Synthesis of new difluoroalkyl propargylic ketones and their use for the preparation of fluorinated heterocycles

Article abstract of DOI:10.1016/j.tetlet.2010.02.116

Synthetic methodology studies are reported towards the preparation of new propargylic ketones with CF₂R side chains. These molecules are used for the synthesis of various types of five- or six-membered heterocycles with difluoroalkyl side chain

Full text of DOI:10.1016/j.tetlet.2010.02.116

Tetrahedron Letters 51 (2010) 2413–2415
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new difluoroalkyl propargylic ketones and their use for the
preparation of fluorinated heterocycles
*
Pierre Bannwarth, Danielle Grée, René Grée
Université de Rennes 1, Laboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510 et Laboratoire Sciences Chimiques de Rennes, CNRS UMR 6226,
Avenue du Général Leclerc, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic methodology studies are reported towards the preparation of new propargylic ketones with
CF2R side chains. These molecules are used for the synthesis of various types of five- or six-membered
heterocycles with difluoroalkyl side chains.
Received 29 January 2010
Revised 16 February 2010
Accepted 19 February 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Difluoralkyl compounds
Propargylic ketones
Cyclocondensation reactions
Pyrimidines
Pyridines
Pyrazoles
Isoxazoles
It is well established that the introduction of fluorine in organic
molecules strongly modifies their physical, chemical, and biologi-
cal activities and this has been already of much use in fluorobior-
ganic chemistry.1 Moreover, heterocycles are widely employed in
bioorganic and medicinal chemistry.2 Therefore, it is of much inter-
est to develop flexible routes to new fluorinated heterocycles. It is
well known that propargylic ketones can be used as a versatile
starting material in the preparation of various types of heterocy-
cles.3 In this context, it appears important to develop easy and effi-
cient access to propargylic ketones which are fluorinated on the
side chains.
Based on our retrosynthetic analysis for type A difluorinated
propargylic ketones, two different routes can be easily envisaged
(Scheme 1).
The first one has strong analogies with the strategy developed
earlier for the preparation of molecules with the difluoromethyl
side chain.4 It involves gemdifluorination of a type C monoprotect-
ed dicarbonyl compound,5 followed by introduction of the required
R2 group in a few steps, starting from the masked aldehyde. The
second pathway, using a different disconnection, involves the gem-
difluorinated intermediates D, easily accessible from propargylic
As part of our research program in fluorine chemistry, we re-
cently published the synthesis of new pyrimidines containing a
difluoromethyl group in benzylic position, starting from propargy-
lic ketones with a CHF2 side chain.4 In order to extend our research
to the preparation of pyrimidines with new difluorinated alkyl side
chains (CF2R), we became interested in the synthesis and uses of
the corresponding fluorinated propargylic intermediates. There-
fore, the purpose of this publication is to report the synthesis of
new difluoroalkyl propargylic ketones (type A) and their use as
precursors, not only of pyrimidines but also for other six- and
five-membered heterocycles.
5- or 6-membered Heterocycles
with a CF2R chain
F
F
O
F
F
F
F
(EtO)2HC
(EtO)2HC
R2
R1
R1
R1
B
A
D
O
O
R1
R1
C
E
* Corresponding author. Tel.: +33 (0) 223235715; fax: +33 (0) 223236978.
E-mail address: rene.gree@univ-rennes1.fr (R. Grée).
Scheme 1. Two different routes to the difluorinated propargylic ketones A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.116

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P. Bannwarth et al. / Tetrahedron Letters 51 (2010) 2413–2415
ketones E.6 Then a direct, or stepwise, introduction of the COR2
groups should afford the desired intermediates A. Following these
strategies, the molecular diversity can be introduced at both the
beginning (for R1 group) and a later stage (in the case of R2 group).
We will describe our results for the preparation of the desired
fluorinated intermediates by using each of these two methods.
The two-step sequence was checked first and the reaction of the
lithium derivatives from 7 and 8 with aldehydes gave the corre-
sponding alcohols 9a–c and 10. After oxidation with IBX, these
intermediates afforded the desired difluorinated propargylic ke-
tones 11a–c and 12. This sequence gave fair (for 12) to good overall
yields in the case of ynones 11 (Table 1). On the contrary, the one-
step sequence to prepare ketones from 7 proved to be less satisfac-
tory. The palladium-mediated coupling (ex. Sonogashira) with acyl
chlorides was ineffective. On the other hand, the use of Weinreb
amine derivatives was possible but the best we could achieve
was a 50% conversion rate and a 31% yield. Furthermore, the reac-
tion conditions must be carefully controlled in order to avoid
in situ addition of the N-methyl-methoxyamine on the ynone
formed during the synthesis.8 Therefore, the two-step path from
7 and 8 is more efficient and it has been used with different alkyl
and aryl substituents R2.
– Our first attempts (by using method A) were about starting from
the known5 gemdifluorinated propargylic acetal 2 (Scheme 2).
After deacetalization with formic acid,7 the crude aldehyde 3
was reacted with acetamidine hydrochloride in the presence of
Na2CO3, thus leading to the pyrimidine 4 in a modest 35% overall
yield from 2. In order to introduce a phenyl group as a model for
the R2 substituent, a phenyllithium addition was performed on
3, affording alcohol in low yield (23%). This was followed by
an IBX oxidation to give fluoride 5 in 15% overall yield from 3.
This propargylic ketone afforded, after reaction with acetami-
dine, the expected pyrimidine 6 in 61% yield. Even if these reac-
tions were not fully optimized, the overall yields were not
satisfactory and the diversification, obtained through the 3 to
6 sequence, might become an issue when considering various
types of functionalized R2 substituents.
The first application of these new intermediates was to prepare
six-membered difluorinated heterocycles, and more specifically
pyrimidines in order to complete our previous work.4 The reaction
of the fluorinated propargylic ketones 11a–c and 12 with various
amidine/guanidine derivatives afforded the desired pyrimidines
in very good yields as indicated in Scheme 4 and Table 2.
– We then checked the second strategy (method B). In that case,
the difluorinated propargylic ketones 11a–c and 12 should be
obtained from the known propargylic intermediates 7,5 and 8,6
which are already gemdifluorinated. By using various coupling
methods, it should be possible to obtain the required propargylic
ketones 11a–c and 12 in one, or two, step(s) from simple
reagents such as aldehydes, ketones, and acylchlorides.
Table 1
Propargylic ketones 11 and 12 produced via Scheme 3
Entry Compound R1
R2
Yield step Yield step
1 (%)
2 (%)
1
2
3
4
11a
11b
11c
12
n-C9H19
n-C9H19
n-C9H19
p-BrC6H4
Me
t-BuPh2SiO(CH2)4 70
88
80
93
79
82
73
(CH2)3CO2Me p-BrC6H4
54
Method A:
F
O
F
i
(EtO)2HC
(EtO)2HC
F
F
C5H11
C5H11
R2
1
2
F
O
NH
+
F
R1
N
N
H2N
R3
F
F
R2
R1
F
F
O
ii
iii
R3
13-14
C5H11
11-12
N
N
H
C5H11
3
4
Scheme 4. Reagents and conditions: Na2CO3, CH3CN, reflux. The yields are given in
Me
iv
Table 2.
F
F
Ph
O
F
C5H11
F
v
Table 2
N
N
Pyrimidines 13 and 14 produced via Scheme 4
Ph
C5H11
6
Me
Entry
Compound
R1
R2
R3
Yield (%)
5
1
2
3
4
5
6
7
13aw
13ax
13ay
13az
13bw
13cw
14
n-C9H19
n-C9H19
n-C9H19
n-C9H19
n-C9H19
n-C9H19
(CH2)3CO2Me
p-BrC6H4
p-BrC6H4
p-BrC6H4
p-BrC6H4
Me
Me
Ph
NH2
NHAc
Me
75
95
82
67
84
82
81
Scheme 2. Reagents and conditions: (i) DAST (2.2 equiv) neat under Ar, 55 °C, 5 h
(90%); (ii) HCO2H/CH2Cl2, reflux 5.5 h (70%); (iii) MeC(NH)NH2ꢀHCl (1.2 equiv),
Na2CO3 (2.4 equiv), CH3CN, reflux overnight (51%); (iv) (1) PhLi (1.5 equiv), THF,
ꢁ70 °C to ꢁ40 °C; 1 h (23%) then IBX (1.2 equiv), DMSO/THF, 35 °C, 5 h (67%) (v)
MeC(NH)NH2ꢀHCl (1.2 equiv), Na2CO3 (2.4 equiv), CH3CN, reflux overnight (61%).
(CH2)4OSiPh2tBu
p-BrC6H4
Me
Me
Method B:
F
HO
R2
F
O
F
F
F
F
ii
i
F
H
F
BrC6H4
N
F
R2
O
R1
R1
R1
C9H19
CO2Et
F
7 R1=C9H19
9a-c R1=C9H19
10 R1=(CH2)3CO2Me 12 R1=(CH2)3CO2Me
11a-c R1=C9H19
8 R1=(CH2)3CO2Me
BrC6H4
C9H19
iii
11a
15
Scheme 3. Reagents and conditions: (i) (1) n-BuLi (1.1 equiv), under Ar, THF,
ꢁ78 °C, 1 h then (2) R2CHO (1.2 equiv), ꢁ78 °C to rt; (ii) IBX (1.2 equiv), DMSO/THF,
35 °C, 5 h. The yields are given in Table 1.
Scheme 5. Reagents and conditions: ethyl acetoacetate (1.7 equiv), NH4OAc
(17 equiv), EtOH, rt overnight then I2.

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-
line version, at doi:10.1016/j.tetlet.2010.02.116.
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).
1. (a) Kitazume, T.; Yamazaki, T. Experimental Methods in Organic Fluorine
Chemistry; Gordon and Breach Science Publishers: Tokyo, 1998; (b) Hudlicky,
M.; Pavlath, A. E.; Chemistry of Organic Fluorine Compounds II: A Critical
Review, ACS Monograph 187, Washington, DC, 1995.; (c) Banks, R. E.; Smart, B.
E.; Tatlow, J. C. Characteristics of C–F systems. In Organofluorine Chemistry:
Principles and Commercial Applications; Plenum: New York, 1994; (d) Ojima, I.;
McCarthy, J. R.; Welch, J. T. Biomedical Frontiers in Fluorine Chemistry, ACS
Symposium Series 639, Washington, DC, 1996.; (e) Welch, J. T.;
Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley Interscience: New
York, 1991; (f) Welch, J. T. Tetrahedron 1987, 43, 3123–3197; (g) Isanbor, C.;
O’Hagan, D. J. Fluorine Chem. 2006, 127, 303–319; (h) Bégué, J.-P.; Bonnet-
Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012; (i) Kirk, K. L. J. Fluorine Chem.
2006, 127, 1013–1029; (j) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn,
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references cited therein.
2. See for instance: Corey, E. J.; Czako, B.; Kürti, L. Molecules and Medicine; Wiley
Interscience: New York, 2007.
3. See for instance: Bagley, M. C.; Hughes, D. D.; Lubinu, M. C.; Merritt, E. A.;
Taylor, P. H.; Tomkinson, N. C. O. QSAR Comb. Sci. 2004, 23, 859–867. and
references cited therein.
4. Bannwarth, P.; Valleix, A.; Grée, D.; Grée, R. J. Org. Chem. 2009, 74, 4646–4649.
5. Kerouredan, E.; Prakesch, M.; Grée, D.; Grée, R. Lett. Org. Chem. 2004, 1, 78–80.
6. (a) Prakesch, M.; Kerouredan, E.; Grée, D.; Grée, R.; De Chancie, J.; Houk, K. N. J.
Fluorine Chem. 2004, 125, 537–541; (b) Manthati, V.; Grée, D.; Grée, R. Eur. J.
Org. Chem. 2005, 3825–3829; (c) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R.
Tetrahedron Lett. 2007, 48, 5305–5307. and references cited therein.
7. Gorgues, A. Bull. Soc. Chim. Fr. 1974, 529–530.
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.
8. Persson, T.; Nielssen, J. Org. Lett. 2006, 15, 3219–3222.
9. Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265–2272.
10. (a) Bagley, M. C.; Glover, C.; Chevis, E. D. Synlett 2005, 649–651; (b) Bagley, M.
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.
12. Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J.; Tang, L. T. J. Chem.
Soc., Perkin Trans. 1 2000, 2311–2316.