Synthesis of α-trifluoromethylated nitrogen bicycles

Article abstract of DOI:10.1055/s-2005-864812

The synthesis of α-trifluoromethylated nitrogen bicycles from trifluoromethylated homoallylamine or piperidine derivatives, through different cyclization reactions, is described.

Full text of DOI:10.1055/s-2005-864812

LETTER
1027
Synthesis of a-Trifluoromethylated Nitrogen Bicycles
Synthesis of
a
-Tr
i
u
r
ated
N
it
é
B
icyc
l
les ien Ferry, Thierry Billard,* Bernard R. Langlois
Laboratoire SERCOF (UMR CNRS 5181), Université Claude Bernard-Lyon 1, Bât Chevreul, 43 Bd du 11 novembre 1918,
69622 Villeurbanne, France
Fax +33(4)72431323; E-mail: billard@univ-lyon1.fr
Received 2 February 2005
the high diastereoselectivity of the PK reaction since de
>95% are observed for 2a and 2b. A NOE experiment was
conducted to determine the relative configuration of the
substituents. The absence of a correlation between H1 and
H3 led us to suppose that H1 and H3 are in anti positions to
each other. Such assertions have been confirmed by
HOESY experiment, showing a correlation between CF3
and H3 (Figures 1, 2).
Abstract: The synthesis of a-trifluoromethylated nitrogen bicycles
from trifluoromethylated homoallylamine or piperidine derivatives,
through different cyclization reactions, is described.
Key words: bicyclic compounds, fluorine, metathesis, cycliza-
tions, Diels–Alder reactions, Heck reaction
Nitrogen heterocyclic moieties are structural elements of
many alkaloids, natural products, and drug candidates.1
Among them, the bicyclic core constitutes a substructure
common to many substrates. It is now well-known that the
presence of the trifluoromethyl moiety generally increas-
es the biological properties of such compounds, as recent-
ly demonstrated for the epothilone derivatives.2
HOE (H-F)
O
H3
R
no NOE
H1
H8a
H8b
F3C
N
Z
In our program towards the synthesis of potential new
drugs bearing a fluoroalkyl group, our attention was
drawn to trifluoromethylated heterobicyclic structures.
We recently described an easy and efficient synthesis of
a-trifluoromethylated homoallylamine derivatives and
fluorinated piperidines,3 such substrates have been used as
starting materials to access bicyclic structures. Our
preliminary results are described in this communication.
Figure 1 Relative configuration of the stereoisomers from the PK
reaction.
A well known methodology to obtain easily functional-
ized bicyclic compounds is the Pauson–Khand (PK) reac-
tion.4 Thus, after N-alkylation by alkynyl moieties;
trifluoromethylated homoallylamines underwent the PK
reaction (Scheme 1).
O
R
Co2CO8 (1 equiv)
NMO (10 equiv)
R
n
CH2Cl2, THF
r.t., 4 h
F3C
N
F3C
N
Figure 2 HOESY spectrum of 2b.
Z
Z
1a (n = 1, R = H)
1b (n = 1, R = Me)
1c (n = 3, R = H)
2a: 54% (de >95%)
2b: 59% (de >95%)
2c: 0%
To rationalize such excellent diastereoselectivity, transi-
tion states of the PK reaction were considered (Figure 3).
Due to the planarity of the CH2NZCH system, imposed by
the amide moiety, the CF3 group must occupy the axial
position (Aax), because of steric and electrostatic repul-
sions occurring in Aeq. Then, in the two possible transition
states showing an axial CF3 (Aax and Bax), if CF3 occupies
position Bax steric hindrance between CF3 and the ethyl-
enic hydrogen occurs. Consequently, the most favorable
transition state is Aax which leads to the diastereomer
observed (Figure 3).
Scheme 1 Synthesis of trifluoromethylated bicyclic by the PK reac-
tion.
Bicyclic compounds were obtained in satisfactory yield
(2a,b), while the largest bicyclic derivative (2c) could not
be obtained since the double and the triple bonds are too
spatially distant from each other. An interesting feature is
SYNLETT 2005, No. 6, pp 1027–1029
0
6.
0
4.
2
0
0
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864812; Art ID: G04205ST
© Georg Thieme Verlag Stuttgart · New York

1028
A. Ferry et al.
LETTER
Br
#
#
H
CF3
H
H
Br
Br
CF3
H
(1.2 equiv)
N
Z
N
Z
F3C
NHZ
NaH, DMF
n-Bu4NI
90 °C, 24 h
F3C
N
CO2CO8
CO2CO8
Aeq
R
Z
R
5
6 (44%)
Aax
#
1) Pd(OAc)2, PPh3, Ag2CO3
MeCN, 90 °C, 6 h
H
H
CF3
2) Dienophile (1 equiv), 90 °C, 18 h
R
H
N
Z
Co2CO8
Bax
R1
R2
Figure 3 Transition states of the PK reaction.
F3C
N
Z
To synthesize other bicyclic structures, we turned our in-
terest towards the Diels–Alder reaction, taking advantage
of the fact that we had previously described the synthesis
of dienic piperidines by RCM of 1a,b.3 Various dieno-
philes and conditions were tested to achieve such a
cycloaddition from 3a (Scheme 2 and Table 1).
7a (dienophile: methyl acrylate): 17%
7b (dienophile: dimethyl maleate): 27%
Scheme 3 Domino Heck/Diels–Alder reaction.
19F NMR, which indicated that the Diels–Alder reaction is
the limiting step. Therefore, it appears that dienic deriva-
tives of trifluoromethylated piperidines are not reactive
enough to undergo Diels–Alder cycloadditions. This can
be rationalized by assuming that the geometrical strain of
such compounds could disfavor the planarity of the p-s-p
system of dienes, lowering their reactivity. Theoretical
modeling calculations of these compounds are presently
being carried out in our laboratory.
R2
R1
Dienophile
F3C
N
Z
F3C
N
Z
4a–c
3a
Scheme 2 Diels–Alder cycloadditions of 3a.
To conclude, these preliminary results have shown that a-
trifluoromethylated nitrogen bicyclic structures can be
synthesized. The Pauson–Khand reaction turned out to be
a very efficient, highly diastereoselective method for the
synthesis of functionalized bicyclic compounds, which
constitute interesting synthons for further synthesis. The
Diels–Alder reaction seems to be more difficult, which
most certainly is a result of the geometry of the starting
substrates. Improvements to this reaction, by using well-
known activation methods, such as high pressure or mi-
crowave irradiation, are in progress and will be published
in due course. The domino sequence, has also allowed us
to underline the possibility of synthesizing cyclic struc-
tures by organometallic processes, other than RCM; such
methods are being further investigated to try to extend
their range.
These Diels–Alder cycloadditions proved to be very diffi-
cult; indicating that diene 3 is quite unreactive. Attempts
to realize these reactions under high pressure are currently
underway. Nevertheless, neither regioselectivity (entry 1)
nor diastereoselectivity (entries 1 and 3) have been ob-
served.
Since diene 3a appears to be too unreactive, we envisaged
using a bis-exo diene derivative of piperidine that we ex-
pected to be more reactive. For this purpose, the domino
Heck/Diels–Alder sequence developed by De Meijere5
was carried out (Scheme 3).
This domino sequence also gave disappointing results.
A more accurate study of this process was carried out by
Table 1 Diels–Alder Cycloadditions of 3a
Entry
Dienophile (1 equiv)
Methyl acrylate
Dimethyl maleate
Dimethyl maleate
DMADa
Conditions
Time (days)
Recovered 3a (%)
4 (%)
1
2
3
4
Toluene/110 °C
6
6
6
1
56
100
62
4a (44)
4b (0)
4b (38)
4c (75)
Toluene/110 °C
Toluene/110 °C, SnCl4 (0.1 equiv)
Toluene/110 °C
25
a DMAD: dimethyl acetylenedicarboxylate.
Synlett 2005, No. 6, 1027–1029 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Trifluoromethylated Nitrogen Bicycles
1029
(4) For recent reviews of the PK reaction see: (a) Frühauf, H.-
W. Chem. Rev. 1997, 97, 523. (b) Geis, O.; Schmalz, H.-G.
Angew. Chem. Int. Ed. 1998, 37, 911. (c) Brummond, K.
M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (d) Fletcher, A.
J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000,
1657.
References
(1) (a) O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637.
(b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(2) Chou, T. C.; Dong, H.; Rivkin, A.; Yoshimura, F.; Gabarda,
A. E.; Cho, Y. S.; Tong, W. P.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2003, 42, 4762.
(5) Ang, K. H.; Bräse, S.; Steinig, A. G.; Llebaria, A.; Voigt, K.;
De Meijere, A. Tetrahedron 1996, 52, 11503.
(3) Gille, S.; Ferry, A.; Billard, T.; Langlois, B. R. J. Org. Chem.
2003, 68, 8932.
Synlett 2005, No. 6, 1027–1029 © Thieme Stuttgart · New York