropriate benzyl-
amines to give the compounds 41 and 42 in good overall
yields (Scheme 6). Boc-deprotection using TFA and subse-
quent sulfonylation (Hünig’s base, sulfonyl chloride,
CH2Cl2) provided the target piperidine derivatives 45 and
39. Although the final step gave a relatively low yield, this Scheme 5.
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mined with a Büchi melting point B-545 apparatus. The microwave
reactions were carried out in a CEM Discover microwave.
sequence gives by far the highest overall yield of all the
sequences that have been evaluated. Also in terms of ease
of functionalization, the latter pathway is preferred: the ver-
satile scaffold 32 was prepared in a scalable manner and
appeared a useful starting point to synthesize series of the
desired piperidines.
Phenyl 2-Fluorobicyclo[2.2.1]hept-5-ene-2-carboxylate (11): To a
solution of 2-fluoroacryloyl fluoride[26] (300 mg, 3.26 mmol) and 4-
(dimethylamino)pyridine (DMAP, 398 mg, 3.26 mmol) in dry
CH2Cl2 (80 mL) was added phenol (307 mg, 3.26 mmol). The mix-
ture was stirred at room temp. until the reaction was complete
(TLC). To this crude reaction mixture was added cyclopentadiene
(4.5 mL, 6.52 mmol) in CH2Cl2 (80 mL) at 110 °C in a sealed-glass
vial for 10 h.[22] After the mixture was cooled to room temp.,
CH2Cl2 and the excess of cyclopentadiene were removed under re-
duced pressure and the residue was purified by column chromatog-
raphy (heptane/EtOAc, 6:1) to give 11 (413 mg, 40%) as a colorless
oil (2:1 mixture of endo/exo-isomers). 1H NMR (300 MHz, CDCl3,
both diastereoisomers): δ = 6.52–6.38 (m, 1 H, CH=CH), 6.17–6.02
(m, 1 H, CH=CH), 3.39–3.20 (m, 1 H, CFCCH), 3.04–2.97 (m, 1
H, CFCCH2CH), 2.58–1.51 (m, 4 H, CF3CCH2, CH2bridge) ppm.
13C NMR (75 MHz, CDCl3, two diastereoisomers, signals sepa-
rated by slashes): δ = 171.06 (d, J = 29.3 Hz, C=OCF), 168.5 (d, J
= 28.1 Hz, C=OCF), 150.4, 142.1/140.3, 132.3/130.9, 129.4, 126.1,
121.3, 101.1 (d, J = 196.1 Hz, CF), 52.07, 49.8/48.6, 48.8, 42.5/41.6,
40.6/40.3 ppm.
(Bicyclo[2.2.1]-5-heptene-2-yl)methanol (12) and Subsequent Flash
Vacuum Thermolysis: A solution of 11 (413 mg, 1.28 mmol) in an-
hydrous diethyl ether (1 mL) was added to a suspension of LiAlH4
(48.5 mg, 1.28 mmol) in anhydrous diethyl ether (1 mL) over
30 min at room temp., and the mixture was stirred for 5 h. EtOAc
(1 mL) was added slowly, followed by saturated aqueous Na2SO4
(a few drops) and solid Na2SO4. After stirring for a few min, the
mixture was filtered. The solvent was evaporated and the residue
was purified by column chromatography (heptane/EtOAc, 6:1) to
give 12 (133 mg, 73%) as a colorless oil (2:1 mixture of endo/exo-
Scheme 6.
1
isomers). H NMR (300 MHz, CDCl3, both diastereoisomers, sig-
nals separated by slashes): δ = 6.13–5.92 (m, 2 H, CH=CH), 3.72–
3.49/3.41–3.21 (m, 2 H, CH2OH), 2.92–2.80 (m, 2 H, C=CCH,
C=CCH), 1.85–1.56 (m, 2 H, C=CCHCH2), 1.48–1.36 (m, 2 H,
CH2bridge) ppm. This product was directly subjected to the tosyl-
ation reaction. As solution of 12 (133 mg, 094 mmol) and tosyl
chloride (193 mg, 1.012 mmol) in dry pyridine (0.8 mL) was stirred
at room temp. for 24 h. The reaction mixture was poured into cold
1  HCl and extracted with diethyl ether. The extract was washed
with dilute aqueous HCl, aqueous NaHCO3, brine and dried
(MgSO4). After evaporation of the solvent, the corresponding tos-
ylate (216 mg, 77%) was obtained as a yellow oil. Subjection of the
tosylate (148 mg, 0.5 mmol) to flash vacuum thermolysis (600 °C,
0.04 mbar) provided allyl tosylate (102 mg, 79%) as a colorless oil.
1H NMR (400 MHz, [D8]THF): δ = 7.78 (d, J = 8.5 Hz, 2 H, ArH),
7.40 (d, J = 8.2 Hz, 2 H, ArH), 5.87–5.78 (m, 1 H, H2C=CH), 5.29
(d, J = 17.2 Hz, 1 H, CH=CH), 5.18 (d, J = 11.5 Hz, 1 H,
CH=CH), 4.49 (d, J = 5.8 Hz, 2 H, CH2O), 2.42 (s, 3 H, CH3)
ppm.
Conclusions
Generally applicable routes were developed for the syn-
thesis of vinyl fluoride-containing building blocks, which
may be relevant for the agrochemical and pharmaceutical
industry. Key step in this sequence is the ring-closing me-
tathesis of vinyl fluorides, which were shown to readily un-
dergo a ruthenium-mediated cyclization process in very
good yields. Furthermore, different pathways were evalu-
ated to probe combinatorial approaches resulting in series
of highly functionalized, fluorinated and potentially bioac-
tive cyclic amino acid derivatives.
Experimental Section
General Information: All reactions were carried out under dry nitro-
gen. Solvents were distilled from the appropriate drying agents im-
mediately prior to use. Infrared (IR) spectra were recorded with an
ATI Mattson Genesis Series FTIR spectrometer and absorptions
are reported in cm–1. NMR spectra were recorded with a Bruker
DMX300 (300 MHz) spectrometer from CDCl3 solutions (unless
otherwise reported) using TMS as internal standard. Mass spectra
and accurate mass measurements were carried out with a Fisons
(VG) Micromass 7070E or a Finnigan MAT900S instrument. Rf
values were obtained by thin layer chromatography (TLC) on silica
gel-coated plates (Merck silica gel 60 F254) with the indicated sol-
vent (mixture). Flash chromatography was performed with Acros
Organics silica gel (0.035–0.070 nm). Melting points were deter-
Epoxide 13: To a solution of 11 (300 mg, 1.29 mmol) in MeOH
(2 mL), at 0 °C, NaBH4 (59 mg, 1.55 mmol) was added in small
portions. The reaction mixture was stirred for 3 h, quenched with
saturated aqueous NaHCO3 (2 mL) and extracted with diethyl
ether (3×2 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 and brine, dried (MgSO4) and the sol-
vents evaporated. The residue was purified by column chromatog-
raphy (heptane/EtOAc, 10:1) to give 13 (19 mg, 12%) as a colorless
oil. This product also contained several other minor impurities. 1H
NMR (200 MHz, CDCl3): δ = 6.37–6.33 (m, 1 H, CH=CH), 6.05–
6.02 (m, 1 H, CH=CH), 3.88–3.70 (m, 3 H, CH2O, COCH), 3.05
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Highly Functionalized Fluorinated Piperidines
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(br. s, 1 H, COCH2CH), 2.81 (br. s, 2 H, COCH2), 1.58–1.51 (m,
General Procedure for the RCM Reactions: To a 0.01  solution of
2 H, CH2bridge) ppm. GC-LRMS: calcd. for C8H10O [M+] 122, the diene in dry toluene under an inert atmosphere, the 2nd genera-
found 122.
tion Grubbs catalyst was added at 100 °C. Stirring was continued
until the reaction was complete (indicated by TLC or GC), fol-
lowed by concentration of the reaction mixture and subsequent pu-
rification with column chromatography.
N-Allyl-N-benzyl-2-fluoroacrylamide (15): A solution of N-allyl-N-
benzylamine[27] (240 mg, 1.63 mmol) and triethylamine (0.227 mL,
164.9 mg, 1.63 mmol) in Et2O (1 mL) was added dropwise at
–78 °C to a solution of 2-fluoroacryloyl fluoride (9, 150 mg,
1.63 mmol) in Et2O (1 mL). The reaction mixture was stirred over-
night thereby slowly reaching room temp. The mixture was concen-
trated and the residue was purified using column chromatography
(heptane/EtOAc, 6:1) to give the fluoride 15 (145 mg, 41%) as a
colorless oil. IR (neat, cm–1): ν = ν = 3062, 2987, 2887, 2800, 1726,
1-Benzyl-3-fluoro-1,5-dihydropyrrol-2-one (18): To a solution of N-
allyl-N-benzyl-2-fluoroacrylamide (15, 50 mg, 0.23 mmol) in dry
toluene (20 mL) the 2nd generation Grubbs catalyst (7 mol-%) was
added at 100 °C in small portions. The reaction was complete in
4 h. The mixture was evaporated and the product was purified
using column chromatography (heptane/EtOAc, 3:1) to give 18
(44 mg, 99%) as a white solid.[28] M.p. 37–41 °C. IR (neat, cm–1):
˜
˜
1443, 1261, 1174, 1080, 1016, 800. 1H NMR (300 MHz, CDCl3): δ
= 7.35–7.23 (m, 5 H, ArH), 5.83–5.70 (m, 1 H, CH2=CH), 5.32
(dd, J = 3.5, 47.3 Hz, 1 H, FC=CHtrans), 5.21 (dd, J = 3.4, 16.8 Hz,
1 H, FC=CHcis), 5.28–5.04 (m, 2 H, CH2=CH), 4.57 (s, 2 H,
CH2Ph), 3.88 (br. s, 2 H, CHCH2) ppm. 13C NMR (75 MHz,
CDCl3, some signals refer to rotamers, C=O signal is lacking): δ =
157.5 (d, J = 271.7 Hz, CF), 132.8, 128.7, 127.6, 118.5, 99.8 (d, J
= 14.4 Hz, CCF), 50.8/50.1, 48.4/47.9 ppm. HRMS (EI): calcd. for
C13H14FNO [M+] 219.1059, found 219.1059.
ν = 3058, 2920, 2854, 1697, 1664, 1452, 1232, 1219, 988, 926, 780,
˜
720, 689. 1H NMR (300 MHz, CDCl3): δ = 7.35–7.20 (m, 5 H,
ArH), 6.24–6.21 (m, 1 H, FC=CH), 4.63 (s, 2 H, CH2Ph), 3.74–
3.72 (m, 2 H, CHCH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
162.7 (d, J = 31.2 Hz, FCC=O), 152.7 (d, J = 275.7 Hz, CF), 136.2,
128.8, 128.1, 127.8, 112.7 (d, J = 7.4 Hz, HC=CF), 47.1, 45.5 (d,
J = 5.4 Hz, CH2CH=CF) ppm. HRMS (EI): calcd. for C11H10FNO
[M+] 191.0764, found 191.0740.
N-Benzyl-N-(but-3-enyl)-2-fluoroacrylamide (16): A solution of N-
benzyl-N-(but-3-enyl)amine[27] (322 mg, 2.01 mmol) and triethyl-
amine (0.31 mL, 2.23 mmol) in Et2O (2 mL) was added dropwise
at –78 °C to a solution of 2-fluoroacryloyl fluoride (9, 205 mg,
2.23 mmol) in Et2O (2 mL). The reaction mixture was stirred over-
night thereby slowly reaching room temp. The mixture was concen-
trated and the residue was purified using column chromatography
(heptane/EtOAc, 6:1) to give 16 (140 mg, 30%) as a colorless oil.
1-Benzyl-3-fluoro-5,6-dihydro-1H-pyridin-2-one (19): To a solution
of
N-benzyl-N-(3-butenyl)-2-fluoroacrylamide
(16,
34 mg,
0.15 mmol) in dry toluene (10 mL) the 2nd generation Grubbs cata-
lyst (7 mol-%) was added at 100 °C in small portions. The reaction
was complete in 4 h. The mixture was evaporated and the product
was purified using column chromatography (heptane/EtOAc, 3:1)
to give 19 (25 mg, 80%) as an amorphous solid. IR (neat, cm–1): ν
˜
= 3058, 2920, 1640, 1428, 1318, 1155, 910, 730, 690. 1H NMR
(300 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H, ArH), 5.97 (dt, J = 4.5,
10.5 Hz, 1 H, FC=CH), 4.61 (s, 2 H CH2Ph), 3.32 (t, J = 7.3 Hz,
2 H, NCH2CH2), 2.39–2.35 (m, 2 H, NCH2CH2) ppm. 13C NMR
(75 MHz, CDCl3, some signals refer to rotamers): δ = 159.6 (d, J
= 30.6 Hz, FCC=O), 149.7 (d, J = 253.3 Hz, CF), 136.6, 128.6,
128.0, 127.6, 112.7 (d, J = 14.5 Hz, HC=CF), 50.0/49.9, 44.8, 21.6
(d, J = 5.6 Hz, CH2CH=CF) ppm. HRMS (EI): calcd. for
C12H12FNO [M+] 205.0903, found 205.0910.
IR (neat, cm–1): ν = 3062, 3036, 2924, 2843, 1640, 1424, 1359, 1178,
˜
996, 919, 884, 728, 689. 1H NMR (300 MHz, CDCl3): δ = 7.32–
7.22 (m, 5 H, ArH), 5.74–5.65 (m, 1 H, CH2=CH), 5.38 (br. s, 1
H, FC=CH), 5.21 (br. s, 1 H, FC=CH), 5.13–5.0 (m, 2 H, CH2 =
CH), 4.61 (s, 2 H CH2Ph), 3.36 (t, J = 7.5 Hz, 2 H, NCH2CH2),
2.32 (q, J = 7.3 14.6 Hz, 2 H, NCH2CH2) ppm. 13C NMR
(75 MHz, CDCl3, some signals refer to rotamers): δ = 162.3 (d, J
= 30.1 Hz, FCC=O), 157.6 (d, J = 269.2 Hz, CF=C), 136.3, 134.7/
134.0, 128.6, 127.6, 126.9, 117.6–116.9 (m, CH2 = CH), 99.8–99.1
(m, CH2 = CF), 52.2–52.0/49.2–49.1 (m, NCH2CH2), 47.3–47.2/
45.5–45.3 (m, CH2Ph), 33.5–33.3/31.7–31.5 (m, NCH2CH2) ppm.
HRMS (EI): calcd. for C14H16FNO [M+] 233.1216, found
233.1209.
[1-Benzyl-5-fluoro-6-oxo-1,2,3,6-tetrahydropyridin-2-yl]methyl
2-
Fluoroacrylate (20): To a solution of 2-fluoroacrylic acid 2-[benzyl-
(2-fluoroacryloyl)amino]pent-4-enyl ester (17, 102 mg, 0.30 mmol)
in dry toluene (40 mL) the 2nd generation Grubbs catalyst (4 mol-
%) was added at 100 °C in small portions. The reaction was com-
plete in 4 h. The mixture was evaporated and the residue was puri-
fied using column chormatography (heptane/EtOAc, 3:1) to give 20
2-[Benzyl(2-fluoroacryloyl)amino]pent-4-enyl 2-Fluoroacrylate (17):
A
solution of
N-benzyl-2-amino-4-pentenol[27]
(425 mg,
2.23 mmol) and triethylamine (0.31 mL, 2.23 mmol) in Et2O
(2 mL) was added dropwise at –78 °C to a solution of 2-fluoroacry-
loyl fluoride (9, 205 mg, 2.23 mmol) in diethyl ether (2 mL). The
reaction mixture was stirred overnight reaching slowly the room
temp. The mixture was concentrated and the residue was purified
using column chromatography (heptane/EtOAc, 6:1) to give 17
(91 mg, 99%) as an amorphous white solid. IR (neat, cm–1): ν =
˜
3050, 2915, 2850, 1744, 1658, 1450, 1260, 1156, 1022, 798, 698. 1H
NMR (300 MHz, CDCl3): δ = 7.33–7.13 (m, 5 H, ArH), 5.87–5.83
(m, 1 H, NCFC=CH), 5.65 (dd, J = 3.6, 42.9 Hz, 1 H, FC=CH),
5.38–5.30 (m,
2 H, FC=CH, CH2Ph), 4.35–4.21 (m, 2 H,
CHCH2O), 4.06 (d, J = 14.4, 1 H, CH2Ph), 3.73–3.67 (m, 1 H,
NCH), 2.33 (s, 2 H, NCHCH2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 159.5 (d, J = 36.5 Hz, FCC=ON), 158.2 (d, J = 30.6 Hz,
FCC=OO), 152.2 (d, J = 268.8 Hz, CH2 = CF), 148.8 (d, J =
260.8 Hz, CH=CF) 136.5, 128.6, 127.7, 125.0, 110.0 (d, J =
15.0 Hz, CH=CF), 103.6 (d, J = 14.6 Hz, CH2 = CF), 63.8, 52.3,
48.5, 23.4 ppm. HRMS (EI): calcd. for C16H15F2NO3 [M+]
307.1020, found 307.1021.
(149 mg, 20%) as a colorless oil. IR (neat, cm–1): ν = 3010, 2919,
˜
1744, 1643, 1446, 1424, 1317, 1163, 988, 926, 780, 720, 689. 1H
NMR (300 MHz, CDCl3): δ = 7.28–7.23 (m, 5 H, ArH), 5.70–5.56
(m,
1 H, CH2=CH), 5.56 (dd, J = 3.3, 42.9 Hz, 1 H,
NCFC=CHtrans), 5.29 (dd, J = 3.3, 13.0 Hz, 1 H, NCFC=CHcis),
5.34–5.05 (m, 4 H, CH2 = CF, CH2 = CH), 4.68 (br. s, 2 H,
CH2Ph), 4.43 (br. s, 2 H, CHCH2O), 4.25 (br. s, 1 H, CHCH2O),
2.44 (br. s, 2 H, NCHCH2) ppm. 13C NMR (75 MHz, CDCl3, some
signals refer to rotamers, signals of the quaternary carbons are not
Methyl 2-[tert-Butoxycarbonyl-(2-fluoroallyl)amino]pent-4-enoate
visible): δ = 135.0, 128.6, 128.0, 127.4, 118.6/118.6, 102.8–102.4 (m, (22): To a suspension of NaH (155 mg, 6.5 mmol) in DMF (10 mL)
FC=CH2), 99.2–99.8 (m, FC=CH2), 64.8/64.8, 57.1/56.9, 56.7/56.6,
was added the Boc-protected allylglycine methyl ester (21,[29]
34.14 ppm. HRMS (EI): calcd. for C18H19F2NO3 [M+] 335.1333, 740 mg, 3.20 mmol) at room temp. After stirring for 15 min, 3-
found 335.1332.
chloro-2-fluoropropene (301 mg, 3.20 mmol) was added. The reac-
Eur. J. Org. Chem. 2006, 1166–1176
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1171

V. De Matteis, F. L. van Delft, J. Tiebes, F. P. J. T. Rutjes
FULL PAPER
tion was stirred for 12 h, quenched with water (7 mL) and extracted
with Et2O (3×10 mL). The ether layer was dried MgSO4, the sol-
vent evaporated and the residue purified using column chromatog-
raphy (heptane/EtOAc, 10:1) to give 22 (726 mg, 79%) as a color-
H, HCCH=CH2), 2.40 (s, 3 H, CH3), 2.23–2.13 (m, 1 H,
HCCH=CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.7, 163.7
(d, J = 249 Hz, CF), 144.0, 137.6, 136.4, 133.5, 129.6, 128.5, 127.7,
127.4, 118.0, 94.7 (d, J = 17.5 Hz, FC=C), 60.1, 44.7 (d, J =
30.2 Hz, FCCH2), 44.1, 33.1, 21.9 ppm. HRMS (EI): calcd. for
less oil. IR (neat, cm–1): ν = 2976, 1744, 1701, 1450, 1368, 1243,
˜
1
1165, 1001, 932, 862, 780. H NMR (300 MHz, CDCl3): δ = 5.84– C22H25FN2O3S [M+] 416.157, found 416.1572.
5.70 (m, 1 H, CH2=CH), 5.14–5.05 (m, 2 H, HC=CH, FC=CH),
2-[(5-Chloro-2-methoxyphenyl)sulfonyl(2-fluoroallyl)amino]-N-(3,4-
4.69–4.39 (m, 3 H, HC=CH, FC=CH, COCH), 4.12–3.71 (m, 2 H,
FCCH2), 3.70 (s, 3 H, CH3), 2.77–2.66 (m, 1 H, HCCH=CH2),
2.65–2.53 (m, 1 H, HCCH=CH2), 1.44 (s, 9 H, 3CH3) ppm. 13C
NMR (75 MHz, CDCl3, some signals refer to rotamers): δ = 171.1/
170.9, 162.1 (d, J = 259 Hz, CF)/159.5 (d, J = 255 Hz, CF), 154.8/
154.3, 133.9/131.9, 119.2/117.8, 92.6 (d, J = 16.1 Hz, FC=C), 91.4
(d, J = 17.8 Hz, FC=C), 81.2/81.0, 60.1/58.9, 53.0/52.1, 48.1 (d, J
= 33.0 Hz, FCCH2)/46.6 (d, J = 35.6 Hz, FCCH2), 35.0/34.0, 28.4
ppm. HRMS (EI): calcd. for C14H22FNO4 [M+] 287.1533, found
287.1534.
difluorobenzyl)-4-pentenamide (30): To a suspension of allylglycine
(2.00 g, 17.4 mmol) in CH2Cl2 (35 mL) was added Me3SiCl
(2.2 mL, 17.4 mmol). The mixture was heated at reflux for 2 h,
Et3N (4.87 mL, 34.8 mmol) was added, followed by a solution of
5-chloro-2-methoxybenzenesulfonyl chloride (4.2 g, 17.4 mmol) in
CH2Cl2 (17.5 mL). The resulting mixture was vigorously stirred for
1 h, MeOH (2.78 mL, 20.0 mmol) was added and the mixture was
evaporated. The residue was dissolved in water and brought to pH
8 using aqueous K2CO3. The aqueous layer was washed with di-
ethyl ether (3×10 mL), acidified to pH 1 using 1  hydrochloric
acid (1 ) and extracted with EtOAc (3×20 mL). The combined
organic layers were dried (MgSO4) and to afford 24 (4.41 g, 80%)
as a yellow solid. A solution of the crude acid 24 (1.00 g,
3.13 mmol) in CH2Cl2 (65 mL) was stirred for 1 h at with HOBt
(466 mg, 3.45 mmol) and EDCI (662 mg, 3.45 mmol). 3,4-Difluo-
robenzylamine (1.1 mL, 9.39 mmol) was added, the mixture was
stirred for 12 h and the solvent was evaporated. The residue was
dissolved in EtOAc (20 mL), washed with brine (10 mL) and aque-
ous NaHCO3 (10 mL). The combined water phases were reex-
tracted with EtOAc (3×10 mL), and the combined organic layers
were dried (MgSO4) and the solvents evaporated. The residue was
crystallized (hepthane/Et2O, 3:1) to give 27 (1.21 g, 87%) as a white
N-Benzyl-2-[(2-fluoroallyl)(p-tosyl)amino]-4-pentenamide (29): To a
suspension of allylglycine (0.57 g, 5.00 mmol) in CH2Cl2 (10 mL)
was added Me3SiCl (0.54 g, 5.00 mmol). The mixture was heated
at reflux for 2 h, Et3N (1.4 mL, 10.0 mmol) was added, followed
by addition of a solution of p-toluenesulfonyl chloride (0.95 g,
5.00 mmol) in CH2Cl2 (5 mL).[30] The resulting mixture was vigor-
ously stirred for 1 h at room temp., MeOH (0.81 mL, 20.0 mmol)
was added, and the mixture was evaporated. The residue was dis-
solved in water and brought to pH 8 using aqueous K2CO3. The
aqueous layer was washed with diethyl ether (3×10 mL), acidified
to pH 1 using 1  hydrochloric acid (1 ) and extracted with EtOAc
(3×20 mL). The combined organic layers were dried (MgSO4) and
the solvent was evaporated to afford 23 (1.15 g, 86%) as a white solid. M.p. 115–118 °C. IR (neat, cm–1): ν = 3309, 3261, 3097, 3075,
˜
solid. The crude acid 23 (1.15 g, 4.29 mmol) was dissolved in
CH2Cl2 (86 mL) and stirred for 1 h with 1-hydroxybenzotriazole
(HOBt, 0.637 g, 4.72 mmol) and 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (EDCI, 0.903 g, 4.72 mmol). Ben-
zylamine (1.4 mL, 12.9 mmol) was added and the mixture was
stirred for 12 h. The solvent was evaporated and the residue was
purified using column chromatography (heptane/EtOAc, 3:1 to 1:1)
2980, 2894, 1653, 1515, 1437, 1329, 1282, 1156, 1113, 1070, 1014,
897, 815, 646. 1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J =
3.2 Hz, 1 H, ArH), 7.55–7.52 (m, 1 H, ArH), 7.15–6.92 (m, 4 H, 1
H, ArH), 6.85 (br. s, 1 H, C=ONH), 5.57–5.44 (m, 2 H, CH2=CH,
TsNH), 5.15–5.05 (m, 2 H, H2C=CH), 4.39–4.25 (m, 2 H, NCH2),
3.95 (s, 3 H, OCH3), 3.74 (t, J = 8.0 Hz, 1 H, COCH), 2.61–2.53
(m, 1 H, HCCH=CH2), 2.34–2.24 (m, 1 H, HCCH=CH2) ppm.
to give 26 (1.18 g, 80%) as a white solid. M.p. 141–144 °C, IR (neat, 13C NMR (75 MHz, CDCl3): δ = 170.3, 154.9, 150.1 (dd, J = 47.1,
cm–1): ν = 3322, 3235, 3067, 3036, 2920, 1645, 1554, 1455, 1338,
247.0 Hz, ArF), 149.9 (dd, J = 47.1, 247.0 Hz, ArF), 135.0–134.9
˜
1161, 1070, 927, 815, 698. 1H NMR (300 MHz, CDCl3, 25 °C, (m, ArF), 134.8, 132.0, 129.8, 127.8, 125.8, 123.6–123.4 (m, ArF),
TMS): δ = 7.69 (d, J = 8.4 Hz, 2 H, Ph), 7.32–7.17 (m, 7 H, Ph), 119.9, 117.0 (dd, J = 17.2, 61.7 Hz, ArF), 116.9 (dd, J = 17.2,
6.72 (br. s, 1 H, C=ONH), 5.44–5.30 (m, 1 H, CH2=CH), 5.06–
4.95 (m, 3 H, TsNH, H2C=CH), 4.43–4.30 (m, 2 H, NCH2Ph), calcd. for C19H19ClF2N2O4S (M+) 444.0722, found 444.0718. To a
3.78–3.71 (m, 1 H, COCH), 2.54–2.43 (m, 1 H, HCCH=CH2), 2.43 suspension of NaH (70 mg, 2.88 mmol) in DMF (6 mL) was added
(s, 3 H, CH3), 2.29–2.20 (m, 1 H, HCCH=CH2) ppm. 13C NMR at 10 °C 27 (640 mg, 1.44 mmol). After stirring for 15 min, 3-
61.7 Hz, ArF), 113.6, 56.6, 56.5, 42.5, 37.1 ppm. HRMS (EI):
(75 MHz, CDCl3, 25 °C): δ = 170.2, 144.2, 137.7, 136.3, 132.2,
129.9, 128.7, 127.7, 127.6, 127.4, 120.3, 56.1, 43.7, 37.0, 21. ppm.
HRMS (EI): calcd. for C19H22N2O3S [M+] 358.1351, found
358.1348. To a solution of 26 (468 mg, 1.31 mmol) in DMF
(3.5 mL) was added NaHMDS (135 µL of a 1  solution in THF,
1.36 mmol), 3-chloro-2-fluoropropene (123 mg, 1.36 mmol) and
NaI (8.5 mg, 0.055 mmol). After stirring at room temp. for 10 h,
water (5 mL) was added and the mixture it was extracted with
EtOAC (3×5 mL). The combined organic layers were washed with
water (3×5 mL), brine (3×5 mL), dried (Na2SO4) and the solvents
evaporated. The residue was purified using column chromatog-
raphy (heptane/EtOAc from, 3:1 to 1:1) to give 29 (55 mg, 9%) as
chloro-2-fluoropropene (135 mg, 1.44 mmol) was added dropwise
at room temp. The reaction was stirred for 12 h, quenched with
water (6 mL) and extracted with Et2O (3×6 mL). The ether layers
were dried (MgSO4), evaporated and the residue was purified using
column chromatography (heptane/EtOAc, 3:1 to 1:1) to give 30
(30 mg, 10%) as a colorless oil. IR (neat, cm–1): ν = 3379, 3087,
˜
2950, 2846, 1679, 1607, 1585, 1519, 1478, 1434, 1390, 1333, 1273,
1155, 1111, 1067, 1015, 913, 877, 817, 735, 647, 584. 1H NMR
(400 MHz, CDCl3): δ = 7.89 (d, J = 2.4 Hz, 1 H, ArH), 7.53–7.50
(m, 1 H, ArH), 7.15–7.00 (m, 4 H, ArH, NH), 6.92 (d, J = 8.8 Hz,
1 H, ArH), 5.37–5.27 (m, 1 H, CH2=CH), 4.99 (dd, J = 1.2,
16.8 Hz, 1 H, HHC=CH), 4.88 (dd, J = 0.8, 10.0 Hz, 1 H,
HHC=CH), 4.62–4.57 (m, 1.5 H, FC=CH2), 4.46–4.25 (m, 4.5 H,
FC=CH2, NCH2, NCH2CF), 3.88 (s, 4 H, CH3, COCH), 2.89–2.82
(m, 1 H, HCCH=CH2), 2.35–2.27 (m, 1 H, HCCH=CH2) ppm.
a yellow oil. IR (neat, cm–1): ν = 3378, 3317, 3062, 3032, 2980,
˜
2924, 1675, 1528, 1338, 1156, 1087, 923, 815, 698, 664, 543. 1H
NMR (300 MHz, CDCl3): δ = 7.67–7.64 (m, 2 H, Ph), 7.32–7.22
(m, 7 H, Ph), 6.78 (br. s, 1 H, NH), 5.37–5.23 (m, 1 H, CH2=CH), 13C NMR (100 MHz, CDCl3, some signals refer to rotamers): δ =
4.93–4.78 (m, 2 H, H2C=CH), 4.66–4.25 (m, 5 H, FC=CH2,
169.2, 160.1 (d, J = 259.2 Hz, C=CF), 155.3, 150.0 (dd, J = 58.4,
NCH2Ph, COCH), 4.15–3.90 (m, 2 H, FCCH2), 2.79–2.70 (m, 1 247.1 Hz, ArF), 149.9 (dd, J = 58.1 Hz, 247.2 Hz, ArF), 134.9–
1172
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1166–1176

Highly Functionalized Fluorinated Piperidines
FULL PAPER
134.8 (m, ArF), 134.7, 133.5, 131.0, 128.7, 125.7, 123.7 (m, ArF),
118.0, 117.3 (d, J = 18.1 Hz, ArF), 116.8 (d, J = 17.7 Hz, ArF),
113.6, 94.9 (d, J = 17.7 Hz, C=CF), 59.3, 56.4, 44.9 (d, J = 29.9 Hz,
C H 2 C F ) , 4 2 . 9 , 3 2 . 6 p p m . H R M S ( E I ) : c a l c d . f o r
C22H23ClF3N2O4S [M+ + H] 503.0965, found 503.1019.
calcd. for C22H29Cl2FN2O4S [M+ + H] 501.0786, found 501.0818.
1-tert-Butyl 2-Methyl 5-Fluoro-3,6-dihydropyridine-1(2H),2-dicar-
boxylate (32): To a solution of 21 (412 mg, 1.44 mmol) in dry tolu-
ene (160 mL) the 2nd generation Grubbs catalyst (2.5 mol-%) was
added at 100 °C in small portions. The reaction was finished in
30 min. The solvent was evaporated and the product purified using
column chromatography (heptane/EtOAc, 10:1) to give 32 (369 mg,
N-(2-Chlorobenzyl)-2-[(5-chloro-2-methoxyphenylsulfonyl)(2-fluo-
roallyl)amino]-4-pentenamide (31): To a suspension of allylglycine
(2.00 g, 17.4 mmol) in dichloromethane (35 mL) was added Me3-
SiCl (2.2 mL, 17.4 mmol). The mixture was heated at reflux for 2 h,
Et3N (4.87 mL, 34.8 mmol) was added, followed by a solution of
5-chloro-2-methoxybenzenesulfonyl chloride (4.20 g, 17.4 mmol) in
CH2Cl2 (17.5 mL). The resulting mixture was vigorously stirred for
1 h, MeOH (2.78 mL, 20.0 mmol) was added and the mixture was
evaporated. The residue was dissolved in water and brought to pH
8 using aqueous K2CO3. The aqueous layer was washed with di-
ethyl ether (3×10 mL), acidified to pH 1 with 1  hydrochloric acid
(1 ) and extracted with EtOAc (3×20 mL). The combined organic
layers were dried (MgSO4), and the solvent was evaporated to af-
ford 25 (4.41 g, 80%) as a yellow solid. A solution of the crude
acid 25 in CH2Cl2 (35 mL) was stirred for 1 h with HOBt (233 mg,
1.75 mmol) and EDCI (331 mg, 1.75 mmol). 2-Chlorobenzylamine
(250 µL, 1.75 mmol) was added, the mixture was stirred for 12 h
and the solvent was evaporated. The residue was dissolved in
EtOAc (20 mL), washed with brine (10 mL) and aqueous NaHCO3
(10 mL). The water layer was reextracted with EtOAc (3×10 mL),
and the combined organic layers were dried (MgSO4) and the sol-
vents evaporated. The residue was crystallized (heptane/Et2O, 3:1)
to give 28 (700 mg, 99%) as a white solid. M.p. 90–100 °C. IR(neat,
99%) as a colorless oil. IR (neat, cm–1): ν = 2971, 2863, 1740, 1697,
˜
1407, 1368, 1329, 1156, 1104, 1022, 888, 811. 1H NMR (300 MHz,
CDCl3): δ = 5.27–5.22 (m, 1 H, FC=CH), 5.00–4.98 (m, 1 H,
COCH), 4.09 (d, J = 17.4 Hz, 1 H, FCCH), 3.84 (d, J = 18.6 Hz,
1 H, FCCH), 3.71 (s, 3 H, CH3), 2.69–2.50 (m, 2 H, H2CCH=CF),
1.49/1.46 (s, 9 H, 3CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
171.3, 155.0, 154.9 (d, J = 248.7 Hz, CF), 98.4 (d, J = 13.5 Hz,
FC=C), 81.2, 52.7, 51.1, 41.6 (d, J = 39.6 Hz, FCCH2), 28.6, 24.3
ppm. HRMS (technique): calcd. for C12H18FNO4 [M+] 259.1220,
found 259.1220.
N-Benzyl-5-fluoro-1-(p-tosyl)-1,2,3,6-tetrahydropyridine-2-carbox-
amide (33): To a solution of 29 (41 mg, 98 µmol) in dry toluene
(4 mL) in a resealable vial was added the 2nd generation Grubbs
catalyst (2.4 mg, 2 mol-%). The mixture was heated in a microwave
for 20 min at 300 W. The reaction was followed by GC and new
portions of catalyst were added, followed by heating until the reac-
tion was complete (at total of 5 mol-% of catalyst, 50 min heating).
The mixture was evaporated and the residue was purified using
column chromatography (heptane/EtOAc, 3:1) to give 33 (35 mg,
74%) as a white solid: M.p. 90–93 °C. IR (neat, cm–1): ν = 3378,
˜
3356, 3317, 3062, 3028, 2924, 2863, 1671, 1524, 1342, 1165, 1091,
962, 815, 698, 569. 1H NMR (300 MHz, CDCl3): δ = 7.66–7.63 (m,
2 H, Ph), 7.33–7.20 (m, 7 H, Ph), 6.90 (br. s, 1 H, NH), 5.16–5.08
(m, 1 H, FC=CH), 4.58–4.34 (m, 3 H, NCH2Ph, COCH), 4.17 (d,
J = 17.4 Hz, 1 H, FCCH), 3.76 (d, J = 18 Hz, 1 H, FCCH), 2.84–
2.76 (m, 1 H, HCCH=CF), 2.41 (s, 3 H, CH3), 1.87–1.80 (m, 1 H,
HCCH=CF) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.1, 152.5
(d, J = 252.2 Hz, CF), 144.4, 137.7, 135.5, 130.0, 128.7, 127.5,
127.4, 127.0, 100.0 (d, J = 13.5 Hz, FC=C), 54.0, 44.2, 41.1 (d, J
= 39.3 Hz, FCCH2), 21.9, 21.4 ppm. HRMS (technique) calcd. for
C20H21FN2O3S [M+] 388.1257, found 388.1258.
cm–1): ν = 3404, 3114, 3075, 2967, 2933, 2846, 1653, 1528, 1480,
˜
1437, 1325, 1277, 1156, 1018, 914, 750. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 7.85 (d, J = 2.4 Hz, 1 H, SO2Ph), 7.49–
7.46 (m, 1 H, SO2Ph), 7.38–7.35 (m, 1 H, Ph), 7.30–7.23 (m, 3 H
Ph), 6.90 (d, J = 8.8 Hz, 1 H, SO2Ph), 6.66 (br. s, 1 H, C=ONH),
5.58–5.48 (m, 2 H, CH2=CH, TsNH), 5.11–5.04 (m, 2 H,
H2C=CH), 4.48–4.37 (m, 2 H, CH2Ph), 3.93 (s, 3 H, OCH3), 3.77–
3.73 (m, 1 H, C=OCH), 2.61–2.54 (m, 1 H, HCCH=CH2), 2.33–
2.26 (m, 1 H, HCCH=CH2) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 170.1, 154.9, 134.9, 134.6, 133.6, 133.4, 132.1, 129.7,
129.6, 129.5, 128.9, 127.9, 127.1, 125.7, 119.7, 113.5, 56.6, 56.5,
41.5, 37.4 ppm. HRMS (EI): calcd. for C19H20Cl2N2O4S [M+]
442.0521, found 442.0514.
1-(5-Chloro-2-methoxyphenylsulfonyl)-N-(3,4-difluorobenzyl)-5-
fluoro-1,2,3,6-tetrahydropyridine-2-carboxamide (34): To a solution
of 30 (30 mg, 0.06 mmol) in dry toluene (12 mL) the 2nd generation
Grubbs catalyst (5 mol-%) was added at 100 °C in small portions.
The reaction was complete in 60 min. The solvent was evaporated
and the residue purified using column chromatography (heptane/
EtOAc from, 3:1 to 1:1) to give 34 (28 mg, 99%) as slightly colored
To a suspension of NaH (34 mg, 1.43 mmol) in DMF (3 mL) was
added 28 (310 mg, 0.714 mmol). After stirring for 15 min, 3-chloro-
2-fluoro-2-propene (67 mg, 0.714 mmol) was added slowly at 50 °C.
The reaction was stirred for 12 h at 50 °C, quenched with water
(3 mL) and extracted with Et2O (3×3 mL).The ether layers were
dried (MgSO4), evaporated and the residue was purified using col-
umn chromatography (heptane/EtOAc, 3:1 to 1:1) to give 31
solid. M.p. 165–167 °C. IR (neat, cm–1): ν = 3329, 3109, 2956, 2923,
˜
2846, 1714, 1648, 1519, 1484, 1429, 1390, 1333, 1273, 1209, 1155,
1
1111, 1015, 949, 814, 647, 592. H NMR (400 MHz, CDCl3): δ =
(90 mg, 30%) as a colorless oil. IR (neat, cm–1): ν = 3379, 2961,
˜
7.92 (d, J = 2.8 Hz, 1 H, ArH), 7.54–7.51 (m, 1 H, ArH), 7.16–
6.93 (m, 5 H, ArH, NH), 5.32–5.26 (m, 1 H, FC=CH), 4.44–4.40
(m, 4 H, NCH2Ph, FCCH2N), 3.86 (s, 4 H, OCH3, COCH), 3.78–
3.72 (m, 1 H, HCCH=CF), 1.87–1.81 (m, 1 H, HCCH=CF) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.5, 153.7 (d, J = 324.6 Hz,
C=CF), 154.6, 150.9, 141.2, 140.1, 135.1, 131.2, 127.6, 125.9,
123.5–123.4 (m, ArH), 117.7, 113.6, 99.5 (d, J = 13.7 Hz, C=CF),
56.5, 53.6, 43.1, 41.1 (d, J = 41.1 Hz, CH2CF), 21.2 ppm. HRMS
(EI): calcd. for C20H19ClF3N2O4S [M+ + H] 475.0660, found
475.0706.
2851, 2758, 2642, 2543, 1747, 1720, 1670, 1533, 1478, 1440, 1390,
1333, 1270, 1198, 1174, 1138, 1070, 1015, 1006, 919, 875, 836, 798,
721, 644, 589. 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J =
2.4 Hz, 1 H, ArH), 7.49–7.46 (m, 1 H, ArH), 7.37–7.35 (m, 2 H,
Ph), 7.27–7.22 (m, 2 H, ArH), 6.98 (br. s, 1 H, NH), 6.88 (d, J =
8.8 Hz, 1 H, ArH), 5.44–5.34 (m, 1 H, CH2=CH), 4.99 (dd, J =
1.6, 17.2 Hz, 1 H, FC=CH), 4.89 (dd, J = 1.2, 10.4 Hz, 1 H,
FC=CH), 4.57–4.51 (m, 3 H, H2C=CH, COCH), 4.43–4.34 (m,
4 H, CH2Ph, FCCH2), 3.85 (s, 3 H, OCH3), 2.87–2.79 (m, 1 H,
HCCH=CH2), 2.37–2.29 (m, 1 H, HCCH=CH2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.9, 160.3 (d, J = 259.3 Hz, CF), 155.2,
135.1, 134.6, 133.6, 133.4, 130.9, 129.9, 129.4, 128.85, 128.8, 126.9,
125.5, 117.9, 113.5, 94.8 (d, J = 17.9 Hz, CH2 = CF), 59.4, 56.3,
44.9 (d, J = 30.5 Hz, NCH2CF), 41.5, 32.9 ppm. HRMS (EI):
N-(2-Chlorobenzyl)-1-(5-chloro-2-methoxyphenylsulfonyl)-5-fluoro-
1,2,3,6-tetrahydropyridine-2-carboxamide (35): To a solution of 31
(33 mg, 66 µmol) in dry toluene (15 mL) the 2nd generation Grubbs
catalyst (5 mol-%) was added at 100 °C in small portions. The reac-
Eur. J. Org. Chem. 2006, 1166–1176
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1173

V. De Matteis, F. L. van Delft, J. Tiebes, F. P. J. T. Rutjes
FULL PAPER
tion was complete in 60 min. The solvent was evaporated and the
residue was purified using column chromatography (heptane/
the solvent evaporated to afford 40 (200 mg, 0.82 mmol, 99%) as a
yellow oil. The crude product was dissolved in CH2Cl2 (7 mL) and
EtOAc, 3:1 to 1:1) to give 35 (28 mg, 90%) as a light yellow solid. reacted for 1 h with HOBt (122 mg, 0.90 mmol) and EDCI
M.p. 145–148 °C. IR (neat, cm–1): ν = 3307, 3104, 2906, 1917, 1714,
(173 mg, 0.90 mmol). 2-Methoxybenzylamine (0.32 mL,
2.46 mmol) was added and the mixture was stirred for 12 h at room
temp. The solvent was evaporated and the residue was purified
using column chromatography (heptane/EtOAc, 4:1 to 4:2) to give
˜
1665, 1514, 1478, 1437, 1388, 1338, 1273, 1245, 1163, 1017, 960,
812, 738, 587. 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J =
3.6 Hz, 1 H, SO2Ph), 7.52–7.48 (m, 1 H, ArH), 7.40–7.23 (m, 4 H,
ArH), 7.03 (br. s, 1 H, NH), 6.91 (d, J = 12.4 Hz, 1 H, ArH), 5.31– 41 (190 mg, 65%) as a colorless oil. IR (neat, cm–1): ν = 3439, 3329,
˜
5.23 (m, 1 H, FC=CH), 4.61–4.38 (m, 4 H, NCH2Ph, FCCH2N),
3065, 2972, 2928, 1692, 1602, 1519, 1492, 1459, 1410, 1363, 1242,
3.82 (s, 3 H, OCH3), 3.74 (s, 1 H, COCH), 2.86–2.79 (m, 1 H, 1166, 1105, 1026, 973, 888, 809, 751. 1H NMR (400 MHz, CDCl3):
HCCH=CF), 1.91–1.84 (m, 1 H, HCCH=CF) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.2, 155.2, 153.4 (d, J = 253.2 Hz, CF),
135.0, 133.6, 131.1, 130.0, 129.7, 129.1, 127.9, 127.1, 125.9, 113.5,
99.7 (d, J = 13.9 Hz, C=CF), 56.4, 53.5, 42.1, 41.0 (d, J = 40.4 Hz,
NCH2CF), 21.3 (d, J = 6.1 Hz, CH2CH=CF) ppm. HRMS: calcd.
for C20H20Cl2FN2O4S [M+ + H] 473.0550, found 473.0505.
δ = 7.29–7.19 (m, 2 H, ArH), 6.92–6.83 (m, 2 H, ArH), 6.53 (br. s,
1 H, NH), 5.34–5.28 (m, 1 H, FC=CH), 4.89–4.74 (br. m, 1 H,
COCH), 4.51–4.15 (m, 3 H, NCH2Ph, FCCH2N), 3.83 (s, 3 H,
OCH3), 3.65–3.59 (br. m, 1 H, FCCH2N), 2.79–2.73 (m, 1 H,
HCCH=CF), 2.39–2.32 (m, 1 H, HCCH=CF) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.5, 157.3, 155.4, 153.3 (d, J = 246.1 Hz,
CF), 129.4, 128.8, 125.7, 120.5, 110.1, 99.1–98.9 (m, CH=CF),
81.3, 55.0, 51.1, 39.6–39.5 (m, CH2CH=CF), 31.6, 28.0, 22.5 ppm.
HRMS calcd. for C19H26FN2O4 [M + H]+, 365.1803, found
365.1877. To a solution of compound 41 (190 mg, 0.52 mmol) in
CH2Cl2 (5 mL) at 0 °C was added trifluoroacetic acid (0.48 mL,
6.3 mmol). The resulting mixture was stirred at room temp. for 6 h,
the solvent was evaporated and residual traces of trifluoroacetic
acid were azeotropically removed with dichloromethane
(3×10 mL). The crude mixture was redissolved in CH2Cl2 (4 mL)
and Hünig’s base (0.29 mL, 1.56 mmol) was added at room temp.
After 15 min, 5-chloro-2-methoxybenzenesulfonyl chloride
(125 mg, 0.52 mmol) was added and the reaction mixture was
stirred overnight. The solvent was evaporated and the residue was
purified using column chromatography (heptane/EtOAc, 3:1 to 1:1)
to give 45 (80 mg, 33%) as a white solid. M.p. 102–105 °C. IR
1-(5-Chloro-2-methoxyphenylsulfonyl)-N-(4-chloro-3-trifluorometh-
ylbenzyl)-5-fluoro-1,2,3,6-tetrahydropyridine-2-carboxamide (39):
As shown in Scheme 3. Trifluoroacetic acid (5.0 mL, 6.45 mmol)
was added to a solution of 32 (730 mg, 2.81 mmol) in CH2Cl2
(20 mL) at 0 °C. The resulting mixture was stirred at room temp.
for 6 h and the solvent was evaporated. Residual traces of trifluoro-
acetic acid were azeotropically removed using CH2Cl2 (3×10 mL).
The crude compound 36 was redissolved in CH2Cl2 (8 mL) and
Hünig’s base (0.98 mL, 5.62 mmol) was added. After 15 min, 5-
chloro-2-methoxybenzenesulfonyl chloride (668 mg, 2.81 mmol)
was added and the reaction mixture was stirred overnight. The sol-
vent was evaporated and the residue was filtered through silica gel
(heptane/EtOAc, 3:1 to 1:1) to give crude 37 (235 mg, 23%) as a
yellow oil. Crude 37 (60 mg, 0.17 mmol) was dissolved in THF/
H2O (4:1 v/v, 1 mL), LiOH (8.2 mg, 0.34 mmol) was added and the
reaction mixture was stirred at room temp. Upon completion, the
solution was acidified to pH 1 with 1  hydrochloric acid and ex-
tracted with EtOAc (3×5 mL). The combined organic phases were
dried (MgSO4) and the solvent evaporated to afford 38 (59 mg,
99%) as a yellow oil. This product was directly dissolved in CH2Cl2
(5 mL) and treated with HOBt (26 mg, 0.189 mmol) and EDCI
(36 mg, 0.189 mmol). Then, 4-chloro-3-trifluoromethylbenzylamine
(108 mg, 0.516 mmol) was added and the mixture was stirred for
12 h. The solvent was evaporated and the residue was purified using
column chromatography (heptane/EtOAc, 3:1 to 1:1) to give 39
(neat, cm–1): ν = 3401, 324, 3071, 3005, 2934, 2840, 1717, 1676,
˜
1588, 1519, 1481, 1440, 1390, 1338, 1270, 1245, 1160, 1113, 1015,
960, 812, 735. 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J =
3.5 Hz, 1 H, ArH), 7.51–7.47 (m, 1 H, ArH), 7.32–7.20 (m, 3 H,
ArH, NH), 6.94–6.88 (m, 3 H, ArH), 5.28–5.20 (m, 1 H, FC=CH),
4.54–4.11 (m, 5 H, NCH2Ph, OCH, FCCH2N), 3.87 (s, 3 H,
OCH3), 3.79 (s, 3 H, OCH3), 3.73–3.67 (m, 1 H, HCCH=CF),
2.85–2.78 (m, 1 H, HCCH=CF) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.9, 157.8, 155.2, 153.6 (d, J = 347.1 Hz, CF), 135.0,
131.1, 129.8, 128.2, 125.8, 125.7, 120.7, 113.5, 110.4, 99.5 (d, J =
18.0 Hz, C=CF), 56.3, 55.3, 53.7, 40.7, 31.9, 22.7 ppm. HRMS
(EI): calcd. for C21H21ClFN2O5S [M+ – H] 467.0876, found
467.0844.
(20 mg, 22%) as a white solid. M.p. 180–182 °C. IR (neat, cm–1): ν
˜
= 3324, 3104, 3054, 2945, 2906, 1717, 1657, 1528, 1478, 1322, 1273,
1
1163, 1144, 1015, 960, 817. H NMR (400 MHz, CDCl3): δ = 7.87
(d, J = 3.5 Hz, 1 H, SO2Ph), 7.53–7.41 (m, 3 H, ArH), 7.33 (d, J
= 10.7 Hz, 1 H, ArH), 7.09 (br. s, 1 H, NH), 6.90 (d, J = 12 Hz, 1
H, ArH), 5.29–5.21 (m, 1 H, FC=CH), 4.46–4.36 (m, 5 H,
NCH2Ph, COCH, FCCH2N), 3.83 (s, 3 H, OCH3), 3.73 (d, J =
23.2 Hz, 1 H, HCCH=CF), 2.77 (br. d, J = 22.7 Hz, 1 H,
1-(5-Chloro-2-methoxyphenylsulfonyl)-N-(4-chloro-3-trifluorometh-
ylbenzyl)-5-fluoro-1,2,3,6-tetrahydropyridine-2-carboxamide (39):
According to Scheme 4. A solution of compound 32 (500 mg,
1.93 mmol) in THF/H2O (3:1 v/v, 12 mL), was treated with LiOH
(93 mg, 3.86 mmol), and the mixture was stirred at room temp.
HCCH=CF) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2, 155.6, until the reaction was complete (TLC). The solution was acidified
153.6 (d, J = 337.6 Hz, CF), 137.5, 135.2, 131.9, 131.8, 131.6–131.4 to pH 1 with 1  hydrochloric acid and extracted with EtOAc
(m, ClC=CCF3), 131.2, 130.8, 129.3 (q, J = 92.4 Hz, CCF3), 127.5, (3×10 mL).
126.6 (q, J = 6.7 Hz, C=CCF3), 125.9, 122.9 (q, J = 362.8 Hz,
The combined organic phases were dried (MgSO4) and the solvent
CF3), 113.9, 99.7 (d, J = 18.3 Hz, C=CF), 56.7, 53.8, 43.2, 41.4
(d, J = 54.5 Hz, CH2FC=C), 21.4 ppm. HRMS (EI): calcd. for
C21H18Cl2F4N2O4S [M+ + H] 541.0450, found 541.0379.
evaporated to afford 40 (200 mg, 0.82 mmol, 99%) as a yellow oil.
The crude product was dissolved in CH2Cl2 (7 mL) and reacted for
1 h with HOBt (122 mg, 0.90 mmol) and EDCI (173 mg,
0.90 mmol). 2-Methoxybenzylamine (0.32 mL, 2.46 mmol) was
added and the mixture was stirred for 12 h at room temp. The sol-
vent was evaporated and the residue was purified using column
chromatography (heptane/EtOAc, 4:1 to 4:2) to give 42 (390 mg,
1-(5-Chloro-2-methoxyphenylsulfonyl)-5-fluoro-N-(2-methoxybenz-
yl)-1,2,3,6-tetrahydropyridine-2-carboxamide (45): Compound 32
(500 mg, 1.93 mmol) was dissolved in THF/H2O (3:1 v/v, 12 mL),
LiOH (93 mg, 3.86 mmol) was added and the reaction mixture was
stirred at until the reaction was complete. The solution was acidi-
fied to pH 1 with 1  hydrochloric acid and extracted with EtOAc
(3×10 mL). The combined organic phases were dried (MgSO4) and
84%) as a colorless oil. IR (neat, cm–1): ν = 3324, 3071, 2972, 2934,
˜
2862, 1695, 1665, 1525, 1478, 1366, 1316, 1256, 1168, 1135, 1111,
1
1037, 984, 888. H NMR (400 MHz, CDCl3): δ = 7.54–7.35 (m, 3
1174
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1166–1176

Highly Functionalized Fluorinated Piperidines
FULL PAPER
Commercial Applications (Eds.: R. E. Banks, B. E. Smart, J. C.
Tatlow), Plenum: New York, 1994, and references cited therein;
b) P. Maienfisch, R. G. Hall, Chimia 2004, 58, 93–99.
H, ArH), 6.4 (br. s, 1 H, NH), 5.44–5.37 (m, 1 H, FC=CH), 4.91
(br. s, 1 H, COCH), 4.52–4.13 (m, 3 H, NCH2Ph, FCCHHN),
3.66–3.62 (m, 1 H, FCCHHN), 2.78–2.73 (m, 1 H, HHCCH=CF),
2.46–2.33 (m, 1 H, HHCCH=CF) ppm. 13C NMR (100 MHz,
CDCl3) some signals are not visible: δ = 170.9, 137.8, 132.1, 126.7,
122.9 (q, J = 362.8 Hz, CF3), 99.5 (d, J = 18.3 Hz, C=CF), 82.3,
47.4, 42.8, 32.1, 28.5, 22.9 ppm. HRMS (EI): calcd. for
C19H20ClF4N2O3 [M – H]– 435.1030, found 435.1099. To a solution
of compound 42 (320 mg, 0.74 mmol) in CH2Cl2 (5 mL) at 0 °C
was added trifluoroacetic acid (0.11 mL, 1.48 mmol). The resulting
mixture was stirred at room temp. for 6 h, the solvent was evapo-
rated and residual traces of trifluoroacetic acid were azeotropically
removed with dichloromethane (3×10 mL). The crude mixture was
redissolved in CH2Cl2 (3 mL) and Hünig’s base (0.3 mL,
1.43 mmol) was added at room temp. After 15 min, 5-chloro-2-me-
thoxybenzenesulfonyl chloride (178 mg, 0.74 mmol) was added and
the reaction mixture was stirred overnight. The solvent was evapo-
rated and the residue was purified using column chromatography
(heptane/EtOAc, 3:1 to 1:1) to give 39 (127.9 mg, 32%) as a white
[7]
For a review article, see, for example: P. Lin, J. Jiang, Tetrahe-
dron 2000, 56, 3635–3671.
The Merck Index, 13th ed., 2001.
[8]
[9]
L. S. Jeong, S. J. Yoo, K. M. Lee, M. J. Koo, W. J. Choi, H. O.
Kim, H. R. Moon, M. Y. Lee, J. G. Park, S. K. Lee, M. W.
Chun, J. Med. Chem. 2003, 46, 201–203.
See, e.g.: http://www.fluoridealert.org/pesticides/profluazol.pa-
ge.htm.
[10]
[11]
a) F. P. J. T. Rutjes, H. E. Schoemaker, Tetrahedron Lett. 1997,
38, 677–680; b) F. P. J. T. Rutjes, T. M. Kooistra, H. Hiemstra,
H. E. Schoemaker, Synlett 1998, 192–194; c) J. J. N. Veerman,
J. H. van Maarseveen, G. M. Visser, C. G. Kruse, H. Hiemstra,
H. E. Schoemaker, F. P. J. T. Rutjes, Eur. J. Org. Chem. 1998,
2583–2589; d) K. C. M. F. Tjen, S. S. Kinderman, H. E. Schoe-
maker, H. Hiemstra, F. P. J. T. Rutjes, Chem. Commun. 2000,
699–700; e) R. Doodeman, F. P. J. T. Rutjes, H. Hiemstra, Tet-
rahedron Lett. 2000, 41, 5979–5982; f) B. Kaptein, Q. B. Broxt-
erman, H. E. Schoemaker, F. P. J. T. Rutjes, J. J. N. Veerman, J.
Kamphuis, C. Peggion, F. Formaggio, C. Toniolo, Tetrahedron
2001, 57, 6567–6577; g) S. S. Kinderman, J. H. van Maarse-
veen, H. E. Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, Org.
Lett. 2001, 3, 2045–2048; h) S. S. Kinderman, R. Doodeman,
J. W. van Beijma, J. C. Russcher, K. C. M. F. Tjen, T. M. Koois-
tra, H. Mohaselzadeh, J. H. van Maarseveen, H. Hiemstra,
H. E. Schoemaker, F. P. J. T. Rutjes, Adv. Synth. Catal. 2002,
344, 736–748; i) S. S. Kinderman, R. de Gelder, J. H.
van Maarseveen, H. E. Schoemaker, H. Hiemstra, F. P. J. T.
Rutjes, J. Am. Chem. Soc. 2004, 126, 4100–4101; j) S. S. Kin-
derman, J. H. van Maarseveen, H. E. Schoemaker, H. Hiem-
stra, F. P. J. T. Rutjes, Synthesis 2004, 1413–1418; k) G. F.
Busscher, F. P. J. T. Rutjes, F. L. van Delft, Tetrahedron Lett.
2004, 45, 3629–3632; l) S. S. Kinderman, M. M. T. Wekking,
J. H. van Maarseveen, H. E. Schoemaker, H. Hiemstra,
F. P. J. T. Rutjes, J. Org. Chem. 2005, 70, 5519–5527.
solid. M.p. 180–182 °C. IR (neat, cm–1): ν = 3324, 3104, 3054, 2945,
˜
2906, 1717, 1657, 1528, 1478, 1322, 1273, 1163, 1144, 1015, 960,
817. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 3.5 Hz, 1 H,
SO2Ph), 7.53–7.41 (m, 3 H, ArH), 7.33 (d, J = 10.7 Hz, 1 H, ArH),
7.09 (br. s, 1 H, NH), 6.90 (d, J = 12 Hz, 1 H, ArH), 5.29–5.21 (m,
1 H, FC=CH), 4.46–4.36 (m, 5 H, NCH2Ph, COCH, FCCH2N),
3.83 (s, 3 H, OCH3), 3.73 (d, J = 23.5 Hz, 1 H, HCCH=CF), 2.80–
2.75 (m, 1 H, HCCH=CF) ppm. 13C NMR (100 MHz, CDCl3): δ
= 169.2, 155.6, 153.6 (d, J = 337 Hz, CF), 137.5, 135.2, 131.9,
131.8, 131.6–131.4 (m, ClC=CCF3), 131.2, 130.8, 129.3 (q, J =
92.4 Hz, CCF3), 127.5, 126.6 (q, J = 6.7 Hz, C=CCF3), 125.9, 122.9
(q, J = 362 Hz, CF3), 113.9, 99.7 (d, J = 18.3 Hz, C=CF), 56.7,
53.8, 43.2, 41.4 (d, J = 54.5 Hz, CH2FC=C), 21.4 ppm. HRMS
(EI): calcd. for C21H18Cl2F4N2O4S [M+ + H] 541.0450, found
541.0379.
[12]
[13]
For some recent reviews in this area, see, for example: a) A.
Deiters, S. F. Martin, Chem. Rev. 2004, 104, 2199–2238; b)
M. D. McReynolds, J. M. Dougherty, P. R. Hanson, Chem.
Rev. 2004, 104, 2239–2258.
a) M.-L. Bennasar, T. Roca, M. Monerris, D. Garcia-Diaz, Tet-
rahedron Lett. 2005, 46, 4035–4038; b) Arisawa, Y. Terada, M.
Nakagawa, A. Nishida, Angew. Chem. Int. Ed. 2002, 41, 4732–
4734; c) J. D. Katz, L. E. Overman, Tetrahedron 2004, 60,
9559–9568.
For recent examples, see, for example: a) C. Taillier, B. Gille,
V. Bellosta, J. Cossy, J. Org. Chem. 2005, 70, 2097–2108; b)
S. F. Oliver, K. Hoegenauer, O. Simic, A. Antonello, M. D.
Smith, S. V. Ley, Angew. Chem. Int. Ed. 2003, 42, 5996–6000;
c) A. K. Chatterjee, J. P. Morgan, M. Scholl, R. H. Grubbs, J.
Am. Chem. Soc. 2000, 122, 3783–3784; d) M. H. D. Postema,
D. Calimente, L. Liu, T. L. Behrmann, J. Org. Chem. 2000, 65,
6061–6068; e) U. Majumder, J. M. Cox, J. D. Rainier, Org. Lett.
2003, 5, 913–916; f) K. F. W. Hekking, F. L. van Delft,
F. P. J. T. Rutjes, Tetrahedron 2003, 59, 6751–6758.
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Acknowledgments
Bayer CropScience is gratefully acknowledged for financial sup-
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Received: October 21, 2005
Published Online: January 3, 2006
1176
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1166–1176