Synthesis of α-Trifluoromethylated Nitrogen Heterocycles

Article abstract of DOI:10.1021/jo035097x

The syntheses of various α-trifluoromethylated nitrogen heterocycles have been achieved from readily available α -(trifluoromethyl)homoallylamine through a ring-closing metathesis.

Full text of DOI:10.1021/jo035097x

Syn th esis of r-Tr iflu or om eth yla ted Nitr ogen Heter ocycles
Se´gole`ne Gille, Aure´lien Ferry, Thierry Billard,* and Bernard R. Langlois
Laboratoire SERCOF (UMR CNRS 5181). Universite´ Claude BernardsLyon 1. Baˆt. Chevreul. 43 Bd du
11 Novembre 1918. 69622 Villeurbanne, France
Billard@univ-lyon1.fr
Received J uly 28, 2003
The syntheses of various R-trifluoromethylated nitrogen heterocycles have been achieved from
readily available R-(trifluoromethyl)homoallylamine through a ring-closing metathesis.
In tr od u ction
In our program on the synthesis of potential new drugs
bearing a fluoroalkyl group, we focused our interest on
an easy access to R-trifluoromethylated nitrogen hetero-
cyclic compounds not only for their potential intrinsic
bioactivity but also as potential fluorinated synthons for
further functionalization.
Nitrogen heterocyclic moieties are structural elements
of many alkaloidic natural products and drug candi-
dates,1 as, for example, solenopsine, balanol, motupor-
amine, or pinidine.2 Among them, the piperidine ring
continues to be extensively used in pharmaceutical
research. Indeed, recently it has been reported that there
were over 12 000 compounds affording piperidine entities
mentioned in clinical or preclinal studies during a recent
10-year period.3
On the other hand, the last years have shown a
tremendous increase of new organofluorine compounds4
due to the unique properties exhibited by such sub-
strates.5 Among them, trifluoromethyl-substituted mol-
ecules constitute a particular class because of the specific
properties, such as the high lipophilicity, brought by the
CF3 moiety. Recently, such molecules found outstanding
applications in the pharmaceutical field,6 as illustrated
by Efavirenz7 (anti-HIV) and Celecoxib8 (antiarthritic),
two recent drugs used in the treatment of human
diseases.
Resu lts a n d Discu ssion
The synthesis of substituted piperidines has been
largely described in the literature through many different
strategies.9 For our part, we have recently described an
easy access to R-(trifluoromethyl) homoallylamine from
fluoral hemiketal10 and it appears to us that this product
should be an interesting starting material to achieve the
synthesis of R-trifluoromethylated nitrogen heterocyclic
compounds. Furthermore, recent works from Brigaud et
al.11 and Enders et al.12 demonstrated the possibility to
obtain this trifluoromethylated precursor in a pure
enantiomeric form, allowing the extrapolation of the
strategy presented below to a stereoselective one.
In this preliminary work, we want to validate the
racemic route to R-trifluoromethylated nitrogen hetero-
cylic compounds, according to the retrosynthetic analysis
given in Sheme 1, in which we have chosen, as a key step,
a ring closure metathesis (RCM), a well-known strategy
for the synthesis of piperidine rings.13 The starting point
of this convergent synthesis was the preparation of the
(1) (a) O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637-651. (b) O’Hagan,
D. Nat. Prod. Rep. 2000, 17, 435-446.
(2) (a) J efford, C. W.; Wang, J . B. Tetrahedron Lett. 1993, 34, 2911-
2914. (b) Poerwono, H.; Higashiyama, K.; Takahashi, H. J . Org. Chem.
1998, 63, 2711-2714. (c) Williams, D. E.; Craig, K. S.; Patrick, B.;
McHardy, L. M.; Van Soest, R.; Roberge, M.; Andersen, R. J . J . Org.
Chem. 2002, 67, 245-258. (d) Laursen, B.; Denieul, M.-P.; Skrydstrup,
T. Tetrahedron 2002, 58, 2231-2238.
(3) Watson, P. S.; J iang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
(4) Schofield, H. J . Fluorine Chem. 1999, 100, 7-11.
(5) (a) Gross, U.; Ru¨diger, S. In Organo-Fluorine Compounds;
Baasner, B., Hagemann, H., Tatlow, J . C., Eds.; Houben-Weyl: Methods
of Organic Chemistry, Vol. E10a; Thieme: Stuttgart, 1999; pp 18-26.
(b) Smart, B. E. J . Fluorine Chem. 2001, 109, 3-11.
(9) For reviews, see: (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D.
J . Chem. Soc., Chem. Commun. 1998, 633-640. (b) Mitchinson, A.;
Nadin, A. J . Chem. Soc., Perkin Trans. 1 2000, 2862-2892. (c) Laschat,
S.; Dickner, T. Synthesis 2000, 1781-1813. (d) Weintraub, P. M.; Sabol,
J . S.; Kane, J . M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-
2989.
(10) Billard, T.; Langlois, B. R. J . Org. Chem. 2002, 67, 997-1000.
(11) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetrahe-
dron Lett. 2002, 43, 2827-2830.
(12) Funabiki, K.; Nagamori, M.; Matsui, M.; Enders, D. Synthesis
2002, 17, 2585-2588.
(13) (a) Akiyama, R.; Kobayashi, S. Ang. Chem. Int. Ed. 2002, 41,
2602-2604. (b) Paquette, L. A.; Ra, C. S.; Schloss, J . D.; Leit, S. M.;
Gallucci, J . C. J . Org. Chem. 2001, 66, 3564-3573. (c) Paquette, L. A.;
Schloss, J . D.; Efremov, I.; Fabris, F.; Gallou, F.; Mendez-Andino, J .;
Yang, J . Org. Lett. 2000, 2, 1259-1261. (d) Evans, P.; Grigg, R.;
Monteith, M. Tetrahedron Lett. 1999, 40, 5247-5250. (e) Evans, P.;
Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M. Tetrahedron Lett.
1999, 40, 3021-3024. For reviews about RCM, see: (f) Fu¨rstner, A.
Ang. Chem. Int. Ed. 2000, 39, 3012-3043. (g) Alkene Metathesis in
Organic Synthesis; Fu¨rstner, A., Ed.; Springer: Berlin, 1998.
(6) (a) Filler, R.; Kobayashi, Y.; Yagulpolskii, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications;
Elsevier: Amsterdam, 1993. (b) Banks, R. E.; Smart, B. E.; Tatlow, J .
C. Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994. (c) Welch, J . T.; Ewarakrishnan, S.
E. Fluorine in Biorganic Chemistry; J ohn Wiley: New York, 1991. (d)
Fluorine-containing Amino Acids. Synthesis and Properties; Kukhar,
V. P., Soloshonok, V. A., Eds.; J ohn Wiley & Sons: Chichester, 1995.
(e) Hiyama, V. A. Organofluorine Compounds: Chemistry and Proper-
ties; Springer-Verlag: Berlin, 2000; Chapter 5, pp 137-182.
(7) (a) Ren, J .; Milton, J .; Weaver, K. L.; Short, S. A.; Stuart, D. I.;
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Pedersen, E. B. Synthesis 2000, 479-495.
(8) (a) J ackson, L. M.; Hawkey, C. J . Drugs 2000, 59, 1207-1216.
(b) Price, M. L. P.; J orgensen, W. J . J . Am. Chem. Soc. 2000, 122,
9455-9466.
10.1021/jo035097x CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003
8932
J . Org. Chem. 2003, 68, 8932-8935

Synthesis of Nitrogen Heterocycles
SCHEME 1. Retr osyn th esis of r-Tr iflu or om eth yla ted Nitr ogen Heter ocyles
SCHEME 2. Syn th esis of r-Tr iflu or om eth yla ted Hom oa llyla m in e
TABLE 1. Alk yla tion of 4
SCHEME 3. Gr u bbs Ca ta lysts
entry
n
5a (%)
TABLE 2. RCM fr om 4
1
2
3
4
5
1
2
3
4
6
5a (80)
5b (0)
5c (56)
5d (70)
5e (71)
a
Isolated yield.
entry 5 (mol L-1
)
n
catalyst solvent/T (°C) time 8a (%)
1
2
3
4
5
6
7
8
9
5a (0.1)
5a (0.1)
5a (0.1)
5c (0.1)
5d (0.1)
5d (0.1)
5d (0.001)
5d (0.001)
5e (0.001)
5e (0.001)
1
1
1
3
4
4
4
4
6
6
6 (5%)
6 (5%)
6 (1%)
6 (1%)
6 (1%)
6 (1%)
6 (10%) CH2Cl2/RT
7 (10%) CH2Cl2/RT
6 (10%) CH2Cl2/RT
7 (10%) CH2Cl2/RT
CH2Cl2/50
CH2Cl2/RT
CH2Cl2/RT
CH2Cl2/RT
CH2Cl2/RT
Toluene/110
5 h 8a (66)
5 h 8a (98)
5 h 8a (91)
5 h 8c (80)
1 d 8d (0)
1 d 8d (0)
5 d 8d (0)
2 d 8d (40)b
5 d 8e (0)
7 d 8e (5)b
trifluoromethylated homoallylamine 4. Following our
previous results,10 the preparation was optimized as
summarized in Scheme 2.
This sequence can be easily scaled up to produce
starting material in large quantities. For instance, 20 g
of 4 have been produced in one batch.
The protected homoallylamine 4 was then alkylated
with various ω-alkenyl bromides (Table 1).
Because of the low nucleophilicity of 4, prior deproto-
nation in DMF was needed to achieve alkylation. Good
yields were generally obtained except with 4-bromo-but-
1-ene, for which â-elimination matched substitution.
These precursors were then engaged in a RCM in the
presence of one of the two commercially available Grubbs
catalysts (Scheme 3, Table 2).
10
a
b
Isolated yield. Crude yield determined by 19F NMR with
internal standard (PhOCF3).
(entries 1-4). Nevertheless, the access to higher homo-
logues was relatively disappointing (entries 5-10), even
under usual high-dilution conditions.
However, this strategy provided an efficient synthesis
of dehydropiperidines, which was our first objective on
our route toward bioactive compounds. As an illustration
of this method, the synthesis of trifluoropipecoline,14 the
RCM was efficient to obtain medium-sized heterocycles
(six- and eight-membered), even with 1% of catalyst 6
J . Org. Chem, Vol. 68, No. 23, 2003 8933

Gille et al.
SCHEME 4. Syn th esis of Tr iflu or op ip ecolin ea
TABLE 3. RCM of En yn es
T
time
11
entry
10
catalyst
(°C)
(days)
(%)
1
2
3
4
5
6
7
8
10a
10a
10a
10b
10b
10b
10b
10c
6 (1%)
6 (5%)
7 (5%)
6 (1%)
7 (1%)
6 (5%)
7 (5%)
7 (5%)
rt
1
1
1
1
3
1
1
1
11a (8)
50
50
rt
11a (40)
11a (44)
11b (6)
11b (60)
11b (70)
11b (75)
11c (0)
rt
50
50
50
formation of dienes was examined through enyne me-
tathesis. For this purpose, various enynes were synthe-
sized from 4. (Scheme 5).
These enynes in hand, the optimal conditions were
determined to achieve RCM with satisfactory yields
(Table 3).
Because of a lower reactivity of 10, compared to 5,
heating at 50 °C was required to obtain good results. The
use of catalyst 7, known to be more efficient than 6, did
not significantly increase the yields. It can be also noticed
that, according to the literature,16 terminal enynes gave
lower yields than internal enynes (entries 2, 3 and 6, 7).
As mentioned previously, larger cycles could not be
obtained (entry 8).
a
Reagents and conditions: (a) benzophenone imine, MS 4 Å,
CH2Cl2, rt, 48 h (90%); (b) ImSiMe3, THF, rt, 5 h (99%); (c)
allylTMS, BF3‚Et2O, CH2Cl2, 50 °C, 24 h (84%); (d) 2 N HClaq
CH2Cl2, 50 °C, 24 h (99%); (e) ClCbz, NaHCO3, H2O, rt, 12 h (88%);
(f) NaH, allylBr, DMF, 3 h (80%); (g) 6 (1% mol), CH2Cl2, rt, 5 h
(91%); (h) (i) Pd/C, H2, EtOH, rt, 24 h, (ii) HCl (99% from 8a ).
,
SCHEME 5. Syn th esis of En yn es 10
Finally, the extension of this strategy to the synthesis
of R-trifluoromethylated lactam was then envisaged
(Scheme 6).
In this case, only catalyst 7 gave rise to cyclization. It
can be also noticed that macrolactam was also obtained
with good yields.
Thus, such routes to various trifluoromethylated ni-
trogen heterocycles seem to be valuable on a synthetic
point of view, since they start from the same R-(trifluo-
romethyl)homoallylamine 3.
fluorinated analogue of a well-known bioactive sub-
stance,15 has been achieved with a global yield of 47%
from fluoral hemiketal. (Scheme 4).
To explore the scope of this strategy toward nitrogen
heterocyclic cores as synthons for further syntheses, the
This method also allowed access to other fluorinated
compounds starting from other fluorinated aldehydes, as
illustrated in Scheme 7 by the synthesis of R-(chlorodi-
fluoromethyl)-dehydropiperidine. In conclusion, we have
described a direct and efficient synthesis of R-fluoroalky-
SCHEME 6 r-Tr iflu or om eth yla ted La cta m Syn th esis
8934 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of Nitrogen Heterocycles
SCHEME 7. Syn th esis of 19a
present valuable synthetic potentials for further synthe-
ses. The use of such synthons in multistep preparations
of fluorinated bioactive compounds is under progress in
our laboratory and will be published in due course.
Ack n ow led gm en t. We thank the CNRS for finan-
cial support.
Su p p or tin g In for m a tion Ava ila ble: Typical procedures
and physical data of compounds 1-19. This material is
available free of charge via the Internet at http://pubs.acs.org.
a
J O035097X
Reagents and conditions: (a) benzophenone imine, MS 4 Å,
CH2Cl2, rt, 48 h (84%); (b) ImSiMe3, THF, rt, 5h (94%); (c)
allylTMS, BF3‚Et2O, CH2Cl2, 50 °C, 24 h (94%); (d) 2 N HClaq
,
(14) (a) Maynard, S. R. J . Org. Chem. 1962, 27, 1406-1409. (b)
Haebich, D.; Roeben, W.; Hansen, J .; Paessens, A. DE 4126485, 1993;
Chem. Abstr. 1994, 120, 271184.
(15) (a) Arneric, S. P.; Decker, M. W. U.S. Patent 5,272,155, 1993;
Chem. Abstr. 1994, 121, 179496. (b) Zimmet, P. Z.; Westerman, R. A.;
Collier, G. WO 9803175, 1998; Chem. Abstr. 1998, 128, 123819.
(16) Kinoshita, A.; Mori, M. Synlett 1994, 1020.
CH2Cl2, 50 °C, 24 h (99%); (e) ClCbz, NaHCO3, H2O, rt, 12 h (88%);
(f) NaH, allylBr, DMF, 3 h (80%); (g) 6 (1% mol), CH2Cl2, rt, 5h
(91%).
lated nitrogen heterocycles from commercial or readily
available fluoroaldehydes. The obtained compounds
J . Org. Chem, Vol. 68, No. 23, 2003 8935