An improved ring-closing metathesis approach to fluorinated and trifluoromethylated nitrogen heterocycles

Article abstract of DOI:10.1002/ejoc.200601119

The synthesis of fluoro- and trifluoromethyl-containing N-sulfonylated nitrogen heterocycles is described. A first crucial step is a Mitsunobu functionalization of intermediate sulfonamides using commercially available unsaturated alcohols, which gives ef

Full text of DOI:10.1002/ejoc.200601119

FULL PAPER
DOI: 10.1002/ejoc.200601119
An Improved Ring-Closing Metathesis Approach to Fluorinated and
Trifluoromethylated Nitrogen Heterocycles
Valeria De Matteis,[a] Olivier Dufay,[a] Dennis C. J. Waalboer,[a] Floris L. van Delft,[a]
Jörg Tiebes,[b] and Floris P. J. T. Rutjes*[a]
Keywords: Ring-closing metathesis / Fluorinated heterocycles / Trifluoromethylated heterocycles / Sulfonamides / Trifluoro-
methylated pyrrole
The synthesis of fluoro- and trifluoromethyl-containing N-
sulfonylated nitrogen heterocycles is described. A first cru-
cial step is a Mitsunobu functionalization of intermediate sul-
fonamides using commercially available unsaturated
alcohols, which gives efficient access to fluorinated ring-clos-
ing metathesis (RCM) precursors. Key step is an RCM reac-
tion of these precursors leading to the corresponding fluoro-
and trifluoromethyl-containing heterocyclic building blocks.
Furthermore, aminopalladation of the same sulfonamide in-
termediates provides access to trifuoromethyl-containing
pyrrole derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
fonylated heterocycles 1 are accessible through RCM from
the precursors 2, which are now envisaged to be prepared
in a different way from the alkylating agents 4 and 5 in a
Mitsunobu process. While Mitsunobu reactions are nor-
mally restricted to aromatic sulfonamides containing elec-
tron-withdrawing nitro substituents, we hoped that the
strongly electron-withdrawing fluorine substituents would
be beneficial in making this process possible for a wider
range of (biologically relevant) sulfonyl groups.
Introduction
There is a strongly increasing interest in fluorine-contain-
ing biologically active compounds for potential application
as agrochemicals and pharmaceuticals.[1] This is due to the
fact that incorporation of fluorine or fluorine-containing
groups such as trifluoromethyl in organic molecules often
leads to improved pharmacological properties of the parent
compound.[2,3] Consequently, in the last few years much re-
search has been aimed at developing general methodology
for the straightforward introduction of fluorine or trifluoro-
methyl substituents in non-aromatic heterocyclic systems.[4]
In developing such general methods, one strategy is ap-
plication of proven ring-closure methodology to appropri-
ate fluorine-containing precursor molecules. This is exem-
plified by work of the Brown group who successfully ap-
plied ring-closing metathesis (RCM) on vinyl fluoride-con-
taining substrates to prepare fluorinated analogues of
seven-membered heterocyclic HIV protease inhibitors,[5]
and related work from the Haufe group.[6] At the same time,
we were developing a similar RCM approach to prepare
small libraries of fluorinated[7] and trifluoromethylated[8]
nitrogen heterocycles, including the development of a route
to a new trifluoromethyl-containing allylating reagent.[9]
Inspired by these successful approaches, we aimed to ex-
tend this methodology to a complementary pathway, which
is retrosynthetically outlined in Scheme 1. The targeted sul-
Scheme 1. Retrosynthetic approach to fluorinated and trifluorome-
thylated nitrogen heterocycles.
Besides the fact that this will lead to a general process
that can be applied on both olefins 4 and 5, the Mitsunobu
reaction will allow for use of commercially available unsatu-
rated alcohols as reaction partners, whereas previous alky-
lation strategies had to rely on less well accessible olefinic
halides. Furthermore, the sulfonamides 3 can be subjected
to aminopalladation with alkoxyallenes, a reaction that has
been developed in our group,[10] which will give access to
an even greater variety of fluorinated heterocycles.
[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
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most of the yields were fairly good, it was obvious that the
Mitsunobu sequence worked more reliably in case of non-
activated substrates (e.g. compare the low alkylation yield
in entries 4 and 5 with the good Mitsunobu yields in entries
2, 3 and 6–10). Hence we concluded that the Mitsunobu
approach allows the use of commercially available unsatu-
rated alcohols to prepare a variety of RCM precursors in a
straightforward manner.
Results and Discussion
The investigation started with exploring the possibility
of transforming the commercially available fluoride 4 in a
nucleophilic amine that may then provide the sulfonamides
7 and 9 (Scheme 2). Compound 4 was reacted at room
temp. with sodium azide in DMSO for 12 h. Initially, the
reaction was performed in deuterated DMSO to monitor
1
the conversion by H NMR, which indicated that the reac-
Precursor molecules 11–20 were then subjected to the
RCM reaction. The second-generation Grubbs catalyst 10
was added portionwise over a period of 2 h to the reaction
mixture, which was heated in toluene at 100 °C. Most of
these precursors led to the corresponding fluoro-substituted
cyclic building blocks in good to excellent yields (Table 1).
There are some exceptions, however. Compound 11, whichs
lacks a substituent adjacent to the nitrogen atom, does not
give any cyclization product, even on prolonged heating and
larger amounts of catalyst (entry 1). Introduction of a
methyl substituent at the 2-position (12) surprisingly led to
the five-membered ring 22 in 72% yield, using similar con-
ditions (entry 2). To further investigate the influence of a
substituent in this position, precursor 13 containing a
phenyl group was synthesized, but unfortunately did not
provide any cyclized product (entry 3). These results suggest
that there is an optimum in the size of the 2-substituent
with respect to cyclization. We then moved on to prepare
six-and seven-membered ring building blocks as shown in
entries 4–7. These cyclizations proceeded readily in good
yields ranging from 72 to 97% to provide rings 24–27, al-
though in case of 27 a larger amount of catalyst was re-
quired. Remarkably, subjection of compound 18 to the me-
tathesis conditions did not provide the eight-membered
tion was complete in 12 h giving rise to azide 6 as a single
product. Initial attempts to reduce the azide via Staudinger
reduction with triphenylphosphane, followed by sulfo-
nylation provided low yields (Ͻ30%) of the corresponding
sulfonamides (exemplified for 7), both on small and on
larger scale.
Scheme 2. Synthesis of vinyl fluoride-containing sulfonamides.
In a modified pathway, azide 6 was first extracted into ring, but instead gave the corresponding seven-membered
diethyl ether, dried (MgSO4), filtered and then directly ring system (entry 8). This must be due to isomerization of
treated with 4.5 equiv. of LiAlH4. Precipitation of the alu- the terminal olefin to the internal position, possibly as a
minum salts via sodium sulfate treatment, followed by fil- result of a relatively slow cyclization process, followed by
tration and extraction with 1  aqueous HCl provided upon ring closure and expulsion of propene.[12,13]
freeze-drying amine 8 as its hydrochloride. The salt was sus-
We have also investigated the possibility of forming
pended in diethyl ether, treated with excess triethylamine larger rings via this process. Precursors 19 and 20 were con-
and tosyl chloride at –78 °C, stirred for 12 h at room temp. veniently prepared via the newly developed Mitsunobu se-
and worked up to provide sulfonamide 9. Although this quence in 78 and 99%, respectively. Exposure of 19 to the
procedure could be readily scaled up to larger quantities, RCM catalyst led to a complex mixture of unidentifiable
the last step reproducibly proceeded in a rather modest 30% products rather than the desired twelve-membered ring 28.
yield (Scheme 2). However, the procedure still compares fa- Moreover, all attempts to form a thirteen-membered vinyl
vorably to a known procedure in which 4 is heated in am- fluoride ring (29) from precursor 20 failed.
monia in a steel bomb to provide 9 in 30%.[11]
Prompted by the successful Mitsunobu reaction and sub-
Having sulfonamides 7 and 9 in hand, the feasibility of sequent RCM results, we aimed to apply this protocol in a
the Mitsunobu approach was probed. To this end, the re- similar fashion on our previously developed trifluorome-
quired RCM precursors 11–20 were either prepared via a thyl-containing allylating reagent 5.[8,9] (Scheme 3).
regular alkylation reaction (method A, entries 1, 4 and 5)
The sequence proceeded via initial alkylation of tert-bu-
or via Mitsunobu conditions (method B, entries 2, 3 and tyl tosylcarbamate[14] with tosylate 5[8] in refluxing acetoni-
6–10). Method A involved addition of sulfonamide 8 to a trile, followed by TFA-mediated liberation of sulfonamide
suspension of NaH in DMF and subsequent treatment with 31 in good overall yield. Compound 31 was alkylated under
the bromide followed by stirring for 12 h. Method B com- Mitsunobu conditions (triphenylphosphane, diethyl azodi-
prised the successive treatment of a solution of sulfonamide carboxylate, toluene, 50 °C) with several unsaturated
8 in toluene with triphenylphosphane, the appropriate alcohols in generally good yields to provide the RCM pre-
alcohol and diethyl azodicarboxylate (DEAD). The mixture cursors 32–35, which in turn, were subjected to the afore-
was then heated at 50 °C for 12 h and worked up. Although mentioned RCM conditions (Table 2).
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Fluorinated Nitrogen Heterocycles
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Table 1. Synthesis of fluoride-containing RCM precursors and products.[a]
[a] Conditions: Method A: (i) NaH, DMF, then add sulfonamide 8, 15 min, room temp., (ii) alkylating agent, 12 h room temp. Method
B: PPh3, alcohol, DEAD, 50 °C, 12 h.
in 65% yield (entry 3), or led to the stable product 39 (entry
4). In the latter case, we hoped that the phenyl substituent
would suppress the isomerization process, but instead a
good yield of the isomerized linear product was obtained.
Comparison of Table 1 and Table 2 clearly shows that the
fluoro and trifluoromethyl substituents play an important
Scheme 3. Synthesis of trifluoromethyl-containing sulfonamides.
role in the RCM process. The fluorinated precursors readily
afford six- and seven-membered ring products without any
Starting from 32, pyrroline 36 was obtained in 57% to- isomerization. The trifluoromethylated precursors on the
gether with the isomerized product 37 (23%, entry 1). This other hand suffered from isomerization processes, which
sharply contrasts with the fluoride-containing precursor 11, were only absent using the six-membered ring precursors.
which failed to cyclize under identical conditions. The ho- Recently, the Grubbs group reported that addition of
mologous six-membered ring 38 was also readily formed in benzoquinone could efficiently suppress undesired isomer-
one hour from precursor 33 in 98% yield. Precursors 34 ization processes.[15] We also applied these conditions to
and 35, however, behaved in a different manner. In both precursors 34 and 35 to see if this would be beneficial for
cases, isomerization took place, which was either followed our RCM processes. In case of precursor 34 (20 mol-% of
by cyclization to the corresponding six-membered ring 38 catalyst 10, 0.4 equiv. of benzoquinone, toluene, 100 °C) the
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F. P. J. T. Rutjes et al.
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Table 2. Synthesis of CF3-containing RCM precursors and prod-
ucts.
Scheme 4. Synthesis of a trifluoromethyl-substituted pyrrole.
chromatography then provided pyrrole 42 in 80% yield.
This example clearly shows that the aminopalladation path-
way provides an efficient and straightforward entry into the
synthesis of trifluoromethylated pyrroles that may be fur-
ther exploited in a general sense.
Conclusions
In conclusion, we have shown that sulfonylated fluoro-
and trifluoromethyl-containing RCM precursors can be
readily synthesized via a Mitsunobu reaction applied on the
corresponding fluorinated sulfonamides involving suitable
olefins. The first class of compounds was obtained from
commercially available 3-chloro-2-fluoropropene, whereas
for the second compound class a trifluoromethyl-containing
allylating reagent – previously developed in our group –
served as the starting material. We also demonstrated that
RCM on these olefins led to fluoro- and trifluoromethyl-
containing five-, six- and seven-membered ring heterocyclic
building blocks. Furthermore, a straightforward synthetic
pathway to prepare trifluoromethylated pyrrole derivatives
has been developed.
isomerization was partially suppressed. GC-MS analysis re-
vealed the presence of the seven-membered ring product,
together with the isomerized precursor and the six-mem-
bered ring 38 in a ratio of 1.3:1.1:1, respectively. In contrast,
precursor 35 was reacted under identical conditions, but so-
lely provided the isomerized product 39, which led us to
conclude that benzoquinone addition in these particular
cases is not very useful.
Another interesting application of sulfonamide 31 lies in
the synthesis of trifluoromethylated pyrrole derivatives.
These compounds represent an industrially relevant com-
pound class, which is poorly accessible via published meth-
ods.[16] Inspired by recent work by Donohue et al.,[17] we
decided to use our recently developed aminopalladation in-
volving alkoxyallenes[10] to open up new entries to such
compounds (Scheme 4).
Experimental Section
General Information: All reactions were carried out under an inert
atmosphere of dry nitrogen. Solvents were distilled from the appro-
priate drying agents immediately prior to use. Infrared (IR) spectra
were recorded on an ATI Mattson Genesis Series FTIR spectrome-
ter and absorptions are reported in cm–1. NMR spectra were re-
corded at 298 K using a Bruker DMX300 (300 MHz) spectrometer
from CDCl3 solutions using TMS as internal standard unless
otherwise reported. Mass spectra and accurate mass measurements
were carried out using a Fisons (VG) Micromass 7070E or a Finni-
gan MAT900S instrument. Melting points were determined with a
Büchi melting point B-545 apparatus.
N-(2-Fluoroallyl)-4-nitrobenzenesulfonamide (7): To a solution of 4
(252 mg, 2.68 mmol) in DMSO (24 mL) NaN3 (720 mg,
11.3 mmol) was added and the resulting mixture was vigorously
stirred for 12 h at room temp. To the gelly mixture containing 6
was added PPh3 (992 mg, 3.78 mmol) and the solution was stirred
for 12 h at room temp. The reaction was slowly quenched with
water (24 mL) and extracted with Et2O (5 ϫ 20 mL). The ether
layer was dried (MgSO4), filtered and directly treated with Et3N
(0.60 mL, 3.78 mmol). After stirring for 15 min at room temp., the
mixture was cooled to –78 °C, NsCl (838 mg, 3.78 mmol) was
Thus, benzyloxyallene 40[18] was treated with sulfon-
amide 31 in the presence of Et3N, catalytic Pd(OAc)2 and
dppp in acetonitrile to provide N,O-acetal 41 in excellent
yield. The RCM precursor 41 was subjected to the pre-
viously described RCM conditions using 7 mol-% of cata-
lyst 10 in toluene at 100 °C. Once TLC indicated that the
conversion was complete, TFA was added and after stirring
for 30 min the mixture was worked up. Concentration and added and the mixture was stirred for 12 h thereby slowly reaching
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Fluorinated Nitrogen Heterocycles
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room temp. The solvent was evaporated and the residue was puri-
fied using column chromatography (heptane/EtOAc, 10:1 to 3:1) to
258.5 Hz, CF), 143.3, 136.9, 132.0, 129.5, 127.1, 119.6, 93.9 (d, J
= 17.2 Hz, C=CF), 49.9, 46.4 (d, J = 31.9 Hz, CH2CF), 21.7 ppm.
HRMS (EI): calcd. for C13H16FNO2S (M+) 269.0886, found
269.0895.
give 7 (100 mg, 14%) as a yellow solid. 7: IR (neat): ν = 3291, 3105,
˜
1
2924, 2867, 1688, 1528, 1437, 1346, 1156, 1091, 849, 737 cm–1. H
NMR (300 MHz, CDCl3): δ = 8.33 (d, J = 9.0 Hz, 2 H, Ar), 8.04
(d, J = 9.0 Hz, 2 H, Ar), 5.28 (br. t, J = 6.0 Hz, 1 H, NH), 4.57
(dd, J = 3.3, 28.5 Hz, 1 H CH2cis=CF), 4.47 (dd, J = 3.6, 60.1 Hz, 1
H, CH2trans=CF), 3.86–3.79 (m, 2 H, CFCH2NH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.7 (d, J = 256.2 Hz, CF), 150.0, 145.8,
128.3, 124.3, 93.7 (d, J = 17.2 Hz, C=CF), 43.8 (d, J = 32.2 Hz,
CH2CF) ppm. HRMS (EI): calcd. for C9H9FN2O4S (M+)
260.0267, found 260.0274.
N-(2-Fluoroallyl)-4-methyl-N-(1-methylallyl)benzenesulfonamide
(12):[19] To a solution of compound 9 (100 mg, 0.38 mmol) in tolu-
ene (5 mL) were added PPh3 (202 mg, 0.77 mmol), 3-buten-2-ol
(40 µL, 0.46 mmol) and diethyl azodicarboxylate (80 µL,
0.61 mmol). The mixture was heated at 50 °C for 12 h, then the
solvent was evaporated and the residue was purified using column
chromatography (heptane/EtOAc, 20:1) to give 12 (86 mg, 79%) as
a pink oil. 12: IR (neat): ν = 3088, 3023, 2980, 2924, 1675, 1593,
˜
1338, 1152, 1092, 1014, 901, 845, 815, 659, 547 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.71 (d, J = 8.1 Hz, 2 H, Ar), 7.27 (d, J =
8.1 Hz, 2 H, Ar), 5.68–5.57 (m, 1 H, CH2=CH), 5.14–5.5 (m, 2 H,
CH2=CH), 4.71–4.48 (m, 3 H, NCHCH3, CH2=CF), 3.89 (dd, J =
11.7, 16.8 Hz, 1 H, CFCH2N), 3.73 (dd, J = 11.7, 16.8 Hz, 1 H,
CFCH2N), 2.42 (s, 3 H, ArCH3), 1.25 (d, J = 6.9 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 162.1 (d, J = 257.6 Hz,
CF), 143.3, 136.9, 129.5, 127.13, 127.12, 117.3, 93.0 (d, J = 17.5 Hz,
C=CF), 55.13, 43.5 (d, J = 34.5 Hz, CH2CF), 21.8, 17.5 ppm.
HRMS (EI): calcd. for C14H18FNO2S (M+) 283.1042, found
283.1034.
N-(2-Fluoroallyl)-4-methylbenzenesulfonamide (9): To a solution of
4
(252 mg, 2.68 mmol) in DMSO (24 mL) NaN3 (720 mg,
11.34 mmol) was added and the resulting mixture was vigorously
stirred for 12 h at room temp. It was diluted with water (10 mL),
extracted with Et2O (3ϫ 20 mL), dried (MgSO4) and filtered. The
filtrate was carefully treated with LiAlH4 (458 mg, 12.1 mmol) at
room temp., after which a strong evolution of gas started. The reac-
tion mixture was stirred overnight, a few drops of EtOAc were
added, followed by aqueous saturated Na2SO4 (a few drops) and
solid Na2SO4. After stirring for a few minutes, the resulting suspen-
sion was filtered and the filtrate was extracted with 1  HCl (3ϫ
20 mL). The aqueous layer was freeze-dried to give 8 (297 mg,
99%) in crude form, which was used for the next step without fur-
N-(2-Fluoroallyl)-4-methyl-N-(1-phenylallyl)benzenesulfonamide
(13): To a solution of compound 9 (158 mg, 0.60 mmol) in toluene
(8 mL) were added PPh3 (315 mg, 1.20 mmol), vinyl benzyl alcohol
(95 µL, 0.72 mmol) and diethyl azodicarboxylate (0.13 mL,
0.96 mmol). The mixture was heated at 50 °C for 12 h, the solvent
was evaporated and the residue was purified using column
chromatography (heptane/EtOAc, 20:1) to give 13 (68 mg, 33%) as
ther purification. IR (neat): ν = 2876, 2625, 1692, 1593, 1502, 1403,
˜
1251, 1100, 927, 879 cm–1. 1H NMR (300 MHz, D2O): δ = 5.0 (dd,
J = 4.2, 16.8 Hz, 1 H, CH2cis=CF), 4.87 (dd, J = 3.9, 49 Hz, 1 H,
CH2trans=CF), 3.8 (d, J = 16.2 Hz, 2 H, CFCH2N) ppm. 13C NMR
(75 MHz, D2O): δ = 157.8 (d, J = 252.5 Hz, CF), 97.4 (d, J =
15.8 Hz, C=CF), 39.9 (d, J = 31.3 Hz, CH2CF) ppm. Crude 8 was
suspended in Et2O (10 mL), treated with Et3N (0.6 mL, 3.78 mmol)
for 15 min at room temp., followed by addition of TsCl (721 mg,
3.78 mmol) at –78 °C and stirring for 12 h thereby allowing the
mixture to warm up to room temp. The solvent was evaporated and
the residue was purified using column chromatography (heptane/
EtOAc, 10:1 to 6:1) to give 9 (185 mg, 30%) as a white solid. 9:
a colorless oil. 13: IR (neat): ν = 3019, 2963, 2920, 2868, 1679,
˜
1593, 1493, 1446, 1342, 1260, 1156, 1096, 1018, 914, 811, 741, 664,
616, 543 cm–1 1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J =
.
8.1 Hz, 2 H, SO2Ar), 7.30–7.20 (m, 7 H, 2H SO2Ar, 5H Ph), 6.45
(d, J = 15.9 Hz, 1 H, CH2=CH); 6.02–5.92 (m, 1 H, CH2=CH),
4.65 (dd, J = 3.0, 53.1 Hz, 1 H, CH2cis=CF), 4.55 (dd, J = 3.0,
84.7 Hz, 1 H, CH2trans=CF), 4.00–3.95 (m, 4 H, 1H CH2=CH,
CFCH2N, NCHPh), 2.42 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.7 (d, J = 259.9 Hz, CF), 143.6, 137.2, 136.1, 134.8,
129.8, 128.7, 128.2, 127.4, 126.6, 123.3, 94.1 (d, J = 17.2 Hz,
C=CF), 49.5, 46.5 (d, J = 31.9 Hz, CH2CF), 21.6 ppm. HRMS
(EI): calcd. for C19H20FNO2S (M+) 345.1199, found 345.1210.
M.p. 89–90 °C. IR (neat): ν = 3279, 2927, 2852, 1680, 1593, 1428,
˜
1320, 1154, 1092, 856, 806, 707, 661 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.73 (d, J = 8.4 Hz, 2 H, Ar), 7.27 (d, J = 8.1 Hz, 2
H, Ar), 5.31 (br. s, 1 H, NH), 4.56 (dd, J = 3.6, 33.6 Hz, 1 H,
CH2cis=CF), 4.46 (dd, J = 3.3, 64.8 Hz, 1 H, CH2trans=CF), 3.70–
3.64 (m, 2 H, CFCH2NH), 2.41 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.5 (d, J = 255.3 Hz, CF), 143.6, 136.6,
129.6, 127.9, 92.6 (d, J = 16.9 Hz, C=CF), 43.4 (d, J = 33.9 Hz,
CH2CF), 21.8 ppm. HRMS (EI): calcd. for C10H12FNO2S (M+)
229.0573, found 229.0580.
N-(But-3-enyl)-N-(2-fluoroallyl)-4-nitrobenzenesulfonamide (14): A
suspension of NaH (13 mg, 0.52 mmol) in DMF (4 mL) was
treated with compound 9 (90 mg, 0.35 mmol). After stirring for
30 min, 4-bromo-1-butene (42 µL, 0.42 mmol) was added dropwise
at room temp. The reaction was stirred for 12 h, quenched with
water (4 mL) and extracted with Et2O (3 ϫ 4 mL). The ether layers
were dried (MgSO4), evaporated and the residue was purified using
column chromatography (heptane/EtOAc, 10:1 to 6:1) to give 14
N-Allyl-N-(2-fluoroallyl)-4-methylbenzenesulfonamide (11): A sus-
pension of NaH (25 mg, 1.05 mmol) in DMF (6 mL) was treated
with compound 9 (162 mg, 0.70 mmol). After stirring for 30 min,
3-bromopropene (73 µL, 0.84 mmol) was added dropwise at room
temp. The reaction was stirred for 12 h, quenched with water
(65 mg, 60%) as a white solid. 14: M.p. 77–79 °C. IR (neat): ν =
˜
(6 mL) and extracted with Et2O (3 ϫ 6 mL). The ether layers were 3110, 3071, 2928, 2868, 1718, 1679, 1528, 1346, 1165, 1091, 923,
1
dried (MgSO4), evaporated and the residue was purified using col-
858 cm–1. H NMR (300 MHz, CDCl3): δ = 8.32 (d, J = 9.0 Hz, 2
H, Ar), 7.98 (d, J = 8.7 Hz, 2 H, Ar), 5.76–5.63 (m, 1 H, CH2=CH),
5.11–5.04 (m, 2 H, CH2=CH), 4.66 (dd, J = 3.6, 44.1 Hz, 1 H,
CH2cis=CF), 4.56 (dd, J = 3.6, 75.4 Hz, 1 H, CH2trans=CF), 4.05
(d, J = 15.9 Hz, 2 H, CFCH2N), 3.30 (t, J = 7.5 Hz, 2 H,
NCH2CH2), 2.39–2.32 (m, 2 H, NCH2CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.5 (d, J = 259.0 Hz, CF), 149.8, 145.6,
umn chromatography (heptane/EtOAc, 10:1 to 6:1) to give 11
(152 mg, 54%) as a colorless oil. IR (neat): ν = 3071, 3015, 2954,
˜
1
2920, 1679, 1597, 1346, 1161, 1096, 927, 798, 659 cm–1. H NMR
(300 MHz, CDCl3): δ = 7.68 (d, J = 8.1 Hz, 2 H, Ar), 7.27 (d, J =
7.8 Hz, 2 H, Ar), 5.68–5.55 (m, 1 H, CH2=CH), 5.19–5.13 (m, 2
H, CH2=CH), 4.61 (dd, J = 3.0, 51.7 Hz, 1 H, CH2cis=CF), 4.51
(dd, J = 3.0, 82.9 Hz, 1 H, CH2trans=CF), 3.91 (d, J = 13.5 Hz, 2 133.7, 128.4, 124.1, 117.7, 95.2 (d, J = 17.2 Hz, C=CF), 47.7 (d, J
H, CFCH2N), 3.83 (d, J = 6.3 Hz, 2 H, NCH2CH), 2.41 (s, 3 H, = 30.2 Hz, CH2CF), 46.9, 32.9 ppm. HRMS (EI): calcd. for
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.3 (d, J = C13H15FN2O4S (M+) 314.0737, found 314.0733.
Eur. J. Org. Chem. 2007, 2667–2675
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2671

F. P. J. T. Rutjes et al.
FULL PAPER
N-(2-Fluoroallyl)-4-methyl-N-(pent-4-enyl)benzenesulfonamide (15):
A suspension of NaH (33 mg, 1.38 mmol) in DMF (10 mL) was
treated with compound 9 (210 mg, 0.92 mmol). After stirring for
30 min, 5-bromo-1-pentene (0.13 mL, 1.10 mmol) was added drop-
wise at room temp. The reaction was stirred for 12 h, quenched
with water (10 mL) and extracted with Et2O (3 ϫ 10 mL). The
ether layers were dried (MgSO4), evaporated and the residue was
purified using column chromatography (heptane/EtOAc, 10:1 to
N-(2-Fluoroallyl)-N-(hex-5-enyl)-4-methylbenzenesulfonamide (18):
To a solution of compound 9 (70 mg, 0.27 mmol) in toluene (3 mL)
were added PPh3 (141 mg, 0.54 mmol), 5-hexenol (39 µL,
0.33 mmol) and diethyl azodicarboxylate (78.7 µL, 0.43 mmol).
The mixture was heated at 50 °C for 12 h, then the solvent was
evaporated and the residue was purified using column chromatog-
raphy (heptane/EtOAc, 10:1) to give 18 (65 mg, 77%) as a colorless
oil. 18: IR (neat): ν = 3071, 2971, 2924, 2863, 1675, 1593, 1442,
˜
6:1) to give 15 (53 mg, 19%) as a yellow oil. 15: IR (neat): ν =
1338, 1161, 1091, 909, 810, 664, 547 cm–1. 1H NMR (300 MHz,
˜
3075, 2963, 2924, 2863, 1679, 1597, 1442, 1342, 1156, 1087, 914,
CDCl3): δ = 7.67 (d, J = 8.4 Hz, 2 H, Ar), 7.26 (d, J = 8.4 Hz, 2
1
811 cm–1. H NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 8.4 Hz, 2 H, Ar), 5.79–5.66 (m, 1 H, CH2=CH), 4.99–4.91 (m, 2 H,
H, Ar), 7.28 (d, J = 8.7 Hz, 2 H, Ar), 5.80–5.66 (m, 1 H, CH2=CH), CH2=CH), 4.63 (dd, J = 3.3, 44.2 Hz, 1 H, CH2cis=CF), 4.52 (dd,
5.02–4.93 (m, 2 H, CH2=CH), 4.63 (dd, J = 3.3, 44.1 Hz, 1 H,
CH2cis=CF), 4.53 (dd, J = 3.3, 75.7 Hz, 1 H, CH2trans=CF), 3.91
(d, J = 13.8 Hz, 2 H, CFCH2N), 3.16 (t, J = 7.5 Hz, 2 H,
J = 3.3, 75.7 Hz, 1 H, CH2trans=CF), 3.91 (d, J = 14.1 Hz, 2 H,
CFCH2N), 3.16 (t, J = 7.5 Hz, 2 H, NCH2CH2), 2.41 (s, 3 H, CH3),
2.05–1.99 (m, 2 H, CH2 =CHCH2 ), 1.66–1.50 (m, 2 H,
N C H 2 C H 2 ) , 2 . 4 1 ( s, 3 H , C H 3 ) , 2 . 0 6 – 1 . 9 9 ( m , 2 H , NCH2CH2CH2), 1.42–1.25 (m, 2 H, NCH2CH2CH2) ppm. 13C
NCH2CH2CH2), 1.70–1.60 (m, 2 H, NCH2CH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.7 (d, J = 258.8 Hz, CF), 143.2,
NMR (75 MHz, CDCl3): δ = 160.7 (d, J = 258.8 Hz, CF), 143.2, 138.1, 136.7, 129.5, 127.2, 114.8, 93.9 (d, J = 17.5 Hz, C=CF),
137.2, 136.7, 129.5, 127.2, 115.3, 94.0 (d, J = 17.2 Hz, C=CF), 47.8 47.9, 47.6 (d, J = 27.3 Hz, CH2CF), 33.4, 27.6, 26.0, 21.8 ppm.
(d, J = 31.9 Hz, CH2CF), 47.6, 30.9, 27.5, 21.8 ppm. HRMS (EI):
HRMS (EI): calcd. for C16H23FNO2S [M + H]+ 312.1433, found
312.1437.
calcd. for C15H20FNO2S (M+) 297.1199, found 297.1203.
N-(2-Fluoroallyl)-4-methyl-N-(3-methylpent-4-enyl)benzenesulfon-
amide (16): To a solution of compound 9 (90 mg, 0.40 mmol) in
toluene (4 mL) were added PPh3 (210 mg, 0.80 mmol), 3-methyl-4-
pentenol (48 mg, 0.48 mmol) and diethyl azodicarboxylate
(0.12 mL, 0.64 mmol). The mixture was heated at 50 °C for 12 h,
then the solvent was evaporated and the residue was purified using
column chromatography (heptane/EtOAc, 20:1) to give 16 (85 mg,
N-Decyl-N-(2-fluoroallyl)-4-methylbenzenesulfonamide (19): To a
solution of compound 9 (110 mg, 0.42 mmol) in toluene (5 mL)
was added PPh3 (222 mg, 0.85 mmol), 9-decenol (91 µL,
0.51 mmol) and diethyl azodicarboxylate (0.13 mL, 0.67 mmol).
The mixture was heated at 50 °C for 12 h, then the solvent was
evaporated and the residue was purified using column chromatog-
raphy (heptane/EtOAc, 20:1) to give 19 (121 mg, 78%) as a yellow
68%) as a colorless oil. 16: IR (neat): ν = 3075, 2958, 2928, 2863,
˜
oil. 19: IR (neat): ν = 3071, 2971, 2928, 2855, 1779, 1675, 1636,
˜
1679, 1593, 1450, 1346, 1156, 1091, 923, 849, 815, 664 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 8.4 Hz, 2 H, Ar), 7.29
(d, J = 9.3 Hz, 2 H, Ar), 5.68–5.56 (m, 1 H, CH2=CH), 5.99–4.91
(m, 2 H, CH2=CH), 4.65 (dd, J = 3.3, 43.5 Hz, 1 H, CH2cis=CF),
4.55 (dd, J = 3.3, 75.4 Hz, 1 H, CH2trans=CF), 3.99–3.83 (m, 2 H,
CFCH2N), 3.23–3.07 (m, 2 H, NCH2CH2), 2.41 (s, 3 H, CH3),
2.16–2.07 (m, 1 H, CHCH3), 1.59–1.51 (m, 2 H, NCH2CH2), 0.98
(d, J = 6.6 Hz, 3 H, CHCH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 161.0 (d, J = 259.6 Hz, CF), 143.4, 143.3, 136.8, 129.7, 127.3,
113.6, 94.0 (d, J = 17.2 Hz, C=CF), 47.7 (d, J = 32.2 Hz, CH2CF),
46.2, 35.6, 34.6, 21.6, 20.3 ppm. HRMS (EI): calcd. for
C16H22FNO2S (M+) 311.1355, found 311.1349.
1593, 1467, 1342, 1234, 1156, 1087, 914, 815, 659, 547 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.67 (d, J = 8.4 Hz, 2 H, Ar), 7.26
(d, J = 8.7 Hz, 2 H, Ar), 5.85–5.71 (m, 1 H, CH2=CH), 5.00–4.88
(m, 2 H, CH2=CH), 4.63 (dd, J = 3.0, 41.2 Hz, 1 H, CH2cis=CF),
4.52 (dd, J = 3.0, 72.7 Hz, 1 H, CH2trans=CF), 3.90 (d, J = 13.5 Hz,
2 H, CFCH2N), 3.14 (t, J = 7.5 Hz, 2 H, NCH2CH2), 2.40 (s, 3
H, CH3), 2.06–1.99 (m, 2 H, CH2=CHCH2), 1.54–1.24 (m, 12 H,
NCH2(CH2)6CH2CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
160.7 (d, J = 258.8 Hz, CF), 143.1, 138.9, 136.7, 129.4, 127.1, 114.1,
93.8 (d, J = 17.2 Hz, C=CF), 47.9, 47.6 (d, J = 31.8 Hz, CH2CF),
33.9, 29.5, 29.3, 29.2, 29.1, 28.2, 26.8 ppm. HRMS (EI): calcd. for
C20H30FNO2S (M+) 367.1981, found 367.1967.
N-(2-Fluoroallyl)-4-methyl-N-(3-phenylpent-4-enyl)benzenesulfon-
amide (17): To a solution of compound 9 (90 mg, 0.40 mmol) in
toluene (4 mL) were added PPh3 (210 mg, 0.80 mmol), 3-phenyl-4-
N-(2-Fluoroallyl)-4-methyl-N-(undec-10-enyl)benzenesulfonamide
(20): To a solution of compound 9 (90 mg, 0.35 mmol) in toluene
penten-1-ol (78 mg, 0.48 mmol) and diethyl azodicarboxylate (4 mL) were added PPh3 (181 mg, 0.69 mmol), 10-decen-1-ol
(0.12 mL, 0.64 mmol). The mixture was heated at 50 °C for 12 h,
then the solvent was evaporated and the residue was purified using
column chromatography (heptane/EtOAc, 20:1) to give 17 (90 mg,
(83.1 µL, 0.42 mmol) and diethyl azodicarboxylate (72 µL,
0.55 mmol). The mixture was heated at 50 °C for 12 h, then the
solvent was evaporated and the residue was purified using column
chromatography (heptane/EtOAc, 20:1) to give 20 (130 mg, 99%)
60%) as a pink oil. 17: IR (neat): ν = 3084, 3058, 3028, 2976, 2928,
˜
2863, 1675, 1597, 1489, 1455, 1342, 1156, 1087, 927, 810, 759, 707, as a yellow oil. 20: IR (neat): ν = 3075, 2924, 2855, 1779, 1675,
˜
664, 547 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J =
1636, 1593, 1463, 1342, 1156, 1087, 919, 811, 664, 543 cm–1. 1H
8.4 Hz, 2 H, SO2Ar), 7.31–7.13 (m, 7 H, 2H SO2Ar, 5H Ph), 5.94–
NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 8.4 Hz, 2 H, Ar), 7.28
5.83 (m, 1 H, CH2=CH), 5.05–4.99 (m, 2 H, CH2=CH), 4.58 (dd, (d, J = 7.8 Hz, 2 H, Ar), 5.87–5.74 (m, 1 H, CH2=CH), 5.02–4.90
J = 3.3, 57.9 Hz, 1 H, CH2cis=CF), 4.47 (dd, J = 3.3, 89.5 Hz, 1 H, (m, 2 H, CH2=CH), 4.65 (dd, J = 3.0, 41.4 Hz, 1 H, CH2cis=CF),
CH2trans=CF), 3.88 (d, J = 14.4 Hz, 2 H, CFCH2N), 3.26–3.12 (m, 4.54 (dd, J = 3.0, 73.3 Hz, 1 H, CH2trans=CF), 3.92 (d, J = 13.5 Hz,
2 H, 1H NCH2CH2, CHPh), 3.06–2.96 (m, 1 H, NCH2CH2), 2.40 2 H, CFCH2N), 3.15 (t, J = 7.5 Hz, 2 H, NCH2CH2), 2.41 (s, 3
(s, 3 H, CH3), 2.04–1.96 (m, 2 H, NCH2CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 160.8 (d, J = 259.6 Hz, CF), 143.5, 143.1,
141.2, 136.7, 129.7, 128.7, 127.6, 127.4, 126.6, 114.8, 94.2 (d, J =
H, CH3), 2.07–1.99 (m, 2 H, CH2=CHCH2), 1.32–1.24 (m, 14 H,
NCH2(CH2)7CH2CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
161.0 (d, J = 259.9 Hz, CF), 143.3, 139.2, 136.9, 129.6, 127.3, 114.2,
17.2 Hz, C=CF), 48.0 (d, J = 31.9 Hz, CH2CF), 47.3, 46.4, 33.6, 93.8 (d, J = 17.5 Hz, C=CF), 47.8, 47.5 (d, J = 32.2 Hz, CH2CF),
21.6 ppm. HRMS (EI): calcd. for C21H24FNO2S (M+) 373.1512,
found 373.1497.
33.8, 29.5, 29.4, 29.2, 29.1, 28.9, 28.0, 26.8 ppm. HRMS (EI): calcd.
for C21H32FNO2S (M+) 381.2138, found 381.2133.
2672
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2667–2675

Fluorinated Nitrogen Heterocycles
FULL PAPER
General Procedure for the RCM Reactions
4.16–4.07 (m, 1 H, CFCH2N), 3.91–3.83 (m, 1 H, CFCH2N), 3.44–
3.28 (m, 2 H, NCH2CH2), 2.42 (s, 3 H, ArCH3), 2.39–2.37 (br. m,
1 H, CHCH3), 1.87–1.77 (m, 1 H, NCH2CH2), 1.69–1.56 (m, 1 H,
NCH2CH2), 1.01 (d, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 156.2 (d, J = 252.3 Hz, CF), 143.7, 135.9,
129.8, 127.3, 113.4 (d, J = 16.9 Hz, C=CF), 47.3, 47.1 (d, J =
44.5 Hz, CH2CF), 34.9 9 (d, J = 0.6 Hz, NCH2CH2), 27.7 (d, J =
9.2 Hz, CF=CHCHCH3), 22.1, 21.6 ppm. HRMS (EI): calcd. for
C14H18FNO2S (M+) 283.1042, found 283.1036.
To a 0.01  solution of the diolefin in dry toluene under an inert
atmosphere was added the second-generation Grubbs catalyst 10
at 100 °C in small portions over 30 min. 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.
4-Fluoro-2-methyl-1-(4-tolylsulfonyl)-2,5-dihydro-1H-pyrrole (22):
RCM was carried out following the general procedure with com-
pound 12 (76 mg, 0.27 mmol) and was completed in 3 h. The mix-
ture was purified using column chromatography (heptane/EtOAc,
6-Fluoro-4-phenyl-1-(4-tolylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine
(27): RCM was carried out following the general procedure with
compound 17 (60 mg, 0.16 mmol) and was completed in 3 h. The
mixture was purified using column chromatography (heptane/
EtOAc, 10:1) to give 27 (40 mg, 72%) as a colorless oil. 27: IR
10:1) to give 22 (50 mg, 72%) as a yellow oil. 22: IR (neat): ν =
˜
3101, 3062, 3028, 2963, 2920, 2872, 1701, 1597, 1450, 1351, 1161,
1091, 1035, 936, 815, 664, 577, 547 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.69 (d, J = 8.4 Hz, 2 H, Ar), 7.31 (d, J = 8.7 Hz, 2
H, Ar), 4.92–4.89 (m, 1 H, FC=CHCH), 4.46–4.44 (m, 1 H,
NCHCH3), 4.16–3.98 (m, 2 H, NCH2CF), 2.42 (s, 3 H, ArCH3),
1.44 (d, J = 6.3 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 153.7 (d, J = 273.4 Hz, CF), 143.7, 143.1, 129.8, 127.4, 104.4
(d, J = 7.5 Hz, C=CF), 59.9 (d, J = 6.9 Hz, CHCH=CF), 50.0 (d,
J = 30.7 Hz, CH2CH=CF), 23.6, 21.8 ppm. HRMS (CI) calcd. for
C12H15FNO2S [M + H]+ 256.0807, found 256.0809.
(neat): ν = 3062, 3028, 2924, 2859, 1697, 1593, 1489, 1446, 1338,
˜
1161, 1091, 936, 815, 754, 698, 659, 547 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.70 (d, J = 8.4 Hz, 2 H, SO2Ar), 7.34–7.11 (m, 5 H,
SO2Ar, Ph), 7.10 (d, J = 6.9 Hz, 2 H, Ph), 5.38 (dd, J = 3.6,
21.0 Hz, 1 H, FC=CHCHPh), 4.29–4.20 (m, 1 H, CFCH2N), 4.05–
3.96 (m, 1 H, CFCH2N), 3.51–3.49 (m, 1 H, CHPh), 3.43–3.28 (m,
2 H, NCH2CH2), 2.44 (s, 3 H, CH3), 2.07–1.99 (m, 2 H,
NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.1 (d, J =
253.3 Hz, CF), 144.4, 143.8, 135.8, 129.9, 128.8, 127.36, 127.35,
126.8, 111.7 (d, J = 19.8 Hz, C=CF), 46.9 (d, J = 44.2 Hz, CH2CF),
46.8, 39.6 (d, J = 9.5 Hz, CF=CHCHPh), 35.6, 21.6 ppm. HRMS
(EI): calcd. for C19H20FNO2S (M+) 345.1199, found 345.1190.
5-Fluoro-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine (24):
RCM was carried out following the general procedure with com-
pound 14 (40 mg, 0.13 mmol) and was completed in 1 h. The mix-
ture was purified using column chromatography (heptane/EtOAc,
10:1) to give 24 (36 mg, 97%) as a white solid. 24: M.p. 116–118 °C.
6-Fluoro-1-(4-tolylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine (25) from
Precursor 18: RCM was carried out following the general procedure
with compound 18 (57 mg, 0.18 mmol) and was completed in 2 h.
The mixture was purified using column chromatography (heptane/
EtOAc, 10:1) to give 25 (20 mg, 41%) as a colorless oil.
IR (neat): ν = 3101, 2963, 2920, 2859, 2790, 1713, 1576, 1528, 1455,
˜
1351, 1260, 1169, 1091, 1009, 824, 798 cm–1. H NMR (300 MHz,
1
CDCl3): δ = 8.37 (d, J = 8.7 Hz, 2 H, Ar), 7.97 (d, J = 8.4 Hz, 2
H, Ar), 5.31 (dt, J = 5.7, 17.1 Hz, 1 H, FC=CHCH2), 3.75–3.73
(m, 2 H, CFCH2N), 3.25 (t, J = 5.7 Hz, 2 H, NCH2CH2), 2.25–
2.19 (m, 2 H, NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
153.4 (d, J = 251.6 Hz, CF), 150.5, 142.6, 128.6, 124.5, 100.9 (d, J
= 13.2 Hz, C=CF), 43.9 (d, J = 39.9 Hz, CH2CF), 42.8 (d, J =
1.4 Hz, CH2CH=CF), 22.7 ppm. HRMS (EI): calcd. for
C11H11FN2O4S (M+) 286.0424, found 286.0417.
tert-Butyl N-Tosyl-N-[2-(trifluoromethyl)allyl]carbamate (30): A
solution of compound 5 (461 mg, 1.64 mmol) and tert-butyl N-tos-
ylcarbamate[14] (0.536 g, 1.98 mmol) in MeCN (70 mL) was treated
with K2CO3 (2.76 g, 2.0 mmol) and the suspension refluxed for
18 h. After cooling to room temp., K2CO3 was filtered off and the
solvent evaporated. The crude product was purified by flash
chromatography (ethyl acetate/heptane, 1:25 to 1:15) to give 30
6-Fluoro-1-(4-tolylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine (25):
RCM was carried out following the general procedure with com-
pound 15 (46 mg, 0.15 mmol) and was completed in 1 h. The mix-
ture was purified using column chromatography (heptane/EtOAc,
(0.505 g, 81%) as a white solid. 30: M.p. 89–91 °C. IR (neat): ν =
˜
1
2981, 2933, 1734, 1597, 1144 cm–1. H NMR (300 MHz, CDCl3):
δ = 7.79–7.83 (m, 1 H), 7.30–7.33 (m, 1 H), 5.87–5.88 (m, 1 H),
5.61–5.62 (m, 1 H), 4.61–4.62 (m, 2 H), 2.45 (s, 3 H), 1.36 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 150.4, 144.8, 136.7, 134.6
(q, J = 29.5 Hz, CCF3), 129.5, 128.4, 123.0 (q, J = 273.7 Hz, CF3),
119.2 (q, J = 5.2 Hz, C=CCF3) 85.1, 45.3, 27.9, 21.8 ppm. HRMS
(ESI) calcd. for C16H20F3NNaO4S [M + Na]+ 402.0963, found
402.0960.
10:1) to give 25 (32 mg, 80%) as a colorless oil. 25: IR (neat): ν =
˜
3058, 2980, 2933, 2872, 2846, 1701, 1597, 1450, 1342, 1161, 1091,
1044, 914, 811, 664, 551 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.65 (d, J = 8.1 Hz, 2 H, Ar), 7.27 (d, J = 8.1 Hz, 2 H, Ar), 5.28
(dt, J = 5.7, 19.8 Hz, 1 H, FC=CHCH2), 4.00 (d, J = 6.6 Hz, 2 H,
CFCH2N), 3.38 (t, J = 6.0 Hz, 2 H, NCH2CH2), 2.42 (s, 3 H, CH3),
2.04–1.97 (m, 2 H, NCH2 CH2 CH2 ), 1.85–1.77 (m, 2 H,
NCH2CH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.2 (d,
J = 251.0 Hz, CF), 143.4, 135.9, 128.6, 127.1, 106.9 (d, J = 18.7 Hz,
C=CF), 49.0, 47.4 (d, J = 43.9 Hz, CH2CF), 27.2, 21.8, 21.4 (d, J
= 9 . 8 Hz , CH2 CH=CF) ppm. HRMS (E I) : c al cd . for
C13H16FNO2S (M+) 269.0886, found 269.0889.
4-Methyl-N-[2-(trifluoromethyl)allyl]benzenesulfonamide (31): TFA
(10 mL) was added to a solution of compound 30 (0.445 g,
1.17 mmol) in CH2Cl2 (10 mL) at 0 °C. After 5 min the reaction
was warmed to room temp. and stirred for an additional 40 min.
Subsequently, the reaction mixture was evaporated and the crude
product purified by column chromatography to give 31 (0.285 g,
6-Fluoro-4-methyl-1-(4-tolylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine
(26): RCM was carried out following the general procedure with
compound 16 (73 mg, 0.23 mmol) and was completed in 1 h. The
mixture was purified using column chromatography (heptane/
EtOAc, 10:1) to give 26 (62 mg, 94%) as a colorless oil. 26: IR
87%) as a white solid. 31: M.p. 69 °C. IR (neat): ν = 3280, 2925,
˜
2856, 1672, 1598, 1321 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.77–7.74 (m, 1 H), 7.74–7.71 (m, 1 H), 7.33–7.32 (m, 1 H), 7.31–
7.29 (m, 1 H), 5.78–5.75 (m, 1 H), 5.63 (dd, J = 2.8, 1.4 Hz, 1 H),
4.87–4.77 (m, 1 H), 3.74 (d, J = 6.6 Hz, 2 H), 2.43 (s, 3 H) ppm.
(neat): ν = 3028, 2963, 2924, 2872, 1692, 1597, 1489, 1446, 1342, 13C NMR (75 MHz, CDCl3): δ = 143.9, 136.6, 134.1 (q, J =
˜
1161, 1100, 923, 879, 815, 754, 655, 590, 547 cm–1
.
1H NMR
29.0 Hz, CCF3), 129.8, 127.1, 122.7 (q, J = 273.5 Hz, CF3), 120.6
(q, J = 5.2 Hz, C=CCF3), 41.7, 21.5 ppm. HRMS (EI): calcd. for
C11H12F3NO2S (M+) 279.0541, found 279.05379.
(300 MHz, CDCl3): δ = 7.67 (d, J = 8.4 Hz, 2 H, Ar), 7.31 (d, J =
7.8 Hz, 2 H, Ar), 5.13 (dd, J = 3.9, 21.0 Hz, 1 H, FC=CHCHPh),
Eur. J. Org. Chem. 2007, 2667–2675
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2673

F. P. J. T. Rutjes et al.
FULL PAPER
N-Allyl-4-methyl-N-[2-(trifluoromethyl)allyl]benzenesulfonamide
(32): To a solution of compound 31 (50 mg, 0.179 mmol) in toluene
50 °C for 40 min, then the solvent was evaporated and the residue
was purified using column chromatography (heptane/EtOAc, 20:1)
(4 mL) were added PPh3 (94 mg, 0.36 mmol), 2-propenol (12.5 mg, to give 35 (31 mg, 74%) as a colorless oil. 35: IR (neat): ν = 3060,
˜
0.214 mmol) and diethyl azodicarboxylate (49.8 mg, 0.286 mmol).
The mixture was heated at 50 °C for 40 min, then the solvent was
evaporated and the residue was purified using column chromatog-
raphy (heptane/EtOAc, 20:1) to give 32 (57 mg, 99%) as a colorless
oil. 32: IR (neat): 2985, 2924, 2858, 1347, 1321. 1H NMR
(300 MHz, CDCl3): δ = 7.68–7.72 (m, 2 H, Ar), 7.29–7.32 (m, 2 H,
Ar), 5.85–5.87 (m, 1 H, CH=CCF3), 5.66–5.68 (m, 1 H,
3027, 2924, 2867, 1637, 1598, 1492, 1452, 1341, 1321, 1158, 1121,
955, 701 cm–1 1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J =
.
8.2 Hz, Ar), 7.08–7.31 (m, 7 H, Ar), 5.84 (ddd, J = 17.1, 10.3,
7.5 Hz CH=CH2), 5.83 (dd, J = 2.8, 1.4 Hz, 1 H, CH=CCF3), 5.64
(dd, J = 2.8, 1.4 Hz, CH=CCF3), 5.00 (dt, J = 25.5, 1.4 Hz, 1 H,
CH=CH2), 5.00–5.02 (m, 1 H, CH=CH2), 3.87 (br. s, 2 H, NCH2),
3.09–3.20 (m, 2 H, NCH2CCF3), 2.91–3.01 (m, 1 H, CHPh), 2.42
CH=CCF3), 5.50 (ddt, J = 6.7, 6.7, 10.1 Hz, 1 H, CH=CH2), 5.06– (s, 3 H, CH3), 1.85–1.93 (m, 2 H, NCH2CH2) ppm. 13C NMR
5.15 (m, 1 H, CH=CH2), 5.10–5.13 (m, 1 H, CH=CH2), 3.90 (s, 2 (75 MHz, CDCl3): δ = 146.0, 142.9, 141.7, 136.4, 134.3 (q, J =
H, NCH2CH), 3.78–3.81 (m, 2 H, NCH2CCF3), 2.42 (s, 3 H, CH3) 30.0 Hz, CCF3), 129.9, 128.8, 127.6, 127.4, 126.8, 123.1 (q, J =
ppm. 13C NMR (75 MHz, CDCl3): δ = 143.9, 136.9, 133.9 (q, J =
29.1 Hz, CCF3), 131.8, 130.0, 127.4, 123.1 (q, J = 273.6 Hz, CF3),
120.6, (q, J = 5.3 Hz, C=CCF3), 120.5, 50.6, 44.9, 21.7 ppm.
HRMS (EI): calcd. for C14H16F3NO2S (M+) 319.0854, found
319.0854.
277 Hz, CF3), 120.8 (q, J = 7.5 Hz, C=CCF3), 115.0, 47.6, 47.5,
46.8, 33.4, 21.7 ppm.
1-Tosyl-3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole (36): RCM was
carried out following the general procedure with compound 32
(40 mg, 0.125 mmol) and was completed in 45 min. The mixture
was purified using column chromatography (heptane/EtOAc, 10:1)
to give 36 (21 mg, 57%) as a white solid and 37 (9.1 mg, 23%) as
N-(But-3-enyl)-4-methyl-N-(2-trifluoromethylallyl)benzenesulfon-
amide (33): To a solution of compound 31 (50 mg, 0.179 mmol)
in toluene (4 mL) were added PPh3 (94 mg, 0.36 mmol), 3-butenol
(18.4 µL, 0.214 mmol) and diethyl azodicarboxylate (52.2 µL,
0.286 mmol). The mixture was heated at 50 °C for 40 min, then the
solvent was evaporated and the residue was purified using column
chromatography (heptane/EtOAc, 20:1) to give 33 (38 mg, 64%) as
an amorphous solid. 36: M.p. 63–64 °C. IR (neat): ν = 3060, 3027,
˜
2956, 2923, 2856, 1679, 1597, 1379 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.73 (d, J = 8.2 Hz, 2 H, Ar), 7.35 (d, J = 8.0 Hz, 2
H, Ar), 6.19–6.20 (m, 1 H), 4.26 (s, 4 H), 2.44 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 144.3, 133.8, 130.2, 129.8 (q, J =
4.8 Hz, C=CCF3), 129.3 (q, J = 35.5 Hz, CCF3), 127.6, 120.8 (q, J
= 269.3 Hz, CF3), 54.9, 52.2, 21.7 ppm. HRMS (EI): calcd. for
C H F NO S (M+) 291.0541, found 291.0539. 37: IR (neat): ν =
a colorless oil. 33: IR (neat): ν = 3071, 2976, 2855, 1455, 1407,
˜
1346, 1321, 1156, 1122, 1091, 953, 919, 811, 754, 664, 543 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 8.1 Hz, 2 H, Ar), 7.32
(d, J = 8.1 Hz, 2 H, Ar), 5.88–5.87 (m, 1 H, F3CC=CH), 5.73–5.70
(m, 1 H, F3CC=CH) 5.68–5.56 (m, 1 H, CH2=CH), 5.05–4.97 (m,
2 H, CH2=CH), 3.93 (s, 2 H, NCH2CCF3), 3.22 (t, J = 7.7 Hz, 2
H, NCH2CH2), 2.43 (s, 3 H, CH3), 2.25–2.17 (m, 2 H, NCH2CH2)
ppm. 13C NMR (75 MHz, CDCl3): δ = 143.9, 136.6, 134.3, 134.2
(q, J = 29 Hz, CCF3), 129.9, 127.3, 123.1 (q, J = 272 Hz, CF3),
120.7 (q, J = 5.2 Hz, C=CCF3), 117.6, 48.3, 46.5, 32.6, 21.6 ppm.
HRMS (ESI): calcd. for C15H18F3NO2S [M+H]+ 334.1089, found
334.1077.
˜
12 12
3
2
3060, 3027, 2959, 2924, 2860, 1662, 1597, 1360, 1322, 1165, 1121,
1
1051, 972, 943 cm–1. H NMR (300 MHz, CDCl3): δ = 7.69 (d, J
= 7.8 Hz, 2 H, Ar), 7.31 (d, J = 7.8 Hz, 2 H, Ar), 6.56 (d, J =
14.1 Hz, 1 H, NCH=CH), 5.79 (m, 1 H, CH=CCF3), 5.55 (m, 1
H, CH=CCF3), 4.72 (m, 1 H, NCH=CHCH3), 4.02 (s, 2 H,
NCH2), 2.42 (s, 3 H, ArCH3), 1.64 (dd, J = 6.6, 1.5 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 144.1, 135.7, 131.8 (q, J =
29.3 Hz, CCF3), 129.9, 126.9, 125.5, 122.9 (q, J = 271.8 Hz, CF3),
119.2, 107.8, 44.2, 21.6, 15.2 ppm.
1-(4-Tolylsulfonyl)-5-(trifluoromethyl)-1,2,3,6-tetrahydropyridine
(38): RCM was carried out following the general procedure with
compound 33 (30 mg, 0.09 mmol) and the reaction was completed
in 1 h. The mixture was purified using column chromatography
(heptane/EtOAc, 10:1) to give 38 (27 mg, 98%) as a colorless oil.
4-Methyl-N-(pent-4-enyl)-N-(2-trifluoromethylallyl)benzenesulfon-
amide (34): To a solution of compound 31 (50 mg, 0.179 mmol) in
toluene (4 mL) were added PPh3 (94 mg, 0.36 mmol), 4-pentenol
(22 µL, 0.21 mmol) and diethyl azodicarboxylate (52.2 µL,
0.286 mmol). The mixture was heated at 50 °C for 40 min, then the
solvent was evaporated and the residue was purified using column
chromatography (heptane/EtOAc, 20:1) to give 34 (37 mg, 60%) as
38: M.p. 90–93 °C. IR (neat): ν = 3036, 2954, 2920, 2846, 1459,
˜
1
1394, 1342, 1316, 1169, 1117, 1091, 966, 879, 746 cm–1. H NMR
(300 MHz, CDCl3): δ = 7.69 (d, J = 8.1 Hz, 2 H, Ar), 7.35 (d, J =
8.1 Hz, 2 H, Ar), 5.39 (t, J = 1.8 Hz, 1 H, F3CC=CHCH2), 3.72
(s, 2 H, F3CCCH2N), 3.21 (t, J = 5.7 Hz, 2 H, NCH2CH2), 2.44
(s, 3 H, CH3), 2.35–2.32 (m, 2 H, NCH2CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 144.2, 133.3, 130.0, 129.1 (q, J = 5.4 Hz,
C=CCF3), 127.8, 125.5 (q, J = 31.0 Hz, CCF3), 122.7 (q, J =
270.3 Hz, CF3), 42.1, 41.9, 24.5, 21.7 ppm. HRMS (EI): calcd. for
C13H14F3NO2S (M+) 305.0697, found 305.0696.
a colorless oil. 34: IR (neat): ν = 3067, 2963, 2924, 2855, 1645,
˜
1597, 1455, 1346, 1325, 1161, 1117, 1091, 1048, 949, 910, 811, 664,
1
551 cm–1. H NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 8.4 Hz, 2
H, Ar), 7.32 (d, J = 8.4 Hz, 2 H, Ar), 5.88 (s, 1 H, F3CC=CH),
5.73 (s, 1 H, F3CC=CH), 5.77–5.64 (m, 1 H, CH2=CH), 5.02–4.95
(m, 2 H, CH2=CH), 3.90 (s, 2 H, F3CCCH2N), 3.13 (t, J = 7.7 Hz,
2 H, NCH2CH2), 2.43 (s, 3 H, CH3), 2.02–1.95 (m, 2 H,
NCH2CH2CH2), 1.61–1.51 (m, 2 H, NCH2CH2CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 143.8, 137.2, 136.6, 134.4 (q, J =
28.7 Hz, CCF3), 129.9, 127.3, 123.1 (q, J = 272 Hz, CF3), 120.6 (q,
J = 5.2 Hz, C=CCF3), 115.7, 48.8, 46.5, 30.9, 27.2, 21.7 ppm.
HRMS (EI): calcd. for C16H20F3NO2S (M+) 347.1167, found
347.1169.
1-(4-Tolylsulfonyl)-5-(trifluoromethyl)-1,2,3,6-tetrahydropyridine
(38) from Precursor 34: RCM was carried out following the general
procedure with compound 34 (20 mg, 0.06 mmol) and the reaction
was completed in 1 h. The mixture was purified using column
chromatography (heptane/EtOAc, 10:1) to give 38 (12 mg, 65%) as
a colorless oil.
4-Methyl-N-(3-phenylpent-4-enyl)-N-[2-(trifluoromethyl)allyl]ben-
zenesulfonamide (35): To a solution of compound 31 (28 mg,
0.1 mmol) in toluene (3 mL) were added PPh3 (52.6 mg,
0.20 mmol), 3-phenyl-4-pentenol (19.5 mg, 0.12 mmol) and diethyl
azodicarboxylate (28 mg, 0.16 mmol). The mixture was heated at
4-Methyl-N-(3-phenyl-3-pentenyl)-N-(2-trifluoromethylallyl)ben-
zenesulfonamide (39): RCM was carried out following the general
procedure with compound 35 (22 mg, 0.05 mmol) and the reaction
was completed in 2 h. The mixture was purified using column
2674
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2667–2675

Fluorinated Nitrogen Heterocycles
FULL PAPER
Symposium Series 639, American Chemical Society, Washing-
ton, DC, 1996; c) J. T. Welch, S. Eswarakrishnan, Fluorine in
Bioorganic Chemistry, Wiley, New York, 1991; d) Enantiocon-
trolled Synthesis of Fluoroorganic Biomedical Targets (Ed.: V. A.
Soloshonok), Wiley, New York, 1999; e) D. F. Halpern, in Or-
ganofluorine Compounds in Medicinal Chemistry and Biomedi-
cal Applications (Eds.: R. Filler, Y. Kobayashi, L. Yagupolskii),
Elsevier, Amsterdam, 1993, pp. 101–133.
chromatography (heptane/EtOAc, 10:1) to give 39 (15 mg, 68%) as
a colorless oil. 39 (major isomer): H NMR (300 MHz, CDCl3): δ
1
= 7.67 (d, J = 8.4 Hz, Ar), 7.34–7.18 (m, 7 H, Ar), 5.88–5.86 (m,
1 H, CH=CCF3), 5.83–5.81 (m, 1 H, CH=CCF3), 5.66 (q, J =
1.2 Hz, 1 H, PhC=CHCH3), 3.99 (s, 2 H, NCH2CCF3), 3.12–3.05
(m, 2 H, NCH2), 2.74–2.69 (m, 2 H, NCH2CH2), 2.45 (s, 3 H,
CH3), 1.76 (d, J = 7.2 Hz, 3 H, =CH3) ppm.
[3] For excellent overviews, see for example: a) R. D. Chambers,
Fluorine in Organic Chemistry, Blackwell, Oxford, 2004; b) P.
Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH,
Weinheim, 2004.
[4] For a review on trifluoromethylation methods, see: P. Lin, J.
Jiang, Tetrahedron 2000, 56, 3635–3671.
[5] S. S. Salim, R. K. Bellingham, V. Satcharoen, R. Brown, Org.
Lett. 2003, 5, 3403–3406.
[6] M. Marhold, A. Buer, H. Hiemstra, J. H. van Maarseveen, G.
Haufe, Tetrahedron Lett. 2004, 45, 57–60.
[7] V. De Matteis, F. L. van Delft, J. Tiebes, F. P. J. T. Rutjes, Eur.
J. Org. Chem. 2006, 1166–1176.
[8] V. De Matteis, F. L. van Delft, H. Jakobi, S. Lindell, J. Tiebes,
F. P. J. T. Rutjes, J. Org. Chem. 2006, 71, 7527–7532.
[9] V. De Matteis, F. L. van Delft, J. Tiebes, F. P. J. T. Rutjes, Tetra-
hedron Lett. 2004, 45, 959–963.
[10] See e. g.: a) 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; b) S. S. Kinderman,
J. H. van Maarseveen, H. E. Schoemaker, H. Hiemstra,
F. P. J. T. Rutjes, Synthesis 2004, 1413–1418; c) S. S. Kinder-
man, 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; 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) S. S. Kinderman, R. Doodeman, J. W. van Beijma,
J. C. Russcher, K. C. M. F. Tjen, M. T. Kooistra, H. Mohaselz-
adeh, J. H. van Maarseveen, H. Hiemstra, H. E. Schoemaker,
F. P. J. T. Rutjes, Adv. Synth. Catal. 2002, 344, 736–748.
[11] L. O. Moore, J. P. Henry, J. W. Clark, J. Org. Chem. 1970, 35,
4201–4204.
[12] For other examples of the isomerization behavior of catalyst
10, see for example: a) K. F. W. Hekking, M. A. H. Moelands,
F. L. van Delft, F. P. J. T. Rutjes, J. Org. Chem. 2006, 71, 6444–
6450; b) S. S. Kinderman, J. H. van Maarseveen, H. E. Schoe-
maker, H. Hiemstra, F. P. J. T. Rutjes, Org. Lett. 2001, 3, 2045–
2048.
N-[1-(Benzyloxy)allyl]-4-methyl-N-[2-(trifluoromethyl)allyl]ben-
zenesulfonamide (41): Compound 41 was prepared according to a
general literature procedure for amidopalladation of tosylam-
ides.[10] To a 0.1  solution of compound 31 (103 mg, 0.36 mmol)
in MeCN were added Et3N (54 mg, 0.54 mmol), Pd(OAc)2 (4 mg,
5 mol-%), dppp (7.4 mg, 5 mol-%) and benzyloxyallene 40
(57.6 mg, 0.39 mmol). After stirring at room temp. for one hour,
the solvent was evaporated and the crude residue purified by col-
umn chromatography (heptane/EtOAc, 6:1 to 4:1) to give product
41 (0.144 g, 92%)as a colorless oil. 41: IR (neat): ν = 3066, 3031,
˜
1
2926, 2868, 1347, 1321, 1160 cm–1. H NMR (300 MHz, CDCl3):
δ = 7.73–7.68 (m, 2 H, Ar), 7.36–7.18 (m, 7 H, Ar), 5.80 (dd, J =
2.9, 1.5 Hz, 1 H, CH=CCF3), 5.73 (dd, J = 3.0, 1.5 Hz, 1 H,
CH=CCF3), 5.67 (dd, J = 3.1, 1.3 Hz, 1 H, CH=CH), 5.50–5.45
(m, 2 H, HC=CH2), 5.28 (ddd, J = 6.7, 2.6, 1.1 Hz, 1 H, HC=CH2),
4.52 (dd, J = 11.8, 3.8 Hz, 2 H, OCH2), 3.94 (q, J = 18.2 Hz, 2 H,
NCH2), 2.42 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
144.1, 137.2, 137.0, 135.0 (q, J = 28.8 Hz, CCF3), 133.0, 129.9,
128.5, 127.9, 127.7, 127.6, 123.2 (q, J = 273.8 Hz, CF3), 120.3 (q,
J = 5.2 Hz, C=CCF3), 119.9, 87.0, 70.0, 41.4, 21.7 ppm. HRMS
(EI): calcd. for C21H22F3NO3S (M+) 426.1351, found 426.1352.
1-Tosyl-3-(trifluoromethyl)-1H-pyrrole (42): To a solution of 41
(0.358 g, 0.842 mmol) in toluene (150 mL) at 100 °C was added cat-
alyst 10 (6.5 mol%) in two portions with an interval of 30 min.
After completion of the RCM (1.5 h), the reaction was cooled to
room temp. and TFA (5.5 mL) was added. After stirring for 30 min
at room temp., the solvent was evaporated and the crude product
purified by flash chromatography (heptane/EtOAc, 40:1) to give 42
(0.195 g, 80%) as a white solid. 42: M.p. 57 °C. IR (neat): ν = 3066,
˜
3031, 2957, 2922, 2852, 1583, 1479, 1378, 1122, 1057 cm–1 1H
.
NMR (300 MHz, CDCl3): δ = 7.80–7.81 (m, 1 H, Ar), 7.77–7.78
(m, 1 H, Ts), 7.45–7.49 (m, 1 H, Ts), 7.35–7.36 (m, 1 H, Ar), 7.32–
7.33 (m, 1 H, Ts), 7.16–7.18 (m, 1 H, Ts), 6.43–6.44 (m, 1 H, Ar),
2.43 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 146.0,
135.1, 130.3, 127.2, 126.0 (q, J = 267.1 Hz, CF3), 121.6, 119.9 (q,
J = 5.0 Hz, C=CCF3), 119.4 (q, J = 37.5 Hz, CCF3), 110.2 (m,
F3CCH=C), 21.7 ppm. HRMS (EI): calcd. for C12H10F3NO2S
(M+) 289.0384, found 289.0387.
[13] For reviews on nonmetathetic behavior of catalyst 10, see: a)
B. Alcaide, P. Almendros, Chem. Eur. J. 2003, 9, 1259; b) B. M.
Trost, F. D. Toste, A. B. Pinkerton, Chem. Rev. 2001, 101, 2067.
[14] For a synthesis of tert-butyl N-tosylcarbamate see: B. R. Neus-
tadt, Tetrahedron Lett. 1994, 35, 379–380.
[15] S. H. Hong, D. P. Sanders, C. W. Lee, R. H. Grubbs, J. Am.
Chem. Soc. 2005, 127, 17160–17161.
[16] J. Leroy, J. Fluorine Chem. 1991, 53, 61–70.
[17] a) T. J. Donohoe, A. J. Orr, M. Bingham, Angew. Chem. Int.
Ed. 2006, 45, 2664–2670; b) T. J. Donohoe, A. J. Orr, K. Gosby,
M. Bingham, Eur. J. Org. Chem. 2005, 1969–1971.
[18] M. Helms, W. Schade, R. Pulz, T. Watanabe, A. Al-Harrasi, L.
Fisera, I. Hlobilová, G. Zahn, H.-U. Reißig, Eur. J. Org. Chem.
2005, 1003–1019.
Acknowledgments
Bayer CropScience GmbH (Frankfurt am Main, Germany) is
gratefully acknowledged for financial support.
[1] See e. g.: A. M. Thayer, Chem. Eng. News 2006, 84, 15–24;
A. M. Thayer, Chem. Eng. News 2006, 84, 27–32.
[2] For recent reviews, see, for example: a) F. M. D. Ismail, J. Flu-
orine Chem. 2002, 118, 27; b) Biomedical Frontiers of Fluorine
Chemistry (Eds.: I. Ojima, J. R. McCarthy, J. T. Welch), ACS
[19] For a typical experimental procedure of the Mitsunobu reac-
tion, see: H. Ito, K. Omodera, Y. Takigawa, T. Taguchi, Org.
Lett. 2002, 4, 1499–1501.
Received: December 22, 2006
Published Online: March 14, 2007
Eur. J. Org. Chem. 2007, 2667–2675
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2675