Exploiting a Difference in Leaving Group Ability: An Approach to β-Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes

Article abstract of DOI:10.1021/acs.orglett.6b00590

The superior nucleofuge character of chlorine over fluorine was taken advantage of in the selective S_N2′ substitution reaction of gem-chlorofluoropropenes, allowing for the clean formation of β-substituted monofluoroalkenes under metal-free conditions. Numerous N-, S-, O-, and C-nucleophiles behaved nicely in this system. Further synthetic transformations of selected monofluoroalkenes were also accomplished.

Full text of DOI:10.1021/acs.orglett.6b00590

Letter
pubs.acs.org/OrgLett
Exploiting a Difference in Leaving Group Ability: An Approach to
β‑Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes
Jean-Denys Hamel, Melissa Cloutier, and Jean-Franco
̧
is Paquin*
́
CCVC, PROTEO, Dep
́
́ ́ ́ ́
artement de chimie, Universite Laval, 1045 Avenue de la Medecine, Quebec, Quebec, Canada G1V 0A6
S
* Supporting Information
ABSTRACT: The superior nucleofuge character of chlorine over fluorine was taken
advantage of in the selective SN2′ substitution reaction of gem-chlorofluoropropenes, allowing
for the clean formation of β-substituted monofluoroalkenes under metal-free conditions.
Numerous N-, S-, O-, and C-nucleophiles behaved nicely in this system. Further synthetic
transformations of selected monofluoroalkenes were also accomplished.
to this important fluorinated motif, they suffer from drawbacks.
rganofluorine compounds occupy a significant place in
Omedicinal chemistry, agrochemistry, and material scien- For instance, the Pd-catalyzed reaction only allowed the use of
aliphatic amines (Scheme 1, eq 1, [M] = Pd).5 Likewise, the Pt-
catalyzed reaction only tolerated secondary aliphatic amines,
and other nucleophiles behaved poorly (Scheme 1, eq 1, [M] =
Pt).6 Concerning the metal-free approach (Scheme 1, eq 2),
only organolithium reagents, lithium thiolates, and lithium
anilides performed well. In this case, the high basicity of those
reagents considerably limits the functional group tolerance.
Considering those issues, we decided to explore a milder and
more versatile alternative that would not only solve the
concerns raised but also extend the scope in terms of
nucleophiles, thus allowing the possibility to prepare more
functionalized β-substituted monofluoroalkenes.
ces due to the unique properties of the fluorine atom.1 It is,
therefore, not surprising that considerable effort has been
dedicated to the discovery and improvement of methods for the
preparation of fluorinated compounds.2 Over the past years, we
have been particularly interested in the synthesis of
monofluoroalkenes,3 a useful enol or amide mimic, from 3,3-
difluoropropenes4 using either transition-metal-catalyzed
(Scheme 1, eq 1)5,6 or metal-free (Scheme 1, eq 2)7,8 reactions.
All of these approaches relied on using one of the fluorine
atoms as a leaving group, even though it is generally considered
a poor one.1,9 While these methods provide a convenient access
To this end, we sought to exploit the difference in leaving
group ability between a fluorine and a chlorine in geminal
relationship,1b,10 a phenomenon that has been rarely taken
advantage of.11−19 Herein, we report a convenient approach to
β-substituted monofluoroalkenes from gem-chlorofluoropro-
penes exploiting this difference in nucleofuge character
(Scheme 1, eq 3).20 Notably, this transformation provides
structurally diverse monofluoroalkenes and is compatible with a
wide range of milder nucleophiles, some of which could not be
employed using previous methods.
Scheme 1. Previous Work and Current Work
The reactivity was initially investigated using chlorofluor-
opropene 1, which was easily obtained from 1-tetralone in three
steps (α-fluorination using Selectfluor, α-chlorination using N-
chlorosuccinimide, and Peterson olefination),21 and morpho-
line as the nucleophile. After some optimization, it was found
that the desired β-aminomonofluoroalkene 2a could be
obtained in 96% isolated yield (Scheme 2). This result
compared favorably with the 72% and 68% yields achieved in
the Pd- and Pt-catalyzed transformations, respectively (i.e.,
Scheme 1, eq 1).5a,6
Delighted with this initial result, we began exploring the use
of other nucleophiles and found that a variety could be
employed successfully upon slight modifications of reaction
Received: March 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00590
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nucleophile to provide the β-iodomonofluoroalkene 2i in good
NMR yield (Table 1, entry 8). While the isolation of the
product did not prove possible, its clean formation, as shown by
NMR, provided an opportunity to use it as an intermediate to
promote substitution with reluctant nucleophiles (Scheme 3).
Scheme 2. Synthesis and Reactivity of Chlorofluoropropene
1 with Morpholine
Scheme 3. Reaction of 1 with (a) N-Methylaniline and (b)
Sodium Acetate in the Presence of a Catalytic Amount of
Iodide
conditions (Table 1). For instance, the use of sodium phenolate
provided the monofluoroalkene 2b in 80% yield (Table 1, entry
Table 1. Reactivity of Chlorofluoropropene 1 with Various
a
Nucleophiles
Indeed, using either N-methylaniline or sodium acetate in the
presence of a catalytic amount of tetrabutylammonium iodide
(TBAI) provided the desired monofluoroalkenes 2j and 2k in
91% and 86% yield, respectively, thus further expanding the
scope to carboxylates and aromatic amines as suitable
nucleophiles for this transformation.
yield
entry
2, Nu
2b, OPh
2c, SPh
conditions
(%)
The reactivity of analogues of successful N-, S-, O-, and C-
nucleophiles was next assessed (Scheme 4). Functionalized
secondary amines such as L-proline methyl ester and 2-
(methylamino)ethanol reacted well with 1 and provided the
desired products 2l and 2m in 85% and 64% yield, respectively.
Notably, in the latter case, protection of the alcohol was not
necessary. An excellent yield of 2n was obtained with n-
butylamine (a primary amine) from 1 as long as an excess of
the nucleophile was used to avoid a mixture of mono- and
dialkylated products. Interestingly, L-cysteine methyl ester
reacted with 1 and provided the S-alkylation product 2o in
70% yield without any need for the protection of the nitrogen.
Using estrone as a source of a functionalized phenolate
provided product 2p in 78% yield. Other chlorofluoropropenes
could also be utilized. For instance, the chlorofluoropropene
derived from 1-indanone 4 reacted with an aliphatic amine, N-
methylbenzylamine, to provide monofluoroalkene 9 in 78%
yield. Similarly, when the chlorofluoropropene obtained from
4-chromanone 6 was used, reaction with indoline, an aromatic
amine, afforded monofluoroalkene 10 in 61% yield. In addition,
monofluoroalkene 11 was isolated in 61% yield after exposure
of the chlorofluoropropene prepared from 4,4-dimethyl-2-
cyclohexen-1-one (6) to sodium thiophenolate. Finally, acyclic
chlorofluoropropenes could also be used, as exemplified by the
transformations of chlorofluoropropenes 7 and 8 into
monofluoroalkenes 12a,b and 13a,b, respectively, which were
obtained in good to excellent yields as a mixture of
diastereoisomers. Interestingly, when 7 was used with either
morpholine 12a or sodium thiophenolate 12b as the
nucleophile, the E/Z selectivity could be modestly modulated
by changing the solvent. In both cases, the use of DMF, a more
polar solvent, favored the E-isomer as the major one, while the
use of a less polar solvent (i.e., toluene or THF) produced the
opposite Z-isomer as the major isomer.24,25 The reason behind
the change in selectivity is not clear at the moment, and further
studies to understand this are in progress.
1
2
3
4
5
6
7
NaOPh, THF, 70 °C, 72 h
NaSPh, THF, rt, 1 h
80
97
90
84
96
82
95
2d, S(CH2)9CH3 NaS(CH2)9CH3, THF, rt, 1 h
2e, SAc
2f, CN
KSAc, THF, 70 °C, 18 h
KCN, DMF, rt, 24 h
2g, CH(CO2Me)2 NaCH(CO2Me)2, CH3CN 70 °C, 18 h
2h, Ph
PhMgBr, CuBr·SMe2, THF, 50 °C,
18 h
b
8
2i, I
NaI, acetone, 60 °C, 18 h
74
a
See the Supporting Information for the detailed experimental
procedures. NMR yield estimated using 2-fluoro-4-nitrotoluene as
b
the internal standard.
1). Notably, a phenolic nucleophile did not work with 3,3-
difluoropropenes (i.e., Scheme 1, eq 2),8 where an elimination
side reaction was predominant. Sulfur-based nucleophiles, such
as an alkyl- and an arylthiolate, as well as a thiocarboxylate, all
behaved nicely (Table 1, entries 2−4), and the desired products
2c−e could be obtained in very good to excellent yields.22 The
use of cyanide (Table 1, entry 5) as the nucleophile provided
the β-cyanomonofluoroalkene 2f in 96% yield. Interestingly, the
nitrile functionality opens the door to further transformations
(vide infra). Dimethyl malonate reacted well, and the
monofluoroalkene 2g was produced in 82% yield (Table 1,
entry 6). Phenyl cuprate (generated in situ from the
corresponding Grignard reagent and copper(I) bromide
dimethyl sulfide complex)23 was a suitable nucleophile, and
the monofluoroalkene 2h was obtained in 95% yield, which
compares favorably with the 80% obtained using highly basic
phenyllithium with a 3,3-difluoropropene (i.e., Scheme 1, eq
2).7 At that point, despite extensive optimization, the use of
either sodium methoxide (an alkoxide), sodium acetate (a
carboxylate), or N-methylaniline (an aromatic amine) did not
provide the desired product in satisfactory yields (not shown in
Table 1). Finally, iodide could be used successfully as a
B
DOI: 10.1021/acs.orglett.6b00590
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Letter
a,b
Scheme 4. Reaction of Cyclic and Acylic Chlorofluoropropenes with Various N-, S-, O-, and C-Nucleophiles
a
b
c
d
See the Supporting Information for the detailed experimental procedures. Isolated yield. 5 equiv of the nucleophile was used. 10 equiv of the
e
nucleophile was used. Isolated as a mixture of stereoisomers; E/Z ratio estimated by H or 19F NMR.
1
Finally, to further extend the utility of this new approach, we
investigated potential transformations of the monofluoroal-
kenes generated (Scheme 5). For instance, reduction of the
thioester moiety of 2c with LiAlH4 provided an excellent yield
of β-mercaptomonofluoroalkene 14.22 Hydrolysis of nitrile 2f
under basic conditions gave acid 15 in 74% yield. As
monofluoroalkenes can be seen as amide mimics,3 this
particular product resembles an amide bond between a glycine
and an N-substituted amino acid. Likewise, a two-step
decarboalkoxylation25/hydrolysis sequence of malonate 2g
provided acid 16, which in this case, corresponds to an amide
bond between a β-glycine and an N-substituted amino acid.
Finally, deprotection of the acetate of 2k through methanolysis
led to the alcohol 17,22c,26 which could be methylated to
provide methyl ether 18. Thus, even if, at this time, preparation
of 18 directly from 1 using methoxide as the nucleophile is not
possible, this short and high-yielding three-step procedure
provides an alternative route to β-alkyloxymonofluoroalkenes.
In conclusion, we have reported the preparation of β-
substituted monofluorolalkenes through allylic substitution of
gem-chlorofluoropropenes. This strategy relies on the difference
in leaving group ability between chlorine and fluorine atoms
bonded to the same carbon atom. As neither a transition metal
nor a highly basic nucleophile is required in this reaction, a
broader range of nucleophiles was shown to be compatible as
compared to our previous work. Overall, this new approach
allows the preparation of structurally diverse monofluoroal-
Scheme 5. Synthetic Transformation of Some
Monofluoroalkenes Obtained
C
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Organic Letters
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(12) For the preparation of fluoroallenes from a fluorochloropro-
pargyl moiety, see: Castelhano, A. L.; Krantz, A. J. Am. Chem. Soc.
1987, 109, 3491.
kenes, potentially useful fluorinated building blocks for
medicinal chemistry efforts, in good to excellent yields.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00590.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
Crystallographic data of (E)-12a·HCl (CIF)
(16) For the nickel-catalyzed Negishi cross-coupling using a α-
chloro-α-fluoroketone, see: Liang, Y.; Fu, G. C. J. Am. Chem. Soc. 2014,
136, 5520.
(17) For the nickel-catalyzed Suzuki cross-coupling using 1-chloro-1-
fluoroalkanes, see: (a) Jiang, X.; Sakthivel, S.; Kulbitski, K.; Nisnevich,
G.; Gandelman, M. J. Am. Chem. Soc. 2014, 136, 9548. (b) Jiang, X.;
Gandelman, M. J. Am. Chem. Soc. 2015, 137, 2542.
(18) For the preparation of 2-fluorophenols from in situ generated α-
chloro-α-fluoroketones using a selective elimination, see: Yasui, N.;
Mayne, C. G.; Katzenellenbogen, J. A. Org. Lett. 2015, 17, 5540.
(19) For an application in 18F-labeling, see: Verhoog, S.; Pfeifer, L.;
Khotavivattana, T.; Calderwood, S.; Collier, T. L.; Wheelhouse, K.;
Tredwell, M.; Gouverneur, V. Synlett 2015, 27, 25.
(20) To the best of our knowledge, only one example of such a
reaction with highly basic nucleophiles has been reported before;
however, a mixture of substitution products resulting from the
departure of either the fluoride or the chloride was observed; see ref 7.
for details.
(21) All of the chlorofluoropropenes were prepared following the
same sequence. See the Supporting Information for more details.
(22) (a) McDonald, I. A.; Bey, P. Tetrahedron Lett. 1985, 26, 3807.
(b) Pirrung, M. C.; Rowley, E. G.; Holmes, C. P. J. Org. Chem. 1993,
58, 5683. (c) Song, Y.; Clizbe, L.; Bhakta, C.; Teng, W.; Li, W.; Wu,
Y.; Jia, Z. J.; Zhang, P.; Wang, L.; Doughan, B.; Su, T.; Kanter, J.;
Woolfrey, J.; Wong, P.; Huang, B.; Tran, K.; Sinha, U.; Park, G.; Reed,
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AUTHOR INFORMATION
■
Corresponding Author
* E-mail: jean-francois.paquin@chm.ulaval.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the
FRQNT Centre in Green Chemistry and Catalysis (CCVC),
the FRQNT Network for Research on Protein Function,
Engineering, and Applications (PROTEO), and the Universite
Laval. J.D.H. thanks NSERC for a Vanier Canada Graduate
Scholarship.
́
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DOI: 10.1021/acs.orglett.6b00590
Org. Lett. XXXX, XXX, XXX−XXX