Synthesis of enones, pyrazolines and pyrrolines with gem-difluoroalkyl side chains

Article abstract of DOI:10.3762/bjoc.9.230

Starting from easily accessible gem-difluoropropargylic derivatives, a DBU-mediated isomerisation affords enones in fair yields with a gem-difluoroalkyl chain. These derivatives were used to prepare pyrazolines and pyrrolines with the desired gemdifluoroalkyl side chain by cyclocondensations in good yields and with excellent stereoselectivity. A one-pot process was also successfully developed for these sequential reactions. By carrying out various types of Pd-catalyzed coupling reactions for compounds with a p-bromophenyl substituent a route to focused chemical libraries was demonstrated.

Full text of DOI:10.3762/bjoc.9.230

Synthesis of enones, pyrazolines and pyrrolines with
gem-difluoroalkyl side chains
Assaad Nasr El Dine1,2, Ali Khalaf1,2, Danielle Grée1, Olivier Tasseau1,
Fares Fares2, Nada Jaber2, Philippe Lesot3, Ali Hachem*2 and René Grée*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1943–1948.
1Université de Rennes 1, Institut des Sciences Chimiques de Rennes,
CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes
Cedex, France, 2Laboratory for Medicinal Chemistry and Natural
Products, Lebanese University, Faculty of Sciences (1) and
PRASE-EDST, Hadath, Beyrouth, Lebanon and 3RMN en Milieu
Orienté, ICMMO, CNRS UMR 8182, Université de Paris Sud, 91405
Orsay cedex, France
doi:10.3762/bjoc.9.230
Received: 03 July 2013
Accepted: 06 September 2013
Published: 26 September 2013
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
Email:
Ali Hachem* - ahachem@ul.edu.lb; René Grée* -
rene.gree@univ-rennes1.fr
© 2013 El Dine et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
19F/1H HOESY; gem-difluoroalkyl derivatives; organo-fluorine
compounds; palladium catalysis; pyrazolines; pyrrolines
Abstract
Starting from easily accessible gem-difluoropropargylic derivatives, a DBU-mediated isomerisation affords enones in fair yields
with a gem-difluoroalkyl chain. These derivatives were used to prepare pyrazolines and pyrrolines with the desired gem-
difluoroalkyl side chain by cyclocondensations in good yields and with excellent stereoselectivity. A one-pot process was also
successfully developed for these sequential reactions. By carrying out various types of Pd-catalyzed coupling reactions for com-
pounds with a p-bromophenyl substituent a route to focused chemical libraries was demonstrated.
Introduction
A widely used strategy in bioorganic, medicinal chemistry and for the preparation of new fluorinated heterocyclic molecules.
in chemical biology is the selected introduction of fluorine in We developed a programme to investigate the preparation and
organic molecules since it strongly modifies their properties uses of new propargylic fluorides [12-14], which have been
[1-9]. On the other hand, heterocyclic molecules – in particular, employed in the synthesis of fluorinated analogues of lipids
the so-called privileged scaffolds – are introduced very classic- [15,16] and in carbocyclic systems [17,18]. They have also been
ally in the core of pharmaceutical products [10,11]. Therefore, it used for the preparation of several 5 and 6-membered hetero-
appears to be of much interest to design novel methodologies cycles [19-22]. The goal of the present work is to demonstrate
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that selected propargylic derivatives [23-25] can be employed
for the preparation of enones with a gem-difluoroalkyl chain by
using an isomerisation process (Scheme 1).
Scheme 1: Strategy towards the target molecules.
These intermediates can be employed for the preparation of
representative 5-membered heterocyclic systems with CF2R
side chains by using cyclocondensation reactions. Furthermore,
selected molecules in these series were functionalized by using
appropriate palladium-catalyzed coupling reactions en route to
chemical libraries.
Scheme 2: Synthesis of enones with a gem-difluoroalkyl side chain.
Table 1: Synthesis of enones 3a–3e.
Entry Ar
Step 1 Yield (%)
Step 2 Yield (%)
1
2
3
4
5
Ph
2a (82)
2b (78)
2c (79)
2d (71)
2e (81)
3a (62)
3b (62)
3c (63)
3d (60)
3e (61)
Results and Discussion
C5H4N
C4H3O
C4H3S
p-PhBr
The first example of a base-mediated isomerisation process for
an alkyne activated by an ester group was reported by Nineham
and Raphael in 1949 [26]. Later, extension to other electro-
philic alkynes was demonstrated by Sonye and Koide [27].
Recently, it has been established by Yamazaki’s group that pro-
pargylic alcohols bearing a CF3 group on the triple bond Therefore, they were selected as first examples of 5-membered
could be isomerised to the corresponding enones. In that heterocyclic targets with the fluorinated side chain. Reaction of
case, Et3N proved to be sufficient as a catalyst to perform this 3a–3e with methylhydrazine gave the desired pyrazolines 4a–4e
transformation [28].
in 79–86% yields (Scheme 3).
The required starting propargylic alcohols were obtained by a
reaction of the lithium salt of easily available gem-difluoro pro-
pargylic derivative 1 [18] with aromatic aldehydes, affording
compounds 2a–2e in 71–82% yields (Scheme 2 and Table 1).
With these gem-difluoro intermediates, Et3N was not an effi-
cient catalyst since only a low conversion was observed and the
reaction was not clean. On the contrary, the DBU-mediated
isomerisation was successful, affording the desired enones
3a–3e in 60–63% yields. The selectivity was excellent since in
Scheme 3: Synthesis of pyrazolines with a gem-difluoro side chain.
all cases the E-isomer was obtained almost exclusively (>98%). It appeared that the reaction conditions for the synthesis of these
Similar reactions were carried out with propargylic derivatives pyrazolines were compatible with the first isomerisation step,
bearing alkyl groups instead of the (Ar) aromatic or heteroaro- therefore the possibility of a "one-pot" reaction was considered.
matic group, but these reactions were not successful. Therefore, Indeed, by heating a mixture of propargylic alcohols 2a–2e with
this reaction appears limited to derivatives with aryl or hetero- DBU (1,8-diazabicycloundec-7-ene) in the presence of methyl-
aryl substituents as in the case of the CF3-substituted propar- hydrazine (Scheme 4) the pyrazolines 4a–4e were obtained after
gylic derivatives [28].
3–7 h in excellent yields (82–92%, Table 2). This very short
and efficient synthesis of pyrazolines 4 can be related to another
Next, we turned towards the preparation of heterocyclic struc- excellent one-pot reaction with 3-components where the first
tures from enones 3. Pyrazolines are well-recognized hetero- step is a Pd-catalyzed coupling–isomerisation process followed
cyclic cores for pharmacologically active molecules [29]. by a cyclocondensation [30].
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Beilstein J. Org. Chem. 2013, 9, 1943–1948.
NMR analysis of the crude reaction mixtures. This is different
from the results obtained by starting from enones with
CF2CF2X side chains, where trans/cis mixtures were reported
[34]. The 3JHH (6.3–6.5 Hz, trans) of our pyrrolines were very
close to those of similar molecules bearing CF2–CF3 chains
(6.4–6.6 Hz), while for latter derivatives the cis coupling
constants were larger (≥ 8.3 Hz) [34]. This was confirmed in the
case of pyrroline 6a by performing additional 19F/1H hOe 2D
experiments which revealed strong correlations between the
fluorine atoms of the CF2 group and the cyclic protons Hc and
Ha (see Scheme 5 and 2D spectrum in the Supporting Informa-
tion File 1 for details).
Scheme 4: One-pot synthesis of pyrazolines with a gem-difluoro side
chain.
Table 2: Synthesis of pyrazolines 4a–4e.
Entry Ar
Yield (%) (3 to 4)
Yield (%) (1 to 4)
Table 3: Synthesis of pyrrolines 6a–6e.
1
2
3
4
5
Ph
4a (85)
4b (79)
4c (81)
4d (82)
4e (86)
4a (86)
4b (82)
4c (84)
4d (83)
4e (92)
C5H4N
C4H3O
C4H3S
p-PhBr
Entry Ar
Yield (%) (3 to 6)
Yield (%) (1 to 6)
1
2
3
4
5
Ph
6a (74)
6b (73)
6c (75)
6d (74)
6e (78)
6a (73)
6b (76)
6c (73)
6d (71)
6e (75)
C5H4N
C4H3O
C4H3S
p-PhBr
Pyrroline is another noteworthy example of a heterocyclic scaf-
fold useful in bioorganic and medicinal chemistry [31,32]. It is
also well-recognized for agrochemicals, especially in combin-
ation with CF3 substituents. Recently, the group of Shibata has The reaction conditions were compatible with both steps and an
developed an elegant organocatalyzed asymmetric approach to example of a one-pot reaction was performed starting from
such pyrrolines [33]. Moreover, an efficient synthesis of β-tri- 2a–2e. The desired pyrrolines 6a–6e were obtained in excellent
fluoromethylated Δ1-pyrrolines has been reported [34]. There- yields (71–76%, Scheme 6 and Table 3).
fore, we selected pyrrolines with CF2R side chains as a second
example of 5-membered heterocyclic targets. Condensation of Another important issue was the possibility of using these
the anion of glycine ester diphenylimine 5 with the enones molecules as scaffolds for the preparation of focused chemical
3a–3e afforded the desired pyrrolines 6a–6e (Scheme 4 and libraries. In order to explore this possibility we developed
Table 3). In all cases good yields were obtained, and a complete representative examples of Pd-catalyzed reactions starting from
selectivity for the trans-isomer was observed as established by p-bromo derivatives 4e and 6e.
Scheme 5: Synthesis of pyrrolines with a gem-difluoro alkyl side chain.
Scheme 6: One-pot synthesis of pyrrolines with a gem-difluoro side chain.
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The results are given in Scheme 7 for pyrazoline 4e. Conclusion
Suzuki–Miyaura coupling [35] gave biphenyl derivative 7e in In summary, we developed an efficient access to enones with
82% yield, while the Heck [36] and Sonogashira [37] reactions gem-difluoroalkyl side chains through a base-mediated isomer-
afforded also the desired targets 8e and 9e in 72% and 77% isation of fluorinated propargylic alcohols. Although this
yield respectively. Similar results were obtained in Pd-medi- method is, to date, limited to compounds with aryl or hetero-
ated reactions starting from pyrroline 6e, as indicated in aryl substituents, corresponding enones appear as versatile
Scheme 8. The desired molecules 10e–12e were obtained in intermediates for the preparation of heterocyclic derivatives.
good yields.
This has been established through the synthesis of pyrazolines
Scheme 7: Pd-catalyzed coupling reactions towards chemical libraries of pyrazolines with a gem-difluoro side chain.
Scheme 8: Pd-catalyzed coupling reactions towards chemical libraries of pyrrolines with a gem-difluoro side chain.
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Beilstein J. Org. Chem. 2013, 9, 1943–1948.
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Supporting Information
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Supporting Information File 1
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