P. Bannwarth et al. / Tetrahedron Letters 51 (2010) 2413–2415
2415
In conclusion, we have established simple and efficient routes
to the new gemdifluoro-ynones 11a–c and 12. Starting from these
versatile intermediates, it was possible to prepare efficiently sev-
eral types of six- and five-membered heteroaromatic systems with
difluoroalkyl side chains. These methodologies should be of much
use for the preparation of new chemical libraries of bioactive fluo-
rinated heterocyclic compounds.
F
F
F
F
R2
R2
i
C9H19
C9H19
11a-b
+
+
N
N
N
N
R3
R3
16
16'
F
F
F
F
BrPh
ii
BrPh
Acknowledgments
C9H19
11a
C9H19
O
N
N
O
This research has been performed as part of the Indo-French
‘Joint Laboratory for Sustainable Chemistry at Interfaces’. We thank
CNRS, MESR, and CSIR for support of this research.We thank CNRS
and MESR for financial support and for a research fellowship (P.B.).
We thank Mrs S Gouazou for some preliminary experiments in the
five-membered series and CRMPO for the MS analyses.
17
17'
Scheme 6. Reagents and conditions: (i) R3NHNH2 (1.4 equiv), EtOH, 1 h, rt or
reflux; (ii) NH2OH (1 equiv), EtOH, reflux, 24 h (47%).
Table 3
Pyrazoles 16, 160, and 17 produced via Scheme 6
Supplementary data
Entry
Compound
R2
R3
Ratio 16:160
Yield (%)
Supplementary data (experimental procedures, spectral and
analytical data) associated with this article can be found, in the on-
1
2
3
16aw
16ax + 160ax
16bx + 160bx
p-BrC6H4
p-BrC6H4
Me
Me
Ph
Ph
100:0
6:94
8:92
73
64
83
References and notes
Moreover, starting from 11a, the Bohlmann–Rahtz reaction9,10
afforded the pyridine (15) with a 70% yield (Scheme 5).
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Another complementary aspect was to study the reactivity of
our new fluorinated propargylic ketones as intermediates for the
synthesis of five-membered heterocycles, such as pyrazoles11 and
isoxazoles12 with a difluoroalkyl side chain. In both cases, we used
literature methodologies and an interesting aspect of these reac-
tions was to determine if the fluorine atoms have any effect on
the regioselectivity of the cyclocondensation processes. The results
are given in Scheme 6 and Table 3.
The reaction of methylhydrazine with gemdifluoro-ynone 11a
afforded exclusively the desired pyrazole 16aw while on reaction
with phenyl hydrazine, a 6/94 ratio of 16ax and 160ax was obtained.
The same reaction was observed in the case of ynone 11b. These re-
sults are fully consistent with the regioselectivities observed in the
literature for nonfluorinated ynones. Therefore for the synthesis of
pyrazoles, thefluorineatoms ontheside chain have nosignificantef-
fect on the regioselectivity of the cyclocondensation.
When it comes to the formation of isoxazoles, a slightly differ-
ent result is obtained. Indeed, according to the literature,12 the
reaction with nonfluorinated ynones (in ethanol at reflux) should
lead to the regioisomers corresponding to 17 only, whereas adding
pyridine should afford a (1:3) mixture of isomers 17 and 170. How-
ever, experiments showed that starting from gemdifluoro-ynone
11a, the same (1:3) mixture of 17 and 170 is obtained in both cases,
with a 47% yield. Therefore, starting from these fluorinated inter-
mediates, the formation of isoxazole is proved to be possible but
the presence of pyridine has no influence on the regioselectivity
of the cyclocondensation.
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C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459–2482. and references cited
therein.
11. Bishop, B. C.; Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 1, 43–
52.
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Soc., Perkin Trans. 1 2000, 2311–2316.