A Unified Strategy for the Synthesis of Difluoromethyl- And Vinylfluoride-Containing Scaffolds

Article abstract of DOI:10.1021/acs.orglett.9b02887

Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.

Full text of DOI:10.1021/acs.orglett.9b02887

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Unified Strategy for the Synthesis of Difluoromethyl- and
Vinylfluoride-Containing Scaffolds
Nicolas Duchemin,† Roberto Buccafusca,† Marc Daumas,‡ Vincent Ferey,§ and Stellios Arseniyadis*,†
†Queen Mary University of London, School of Biological and Chemical Sciences, Mile End Road, London E1 4NS, United Kingdom
‡Sanofi Chimie, Route d’Avignon, 30390 Aramon, France
§Sanofi R&D, 371 rue du Professeur Blayac, 34080 Montpellier, France
S
* Supporting Information
ABSTRACT: Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds
and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic
difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical,
scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl
group, this approach provides a valuable tool for late-stage functionalization and drug development.
recently developed. Hu and co-workers, for instance, were the
or several decades now, the introduction of fluorine atoms
Fand fluorinated groups has drawn the attention of the first to introduce a tosylsulfoximine-based reagent to promote
the difluoromethylation of C-nucleophiles (I; see Figure 1),8
while Shibata and co-workers reported the sulfonium and
sulfoxinium salts II and III (Figure 1), which both displayed
high reactivity albeit moderate C/O selectivity.6,9 More
recently, Shen,7c Liu,7d and Shibata7e unveiled three new
reagents (IV, V, and VI; see Figure 1), which induced excellent
C-selectivities in the difluoromethylation of β-keto esters.
These fundamental advances were completed by a recent study
by Hu and co-workers, who generalized the use of TMSCF2Br
(VI; see Figure 1) to a larger range of C-centered
nucleophiles.7f Surprisingly, while all of these reagents have
been used to prepare quaternary difluoromethylated com-
pounds, they all failed to provide the related tertiary
derivatives. In this context, we were interested in developing
a general method that would not only allow a straightforward
access to a wide range of synthetically and biologically relevant
quaternary (Q-CHF2) and tertiary (T-CHF2) C-difluorome-
thylated scaffolds, but also their vinylfluoride (V-CHF)
analogues. As we will see, the combination of a highly C-
selective difluoromethylation with either a palladium-catalyzed
synthetic organic chemistry community1 because these func-
tional groups have a tendency to exhibit enhanced properties,
compared to their nonfluorinated counterparts; these include
greater metabolic stability, lipophilicity, membrane perme-
ability, and bioavailability.2,3 The difluoromethyl group in
particular was shown to exhibit a weak hydrogen bond
donating ability and thus act as a bioisostere to carbinols,
thiols, amides, and hydroxamic acids.4 Interestingly, although
fluorination and perfluoroalkylation reactions have now
reached a certain maturity, the development of an efficient
and reliable difluoromethylation reaction to access tertiary
difluoromethylated compounds still remains a challenge.5
Indeed, several limitations such as the choice of the
difluoromethylating agent, its regioselectivity, its rather limited
substrate scope and the stability of the difluoromethylated
products themselves still preclude the use of this reaction as a
reliable synthetic tool.6 While significant progress has recently
been made to access quaternary difluoromethylated com-
pounds through electrophilic C-selective difluoromethylation
processes by Mikami,7a Kappe,7b Shen,7c Liu,7d Shibata,7e and
Hu7f (see Figure 1), examples of methods affording tertiary
difluoromethylated derivatives are still rather scarce. In this
context, several effective difluoromethylating agents have been
Received: August 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02887
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a
Table 1. Systematic Study
b
entry
base (equiv)
I (equiv) solvent
temperature
yield (%)
1
2
3
4
5
6
7
8
9
Et3N (2.1)
DBU (2.6)
NaH (2.1)
LiHMDS (2.1)
KHMDS (2.1)
t-BuOK (2.1)
t-BuOK (1.1)
t-BuOK (2.1)
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
DCM
DCM
THF
THF
THF
THF
THF
THF
THF
THF
DCM
−78 °C to rt
−78 °C to rt
−78 °C to rt
−78 °C to rt
−78 °C to rt
−78 °C to rt
0 °C
0 °C
0 °C
0 °C
−40 °C
trace
trace
34
56
52
66
36
66
10
c
t-BuOK (2.1)
t-BuOK (2.1)
t-BuOK (2.1)
10
11
69
81
d
a
All reactions were performed on a 0.1 mmol scale during 24 h. I is
b
added after stirring 1 with the base for 30 min. Yield determined by
c
1H NMR, using dibromomethane as an internal standard. Reaction
d
performed using 2.1 equiv of 18-crown-6. Reaction completed after
12 h.
being the best conditions (see Table 1, entry 8). A drastic loss
in reactivity was observed when the “naked” enolate was
engaged. Indeed, in the presence of 18-crown-6, the yield
decreased from 66% to 10%, although 1 equiv of I was
consumed (Table 1, entry 9), thus clearly stressing the dual
role of the enolate, which acts as both a base and a nucleophile.
A thorough screening of the nature of the solvent showed
the superiority of DCM over all the other solvents as the
corresponding C-difluoromethylated product was obtained in
69% yield after 6 h (see the Supporting Information for a
complete solvent screen). This yield could be further improved
by simply conducting the reaction at −40 °C (81%; see Table
1, entry 11).
With these optimal conditions in hand, we naturally turned
our attention toward the scope of the reaction. As a general
trend, no discrepancies were observed when varying either the
protecting group on the nitrogen atom, the nature of the ester,
or the scale of the reaction (2−5). This prompted us to use the
less bulky Bn-protecting group for the rest of the study. Other
six-membered ring heterocyclic scaffolds were evaluated such
as glutaramides (6), quinolinones (7), and tetrahydro-
pyrimidine-2,4-diones (8); all afforded high yields ranging
from 58% to 96%. Good to excellent reactivities were also
observed with the smaller five-membered ring γ-lactams (9),10c
succinimides (11) and oxindoles (12), as the corresponding C-
difluoromethylated products were obtained in good to
excellent yields, ranging from 74% to 93%. Replacing the
ester by a ketone was not detrimental to either the reactivity or
the selectivity as the corresponding C-difluoromethylated
product 10 was obtained in 74% yield. The method could
also be successfully applied to the seven-membered ring
caprolactam 14 and to the four-membered ring β-lactam 13;
however, the latter was isolated in only 17% yield. This was
associated with the relative instability of the corresponding
enolate intermediate. Finally, butyrolactones also proved to be
good candidates, as showcased by the moderate to good yields
obtained for 15 and 16. Several attempts to conduct a direct α-
difluoromethylation on substrates lacking the ester moiety
were made, first on the Boc-protected δ-valerolactam itself and
then on the Boc-protected δ-valerolactam bearing a phenyl
Figure 1. Unified preparation of difluoromethyl- and vinylfluoride-
containing scaffolds.
decarboxylative protonation or a Krapcho decarboxylation/
dehydrofluorination enables a practical and scalable route to a
variety of fluorinated building blocks (Figure 1).10,11 These
methods were eventually applied to the late-stage functional-
ization of various natural products and APIs.
The choice of the difluoromethylating agent was the starting
point of our study. Indeed, several criteria needed to be met;
ideally, the difluoromethylating agent needed to exhibit high
regioselectivity while the transient difluoromethylating species
needed to be generated in an unbiased and controlled fashion
to minimize any undesirable side reaction that could occur
during the process. Hu’s reagent, S-(difluoromethyl)-S-phenyl-
N-tosylsulfoximine I, appeared to be the perfect candidate as
the generation of the difluorocarbene was proven to be solely
induced by the enolate, independent of the base used.8,12 In
addition, this solid and bench-stable reagent is easy to use and
can be prepared on a multigram scale in only three steps,
starting from thiophenol.13
To conduct the optimization of the difluoromethylation
step, we chose N-Boc-protected β-methylester valerolactam 1
as a model substrate. Interestingly, a complete C-selectivity of
the reaction was observed; the desired C-difluoromethylated
1
lactam 2a, being the only product detected by 19F and H
nuclear magnetic resonance (NMR) of the crude reaction
mixture. A thorough screening of the conditions showed the
ineffectiveness of organic bases such as Et3N and DBU (see
Table 1, entries 1 and 2) and mild inorganic bases such as
K2CO3 (see the Supporting Information for a complete base
screen). The use of stronger bases such as NaH, LiHMDS, or
KHMDS led to higher yields (see Table 1, entries 3−5);
however, the best results were obtained with non-nucleophilic
alkoxides, such as potassium tert-butoxide, which afforded the
desired lactam in 66% yield (see Table 1, entry 6).
Both the concentration and the stoichiometry proved to be
crucial for the reaction to proceed efficiently with a
concentration of 0.15 M, 2.1 equiv of base, and 2 equiv of I
B
DOI: 10.1021/acs.orglett.9b02887
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Figure 2. C-selective difluoromethylation with Q-CHF2 and Krapcho decarboxylative dehydrofluorination with V-CHF. The superscripted “[a]”
indicates that the reaction was performed in THF (0.1 M) at rt for 3 d. The superscripted “[b]” indicates that the yield was based on recovered
starting material (26% isolated yield). The superscripted “[c]” indicates that the reaction was allowed to warm up to rt after 12 h of stirring at −40
°C, and stirring was continued at the same temperature for an additional 36 h.
substituent at the α-position; however, no conversion was
observed, confirming the importance of the β-keto ester motif
for the difluoromethylation step (see the Supporting
Information for more details).
sequence showed relatively wide applicability, as showcased by
the various exocyclic (E)-monofluoroalkene derivatives
obtained.
In our effort to develop a viable route to tertiary
difluoromethylated compounds17,18 and considering our
expertise in the field of Pd-AAA,19 we next decided to
investigate yet another route involving a palladium-catalyzed
decarboxylative protonation of substrates bearing an activated
allyl ester.20 Indeed, if successful, this would not only provide
the straightforward access to the tertiary difluoromethylated
scaffolds that we were aiming for, it would also be the first
example of a palladium-catalyzed decarboxylative protonation
applied to a difluoromethylated precursor. Therefore, a second
and wider difluoromethylation scope was conducted; the
results are depicted in Figure 3.
As expected, the differences between the allyl and the methyl
esters in the difluoromethylation step were negligible; all the
substrates engaged led to the C-difluoromethylated products in
high yields ranging from 69% to 92% (24−31) with the
exception of glutaramide 25 and butyrolactone 31, which were
obtained in only 26% and 37% yield, respectively.
Considering the importance of Weinreb amides in routine
organic synthesis,11 we decided to apply the method to such
compounds. We were pleased to observe that these acyclic
scaffolds could also be successfully difluoromethylated in good
to excellent yields, ranging from 54% to 97% (see Figure 3,
32−39). The reaction proved to tolerate various substitution
patterns at the α-position, from simple alkyls to more-complex
side chains without showing any side reactivity.
Keeping in mind our objective to provide a tool for the
synthesis of tertiary difluoromethylated scaffolds, we decided
to subject our quaternary difluoromethylated methyl ester
derivative 3 to the traditional Krapcho decarboxylation
conditions (DMSO, LiCl, H2O, heating). Unfortunately,
instead of the desired decarboxylation product, we isolated
the corresponding E-vinylfluoride analogue 17 in 92% yield
(see Figure 2). This outcome, which is most likely due to the
increased acidity of the tertiary difluoromethylated intermedi-
ate, which favors the loss of HF through an E1cB process, was
actually also observed by Tunemoto and co-workers.16
Nevertheless, we decided to take advantage of this reactivity
pattern to synthesize various key vinylfluoride derivatives. We
rapidly realized that only 15 min were necessary to achieve full
conversion, high yields, and exclusive E stereoselectivity.
We believe this selectivity is due to the increased stability of
the pro-E enolate intermediate obtained upon decarboxylation
and the E1CB type mechanism, which forces an anti elimination
(see the Supporting Information for full discussion). Generally,
the 5-, 6-, and 7-membered ring lactams and quinolinones were
readily converted to the corresponding vinylfluorides in good
to excellent yields, ranging from 61% to 96% (17−20; see
Figure 2). Slightly milder conditions were used in the case of
the tetrahydropyrimidine-2,4-dione, glutaramide, and succini-
mide derivatives, because of stability issues; however the yields
remained relatively high (21−23; see Figure 2). Hence,
although the oxindole derivative could not be isolated, this
metal-free, fast, trivial to set up, and entirely diastereoselective
Following these results, we next evaluated the palladium-
catalyzed decarboxylative protonation. Luckily, we rapidly
managed to obtain the desired decarboxylated products by
C
DOI: 10.1021/acs.orglett.9b02887
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Figure 3. C-selective difluoromethylation with Q-CHF2 and Pd-carboxylative pronation with T-CHF2. The superscripted “[a]” indicates that
reactions were performed in THF (0.1 M) at room temperature for 3 d. The superscripted “[b]” indicates that the yield is based on recovered
starting material (37% isolated yield).
simply heating the allyl esters in the presence of Pd(OAc)2,
dppe, and formic acid.21 Lactams, glutaramides, succinimides,
and quinolinones all proved to be good candidates as the
corresponding tertiary difluoromethylated compounds were
obtained in good to high yields, ranging from 59% to 87%,
including the azapirone derivative 42.22 Most importantly, the
reaction could be run on a gram scale without any noticeable
loss in efficiency (40; see Figure 3). The reaction also proved
to be applicable to Weinreb amides, as showcased by the
formation of the corresponding tertiary difluoromethylated
products 48−51 in yields ranging from 26% to 83%.
The scope culminated with the application of this C-
selective difluoromethylation to the late-stage functionalization
of biologically relevant targets including natural products
[matrine (53, 33%), sclareolide (54, 65%), pyroglutaminol
(57, 44%)] and APIs [aniracetam (52, 45%), phensuximide
(55, 60%)] (see Figure 4). In the case of sclareolide, the
difluoromethylation also proved to be remarkably stereo-
selective as the corresponding difluoromethylated product 54
was obtained as a single diastereomer. The difluoromethylated
analogues of aniracetam, matrine, and sclareolide were
eventually subjected to the Pd-catalyzed decarboxylative
protonation conditions and the desired tertiary difluoromethy-
lated products 58, 59, and 60 were all obtained in good yields
and an excellent diastereoselectivity in the case of the
sesquiterpene lactone. Surprisingly, in the case of compounds
55, 56, and 57, the decarboxylation predominantly led to the
vinylfluorides 61, 62, and 63, along with the desired tertiary
difluoromethylated products due to the increased acidity of
these compounds, which favors the E1cB elimination process.
To push the reaction toward the complete formation of the
vinylfluoride derivatives, the crude reaction mixtures were
adsorbed onto silica in the presence of Et3N, which allowed
isolation of the phensuximide (61, 75%), costinone B23 (62,
79%), and pyroglutaminol (63, 79%) derivatives in overall
good yields and with an exclusive (E)-configuration.
Interestingly, these last three compounds could not be
obtained under the Krapcho decarboxylation conditions,
which showcases the complementarity between the two
methods. Finally, the Yamazaki conditions [LDA, THF, − 78
°C], initially developed for the dehydrofluorination of
trifluoromethyl moieties, could also be applied (Ⓐ in the
bottom panel of Figure 4),24 while alternative post-
functionalization reactions, including the conversion of
valerolactam 3 to the corresponding amide 64 [NH3,
MeOH, reflux, 78% yield (Ⓑ in the bottom panel of Figure
4)] and piperidine 65 [LiAlH4, THF, reflux, 52% yield (Ⓒ in
the bottom panel of Figure 4)] were relatively trivial (see the
Supporting Information for details). This latter result is all the
more appealing, since piperidines are arguably the most
prevalent heterocycle in approved drugs.10a
In summary, we have developed a highly straightforward,
synthesis of both quaternary and tertiary difluoromethylated
scaffolds and their (E)-vinylfluoride analogues. This strategy,
which combines a C-selective difluoromethylation with either a
palladium-catalyzed decarboxylative protonation or a Krapcho
decarboxylation, is practical, usually high-yielding and scalable.
Moreover, it can be applied to the late-stage functionalization
D
DOI: 10.1021/acs.orglett.9b02887
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Figure 4. Late-stage functionalization of various natural products and APIs such as aniracetam, matrine, sclareolide, phensuximide, Costinone B,
and pyroglutaminol. The superscripted [a] indicates that the reaction was run using 3 equiv of I and 3.1 equiv of t-BuOK stirring for 12 h at −40
°C and 72 h at 40 °C. The superscripted [b] indicates that the yield determined by NMR on the crude reaction mixture, using an internal standard
(26% isolated yield).
of natural products and APIs, which is particularly useful in the
context of drug development.
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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.9b02887.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s.arseniyadis@qmul.ac.uk.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Sanofi is gratefully acknowledged for financial support. An
early preprint of this work appeared on ChemRxiv (No.
8091314).25
E
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DOI: 10.1021/acs.orglett.9b02887
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