Fluorinated (hetero)cycles via ring-closing metathesis of fluoride- and trifluoromethyl-functionalized olefins

Article abstract of DOI:10.1016/j.tetlet.2003.11.093

Ring-closing metathesis (RCM) has been shown to be a viable tool to incorporate fluoride and trifluoromethyl substituents in (hetero)cyclic ring systems. 2-Fluoroacrylamides were cyclized to the corresponding lactams, and trifluoromethyl-substituted olefi

Full text of DOI:10.1016/j.tetlet.2003.11.093

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 959–963
Fluorinated (hetero)cycles via ring-closing metathesis of fluoride-
and trifluoromethyl-functionalized olefins
a
a
b
c
ꢀ
€
Valeria De Matteis, Floris L. van Delft, Rene de Gelder, Jorg Tiebes
and Floris P. J. T. Rutjesa,*
aDepartment of Organic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
bDepartment of Inorganic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
cBayer CropScience GmbH, Chemical Research, Industriepark Hoechst, G836, 65926 Frankfurt am Main, Germany
Received 9 October 2003; revised 12 November 2003; accepted 21 November 2003
Abstract—Ring-closing metathesis (RCM) has been shown to be a viable tool to incorporate fluoride and trifluoromethyl sub-
stituents in (hetero)cyclic ring systems. 2-Fluoroacrylamides were cyclized to the corresponding lactams, and trifluoromethyl-
substituted olefins were cyclized to yield trifluoromethylated cyclopentenes, pyrrolines and a dihydrofuran derivative.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Over the past few years, there has been a significantly
growing interest from the pharmaceutical and agro-
chemical industry in fluorine- and trifluoromethyl-con-
taining (hetero)cyclic building blocks.1 This interest
stems from the fact that fluorine substituents often dis-
play a positive effect on the pharmacokinetics and
pharmacodynamic properties of potential drugs. The
incorporation of both types of fluorine substituents in
(hetero)cycles has so far, to a large extent, been limited
to aromatic systems, since many fluorinated and triflu-
oromethylated aromatics are commercially available
and there are various well-established synthetic methods
to introduce these functional groups in (hetero)aromatic
compounds.2 This contrasts with the application of the
Scheme 1. RCM approach to fluorinated (hetero)cyclic systems.
same substituents in nonaromatic (hetero)cycles, which
is considerably thwarted by the lack of general meth-
odology to incorporate fluorine substituents.3 Being
Olefin RCM has gained widespread use in organic syn-
thesis owing to the ease of handling and high functional
group tolerance of the Ru-catalysts A–C.7 In the past
few years, it has been demonstrated that RCM is not
only restricted to isolated or alkyl-substituted olefins,
but is also applicable to olefins that bear heteroatoms
such as oxygen6;8 and nitrogen.5;9
aware of the general demand for such (hetero)cycles and
in conjunction with previously developed methodology
in our group concerning the determination of the scope
of ring-closing metathesis (RCM) reactions,4–6 we set
out to study the use of RCM as a potentially powerful
way to access both fluoro- and trifluoro-substituted
(hetero)cyclic olefins (Scheme 1).
Furthermore, it has been demonstrated that P-, Si- and
B-substituted olefins can be readily cyclized under the
influence of the same catalysts.10;11 Very recent other
RCM examples, that once more emphasize the versa-
tility and importance of this particular transformation,
include application to a-alkoxyethers by our own
group,6 to vinyl chlorides by the Weinreb group12 and to
* Corresponding author. Tel.: +31-24-365-3202; fax: +31-24-365-3393;
e-mail: rutjes@sci.kun.nl
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.093

960
V. De Matteis et al. / Tetrahedron Letters 45 (2004) 959–963
vinyl fluorides by the group of Brown.13 The latter two
examples are especially important, since they show for
the first time that vinyl halides can successfully partici-
pate in this reaction. The latter two publications also
prompted us to disclose our own results in this area
involving the use of fluoroacrylates and trifluoro-
methylalkenes as potential metathesis substrates, which
may give rise to the corresponding fluoride- and triflu-
oromethyl-substituted carbo- and heterocyles. To the
best of our knowledge, there have been no reports
concerning RCM of fluoroacrylates, nor from tri-
fluoromethylalkenes, except for a few articles about
related metathesis examples of olefins with fluoride
atoms at the allylic position.14
Encouraged by the vinyl chloride cyclizations, we com-
menced with the synthesis of the fluoroacrylates 5–8 as
RCM precursors. This involved acylation of the amines
with 2-fluoroacryloyl fluoride, which was readily pre-
pared from 3,3,2,2-tetrafluoropropanol in three steps.17
Optimal results were obtained by heating at 100 ꢁC for
the indicated time, during which the catalyst B was
added in small portions to the reaction mixture. As can be
seen in Table 1, RCM of precursors 5 and 6 proceeded
readily under these conditions to form the correspond-
ing unsaturated five- and six-membered lactams 11 and
12 in 68% and 80% yields, respectively (entries 3 and 4).
It appeared that in these cases the benzyl protecting
group on the nitrogen was essential for the cyclization to
occur. Without a protecting group, subjection to the
different catalysts B and C did not lead to cyclization,
but eventually (upon prolonged reaction times) to
decomposition of the amides.
In order to probe the viability of the concept of vinyl
fluoride metathesis, we initially conducted several
experiments involving vinyl chloride precursors (Table
1). Despite some early reports of the Grubbs group
describing unsuccessful attempts involving vinyl halides
with the first generation catalyst A,15 we anticipated that
better results might be obtained with the second gener-
ation catalysts. Indeed, the vinyl chloride precursors 3
(previously cyclized by Weinreb)12 and 4 readily ring
closed to the corresponding cycloalkenes 9 and 10 in
good yields using catalyst B in toluene at 100 ꢁC for the
indicated time.16 Use of the Grubbs/Hoveyda catalyst C
under the same conditions gave approximately the same
result.
The identity of the five-membered ring lactam 11 was
unambiguously confirmed through an X-ray crystallo-
graphic determination of the crystal structure (Fig. 1).18
Unfortunately, the eight-membered ring precursor 7 did
not provide any cyclization product at all.
Furthermore, the allylglycinol-derived precursor
8
underwent selective ring closure to the six-membered
lactam in an excellent yield. Thus, it has been shown
that RCM of fluoroacrylates proceeds well and therefore
Table 1. RCM of vinyl halides
Entry
Precursor
Cat B (mol %)
Time (h)
Product (yield)
Cl
Cl
EtO2C
CO2Et
EtO2C
CO2Et
1
3
12
120
9 (68%)
Cl
Cl
N
Bz
N
Bz
2
4
15
72
10 (51%)
F
F
Bn
N
( )n
( )n
O
N
O
Bn
3
4
5
5: n ¼ 1
6: n ¼ 2
7: n ¼ 4
7
7
7
4
4
11: n ¼ 1 (68%)
12: n ¼ 2 (80%)
13: n ¼ 4 (0%)
72
F
F
Bn
F
N
O
O
O
N
O
Bn
O
O
F
6
8
4
4
14 (99%)

V. De Matteis et al. / Tetrahedron Letters 45 (2004) 959–963
961
Figure 1. Crystal structure of lactam 11.
represents a convenient way to synthesize fluorine-
substituted heterocyclic building blocks.
Scheme 2. Synthesis of the alkylating agent 20.
We then focused on the incorporation of trifluoromethyl
substituents in cyclic systems in a similar manner. This
required the availability of 2-trifluoromethylacrylic acid
(or derivatives thereof) and of 2-trifluoromethyl-2-pro-
penol (or the corresponding halides). While the acid is
commercially available, reproducible synthetic access to
the corresponding alcohol does not exist. Because effi-
cient procedures to prepare the alcohol (e.g., LiAlH4
reduction of the acid,19 or acid chloride formation,20
followed by LiAlH4 reduction)21 appeared either unre-
liable or laborious, we decided to develop a novel
pathway for its synthesis (Scheme 2). Since the majority
of problems associated with the existing procedures
arose from the reactivity of the a,b-unsaturated system,
we envisaged that it would be advantageous to protect
the olefin in some way. The protection strategy that was
chosen proceeded via a Diels–Alder/retro Diels–Alder
sequence; 2-trifluoromethylacrylic acid (15) was reacted
with cyclopentadiene to give the corresponding Diels–
Alder adduct 16 as a 2:1 mixture of endo/exo-diastereo-
isomers in excellent yield after recrystallization.22 This
mixture was then esterified ((MeO)2SO2), reduced
(LiAlH4) and reacted with TsCl to yield tosylate 19 in an
excellent overall yield. Finally, subjection of 19 to flash
vacuum thermolysis (FVT) afforded, after some opti-
mization of the conditions (oven temperature 600 ꢁC,
0.04 mbar), the required tosylate 20 in essentially pure
form and excellent yield.23 It was used without further
purification for subsequent follow-up chemistry, but
could also be further purified over a short silica gel
column. Initial attempts to subject the alcohol 18 to the
FVT conditions also provided the corresponding alco-
hol (T ¼ 550 ꢁC, 0.04 mbar), but due to the fact that
additional manipulation and purification of the alcohol
was necessary, we decided to choose the more practical
procedure. Thus, this pathway represents an efficient
synthesis of a potentially useful fluorinated alkylating
agent.
malononitriles 21–24 were prepared via consecutive
alkylation with allyl bromide and the tosylate 20 under
standard conditions. The other precursors were pre-
pared via acylation of the amine (25, reaction with the
acid chloride derived from 2-trifluoromethylacrylic
acid),20 or by alkylation of the corresponding amine or
alcohol with tosylate 20 (precursors 26–30).
The malonates 21 and 22 and malononitriles 23 and 24
(entries 1–4) gave facile cyclization to the corresponding
cyclopentenes in moderate to good yields under the
previously optimized conditions (catalyst B, added in
portions during the reaction, toluene, 100 ꢁC). The
cyanides gave partial decomposition under these reac-
tion conditions so that different temperatures were tried;
precursor 24 gave the best result at 55 ꢁC. Unfortu-
nately, both acrylamides 25 and 26 did not give any
cyclized product (entries 5 and 6). Probably, in these
cases both olefins become too electron poor for the
RCM reaction to take place. In contrast, the diolefins 27
and 28––bearing an acyl group at the nitrogen––readily
cyclized to the desired pyrrolidines 37 and 38 in good
yields under the same conditions (entries 7 and 8). An
attempt to cyclize 29 to the corresponding tetrahydro-
pyridine 39 failed, which may well be due to the presence
of the basic amine functionality (entry 9).
Gratifyingly, the ether precursor 30 underwent facile
cyclization under identical conditions to give the triflu-
oromethyl-substituted dihydrofuran 40 in a good yield
(entry 10). Thus, it has been shown that trifluoromethyl-
substituted olefins in many cases readily cyclize to the
corresponding cyclic olefins, which represent versatile
building blocks for further synthetic transformations
and potentially biologically active compounds.
Having reliable access to the acid 15 and the tosylate 20,
a set of RCM precursors 21–30 was prepared via well-
established procedures (Table 2). The malonate and
In conclusion, we have identified RCM as a viable tool to
incorporate fluoride and trifluoromethyl substituents in
(hetero)cyclic ring systems. Several 2-fluoroacrylamides

962
V. De Matteis et al. / Tetrahedron Letters 45 (2004) 959–963
Table 2. RCM of trifluoromethylated olefins
Entry
Precursor
Cat (mol %)
Time (h)
Product (yield)
F3C
F3C
RO2C
CO2R1
RO2C
CO2R1
1
2
21: R ¼ R1 ¼ Et
4
7
4
2
31: R ¼ R1 ¼ Et (88%)
22: R ¼ tBu, R1 ¼ Me
32: R ¼ tBu, R1 ¼ Me (45%)
F3C
F3C
R
C N
R
C N
3
4
23: R ¼ CO2Me
24: R ¼ CN
3
15
4
24
33: R ¼ CO2Me (52%)
34: R ¼ CN (42%)
X
X
Y
Y
O
N
O
N
Bn
Bn
5
6
25: X ¼ CF3, Y ¼ H
26: X ¼ H, Y ¼ CF3
3
7
72
4
35: X ¼ CF3, Y ¼ H (0%)
36: X ¼ H, Y ¼ CF3 (0%)
F3C
F3C
N
R
N
R
7
8
27: R ¼ Bz
10
10
24
2
37: R ¼ Bz (68%)
38: R ¼ Boc (97%)
28: R ¼ Boc
F3C
CF3 Bn
N
N
Bn
9
29
7
5
48
24
39 (0%)
F3C
F3C
O
Ph
Ph
O
10
30
40 (78%)
were readily cyclized to the corresponding unsaturated
lactams, which are useful synthetic building blocks. In
addition, a novel, reliable and efficient method has been
developed for the synthesis of 2-trifluoromethyl-2-
propenol and the corresponding tosylate, which is a
strategic synthon for incorporating trifluoromethyl-
substituted olefins into various systems. Finally, the
viability of RCM on olefins bearing trifluoromethyl
substituents has been demonstrated via the synthesis of
a series of trifluoromethyl-substituted cyclopentenes,
pyrrolines and a dihydrofuran derivative.
References and notes
1. See, for example: (a) Ismail, F. M. D. J. Fluorine Chem.
2002, 118, 27; (b) Biomedical Frontiers of Fluorine Chem-
istry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS
Symposium Series ACS, Washington, D.C. 1996; (c)
Jeschke, P. The Unique Role of Fluorine in the Design of
Active Ingredients for Modern Crop Protection, Book of
€
abstracts, Fluorine in the life sciences symposium, Burgen-
stock, 2003, pp 17–20.
2. For recent entries, see, for example: (a) Zhu, S. Z.; Wang,
Y. L.; Peng, W. M.; Song, L. P.; Jin, G. F. Curr. Org.
Chem. 2002, 6, 1057; (b) Saloutin, V. I.; Burgart, Y. V.;
Chupakhin, O. N. Russ. Chem. Rev. 1999, 68, 203; (c)
Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D. J. Fluorine
Chem. 2002, 118, 135.
3. For a review on trifluoromethyl-substituted saturated
cycles, see: Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
4. (a) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron
Lett. 1997, 38, 677; (b) Rutjes, F. P. J. T.; Kooistra, T. M.;
Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192; (c)
Tjen, K. C. M. F.; Kinderman, S. S.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. J. T. Chem. Commun. 2000,
Acknowledgements
Bayer CropScience GmbH is gratefully acknowledged
for providing a research grant to V. De M. Dr. L. Thijs
(Department of Organic Chemistry, University of
Nijmegen, The Netherlands) is kindly thanked for
suggesting the Diels–Alder strategy.

V. De Matteis et al. / Tetrahedron Letters 45 (2004) 959–963
963
699; (d) Doodeman, R.; Rutjes, F. P. J. T.; Hiemstra, H.
Tetrahedron Lett. 2000, 41, 5979; (e) Kaptein, B.; Brox-
terman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.;
Veerman, J. J. N.; Kamphuis, J.; Peggion, C.; Formaggio,
F.; Toniolo, C. Tetrahedron 2001, 57, 6567; (f) Kinder-
man, S. S.; Doodeman, R.; Van Beijma, J. W.; Russcher,
J. C.; Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh,
H.; Van Maarseveen, J. H.; Hiemstra, H.; Schoemaker,
H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 736.
5. Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3,
2045.
6.24–6.21 (m, 1H, FC@CH), 4.63 (s, 2H, CH2Ph), 3.74–
3.72 (m, 2H, CHCH2); 13C NMR (75 MHz, CDCl3)
d ¼ 162.7 (d, J ¼ 31.2 Hz, FCC@O), 152.7 (d,
J ¼ 275.7 Hz, CF), 136.2, 128.8, 128.1, 127.8, 112.7 (d,
J ¼ 7.4 Hz, HC@CF), 47.1, 45.5 (d, J ¼ 5.4 Hz,
CH2CH@CF); IR (neat, cmꢀ1): 3058, 2920, 2854, 1697,
1664, 1452, 1232, 1219, 988, 926, 780, 720, 689; HRMS
calcd for C11H10NOF (Mþ) 191.0764, found 191.0740. 20:
1H NMR (200 MHz, CDCl3) d ¼ 7.77 (d, J ¼ 8.5 Hz, 2H,
ArH), 7.34 (d, J ¼ 7.8 Hz, 2H, ArH), 5.89 (br s, 1H,
CH@CCF3), 5.73 (d, J ¼ 1.2 Hz, 1H, CH@CCF3), 4.62 (s,
2H, CH2O), 2.45 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3) d ¼ 145.3, 132.4, 129.9, 127.9, 123.5 (q, J ¼ 5.1 Hz,
CH2@CCF3), 122.1 (q, J ¼ 270.8 Hz, CF3), 65.6, 21.9; IR
(neat, cmꢀ1): 3118, 3068, 3041, 2962 1598, 1369, 1176,
1132, 1176, 972, 841, 777; HRMS calcd for C11H11SO3F3
6. Hekking, K. F. W.; Van Delft, F. L.; Rutjes, F. P. J. T.
Tetrahedron 2003, 59, 6751.
€
7. For review articles, see: (a) Furstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012; (b) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18; (c) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592.
1
(Mþ) 280.0381, found 280.0375. 31: H NMR (300 MHz,
CDCl3) d ¼ 6.14–6.12 (m, 1H, CF3C@CH), 4.20 (q,
J ¼ 7.2 Hz, 4H, 2 · CH2CH3), 3.18–3.14 (m, 4H,
CF3CH2+HCCH2), 1.26 (t, J ¼ 7.3 Hz, 6H, 2 · CH2CH3);
13C NMR (75 MHz, CDCl3) d ¼ 170.6, 132.1, 130.7 (q,
J ¼ 33.6 Hz, CCF3), 121.8 (q, J ¼ 266.8 Hz, CH3), 62.2,
59.1, 40.6, 38.2, 14.3; IR (neat, cmꢀ1): 2985, 2939, 1733,
1671, 1446, 1367, 1276, 1253, 1159, 1122, 1037; HRMS
calcd for C12H15F3O4 (Mþ) 280.0923, found 280.0918. 38:
1H NMR (300 MHz, CDCl3, some signals appear as
rotamers) d ¼ 6.32 + 6.27 (br s, 1H, CF3C@CH), 4.26 (br s,
4H, CF3CCH2+HCCH2), 1.47 (s, 3H, (CH3)3); 13C NMR
(75 MHz, CDCl3, some signals appear as rotamers)
d ¼ 153.7, 130.1–129.7 (m), 129.3 (q, J ¼ 35.1 Hz, CCF3),
122.8 (q, J ¼ 263.9 Hz, CF3), 80.5 + 80.4, 53.4 + 53.2,
50.8 + 50.6, 28.6; IR (neat, cmꢀ1): 3058, 2919, 2867,
1713, 1632, 1385, 1303, 1269, 1165, 1122, 1043, 789, 694,
672; HRMS calcd for C10H14NO2F3 (Mþ) 237.0977, found
237.0978.
8. For recent examples, see: (a) Chatterjee, A. K.; Morgan, J.
P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783; (b) Postema, M. H. D.; Calimente, D.; Liu, L.;
Behrmann, T. L. J. Org. Chem. 2000, 65, 6061; (c) Clark,
J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123, 127; (d)
Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39,
9623; (e) Rainier, J. D.; Cox, J. M.; Allwein, S. P.
Tetrahedron Lett. 2001, 42, 179.
9. Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A.
Angew. Chem., Int. Ed. 2002, 41, 4732.
10. Phosphorus-substituted olefins: (a) Hanson, P. R.; Stoia-
nova, D. S. Tetrahedron Lett. 1999, 40, 3297; (b) Timmer,
M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.;
van Boom, J. H. Tetrahedron Lett. 2000, 41, 8635; (c)
Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769;
Silicon-substituted olefins: Denmark, S. E.; Yang, S.-M.
Org. Lett. 2001, 3, 1749; Boron-substituted olefins: Ashe,
A. J., III; Fang, X. Org. Lett. 2000, 2, 2089.
17. Nguyen, T.; Wakselman, C. J. Org. Chem. 1989, 54, 5640.
18. Crystallographic data have been deposited at the Cam-
bridge Crystallographic Data Centre as supplementary
publication no. CCDC 223956.
11. For cross-metathesis examples of P-, Si- and B-substituted
olefins, see: Chatterjee, A. K.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 3172.
12. Chao, W.; Weinreb, S. M. Org. Lett. 2003, 5, 2505.
13. Salim, S. S.; Bellingham, R. K.; Satcharoen, V.; Brown, R.
C. D. Org. Lett. 2003, 5, 3403.
19. For LiAlH4 reduction of the corresponding fluoroac-
rylic acid, see: Laue, K. W.; Haufe, G. Synthesis 1998,
1453.
14. (a) Imhof, S.; Randl, S.; Blechert, S. Chem. Commun.
2001, 1692; (b) Percy, J. M.; Pintat, S. Chem. Commun.
2000, 607; (c) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783.
15. Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62,
7310.
16. All compounds were fully characterized using spectro-
scopic techniques. Data of selected compounds: 11: 1H
NMR (300 MHz, CDCl3) d ¼ 7.35–7.20 (m, 5H, ArH),
20. Furuta, S.; Saito, Y.; Fuchigami, T. J. Fluorine Chem.
1998, 87, 209.
21. Solomon, M.; Hoekstra, W.; Zima, G.; Liotta, D. J. Org.
Chem. 1988, 53, 5058.
22. (a) Hanzawa, Y.; Suzuki, M.; Kobayashi, Y. Tetrahedron
Lett. 1989, 30, 571; (b) Hanzawa, Y.; Suzuki, M.;
Kobayashi, Y.; Taguchi, T. J. Org. Chem. 1991, 56,
1718.
23. Carried out at scales ranging from 50 mg to 3 g.