RCM-mediated synthesis of trifluoromethyl-containing nitrogen heterocycles

Article abstract of DOI:10.1021/jo060893z

(Chemical Equation Presented) A ring-closing metathesis mediated pathway to trifluoromethyl-containing piperidines is detailed. This involves the development of a synthetic route to a new (trifluoromethyl)allylating reagent via a Diels-Alder/retro-Diels-Alder strategy, its application in the synthesis of a series of trifluormethyl-substituted diolefin recursors for ring-closing metathesis, and eventually the successful cyclization of these precursor molecules into the corresponding functionalized piperidines.

Full text of DOI:10.1021/jo060893z

RCM-Mediated Synthesis of Trifluoromethyl-Containing Nitrogen
Heterocycles
Valeria De Matteis, Floris L. van Delft, Harald Jakobi,† Stephen Lindell,† Jo¨rg Tiebes,† and
Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud UniVersity Nijmegen, ToernooiVeld 1,
NL-6525 ED Nijmegen, The Netherlands
f.rutjes@science.ru.nl
ReceiVed April 28, 2006
A ring-closing metathesis mediated pathway to trifluoromethyl-containing piperidines is detailed. This
involves the development of a synthetic route to a new (trifluoromethyl)allylating reagent via a Diels-
Alder/retro-Diels-Alder strategy, its application in the synthesis of a series of trifluormethyl-substituted
diolefin precursors for ring-closing metathesis, and eventually the successful cyclization of these precursor
molecules into the corresponding functionalized piperidines.
CHART 1. Trifluoromethylated Heterocycles
Introduction
Over the past decade or so, it has become increasingly clear
that fluorine substituents often display a positive effect on the
pharmacokinetics and pharmacodynamic properties of potential
drugs.1 As a result, the introduction of fluorinated substituents
has become an important tool to modulate the properties of
biologically active substances. Subsequently, the interest of the
pharmaceutical industry in trifluoromethyl-containing com-
pounds has grown significantly: nowadays, many trifluoro-
methylated products exist on the market such as analgesic,
cardiovascular, respiratory, and gastrointestinal drugs.2 Some
particular examples of important trifluoromethyl-containing
drugs are shown in Chart 1.
Trifluridine (1)3 and efavirenz (2)4 are both antiviral drugs
and Celebrex (3)4 is an antiinflammatory drug that are currently
† Bayer CropScience GmbH, 65926 Frankfurt am Main, Germany.
(1) For recent reviews, see, e.g.: (a) Ismail, F. M. D. J. Fluorine Chem.
2002, 118, 27. (b) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series 639; American
Chemical Society: Washington, DC, 1996. (c) Welch, J. T.; Eswarakrishnan,
S. Fluorine in Bioorganic Chemistry, Wiley: New York, 1991. (d)
Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets; Solos-
honok, V. A., Ed.; Wiley: New York, 1999. (e) Halpern, D. F. In
Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Filler, R., Kobayashi, Y., Yagupolskii, L., Eds.; Elsevier:
Amsterdam, 1993; pp 101-133.
on the market. Another new promising candidate is the
epothilone derivative fludelone (4), which shows an extremely
high therapeutic efficacy against various carcinomas.5
Considering the general biological relevance of trifluoro-
methyl-containing heterocycles, combined with the difficulty
(2) For excellent overviews, see, e.g.: (a) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Oxford, 2004. (b) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.
10.1021/jo060893z CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/31/2006
J. Org. Chem. 2006, 71, 7527-7532
7527

De Matteis et al.
SCHEME 1. Retrosynthetic Approach
SCHEME 2. Masking of the Acrylatea
a Reagents and conditions: (a) cyclopentadiene, CH2Cl2, rt, 12 h; (b)
(MeO)2SO2, dry acetone, K2CO3, reflux, 5 h; (c) LiAlH4, dry Et2O, rt, 5 h;
(d) TsCl, dry pyridine, rt, 24 h.
olefins. We were the first to report examples of disubstituted
trifluoromethyl-containing olefins,8,12 of which in this contribu-
tion a detailed account is provided, including the functional-
ization to heavily functionalized nitrogen heterocyclic systems.
of introducing trifluoromethyl substituents in nonaromatic ring
systems,6 we started to investigate whether ring-closing
metathesis (RCM) could serve as a potential approach to
synthesize trifluoromethyl-substituted (hetero)cyclic building
blocks.7 Retrosynthetically, we envisaged that trifluorometh-
ylated olefins (viz. 7, Scheme 1) might serve as suitable
precursors for the preparation of the corresponding ring systems
6 using the second generation Grubbs Ru-carbene catalyst 5.8
Such an approach would commence with the development of a
synthetic route to an appropriate allylating reagent of type 8.
Nowadays, owing to the emergence of relatively stable,
tolerant, and versatile Ru-carbene catalysts, the applicability
of RCM processes is well-established.9 As a result, a wide range
of differently substituted olefins have been successfully trans-
formed into the corresponding (hetero)cyclic systems. Only
relatively few examples of olefins with allylic fluoride substit-
uents exist,10,11 which are all examples of monosubstituted
Results and Discussion
To have facile and straightforward access to the required
trifluoromethylated olefins, a method had to be developed to
incorporate the trifluoroallyl moiety in the RCM precursors 7.
In our view, N-alkylation with compounds of type 8 would serve
this purpose, where X is a good leaving group such as chloride,
bromide, or tosylate. However, these latter compounds are not
commercially available nor easy to prepare from commercially
available sources. In addition, the corresponding alcohol,
2-trifluoromethyl-2-propenol, is not trivial to make. For example,
straightforward reduction of the corresponding carboxylic acid,
2-trifluoromethylacrylic acid, either direct via LiAlH4 reduction13
or indirect via acid chloride formation14 followed by LiAlH4
reduction15 appeared in our hands to be either unreliable or
laborious, so that we decided to develop a novel pathway for
its synthesis (Scheme 2). Since the reported problems were
generally associated with the reactivity of the R,â-unsaturated
acrylic system, we envisaged that it would be advantageous to
protect the olefin in some way. Hence, we chose to mask the
double bond in a Diels-Alder reaction with cyclopentadiene,
which may then be unveiled in a later stage. 2-Trifluoromethyl-
acrylic acid (9) was reacted with freshly distilled cyclopenta-
diene to give the Diels-Alder adduct 10 as a 2:1 mixture of
endo/exo-diastereoisomers in excellent yield after recrystalli-
zation.16 This mixture was esterified ((MeO)2SO2, dry acetone,
K2CO3, reflux, 5 h), reduced (LiAlH4, dry Et2O, rt, 5 h), and
reacted with TsCl (TsCl, dry pyridine, rt, 24 h) to yield tosylate
13 in an excellent overall yield.
(3) For an entry into relevant literature, see: Carmine, A. A.; Brogden,
R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. Drugs 1982, 23, 329.
(4) The Merck Index, 13th ed.; Merck and Co.: Whitehouse Station,
NJ, 2001.
(5) Rivkin, A.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2005, 44, 2838.
(6) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635-3671.
(7) Previous reports from our group in RCM-mediated heterocycle
synthesis: (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) Veerman, J. J. N.; van Maarseveen, J. H.; Visser,
G. M.; Kruse, C. G.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T.
Eur. J. Org. Chem. 1998, 2583. (d) Tjen, K. C. M. F.; Kinderman, S. S.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Chem. Commun. 2000,
699. (e) Doodeman, R.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett.
2000, 41, 5979. (f) Kaptein, B.; Broxterman, 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. (g) Kinderman, S. S.; van
Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T.
Org. Lett. 2001, 3, 2045. (h) Kinderman, 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. (i) Hekking, K. F. W.; Van Delft,
F. L.; Rutjes, F. P. J. T. Tetrahedron 2003, 59, 6751. (j) Kinderman, S. S.;
de Gelder, R.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.;
Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100. (k) Kinderman, S.
S.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P.
J. T. Synthesis 2004, 1413. (l) Busscher, G. F.; Rutjes, F. P. J. T.; van
Delft, F. L. Tetrahedron Lett. 2004, 45, 3629. (m) Kinderman, S. S.;
Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra,
H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519.
At this stage, the retro-Diels-Alder reaction was investigated.
Initially, we chose to unmask the olefin using flash vacuum
thermolysis (FVT) conditions.8 Both T1 (the oven where the
(11) RCM examples: (a) Percy, J. M.; Pintat, S. Chem. Commun. 2000,
607. (b) Audouard, C.; Fawcett, J.; Griffiths, G. A.; Percy, J. M.; Pintat,
S.; Smith, C. A. Org. Biomol. Chem. 2004, 2, 528. (c) Masuda, T.; Shibuya,
S.; Arai, M.; Yoshida, S.; Tomozawa, T.; Ohno, A.; Yamashitab, M.; Honda,
T. Bioorg. Med. Chem. Lett. 2003, 13, 669.
(12) For a similar approach to the synthesis of fluoro-substituted
heterocycles, see: De Matteis, V.; van Delft, F. L.; Tiebes, J.; Rutjes, F. P.
J. T. Eur. J. Org. Chem. 2006, 1166.
(8) Part of this research has been previously published in a preliminary
account: De Matteis, V.; Van Delft, F. L.; De Gelder, R.; Tiebes, J.; Rutjes,
F. P. J. T. Tetrahedron Lett. 2004, 45, 959.
(13) For LiAlH4 reduction of the corresponding fluoroacrylic acid, see:
Laue, K. W.; Haufe, G. Synthesis 1998, 1453.
(9) For review articles, see: (a) Deiters, A.; Martin, S. F. Chem. ReV.
2004, 104, 2199. (b) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R.
Chem. ReV. 2004, 104, 2239. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(10) Cross-metathesis examples: (a) Imhof, S.; Randl, S.; Blechert, S.
Chem. Commun. 2001, 1692. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl,
M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783.
(14) Furuta, S.; Saito, Y.; Fuchigami, T. J. Fluorine Chem. 1998, 87,
209.
(15) Solomon, M.; Hoekstra, W.; Zima, G.; Liotta, D. J. Org. Chem.
1988, 53, 5058.
(16) (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.
7528 J. Org. Chem., Vol. 71, No. 20, 2006

Synthesis of Trifluoromethyl-Containing Nitrogen Heterocycles
TABLE 1. Retro-Diels-Alder Reaction
SCHEME 3. RCM Examples of Trifluoromethylated
Olefinsa
entry
conditions
yield (%)
1
2
3
4
5
FVT, T1 ) 120 °C, T2 ) 600 °C, 0.04 mbar, 13 h
diphenyl ether, 260 °C, 12 h
diphenyl ether, 190 °C, 5 h
diphenyl ether, 250 °C, 8 h
microwave, 185 W, diphenyl ether, BMIMPF6,
232 °C, 30 min
95
31
10
82
41
a Reagents and conditions: (a) catalyst 5 (10 mol %), toluene, 100 °C,
24 h for 17 and 2 h for 18.
6
7
8
9
microwave, 200 W, diphenyl ether, BMIMPF6,
240 °C, 20 min
microwave, 300 W, diphenyl ether, BMIMPF6,
250 °C, 30 min
microwave, 182 W, diphenyl ether, BMIMPF6,
maleic anhydride, 240 °C, 50 min
microwave, 182 W, diphenyl ether, BMIMPF6,
240 °C, 50 min
27
trace
68
were reproducibly repeated at gram scale (entry 9). Thus,
tosylate 13 dissolved in 25 mL of diphenyl ether was heated in
the presence of six drops of BMIMIPF6 in an open vessel at a
power of 182 W for 50 min (temperature of the vessel was 240
°C) to give the tosylate 8 in 85% yield. This latter procedure
for the retro-Diels-Alder step now ensures facile and efficient
access to this potentially important trifluoromethylated allylating
agent. Having reliable access to tosylate 8, a preliminary
investigation was performed to synthesize trifluoromethyl-
containing heterocyclic building blocks via RCM (Scheme 3).
The precursors 14-16 were prepared via alkylation of the
corresponding amine with tosylate 8 following well-known
procedures, involving either N-benzylbut-3-en-1-amine, Et3N,
Et2O, room temperature overnight (for 14) or NaH, acylating
agent, DMF, or rt (for 15 and 16). Attempts to cyclize 14 to
tetrahydropyridine 14a failed under a variety of conditions,
which may be due to the presence of the basic amine
functionality. In contrast, in the case of substrates 15 and 16,
the N-acylated precursors readily cyclized to the corresponding
trifluoromethyl-substituted cyclic building blocks in moderate
to good yields of 68% and 97%, respectively, using catalyst 5,
which was added in portions to the reaction mixture in toluene,
at 100 °C. This preliminary study gave us an initial idea of the
viability of these types of metathesis reactions, and we set out
to explore its possibilities for generating potentially biologically
active heterocyclic compounds.
A set of precursor molecules 26-30 (Table 2) was prepared
from compound 19-20 via a one-pot, three-component reac-
tion,17 which afforded compounds 21-25. This reaction was
followed by the introduction of the trifluoromethyl-containing
side chain, yielding products 26-30. The first step usually
proceeded in moderate to good yields. The low yield (22%)
observed in the formation of amide 21 might be due to partial
decomposition of the acid-labile tert-butyl carbamate. All
compounds 21-25 were alkylated with tosylate 8 (1 equiv, NaH,
DMF, rt), which proceeded uneventfully to produce the
metathesis precursors 26-30 in moderate to reasonable yields.
Precursor molecules 26 and 27 were then subjected to the
previously used RCM conditions (catalyst 5, toluene) at a
somewhat lower temperature of 80 °C to prevent decomposition
from taking place. This led to the corresponding trifluoromethyl-
substituted cyclic building blocks 31 and 32 in good to excellent
yield (Table 3). To investigate whether the reaction times could
be decreased, cyclizations of compounds 28-30 were performed
in a microwave oven at 80 °C and 300 W (entries 3-5). As
shown in Table 3, the reaction times indeed were decreased to
85
compound is evaporated) and T2 (the oven where the uni-
molecular reaction takes place) were varied, while the pressure
was kept at 0.04 mbar. The optimum result is depicted in Table
1, where 100-200 mg batches were subjected to T1 ) 120 °C
and T2 ) 600 °C, providing the required tosylate 8 in essentially
pure form and excellent yield (entry 1). It was used without
further purification for subsequent follow-up chemistry but could
also be further purified over a short silica gel column. Although
this pathway represents an efficient synthesis of the trifluoro-
methylated alkylating agent, a drawback is the fact that this
procedure is rather laborious and time-consuming and therefore
difficult to scale-up.
For this reason, we have been exploring pathways that would
provide alternative means for the retro-Diels-Alder reaction.
One of the alternatives is a thermal solution-phase reaction using
a high-boiling solvent such as diphenyl ether (entries 2-4).
Again, a series of reactions was performed to screen several
conditions, and it appeared that an optimum was reached at 250
°C with a reaction time of 8 h to give the tosylate 8 in 82%
yield after filtration over a short path of silica gel. Although
this result by itself was satisfactory, scaling up of this reaction
appeared somewhat problematic due to the fact that reaction
times had to be optimized again for each experiment. Finally,
we also considered using a monomode microwave oven to
perform the retro-Diels-Alder reaction (entries 5-9). In view
of the vast increase of examples of microwave reactions that
show the capacity of this technique for increasing the yield of
the products or reducing the reaction time, this particular
decomposition event might also benefit from it. Initially we
performed the reactions in neat diphenyl ether, but due to the
relative apolar character of the solvent, the temperature of the
system did not reach sufficiently high temperatures. Therefore,
in all cases a small amount of the ionic liquid 1-butyl-3-
methylimidazolium hexafluorophosphate (BMIMPF6) was added,
so that reflux temperatures could be readily reached. The
irradiation power and the reaction times were varied, but also
reactions were carried out in open and closed vessels. It appeared
that the retro reaction went considerably faster in open vessels,
probably due to the fact that the cyclopentadiene escapes from
the mixture and the forward reaction is no longer possible.
Alternatively, addition of an excess of a trapping reagent (e.g.,
maleic anhydride (entry 8)) in a closed system did not lead to
better results. Eventually optimal conditions were reached, which
(17) (a) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674. (b)
Veenstra, S. J.; Schmid, P. Tetrahedron Lett. 1997, 38, 997. (c) Meester,
W. J. N.; van Maarseveen, J. H.; Kirchsteiger, K.; Hermkens, P. H. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. ArkiVoc 2004, 122.
J. Org. Chem, Vol. 71, No. 20, 2006 7529

De Matteis et al.
TABLE 2. Synthesis of the RCM Precursors
TABLE 3. RCM Resultsa
only 30 min, while the yields were largely comparable to those
in the first two entries.
Confident by these successful cyclizations, the RCM was
applied to the synthesis of cyclic amino acid derivatives.
Precursor 38 was prepared from Boc-protected allylglycine
methyl ester (37)18 via alkylation with 8 (NaH, DMF) in 61%
yield (Scheme 4). Upon subjection of 38 to similar RCM
conditions, this time in toluene at 100 °C, with catalyst 5 added
in portions to the reaction mixture, RCM product 39 was
obtained in a satisfactory yield of 67%.
Other amino acid derivatives were synthesized next, as shown
in Table 4. Thus, allylglycine (36, Table 4) was reacted with
5-chloro-2-methoxybenzenesulfonyl chloride (Et3N, CH2Cl2, 1
h, rt) to afford the acid 40 in 80% yield. The acid 40 was then
coupled to four different benzylic amines under standard peptide
coupling conditions (EDCI, HOBt, CH2Cl2, rt), which also
proceeded smoothly to afford the amides 41-44. Finally, the
trifluoromethylallyl substituent was introduced via coupling with
8 (NaH, DMF, 12 h, rt) leading to RCM precursors 45-48.
This step appeared to be somewhat more problematic as is
shown by the moderate yields, which is probably due to the
fact that there is an amide function present in the molecule.
a Method A: catalyst 5, toluene, 80 °C. Method B: The reaction was
conducted in a microwave, 300 W, catalyst 5, toluene, 80 °C.
This might lead to side reactions, or loss of the base and
therefore incomplete conversion.
Precursors 45-48 were subjected to the previous RCM
conditions (Table 5) and readily proceeded to provide the
trifluoromethylated heterocycles 49-52 in good to excellent
yields.
Considering the versatility of this approachsat various stages,
different functionalities can be introducedsand the generally
good yields in the cyclization processes, this pathway provides
a potentially very useful route to appreciable quantities of highly
functionalized trifluoromethyl-containing cyclic amino acid
derivatives.
Conclusions
In summary, a detailed account is provided on investigations
toward a RCM-mediated pathway leading to trifluoromethyl-
substituted heterocycles. This involves the synthesis of a new
(18) Collet, S.; Bauchat, P.; Danion-Bougot, R.; Danion, D. Tetrahedron:
Asymmetry 1998, 9, 2121.
7530 J. Org. Chem., Vol. 71, No. 20, 2006

Synthesis of Trifluoromethyl-Containing Nitrogen Heterocycles
TABLE 5. RCM Results
SCHEME 4. Synthesis and RCM of Compound 38
TABLE 4. Synthesis of RCM Precursors
a Ar ) 4-Cl-2-MeOC6H3.
Experimental Section
Toluene-4-sulfonic Acid 2-Trifluoromethylallyl Ester (8) via
FVT. Compound 13 (410 mg, 1.19 mmol) was introduced in a
flash vacuum thermolysis (FVT) instrument under the following
conditions: temperature of the first oven was 120 °C, temperature
of the second oven was 600 °C, pressure of 0.04 mbar for 4 h. The
ester 8 (314 mg, 95%) was obtained as a colorless oil: IR (neat,
cm-1) 3118, 3068, 3041, 2962, 1598, 1369, 1176,1132, 1176, 972,
1
841, 777; H NMR (200 MHz, CDCl3) δ ) 7.77 (d, J ) 8.5 Hz,
2H), 7.34 (d, J ) 7.8 Hz, 2H), 5.89 (br s, 1H), 5.73 (d, J ) 1.2 Hz,
1H), 4.62 (s, 2H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ )
145.3, 132.4, 131.9 (q, J ) 31.0 Hz), 129.9, 127.9, 123.5 (q, J )
5.1 Hz), 122.1 (q, J ) 270.8 Hz), 65.6, 21.9; HRMS (EI) calcd for
C11H11 F3O3S (M+) 280.0381 found 280.0375.
N-Benzoyl-3-trifluoromethyl-2,5-dihydropyrrole (17). To a
solution of 15 (45 mg, 0.167 mmol) in dry toluene (20 mL) was
added catalyst 5 (10 mo l%) at 100 °C in small portions. The
reaction was complete in 24 h. The mixture was evaporated, and
the product was purified using column chromatography (heptane/
EtOAc 6:1) to give 17 (28 mg, 68%) as a yellow solid: mp 89-
92 °C; IR (neat, cm-1) 3058, 2919, 2867, 1713, 1632,1385, 1303,
1269, 1165, 1122, 1043, 789, 694, 672; 1H NMR (300 MHz, CDCl3,
some signals appear as rotamers) δ ) 7.52-7.42 (m, 5H), 6.44 +
6.26 (d, J ) 1.8 Hz, 1H), 4.61 + 4.36 (br s, 4H); 13C NMR (75
MHz, CDCl3, some signals appear as rotamers) δ ) 170.3 + 169.9,
131.6, (q, J ) 180 Hz), 132.5, 130.4 +130.3, 130.1 + 129.0 (q, J
) 4.9 Hz), 128.6 + 128.5, 126.8 + 126.8, 122.2, 56.0 + 53.3,
53.8 + 51.3; HRMS (EI) calcd for C12H10F3NO (M+) 241.0715,
found 241.0714.
(trifluoromethyl)allylating reagent via a Diels-Alder/retro-
Diels-Alder strategy, its application in the synthesis of a series
of RCM precursors, and eventually the successful cyclization
of these precursor molecules to the corresponding nitrogen
heterocycles. Thus, we have clearly established that RCM
represents a viable pathway to several classes of biologically
relevant trifluoromethylated piperidine derivatives.
2-(4-Fluorophenyl)-5-trifluoromethyl-3,6-dihydro-2H-pyridine-
1-carboxylic Acid tert-Butyl Ester (31). To a solution of 26 (83
J. Org. Chem, Vol. 71, No. 20, 2006 7531

De Matteis et al.
mg, 0.22 mmol) in dry toluene (40 mL) was added catalyst 5 (4
mol %) at 80 °C in small portions. The reaction was complete in
60 min. The solvent was evaporated and the residue purified using
column chromatography (heptane/EtOAc 6:1) to give 31 (75 mg,
99%) as a colorless oil: IR (neat, cm-1) 3065, 2980, 2928, 1705,
1601, 1515, 1411, 1312, 1238, 1165, 1109, 983, 849, 763; 1H NMR
(300 MHz, CDCl3) δ ) 7.16 (dd, J ) 6.0, 9.3 Hz, 2H), 6.97 (dd,
J ) 8.7, 8.7 Hz, 2H), 6.5 (br s, 1H), 5.56 (br s, 1H), 4.37 (d, J )
18.0 Hz, 1H), 3.32 (d, J ) 18.3 Hz, 1H), 2.82-2.62 (m, 2H), 1.50
(s, 9H); 13C NMR (75 MHz, CDCl3) δ ) 161.9 (d, J ) 243.8 Hz),
154.4, 135.3, 128.1 (d, J ) 8.0 Hz), 127.5-127.2 (m), 126.5 (q, J
) 30 Hz), 122.6 (q, J ) 268.8 Hz), 115.4 (d, J ) 20.9 Hz), 81.0,
49.6, 37.4, 28.7, 27.4; HRMS (EI) calcd for C17H19F4NO2 (M+)
345.1352, found 345.1352.
2872, 1744, 1701, 1403, 1364, 1308, 1251, 1212, 1161, 1113, 1035,
1
1001, 823, 607; H NMR (300 MHz, CDCl3) δ ) 6.37 (s, 1H),
5.11-4.89 (m, 1H), 4.34-4.17 (m, 1H), 3.91-3.76 (m, 1H), 3.71
(s, 3H), 2.84-2.77 (m, 1H), 2.62-2.53 (m, 1H), 1.50 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ ) 171.0, 155.1, 126.5-126.3 (m),
125.9-125.8 (m), 122.6 (q, J ) 267.9 Hz), 81.4, 52.7, 50.3, 39.4,
30.0, 28.6; HRMS (EI) calcd for C13H19F3NO4 (M + H)+ 310.1266,
found 310.1260.
1-(5-Chloro-2-methoxybenzenesulfonyl)-5-trifluoromethyl-
1,2,3,6-tetrahydropyridine-2-carboxylic Acid 2-Chlorobenzyl-
amide (52). To a solution of 48 (173 mg, 0.31 mmol) in dry toluene
(69 mL) was added catalyst 5 (10 mol %) 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 3:1 to 1:1) to give 52 (145 mg, 90%) as a white
solid: mp ) 137-140 °C; IR (neat, cm-1) 3384, 3329, 3071, 2939,
2917, 2846, 1676, 1591, 1572, 1522, 1478, 1440, 1390, 1344, 1305,
1273, 1209, 1163, 1113, 1078, 1015, 960, 897, 839, 814, 751, 644,
2-(4-Fluorophenyl)-5-trifluoromethyl-3,6-dihydro-2H-pyridine-
1-carboxylic Acid Methyl Ester (32). To a solution of 27 (110
mg, 0.33 mmol) in dry toluene (45 mL) was added catalyst 5 (4
mo l%) at 80 °C in small portions. The reaction was complete in
60 min. The solvent was evaporated and the residue purified using
column chromatography (heptane/EtOAc 10:1) to give 32 (80 mg,
80%) as a colorless oil: IR (neat, cm-1) 3065, 2954, 2898, 2855,
1705, 1605, 1515, 1446, 1316, 1247, 1156, 1113, 1022, 966, 858,
1
589; H NMR (400 MHz, CDCl3) δ ) 7.92 (d, J ) 2.8 Hz, 1H),
7.51-7.48 (m, 1H), 7.38-7.35 (m, 1H), 7.30-7.22 (m, 3H), 7.12
(br s, 1H), 6.9 (d, J ) 8.8 Hz, 1H), 6.41 (br s, 1H), 4.61-4.45 (m,
4H), 3.84 (s, 1H), 3.79 (s, 3H), 2.95-2.89 (m, 1H), 1.91-1.85
(m, 1H); 13C NMR (100 MHz, CDCl3) δ ) 167.7, 154.8, 134.7,
134.6, 134.0, 133.2, 130.7, 129.5, 129.3, 128.8, 127.6 (q, J ) 5.3
Hz), 126.8, 125.6, 124.1 (q, J ) 31.2 Hz), 122.1 (q, J ) 271.1
Hz), 113.6, 56.1, 52.3, 41.6, 38.8, 31.5; HRMS (EI) calcd for
C21H20Cl2F3N2O4S (M + H)+ 523.0473, found 523.0439.
1
767; H NMR (300 MHz, CDCl3) δ ) 7.18 (dd, J ) 6.0, 9.3 Hz,
2H), 6.98 (dd, J ) 8.7, 8.7 Hz, 2H), 6.5 (br s, 1H), 5.62 (br s, 1H),
4.44 (d, J ) 18.0 Hz, 1H), 3.78 (s, 3H) 3.36 (d, J ) 20 Hz, 1H),
2.85-2.64 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ) 161.9 (d, J
) 244.1 Hz), 155.7, 134.8, 128.4 (d, J ) 8.0 Hz), 127.5 (br s),
126.2 (q, J ) 31 Hz), 122.5 (q, J ) 269.1 Hz), 115.5 (d, J ) 21
Hz), 53.3, 49.9, 37.4, 27.3; HRMS (EI) calcd for C14H13F4NO2 (M+)
303.0882, found 303.0883.
Acknowledgment. Bayer CropScience is gratefully acknowl-
edged for financial support.
5-Trifluoromethyl-3,6-dihydro-2H-pyridine-1,2-dicarboxyl-
ic Acid 1-tert-Butyl Ester 2-Methyl Ester (39). To a solution of
38 (46 mg, 0.14 mmol) in dry toluene (20 mL) was added catalyst
5 (10 mol %) 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 10:1 to 6:1) to give
39 (29 mg, 67%) as a colorless oil: IR (neat, cm-1) 2976, 2924,
Supporting Information Available: Experimental procedures
and spectroscopic and analytical data of all the compounds both
mentioned and not mentioned in the Experimental Section. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO060893Z
7532 J. Org. Chem., Vol. 71, No. 20, 2006