Alkyltriflones in the Ramberg-B?cklund Reaction: An Efficient and Modular Synthesis of gem-Difluoroalkenes

Article abstract of DOI:10.1021/jacs.0c07924

The unprecedented synthesis of gem-difluoroalkenes through the Ramberg-B?cklund reaction of alkyl triflones is described herein. Structurally diverse, fully substituted gem-difluoroalkenes that are difficult to prepare by other methods can be easily prepared from readily available triflones by treatment with specific Grignard reagents. Experimental and computational studies provide insight into the unique and critical role of the Grignard reagent, which serves both as a base to remove the α-proton and as a Lewis acid to assist C-F bond activation.

Full text of DOI:10.1021/jacs.0c07924

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Communication
Alkyltriflones in the Ramberg–Bäcklund Reaction: An
Efficient and Modular Synthesis of gem-Difluoroalkenes
Yuuki Maekawa, Masakazu Nambo, Daisuke Yokogawa, and Cathleen M. Crudden
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07924 • Publication Date (Web): 16 Aug 2020
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Alkyltriflones in the Ramberg–Bäcklund Reaction: An Efficient and
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Yuuki Maekawa†,‡, Masakazu Nambo*,‡, Daisuke Yokogawa§, Cathleen M. Crudden*,†,‡
†Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, Ontario, Canada.
‡Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, Japan
§Graduate School of Arts and Science, The University of Tokyo, Komaba, Meguro-ku, Tokyo, Japan
ABSTRACT: The unprecedented synthesis of gem-difluoroalkenes through the Ramberg–Bäcklund reaction of alkyl triflones is
described herein. Structurally diverse, fully-substituted gem-difluoroalkenes that are difficult to prepare by other methods can be
easily prepared from readily available triflones by treatment with specific Grignard reagents. Experimental and computational studies
provide insight into the unique and critical role of Grignard reagent, which serves both as a base to remove the -proton, and as a
Lewis acid to assist C–F bond activation.
The Ramberg–Bäcklund reaction is a textbook method for
the preparation of functionalized alkenes from readily available
-halogenated alkylsulfones.1,2 It has been applied to the
synthesis of numerous natural products and biomolecules.3 The
SO2 group serves two purposes: first to increase the acidity of
the adjacent proton, enabling the deprotonation and subsequent
intramolecular SN2 reaction generating a strained episulfone;
and second, as a chelotropic leaving group to generate the
desired alkene (Scheme 1a). Despite the importance of this
reaction and of fluorinated compounds, fluorinated
alkylsulfones have not been employed, likely due to the low
leaving ability of fluoride.
(entries 7 and 8). We chose cyclohexyl magnesium bromide
(CyMgBr) as the optimal promoter for further optimization due
to its efficiency and commercially availability.
Scheme 1. Ramberg–Bäcklund Reaction
With triflones and related sulfones gaining increased
interest for their application in cross-coupling chemistry
(Scheme 1b),4,5 we decided to examine their applicability in a
Ramberg–Bäcklund-type synthesis of gem-difluoroalkenes,
since these compounds have attracted considerable attention in
the area of medicinal chemistry.6,7 Hu and co-workers have
described the versatile synthesis of fully substituted gem-
difluoroalkenes from diazo compounds,6b but there is still need
for straightforward and modular routes to dialkyl gem-
difluoroalkenes. Herein we report the first example of the use of
alkyltriflones in the Ramberg–Bäcklund reaction, providing
ready access to gem-difluoroalkenes (Scheme 1c). Combined
with the ease of the preparation of sec-alkyltriflones through -
alkylation, this protocol allows for rapid synthesis of gem-
difluoroalkenes in a modular manner. Notably, the use of
organomagnesium compounds is critical to the success of the
transformation, playing the dual roles of base and activator of
the C–F bond.
Carrying out reactions at lower temperatures or with only 1
equivalent of CyMgBr gave lower yields (entries 9 and 10).
Finally, increasing the reaction concentration to 0.3 M gave
higher conversion, and 2a was isolated in 81% yield (entry 11).
Remarkably, the bases typically employed in the Ramberg–
Bäcklund reaction were completely inactive (entries 12-15),
indicating that magnesium cation is critically important for
transformation of the alkyltriflone into the desired
difluoroalkene.
We began our study by examining the reactivity of sec-alkyl
triflone 1a with a variety of bases and organometallic reagents
(Table 1). To our delight, the desired gem-difluoroalkene 2a
was obtained in 60% yield when 2 equivalents of i-propyl
magnesium bromide (iPrMgBr) were used (entry 1). By
screening of a series of alkyl magnesium reagents, we found that
cyclohexyl magnesium reagents were particularly effective,
affording the desired product 2a in the high yield (entries 2-6).
While other alkyl magnesium reagents were effective,
magnesium ethoxide and amide were significantly less reactive
Table 1. Optimization of Reaction Conditionsa
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Entry
1
Promoter
iPrMgBr
MeMgBr
CyMgBr
tBuMgBr
PhMgBr
Cy2Mg
Yield (%)b
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6 c
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Mg(OEt)2
(TMP)2Mg2LiCl
CyMgBr
CyMgBr
CyMgBr
nBuLi
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9 d
10 e
11 f
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87 (81)g
5
0
0
0
tBuONa
tBuOK
Et2Zn
a Conditions: 1a (0.1 mmol), promoter (2.0 equiv), THF (0.1 M).
b
1
Yield was determined by H NMR using 1,3,5-trimethoxy
benzene as an internal standard. c1 equivalent of Cy2Mg.
d
e
Reaction temperature: 50 ºC. 1 equivalent of CyMgBr was
used. f Concentration: 0.3 M. g Isolated yield (1 mmol scale).
With optimized conditions in hand, we next investigated the
scope of alkyltriflones (Table 2). Triflones bearing 2-naphthyl
(1b) and 2-theinyl (1c) groups were converted to the
corresponding difluoroalkenes in reasonable yields (2b, 2c). A
variety of useful functional groups such as chlorine, alkenyl,
alkynyl, acetal, siloxy, and amino groups were tolerated,
providing the corresponding products in moderate to good
yields (2d-2i). Sterically hindered substituents were also
tolerated, giving 2j in high yield. Moreover, this reaction can be
used to install two gem-difluoroalkenyl units starting from a bis
sulfone with excess CyMgBr (2k).
a Conditions: 1 (0.2 mmol), CyMgBr (2.0 equiv), THF (0.3 M),
80 ºC, 16 h. b EtMgBr (2.0 equiv) was used instead of CyMgBr.
Ar = 4-tBuC6H4
Benzylic triflones having trifluoromethyl (1m) or phenoxy
(1n) groups on the aryl ring showed high reactivities. Although
bulky benzyl triflone (1o) was less reactive, the use of EtMgBr
instead of CyMgBr was found to be a good solution to afford
the corresponding product. Heteroaryl groups such as quinoline
(1p) and indole (1q) were compatible, and 1,2,34-tetrahydro-1-
naphthyltriflone (1r) also reacted smoothly. Interestingly,
conjugated difluoroalkene products (2s, 2t) were also obtained
under standard condition, albeit in low yields.8
Scheme 2. Reaction of Perfluoroalkyl Sulfones
The present reaction is applicable not only to triflones but
also to perfluoroalkylsulfones (Scheme 2). When
pentafluoroethyl- or nonafluorobutyl sulfones (1u, 1v) were
reacted under optimized conditions, the corresponding
polyfluorinated alkenes (2u, 2v) were obtained, which are
challenging to prepare by conventional methods.7a
Next, the utility of this method was demonstrated through
the synthesis of a variety of more complex fluorinated structures
(Scheme 3). The gem-difluoroalkenes generated from this
method underwent a series of transformations (Scheme 3A). For
example, hydrogenation of 2a by Pd/C gave difluoroalkane 3 in
high yield. Compound 2a was also converted into
tetrafluorocyclopropane 4 by treatment with TMSCF3 and
sodium iodide.9 Fluoro-hydroxylation of 2n proceeded to give
fluorinated tertiary alcohol 5.10 Interestingly, photoredox-
catalyzed coupling of 2n with N,N-dimethylaniline led to the
Table 2. Synthesis of gem-Difluoroalkenesa
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formation of tetrasubstituted monofluoroalkene 6 in good
(Scheme 4B). This result indicates that the Mg cation is
essential in the SN2 step rather than the deprotonation.
yield.11
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7
When the reaction of 1a was monitored by 19F NMR
spectroscopy, signals corresponding to 1a and product 2a were
mainly observed, suggesting that the episulfone intermediate is
rapidly converted to 2a. A signal corresponding to a Mg–F
species was also detected at -189 ppm (see supporting
information).14
Scheme 3. Synthetic Applications
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Scheme 4. Mechanistic Studies
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aReaction conditions: (a) H2, Pd/C, MeOH, 50 ºC. (b) TMSCF3,
NaI, THF, 80 ºC. (c) Selectfluor, H2O, MeOH, 40 ºC. (d)
Ir[dFCF3ppy]2dtbpyPF6, Na2CO3, blueLED, DMF, r.t. (e)
LiHMDS, MeI, THF, -78 ºC to r.t. (f) CyMgBr, THF, 80 ºC. (g)
TBAF, THF, 0 ºC.
Possible reaction pathways were also evaluated by
theoretical calculations for the model reaction of iPrSO2CF3 10
i
with PrMgBr(THF)2. All structures were optimized using
The 1,1-difluoralkene moiety is also employed as a
bioisostere of the carbonyl group.12 Thus, we applied our
method to the synthesis of fluorinated analogue (7-F) of
Zingerone 7, which is responsible for the strong odor in dried
ginger root, and has multiple different biological activities
including for hepatic inflammation, irritable bowel syndrome
and is an antioxidant (Scheme 3B).13 The alkyltriflone 8, which
was readily prepared from inexpensive Eugenol, was converted
into sec-alkyl triflone 9 through -methylation. Subsequently,
subjecting 9 to optimized reaction conditions afforded 7-F after
deprotection of the TBS group in 7 total steps from Eugenol.
These results illustrate how sequential functionalizations
starting from readily available substrates can be useful for the
further derivatization of fluorinated biomolecules.
B3LYP/6-31+G(d) at 353.15 K, and Gibbs free energies were
calculated using SCSMP2 with PCM solvation modeling
(THF). In the SCSMP2 calculations, we employed the cc-pVDZ
basis set for H, C, Mg, and S atoms, and the aug-cc-pVDZ basis
set for other atoms. The energy profile is summarized in Figure
1.
i
-Deprotonation of 10 with PrMgBr(THF)2 was found to
be exothermic, generating a enolate-like C-bound or O-bound
magnesium species (11, and 16).15 The subsequent episulfone
formation should undergo C–C bond formation along with
elimination of fluoride anion. Considering the significant effect
of magnesium cations on the reaction, the formation of a strong
Mg–F bond is a likely driving force to promote this step. Thus,
transition states were calculated after dissociation of one THF
molecule from the Mg center to generate a vacant coordination
site (12, and 17). A concerted reaction from 12 involving a
strained 4-membered cyclic transition state (TS12–13) was
examined, but with a calculated Gibbs free energy of activation
(Go‡Mg-C) of 46.3 kcal/mol, this is not likely to be a reasonable
pathway.
Control experiments were carried out to gain mechanistic
insight into the reaction (Scheme 4). When the reaction was
conducted in the presence of two different triflones 1a and 1v
under standard conditions, the corresponding products 2a and
2v were obtained without the formation of crossover products
(Scheme 4A). This clearly shows that this reaction proceeds via
intramolecular pathway as would be expected for a typical
Ramberg–Bäcklund reaction. As shown in Table 1, strong bases
such as n-BuLi were not effective activators for this reaction,
however, -deprotonation of 1a with n-BuLi followed by the
addition of MgI2 was effective, giving product 2a in 60% yield
On the other hand, 17 could reach the episulfone through an
SN2 reaction, which is predicted to have a much more
reasonable activation energy (Go‡Mg-O, 24.2 kcal/mol). Notably,
in the transition state TS17–14 from 17, the Mg cation interacts
with the departing fluoride, enabling a rare SN2 reaction with
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fluoride as the leaving group.16 The final SO2 elimination
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1
(complexed to
2
3
Figure 1. Energy profile for Ramberg–Bäcklund reaction of iPrSO2CF3 10 with iPrMgBr(THF)2 or MeLi(THF)3.
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magnesium) was thermodynamically downhill, forming gem-
difluoro alkene 15 spontaneously. These results clearly indicate
that episulfone formation is rate-limiting, which is supported by
the fact that no any intermediates were observed by 19F NMR
spectroscopy.
To compare the effect of the nature of the cation, the
reaction pathway using MeLi(THF)3 was also calculated. A
AUTHOR INFORMATION
similar transition state structure was obtained (TS19–20), but the
predicted activation energy (Go‡Li-O) was higher than that for
Mg (30.4 kcal/mol). This is primarily due to the generation of a
stabilized lithiated sulfone intermediate (19), which is
consistent with our experimental results. These theoretical
calculations support the importance of the counter cation, which
has not received much attention in the Ramberg–Bäcklund
reaction.
Corresponding Author
*E-mail: mnambo@itbm.nagoya-u.ac.jp
*E-mail: cruddenc@chem.queensu.ca
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
In conclusion, we have established a new synthetic route to
gem-difluoroalkenes through the reaction of alkyltriflones with
Grignard reagents. This synthetic strategy can provide a rapid
access to fluorinated compounds in a modular manner. In
addition, mechanistic studies supported by control experiments
and theoretical calculations provide important insight into the
involvement of Grignard reagents, which are shown to act in
both deprotonation of substrate and complexation of fluoride
leaving groups, enabling the unusual use of fluoride as the
leaving group. This observation of the effect of counterion on
the reaction will hopefully spur other reactions of
organofluorine compounds.
We acknowledge the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the Canada Foundation for
Innovation (CFI) for funding of the work from her lab described in
this article. Y.M. is a recipient of a JSPS postdoctoral fellowship
(No.19J01814). This work was supported by KAKENHI from
JSPS (26810056 to M.N.). JSPS and NU are acknowledged for
funding of this research through the World Premier International
Research Center Initiative (WPI) program.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and NMR spectra (PDF)
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metal species: (a) Amii, H.; Uneyama, K., C–F Bond Activation in
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Matsubara, K.; Ishibashi, T.; Koga, Y., C−F Bond-Cleavage
Reactions of Fluoroalkanes with Magnesium Reagents and without
R2
Modular synthesis of functionalized
gem-difluoroalkenes
O O
S
CyMgBr
HF SO
R2
R1
F
F
F
R1
Synthesis of fluorinated biomolecules
-
,
2
H
F
F
(R1, R2 = alkyl, aryl)
23 examples
up tp 97%
Dual role of Grignard reagent
based on mechanistic studies
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