Synthesis of vinyl fluorides by ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2003.10.127

The first ring-closing olefin metatheses of alkenyl α- fluoroacrylamides or acrylates incorporating a fluorinated double bond are reported. Several N-benzyl-N-alkenyl-α-fluoroacrylamides were cyclized in the presence of 2mol% of Grubbs II catalyst at room

Full text of DOI:10.1016/j.tetlet.2003.10.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 57–60
Synthesis of vinyl fluorides by ring-closing metathesis
Michael Marhold,a Anna Buer,a Henk Hiemstra,b Jan H. van Maarseveenb
a,
*
€
and Gunter Haufe
aOrganisch-Chemisches Institut, Universit€at M€unster, Corrensstr. 40, D-48149 M€unster, Germany
bLaboratory of Organic Chemistry, Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands
Received 26 September 2003; revised 14 October 2003; accepted 22 October 2003
Abstract—The first ring-closing olefin metatheses of alkenyl a-fluoroacrylamides or acrylates incorporating a fluorinated double
bond are reported. Several N-benzyl-N-alkenyl-a-fluoroacrylamides were cyclized in the presence of 2 mol % of Grubbs II catalyst at
room temperature to form an unsaturated c-lactam, and at 80 °C to form the corresponding d-lactams bearing a fluoro vinyl moiety.
At elevated temperature, cyclization of an N-methallyl 2-fluoroacrylamide to form a fluorinated, tetrasubstituted double bond was
achieved. Similarly, 3-fluorocoumarin was prepared from (2-vinylphenyl)-a-fluoroacrylate.
Ó 2003 Elsevier Ltd. All rights reserved.
Vinyl fluorides are versatile building blocks and are
widely used in organic and medicinal chemistry, for
example, as isosteres of peptides or amides.1 Recently,
synthesis of different types, particularly of terminal vinyl
fluorides has been reviewed.2 In principle, internal
fluoro-substituted double bond systems should be ac-
cessible either by intermolecular cross-coupling meta-
thesis (CM)3 of a 2-fluoroalkene and an a-olefin or,
for cyclic systems, by intramolecular ring-closing meta-
thesis (RCM) of monofluorinated a,x-dienes.4 How-
ever, no example of this type of C@C-bond formation
was known until very recently.5 In 2000, Grubbs and
co-workers6 reported their unsuccessful attempts to
cross-couple vinyl halides with olefins. Earlier, Beau-
champet al. speculated about the metathesis of directly
fluorinated olefins with nickel or manganese complexes7
and experiments by Grubbs and co-workers8 to incor-
porate a 1,1-difluoroethylene in a metathesis reaction led
to a stable ruthenium difluorocarbene complex. A recent
paper by Chao and Weinreb9 on the synthesis of vinyl
chlorides by RCM led us to report our results on ring-
closing olefin metathesis involving fluorinated double
bonds.10
Unsaturated fluorinated carbocycles bearing fluorine
substituents in positions remote from the double bond
have already been prepared by RCM.6;11 Our first
attempts to synthesize vinyl fluorides by this methodology
were not successful. Reactions of the ether 1 and esters 2
of 2-fluorodec-1-en-3-ol, which is available in a three-
12
stepsynthesis starting from dec-1-ene, in the presence
of 2 mol % of GrubbsÕ II or HoveydaÕs catalysts resulted
in very slow reactions and if any, only minor amounts of
homodimeric3b products were detected. These com-
pounds were formed in reactions of the non-fluorinated
double bonds. Products of RCM were not detected,
while similar non-fluorinated dienes are known to
cyclize in moderate to good yields using the same cata-
lyst.13
O
O
O
O
O
n
F
H15C7
H15C7
H11C5
F
F
1
2 (n = 0,1,2)
CO2Et
3
EtO2C
O
Keywords: 2-Fluoroacrylamides; 3-Fluorocoumarin; Lactams; Ring-
closing olefin metathesis; Vinyl fluorides.
H15C7
F
* Corresponding author. Tel.: +49-251-833-3281; fax: +49-251-833-
9772; e-mail: haufe@uni-muenster.de
F
4
5
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.127

58
M. Marhold et al. / Tetrahedron Letters 45 (2004) 57–60
Also the reverse substitution pattern, namely the oct-1-
en-3-yl ester of a-fluoroacrylic acid 3, could not be
cyclized in the presence of GrubbsÕ or HoveydaÕs
metathesis catalysts.
derivative 10. Allylation with allyl trimethylsilane gave
the monofluorinated 4-aza-1,7-diene 11. Treatment of
this compound with 2 mol% of Grubbs II catalyst A, in
contrast to the corresponding reaction of the non-fluo-
rinated parent compound,16 gave only traces of the
RCM product 12.
It was also shown that the corresponding carbocycles
could not be synthesized and that the Thorpe–Ingold
effect did not helpto force a RCM reaction with the
fluorinated 1,6-diene 4, even though the cyclization of
the corresponding non-fluorinated compound was suc-
cessful in high yields using different Ru-catalysts.14
This low-yielding reaction and our experience with dif-
ferent ester-type a,x-diene systems (see above) demon-
strated that vinyl fluorides that are part of an
a,b-unsaturated carbonyl system seem to be more suit-
able for RCM reactions. Therefore, in the following
investigations, we focused on a-fluoroacrylamides,
which have a decreased p-electron density about the
fluorinated double bond.
Furthermore, attempts to profit from the effect of a rigid
aromatic system, were not successful in the case of the 2-
fluorodecenyl ether of o-vinyl phenol 5, which did not
lead to the expected fluorinated dihydrobenzopyran
derivative. In contrast, a rigid backbone was helpful in
the reaction of the a-fluoroacrylate 6 to give 3-fluoro-
coumarin 7 (16% isolated yield) in a Grubbs II (A)
catalyzed RCM reaction.15 Additionally, 44% of a ho-
modimer involving the non-fluorinated double bonds
was isolated (Scheme 1).15
Several examples of RCM reactions of N-alkenyl
acrylamides17 and the corresponding allylglycine deriv-
atives18 have been reported and used in the frame of
natural product synthesis.19 In several cases reactions
with N-protected compounds of this type were more
successful.20 We synthesized a number of terminal N-
alkenyl-N-benzyl-a-fluoroacrylamides 1421 by acylation
of compounds 13 with a-fluoroacrylic acid (Scheme 3).
Some derivatives bearing fluorine or a methoxy groupin
the phenyl ring of the protecting group were also pre-
pared (Table 1).
N
Cl
N
Mes
Mes
Ph
Ru
2 mol%
Cl
F
(A)
PCy3
O
O
O
16 %
O
O
F
HO
6
7
N
H
F
N
n
n
R
R
EDC / HOBT
Scheme 1. RCM to 3-fluorocoumarin 7.
X
X
O
F
13a-g
14a-g
In attempts to favor the RCM product, we performed
high dilution experiments. However, from 0.5 M down
to 0.05 M solutions there was no significant change in
the product ratio.
Scheme 3. Synthesis of N-alkenyl-N-benzyl-a-fluoroacrylamides 14.
The compounds 14 were reacted in the presence of
2 mol % of Grubbs II catalyst (A) to give good yields of
the unsaturated fluorinated c-lactam 15a at room tem-
perature and of the corresponding d-lactams 15b,f and
15g at 80 °C.22 Conversion was >95% in all cases. Pure
products were isolated in 76–86% yields (Table 1).
Corresponding seven and eight-membered N-hetero-
cycles were not formed under identical conditions, while
related non-fluorinated medium-sized rings could be
synthesized (Scheme 4).19
We then carried out experiments with nitrogen hetero-
cycles. In analogy to the non-fluorinated system,16 we
synthesized the monofluorinated metathesis precursor
11 according to Scheme 2.
F
O
O
O
OEt
OTs
N
N
NaBH4
O
O
N
H
EtOH
62%
NaH
64%
F
F
8
9
10
R
N
N
n
n
RCM, (A)
R
X
O
X
F
O
TMS
O
O
RCM, (A)
N
N
F
BF3(OEt2)
78%
1% (GC/MS)
14a-g
15a-g
F
F
Scheme 4. RCM of N-alkenyl-N-benzyl-a-fluoroacrylamides 14.
11
Scheme 2. Synthesis of amide 11 as an RCM precursor.
12
Furthermore, the N-methallyl-2-fluoroacrylamide 14e
could be cyclized under the same conditions to form the
c-lactam 15e22 with a fluorinated tetrasubstituted double
bond in 46% isolated yield.
Alkylation of succinimide 8 with 2-fluoropropenol tos-
ylate gave the imide 9, which was reduced to the aminal

M. Marhold et al. / Tetrahedron Letters 45 (2004) 57–60
59
Table 1. Formation and RCM reactions of N-alkenyl-N-benzyl-a-fluoroacrylicamides 14
Entry
Educts 13
R
X
n
Products 14
Yield
[%]
Time
[min]
Temperature
[°C]
Products
15
Yield
[%]
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13f
13g
H
H
1
2
3
4
1
2
2
14a
14b
14c
14d
14e
14f
14g
70
48
52
52
77
73
57
10
rt
15a
15b
15c
15d
15e
15f
15g
79
86
H
H
120
240
240
480
240
240
80
80
80
80
80
80
H
H
Not detecteda
H
H
Not detecteda
CH3
H
H
46
81
76
OMe
F
H
a Only a homodimeric product involving the non-fluorinated double bond was found.
2. Van Steenis, J. H.; van der Gen, A. J. Chem. Soc., Perkin
Trans. 1 2002, 2117–2133, and references cited therein.
3. Reviews: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413–4450; (b) Connon, S. J.; Blechert, S. Angew.
Chem. 2003, 115, 1944–1968; Angew. Chem. Int. Ed. 2003,
42, 1900–1902.
4. Reviews: (a) Schuster, M.; Blechert, S. Angew. Chem.
1997, 109, 2124–2144; Angew. Chem. Int. Ed. 1997, 36,
2037–2055; (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18–29.
5. During the preparation of this manuscript, a paper
reporting on the synthesis of fluoro-olefins by RCM
appeared: Salim, S. S.; Bellingham, R. K.; Satchoroen, V.;
Brown, R. C. D. Org. Lett. 2003, 5, 3403–3406.
6. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs,
R. H. J. Am. Chem. Soc. 2000, 122, 3783–3784.
7. Halle, L. F.; Armentrout, P. B.; Beauchamp, J. L.
Organometallics 1983, 2, 1829–1833.
In conclusion, the first ring-closing olefin metatheses of
alkenyl a-fluoroacrylamides or acrylates incorporating
fluorinated double bonds were realized. These reactions
seem to profit from the combined but opposite action of
fluorine and the carbonyl groupon the electronic
properties of the double bond. We are continuing our
investigations in this direction.
Typical procedure for RCM reactions of a-fluoroacryl-
amides: In a flame-dried Schlenk tube N-but-4-enyl-N-
benzyl-2-fluoroacrylamide 14b (163.3 mg, 0.7 mmol) in
dry toluene (1.4 mL) was degassed under argon before
Grubbs II catalyst (A) (11.9 mg, 2 mol %) was added.
After the mixture had been heated at 80 °C for 2 h, the
solvent was removed under reduced pressure and the
black residue was purified by column chromatography
(diethyl ether) to give 123 mg (86%) of pure colorless
crystals of compound 15b.
8. Trnka, T. M.; Day, M. W.; Grubbs, R. H. Angew. Chem.
2001, 113, 3549–3552; Angew. Chem. Int. Ed. 2001, 40,
3441–3444.
9. Chao, W.; Weinreb, S. M. Org. Lett. 2003, 5, 2505–
2507.
10. These results were presented at the Third RSC Fluorine
Subject GroupPostgraduate Meeting, St Andrews, UK,
4–5th September 2003, see abstracts of papers.
11. (a) Itoh, T.; Mitsukura, K.; Ishida, N.; Uneyama, K. Org.
Lett. 2000, 2, 1431–1434; (b) Percy, J. M.; Pintat, S. Chem.
Commun. 2000, 607–608; (c) Imhof, S.; Randl, S.; Blec-
hert, S. Chem. Commun. 2001, 1692–1693; (d) Fustero, S.;
Acknowledgements
This project has been financially supported by the
Deutsche
Forschungsgemeinschaft
(International
Graduate College ÔTemplate Directed Chemical Syn-
thesisÕ) and the Council for Chemical Sciences of The
Netherlands Organization for Scientific Research.
ꢀ
ꢀ
Navarro, A.; Pina, B.; Garcıa Soler, J.; Bartolome, A.;
Asensio, A.; Simon, A.; Bravo, P.; Fronza, G.; Volonte-
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rio, A.; Zanda, M. Org. Lett. 2001, 3, 2621–2624.
12. Ernet, T.; Haufe, G. Synthesis 1997, 953–956.
€
13. Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204–2207.
14. (a) Louie, J.; Grubbs, R. H. Angew. Chem. 2001, 113,
253–255; Angew. Chem. Int. Ed. 2001, 40, 247–249; (b)
Wakamatsu, H.; Blechert, S. Angew. Chem. 2002, 114,
2509–2511; Angew. Chem. Int. Ed. 2002, 41, 2403–2405;
(c) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew.
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41, 4038–4040.
References and Notes
€
1. (a) Allmendinger, T.; Felder, E.; Hungersbuhler, E. In
Selective Fluorination in Organic and Bioorganic Chemis-
try; Welch, J. T., Ed.; ACS Symposium Series; American
Chemical Society: Washington, 1991; Vol. 456, pp 186–
195; (b) Welch, J. T.; Lin, J.; Boros, L. G.; DeCorte, B.;
Bergmann, K.; Gimi, R. Fluoro-olefin Isosteres as Pep-
tidomimetics, In Biomedicinal Frontiers of Fluorine Chem-
istry. ACS Symposium Series; American Chemical
Society: Washington, 1996; Vol. 639, pp 129–142; (c)
Cieplak, P.; Kollmann, P. A.; Radomski, J. P. Molecular
Design of Fluorine-Containing Peptide Mimetics, In
Biomedicinal Frontiers of Fluorine Chemistry. ACS Sym-
posium Series; American Chemical Society: Washington,
15. Spectroscopic data of 7: 1H NMR (CDCl3, 300 MHz,
ppm): d 7.13–7.65 (m, 5H); 13C NMR (CDCl3, 75 MHz,
3
ppm): d 116.7 (d, C-8), 118.0 (s, JC;F ¼ 3:7 Hz, C-4a),
2
121.1 (d, JC;F ¼ 16:4 Hz, C-4), 125.2 (d, C-6), 127.7 (d,
4JC;F ¼ 6:2 Hz, C-5), 130.7 (d, C-7), 146.5 (s, 1JC;F ¼ 259:1,
2
C-3), 147.6 (s, C-8a), 154.2 (s, JC;F ¼ 32:9Hz, C-2).
3
19F NMR (CDCl3, 282MHz, ppm): d )129.8 (d, JF;H
9:9Hz).
¼
Spectroscopic data of the ÔhomodimerÕ: 1H NMR (CDCl3,
€
1996; Vol. 639, pp 143–156; (d) Laue, K. W.; Muck-
3
2
Lichtenfeld, C.; Haufe, G. Tetrahedron 1999, 55, 10413–
10424; (e) Zhao, K.; Lim, D. S.; Funaki, T.; Welch, J. T.
Bioorg. Med. Chem. Lett. 2003, 11, 207–215.
300MHz, ppm): d 5.54 (dd, JH;F ¼ 12:9Hz, JH;H
¼
3:3Hz, 2H, Hcis), 5.94 (dd, 3JH;F ¼ 42:6Hz, 2JH;H ¼ 3:3Hz,
2H, Htrans), 7.13–7.65 (m, 10H); 13C NMR (CDCl3,

60
M. Marhold et al. / Tetrahedron Letters 45 (2004) 57–60
2
3
75MHz, ppm): d 104.6 (t, JC;F ¼ 15:0Hz, @CH2), 122.4
(CDCl3, 282 MHz, ppm): d )104.2 (d, JF;H ¼ 38:8 Hz),
3
(d), 124.5 (d), 126.8 (d), 127.1 (d), 129.0 (d), 129.6 (d),
147.6 (s), 152.7 (s, JC;F ¼ 260:3Hz, @C–F), 158.5 (s,
)105.6 (d, JF;H ¼ 38:8 Hz).
1
1
Spectroscopic data of 14e: H NMR (CDCl3, 300 MHz,
ppm): d 1.69 (s, 3H), 3.87 (s, 2H), 4.58 (s, 2H), 4.81 (s, 1H,
2JC;F ¼ 36:8Hz, C@O); 19F NMR (CDCl3, 282MHz,
3
3
ppm): d )116.8 (dd, JF;H ¼ 12:4Hz, JF;H ¼ 42:6Hz).
Hcis), 4.97 (s, 1H, Htrans), 5.10 (dd, 2JH;H ¼ 3:5 Hz, 3JH;F
¼
2
3
16. Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.;
17:1 Hz, 1H, Hcis), 5.31 (dd, JH;H ¼ 3:3 Hz, JH;F
¼
47:4 Hz, 1H, Htrans), 7.24–7.35 (m, 5H, Harom); 13C NMR
(CDCl3, 75 MHz, ppm): d 19.8 (q), 47.9 (t), 52.6 (t), 99.2
€
Patzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron
1996, 52, 7251–7264.
2
17. Østergaard, N.; Pedersen, B. T.; Skjærbæk, N.; Vedsø, P.;
Begtrup, M. Synlett 2002, 23, 1889–1891.
(t, JC;F ¼ 17:3 Hz), 112.9 (t), 127.6 (d), 128.3 (d), 128.6
1
(d), 136.2 (s), 139.6 (s), 157.5 (s, JC;F ¼ 271:8 Hz, C-F),
2
18. (a) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron
Lett. 1997, 38, 677–680; (b) Tjen, K. C. M. F.; Kinder-
man, S. S.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P.
J. T. Chem. Commun. 2000, 699–700; (c) Kinderman, S.
S.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra,
H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3, 2045–2048; (d)
Abell, A. D.; Gardiner, J. Org. Lett. 2002, 4, 3663–3666.
19. Review: Maier, M. E. Angew. Chem. 2000, 112, 2153–
2159; Angew. Chem. Int. Ed. 2000, 39, 2073–2077.
20. Humphries, M. E.; Murphy, J.; Phillips, J.; Abell, A. D.
J. Org. Chem. 2003, 68, 2432–2436.
162.7 (s, JC;F ¼ 32:9 Hz); 19F NMR (CDCl3, 282 MHz,
3
3
ppm): d )103.9 (d, JH;F ¼ 45:1 Hz), )104.5 (d, JF;H
¼
3
45:1 Hz, JF;H ¼ 11:6 Hz).
1
22. Spectroscopic data of 15b: H NMR (CDCl3, 300 MHz,
3
ppm): d 2.37 (m, 2H), 3.33 (t, JH;H ¼ 7:0 Hz, 2H), 4.63
3
3
(s, 2H), 5.99 (dt, JH;H ¼ 4:5 Hz, JH;F ¼ 10:5 Hz, 1H),
7.25–7.37 (m, 5H, Harom); 13C NMR (CDCl3, 75 MHz,
3
ppm): d 21.3 (t, JC;F ¼ 6:4 Hz), 44.6 (t), 49.8 (t), 112.7
2
(d, JC;F ¼ 15:1 Hz), 127.7 (d), 128.1 (d), 128.1 (d), 136.7
(s), 149.9 (s, 1JC;F ¼ 251:2 Hz, C–F), 159.8 (s,
2JC;F ¼ 30:3 Hz); 19F NMR (CDCl3, 282 MHz, ppm):
d )127.1 (m).
1
21. Spectroscopic data of 14b: H NMR (CDCl3, 300 MHz,
ppm): d 2.32 (dt, 3JH;H ¼ 7:2 Hz, 3JH;H ¼ 7:2 Hz, 2H), 3.37
1
Spectroscopic data of 15e: H NMR (CDCl3, 300 MHz,
3
3
3
(t, JH;H ¼ 7:2 Hz, 2H), 4.62 (s, 2H), 5.05 (dd,
ppm): d 1.91 (d, JH;F ¼ 2:1 Hz, 3H), 3.61 (d, JH;F ¼
2JH;H ¼ 1:5 Hz, JH;F ¼ 18:6 Hz, 1H, Hcis), 5.08 (m, 2H),
5:7 Hz, 2H), 4.59 (s, 2H), 7.22–7.36 (m, 5H, Harom); 13C
NMR (CDCl3, 75 MHz, ppm): d 9.6 (q), 46.5 (t), 48.9 (t,
3
3
5.30 (d, JH;F ¼ 47:4 Hz, 1H, Htrans), 5.73 (m, 1H), 7.23–
7.37 (m, 5H, Harom); 13C NMR (CDCl3, 75 MHz, ppm): d
30.9 (t), 47.0 (t), 49.1 (t), 99.3 (t), 117.1 (t), 127.6 (d), 128.6
3JC;F ¼ 5:0 Hz), 124.3 (s, JC;F ¼ 4:9 Hz), 127.7 (d), 128.0
2
1
(d), 128.8 (d), 136.5 (s), 148.2 (s, JC;F ¼ 267:6 Hz, C-F),
1
2
(d), 128.7 (d), 134.3 (d), 136.4 (s), 157.9 (s, JC;F
¼
163.4 (s, JC;F ¼ 30:3 Hz); 19F NMR (CDCl3, 282 MHz,
274:4 Hz, C-F), 162.5 (s, JC;F ¼ 30:7 Hz); 19F NMR
ppm): d )147.4 (s).
2