Stereoselective Ring-Opening of gem-Difluorocyclopropanes: An Entry to Stereo-defined (E,E)- and (E,Z)-Conjugated Fluorodienes

Article abstract of DOI:10.1002/chem.201704956

The ring-opening of gem-difluorocyclopropyl acetaldehydes producing selectively (E,E)- and (E,Z)-conjugated fluorodienals is described. Two stereo-divergent methods are presented to access both stereoisomers from a common precursor, in high yield and selectivity. The mechanistic aspect of these transformations is discussed.

Full text of DOI:10.1002/chem.201704956

DOI: 10.1002/chem.201704956
Communication
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Stereoselective Ring-Opening of gem-Difluorocyclopropanes: An
Entry to Stereo-defined (E,E)- and (E,Z)-Conjugated Fluorodienes
Simon Specklin, Johan Fenneteau, Parthasarathi Subramanian, and Janine Cossy*[a]
Abstract: The ring-opening of gem-difluorocyclopropyl
acetaldehydes producing selectively (E,E)- and (E,Z)-conju-
gated fluorodienals is described. Two stereo-divergent
methods are presented to access both stereoisomers from
a common precursor, in high yield and selectivity. The
mechanistic aspect of these transformations is discussed.
Incorporation of fluorine or fluorine-containing functional
groups can modify the physicochemical properties of parent
molecules.[1] Among fluorinated compounds, fluoro-olefins
have been recognized as efficient mimics of amide bond due
to their similarities in respect to steric and electronic proper-
ties.[2] In particular, fluorodienes are a class of molecules under-
represented in the chemical space as only few methods are
available for their selective preparation.
The Wittig reaction was first applied to the synthesis of sev-
eral fluorinated dienes,[3] the related Horner–Wadsworth–
Emmons (HWE) reaction as well as the Julia olefination also
proved to be suitable for this purpose [Scheme 1, Eq. (1)].[4]
However, the yields are generally modest and the products are
typically obtained with moderate to good (E,E)/(E,Z) selectivity.
Nonetheless, the olefination approach has found applications
to prepare fluoro-olefins,[5] or fluorodienes such as fluoro-reti-
nal.[6] In addition, fluorinated phosphonates could be used to
Scheme 1. Synthesis of fluorodienes.
construct mono- or difluorinated conjugated dienes.[7] Another
approach relies on palladium-catalyzed cross-coupling of 1,1-
bromo-fluoro-olefins and electron-deficient olefins,[8a–c] boronic
acids,[8d,e] or organostannanes,[8e] but the tedious preparation
and the stereochemical purity of the starting 1,1-bromofluoro-
The same type of reactivity has also been encountered with 1-
silyloxy-2,2-difluorocyclopropanes [Scheme 1, Eq. (3)].[13] The
weakness of this distal C1ÀC3 bond has been recently exploit-
ed under Pd and Ni catalysis to form fluoro-olefins.[14] Finally,
thermal pyrolysis of 2,2-difluorocyclopropanes has also been
documented to produce fluorinated heterocycles.[15] Consider-
ing conjugated systems, Schlosser and co-workers showed that
a-iodo and a-trimethylsilyl 2-chloro-2-fluorocyclopropanes can
be transformed to fluorodienes by cleavage of the distal C1À
C3 bond, when treated with activated zinc or with a fluoride
source [Scheme 1, Eq. (4)].[16] Furthermore, a report from Ko-
bayashi and co-workers indicates that gem-difluorocyclopro-
panes bearing an electron-withdrawing group (-CO2Me, -CN,
-SO2Ph) in the a-position were converted to the corresponding
fluorodienes when treated with a strong base (lithium diiso-
propylamide (LDA), THF, À788C) [Scheme 1, Eq. (5)].[17] Howev-
er, these fluorodienes were obtained in modest yields and with
olefins remains
Eq. (2)].[8,9]
a limitation of this method [Scheme 1,
Difluorocyclopropanes have been recognized as possible en-
tries to fluoro-olefins as cleavage of the distal C1ÀC3 bond of
2,2-difluorocyclopropanes is easier than of the parent cyclopro-
panes,[10] which has been intensively studied by Dolbier et al.
and Borden et al.[11] For example, solvolysis of 1-acetoxy-2,2-di-
fluorocyclopropanes led to fluoro-olefins or fluorodienes.[12]
[a] Dr. S. Specklin, Dr. J. Fenneteau, Dr. P. Subramanian, Prof. Dr. J. Cossy
Institute of Chemistry, Biology and Innovation (CBI)
ESPCI Paris/CNRS (UMR8231), PSL Research University
10 rue Vauquelin, 75231 Paris Cedex 05 (France)
E-mail: janine.cossy@espci.fr
Supporting information and the ORCID identification numbers for the
authors of this article can be found under https://doi.org/10.1002/
chem.201704956.
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variable (E,E)/(E,Z) selectivities depending on the nature of the
electron-withdrawing group.
Table 1. Optimization for the selective formation of (E,E)-fluorodienals 6a
(conditions A).
Despite the elegance of this process and the interest of the
obtained products, no further latter synthetic studies were de-
scribed since this pioneering work. Starting from this observa-
tion, we were wondering if such process would be applicable
to mildly enolizable functions and if the C1ÀC3 bond cleavage
of the difluorocyclopropane would be selective. Herein, we de-
scribe the selective ring-opening of difluorocyclopropyl acetal-
dehydes to selectively access the corresponding (E,E)- and
(E,Z)-fluorodienals.
Entry
Base (equiv)
Solvent
Yield [%][a]
6a/7a[b]
1
2
3
4
5
6
7
8
K2CO3 (2)
KOH (2)
NaH (2)
MeOH
MeOH/H2O
THF
61
36
65
84
60
92
47
89
92
93
80
77
95:5
88:12
90:10
93:7
90:10
89:11
21:79
94:6
93:7
96:4
93:7
91:9
We first focused on the preparation of the difluorocyclo-
propyl acetaldehydes 5a–o (Scheme 2). A Wittig reaction using
(2-carboxyethyl)triphenylphosphonium bromide, applied to ar-
omatic aldehydes 1a–o, followed by a Fischer esterification
(H2SO4 in MeOH) gave the corresponding methyl but-3-enoates
Et3N (2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
iPr2NEt (2)
iPr2NH (2)
piperidine (2)
DABCO (2)
DBU (2)
TMG (2)
TMG (2)
TMG (2)
TMG (1.2)
9
10
11
12
13
THF
CH2Cl2
95 (91)[c]
96:4
[a] Yields were determined by 1H NMR spectroscopy using hexamethyl-
benzene as internal standard. [b] 6a/7a ratio was measured by analysis
of 1H NMR spectrum of the crude reaction mixture. [c] Isolated yield.
DABCO=1,4-diazabicyclo[2.2.2]octane.
ene. TMG=1,1,3,3-tetramethyl-guanidine.
DBU=1,8-diazabicycloundec-7-
Scheme 2. Synthesis of difluorocyclopropyl acetaldehydes 5a–o.
During the screening of the bases, we noticed an inversion
of the stereoselectivity in favor of the (E,Z)-isomer 7a when pi-
peridine was used (Table 1, entry 7). Motivated by this interest-
ing result, we aimed to develop a second set of conditions
leading selectively to the (E,Z)-isomer. As we suspected that an
enamine intermediate was inducing the cyclopropane ring-
opening, several secondary amines were screened in protic
media to enhance the aldehyde/enamine equilibrium
(Table 2).[20]
3a–o as a single (E)-isomer after purification on silica gel.[18]
Treatment of the non-conjugated butenoates 3a–o with the
difluorocarbene, generated in situ by thermal pyrolysis of
sodium chlorodifluoroacetate (diglyme, 1668C),[19] led to the
corresponding gem-difluorocyclopropanes 4a–o. A controlled
reduction of the methyl esters to the corresponding aldehydes
(DIBAL-H, CH2Cl2, À788C) produced the desired trans-difluoro-
cyclopropyl acetaldehydes 5a–o (Scheme 2).
The fragmentation of the difluorocyclopropane ring of di-
fluorocyclopropyl acetaldehydes was evaluated in the presence
of different bases, using 5a as a model substrate (Table 1). To
our delight, treatment of 5a with inorganic bases, such as
K2CO3, KOH, NaH, induced the expected C1ÀC3 bond cleavage
leading to the corresponding fluorodienals 6a and 7a in
modest yields (36–65%) but with a good stereoselectivity of
88:12 to 95:15 in favor of the (E,E)-isomer 6a (Table 1, en-
tries 1–3). Substantial improvement in yield and selectivity was
observed when organic bases were used in CH2Cl2 (Table 1, en-
tries 4–8). Strong and non-nucleophilic bases such as amidine
(DBU) or guanidine (TMG) gave the best results in terms of
yield and selectivity (Table 1, entries 9 and 10). Yield in 6a de-
creases in PhMe and THF compared to the one obtained in
CH2Cl2 (Table 1, entry 10 vs. 11, 12). It is worth noting that the
amount of base can be lowered to 1.2 equivalents without af-
fecting the reaction as 6a was isolated in 91% with an excel-
lent (E,E)/(E,Z) ratio of 96:4 (Table 1, entry 13). Thus, the best
conditions for the selective formation of (E,E)-fluorodienal 6a
were identified: TMG (1.2 equiv) in CH2Cl2 (conditions A).
When 5a was treated with a catalytic amount of piperidine
in aqueous CH3CN, the expected C1ÀC3 bond cleavage of the
2,2-difluorocyclopropane ring occurred with improved conver-
sion of 5a to 6a and 7a, slightly in favor of the stereoisomer
6a (Table 2, entry 1). We reasoned that the presence of formal-
ly generated HF in the medium would jeopardize the outcome
of the ring-opening. Gratifyingly, addition of NaHCO3 to buffer
the reaction medium afforded the desired compound 7a in
good yield and stereoselectivity (Table 2, entry 2). Other bases
such as NaOAc, imidazole and 2,6-lutidine proved to be less ef-
ficient to buffer the system (Table 2, entries 3–5). Pyridine was
identified as the best candidate, especially when used in
excess (Table 2, entries 6 and 7). Other secondary amines (pyr-
rolidine, Et2NH, l-proline) were tested under the same condi-
tions, despite the interesting selectivity, 7a was obtained with
lower yield than with piperidine (Table 2, entries 8–10). Thus,
the following conditions to access (E,Z)-fluorodienal were iden-
tified: piperidine (0.2 equiv), pyridine (3 equiv) in CH3CN/H2O
(4:1) (conditions B).
We next explored the scope of the reaction under condi-
tions A and B with various difluorocyclopropyl acetaldehydes
5a–o (Scheme 3).
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under these conditions. Aryl halides (p-F, p-Br, 5g,h), protected
phenol (p-OBn, 5i) or nitro-aryl derivatives (m-NO2, 5j) gave as
well the corresponding fluorodienes. Heteroaromatics (2-thien-
yl, 5k, 2-furyl 5l) were also tolerated. Functionalized cycloprop-
yl acetaldehyde 5m also delivered the desired corresponding
fluorodienal. However, no difluorocyclopropyl ring fragmenta-
tion was observed for aldehyde bearing an alkyl side chain (n-
pentyl), such as 5o, by using both conditions A and B.
Further experiments were carried out to understand the out-
come and the high level of stereoselectivity of the difluorocy-
clopropyl ring-opening. The cis-difluorocyclopropyl acetalde-
hyde 8 was prepared and subjected to conditions A and B. In
both cases the (E,Z)-isomer 7a was obtained as a single isomer
[Scheme 4, Eq. (1)].
Table 2. Optimization for the selective formation of (E,Z)-fluorodienals 7a
(conditions B).
Entry
HNR2 (equiv)
Base (equiv)
Yield [%][a]
6a/7a[b]
1
2
3
4
5
6
7
8
9
10
piperidine (0.2)
piperidine (0.2)
piperidine (0.2)
piperidine (0.2)
piperidine (0.2)
piperidine (0.2)
piperidine (0.2)
pyrrolidine (0.2)
Et2NH (0.2)
–
92
76
85
71
86
88
93
78
32
82
57:43
4:96
NaHCO3 (1.2)
NaOAc (1.2)
imidazole (1.2)
2,6-lutidine (1.2)
pyridine (1.2)
pyridine (3)
pyridine (3)
pyridine (3)
pyridine (3)
88:12
69:31
88:12
18:82
4:96
2:98
11:89
2:98
l-proline (0.2)
[a] Yields were determined by 1H NMR spectroscopy using hexamethyl-
benzene as internal standard. [b] 6a/7a ratio was measured by analysis
of 1H NMR spectrum of the crude reaction mixture. Reactions were per-
formed in a MeCN/H2O (4:1) mixture.
Scheme 4. Unexpected reversal of selectivity in specific cases. [a] Starting
material was recovered (87%). Isolated yields.
This interesting result suggests that the stereochemical out-
come of the reaction under conditions A and B might be dif-
ferent, as difluorocylopropyl ring-opening under conditions A
is stereospecific whereas difluorocylopropyl ring-opening using
conditions B is not. A methylketone derivative 9 was prepared
to prove the potential role of an enamine intermediate under
conditions B. Thus, when 9 was subjected to conditions A,
(E,E)-fluorodienone 10 was obtained in good yield and selectiv-
ity. On the contrary, no ring-opening was observed under con-
ditions B, as 9 was recovered nearly quantitatively (87%)
[Scheme 4, Eq. (2)]. We suspected that the formation of the
less substituted enamine intermediate formed between 9 and
piperidine, that is non-conjugated to the difluorocyclopropane
ring, could not evolved toward 11.[21]
Scheme 3. Scope of the reaction using both conditions A and B. [a] Isolated
yields; nd=not detected.
Under conditions A and B, the corresponding (E,E)- and
(E,Z)-fluorodienals were isolated in good yields and stereoselec-
tivities independently of the position of the chloride substitu-
ent on the aromatic ring (o-Cl, m-Cl, p-Cl, 5b–d). Aryl groups
substituted by electron-donating groups (p-MeO, 5e) or strong
electron-withdrawing groups (p-CF3, 5 f) are also suitable
In addition, when aldehyde 12 was treated under both con-
ditions A and B, only the (E,E)-fluorodienal 13 was obtained
[Scheme 4, Eq. (3)], suggesting that under conditions B, a two-
step process was taking place with the (E,E)-isomer 13 as a
possible intermediate. This hypothesis has been confirmed as
the pure (E,E)-isomer 6d was thermodynamically isomerized to
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the corresponding (E,Z)-isomer 7d by treatment with piperi-
dine (conditions B).[22]
dienals by cleavage of the weak distal bond of gem-difluorocy-
clopropyl acetaldehydes. The corresponding dienals were ob-
tained in high yield and stereo-selectivity. Some experimental
evidences lead us to propose that a concerted disrotatory
mechanism is responsible of the observed stereoselectivity of
the difluorocyclopropyl acetaldehydes ring-opening.
To clarify our assumptions, the difluorocylopropyl ring-open-
1
ing under conditions A and B was monitored by H NMR analy-
sis to follow the formation of intermediates and the stereo-
chemical outcome. When 5d was reacted in the presence of
TMG in CD2Cl2 (0.1m), the reaction was instantaneous, as the
(E,E)-fluorodienal 6d was quantitatively observed as a single
product within 5 min [Scheme 5, Eq. (1)]. When conditions B
were used, the same clean conversion of 5d to 6d was ob-
served but a longer reaction time was necessary (1 h), and a
smooth isomerization of 6d to 7d took place to afford, after
48 h, the corresponding (E,Z)-fluorodienal 7d as a single ste-
reoisomer (Scheme 5, Eq. 2). (see the Supporting Information
for detailed experimental data and spectra).
Acknowledgements
We thank the European Commission for financial support. MI-
CROFLUSA project received funding from the European
Union’s Horizon 2020 research and innovation programme
under grant agreement No 664823.
Conflict of interest
The authors declare no conflict of interest.
Keywords: fluorine
·
gem-difluorocyclopropanes
·
isomerization · ring opening · stereodivergent methods
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Manuscript received: October 18, 2017
Version of record online: && &&, 0000
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COMMUNICATION
&
Synthetic Methods
S. Specklin, J. Fenneteau, P. Subramanian,
J. Cossy*
&& – &&
Stereoselective Ring-Opening of gem-
Difluorocyclopropanes: An Entry to
Stereo-defined (E,E)- and (E,Z)-
Conjugated Fluorodienes
The cyclopropane ring-opening of
gem-difluorocyclopropyl acetaldehydes
producing selectively (E,E)- and (E,Z)-
conjugated fluorodienals is described.
Two stereodivergent methods are pre-
sented to access both stereoisomers in
high yield and selectivity. The mechanis-
tic aspect of these transformations is
discussed.
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Chem. Eur. J. 2017, 23, 1 – 6
www.chemeurj.org
6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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