Direct and Chemoselective Synthesis of Tertiary Difluoroketones via Weinreb Amide Homologation with a CHF2-Carbene Equivalent

Article abstract of DOI:10.1021/acs.orglett.9b03024

The homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF₂ transfer agent is reported. Activating TMSCHF₂ with potassium tert-amylate enables a convenient access to the difluorinated homologation re

Full text of DOI:10.1021/acs.orglett.9b03024

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct and Chemoselective Synthesis of Tertiary Difluoroketones via
Weinreb Amide Homologation with a CHF2‑Carbene Equivalent
Margherita Miele,†,§ Andrea Citarella,†,‡,§ Nicola Micale,‡ Wolfgang Holzer,† and Vittorio Pace*,†
†University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse, 14, 1090 Vienna, Austria
‡University of Messina, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, Viale F. Stagno
D’Alcontres, 31, 98166 Messina, Italy
S
* Supporting Information
ABSTRACT: The homologation of Weinreb amides into
difluoromethylketones with a formal nucleophilic CHF2
transfer agent is reported. Activating TMSCHF2 with
potassium tert-amylate enables a convenient access to the
difluorinated homologation reagent, which adds to the
acylating partners. The high chemoselectivity showcased in
the presence of variously multifunctionalized Weinreb amides,
jointly with uniformly high yields, enables the strategy of
general applicability without requiring any stabilization
element for the putative carbanion.
mbodying a difluoromethyl unit into an organic array
ester difluorination coupling with lithiated bis(boron) species:
Eprofoundly tunes the chemico-physical properties of the accordingly, quaternary difluoromethyl ketones can be
prepared under full regio- and chemocontrol.9 As a common
feature, these strategies are valuable platforms for accessing
fully substituted difluoroketones, but unfortunately, the
flexibility and adaptability to prepare tertiary α-CHF2
analogues appear limited. A conceptually different disconnec-
tion would suggest adopting an intuitive C−C bond formation
strategy by transferring the formal CHF2-containing nucleo-
phile onto an electrophilic partner.10 To be productive, the
tactic should overcome the inherent high instability of putative
CHF2-type carbanions.11 In this context, the installation of
stabilizing electron-withdrawing elements on them emerged as
an effective solution to tackle the challenge; however, the
requirement of unnecessary extra steps (installation and
removal of these stability enhancing factors under forcing
conditions) undoubtedly decreases the overall synthetic
efficiency as, for example, evidenced in recent work by
Kuhakarn.12 In 2011, Hu and co-workers introduced
Me3SiCF2H (I) as a valid equivalent of the CF2H carbanion,
pointing out some remarkable characteristics of the
reagent:1g,13 unlike the similar Ruppert−Prakash reagent
(Me3SiCF3),14 I requires proper activation to be synthetically
useful as a consequence of the very strong Si−C bond it
possesses.13 We reasoned a homologation event carried out
with a formal CHF2 nucleophile, i.e., presenting the exact
degree of substitution as the targeted structures, on a Weinreb
amide acting as the electrophilic acylating partner15 would
represent an effective solution to the problem of preparing
tertiary difluoromethylketones. As documented in recent work
resulting scaffold.1 In more detail, the weakly acidic CHF2
motif represents a rare example of a methinic carbon capable of
establishing hydrogen-bonding interactions2 to improve the
binding selectivity of pharmaceuticals.3 Thus, valuable
optimization processes in drug design can be realized by
introducing the CHF2 unit acting as a competent more
lipophilic isostere of widespread functionalities such as
hydroxyl, mercapto, hydroxamic, or amidic species.3a,4 Placing
the CHF2 fragment at the vicinal position of a ketone carbonyl
results in the simultaneous modulation of the reactivity profile
of both moieties: the carbonyl and the difluorinated C−H
group (Scheme 1).5 Evidently, the electron-withdrawing effect
exerted by CHF2 guarantees a significant increase of the
electrophilicity of the carbonyl carbon, whereas it causes a
remarkable inertness of the corresponding enolates.6 However,
the remarkable significance of difluoroketones in the general
context of the chemical sciences is somehow counterbalanced
by the lack of a general tactic to access them.7 Accordingly, the
most common logical approaches to the motif can be
summarized as follows: (1) progressive introduction of fluorine
through C−F bond formation operations (Scheme 1a) and (2)
transfer of the difluorinated building block onto a proper
acceptor, thus formally constituting a C−C bond formation
event (Scheme 1b). Techniques belonging to the first tactic
(e.g., use of enolate-like materials, alkynes, etc.) are often
plagued by important concerns on the regioselectivity of the
transformation observed during the fluorination under electro-
philic regime, also manifesting a strong dependence on the
structure of the nucleophilic scaffold (mainly in the presence of
different enolization centers).7a,8 A breakthrough in the field
has been introduced by Pattison through the homologative
Received: August 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03024
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a
Scheme 1. Difluoromethyl Ketones: State of the Art
Table 1. Model Reaction: Optimization.
a
reaction time yield of 2
entry
solvent
base
TBAT
KF/18-crown-6
CsF
KF/18-crown-6
t-BuOK
t-BuOK
t-PentOK
t-PentOK
t-BuOK
t-PentOK
t-PentOK
t-PentOK
(h)
(%)
er of 2
1
2
3
4
DMF
DMF
DMF
THF
THF
THF
THF
Et2O
toluene
THF
THF
THF
8
8
8
8
4
4
4
8
8
8
4
4
traces
27
15
traces
63
75
91
52
75
77
95:5
96:4
b
5
c
96:4
96:4
99:1
97:3
98:2
99:1
98:2
6
7
8
9
10
11
d
e
36
<10
f
12
a
Otherwise stated reactions were run at 0 °C with t-PentOK 1 M
b
solution in cyclohexane under Barbier-type conditions. t-BuOK solid.
c
d
t-BuOK 1.0 M in THF. Me3SiCHF2 (1.5 equiv) and t-PentOK (1.4
e
f
equiv) were used. Reaction run at rt (23 °C). Non-Barbier-type
conditions (e.g., CHF2-transfer agent generated from Me3SiCHF2
(2.0 equiv) and t-PentOK (1.8 equiv)) and then Weinreb amide 1
was added.
the existence of an enolization site at the α-position of the
starting Weinreb amide, no deleterious effect was evidenced,
thus making the reaction productive. This is a particularly
remarkable result compared to the elusive attitude of similar
enolizable ketones to undergo difluoromethylation observed by
Hu.13 (b) THF represented the ideal solvent for the
transformation as indicated by compared with diethyl ether
and toluene even after prolonged reaction times (entries 8 and
9). (c) Decreasing the nucleophile loading to 1.4 equiv was
detrimental for the yield (entry 10). (d) By increasing the
temperature up to rt, a dramatic lost of efficiency was observed,
presumably as a consequence of the nucleophile thermal
stability (entry 11). It is worth mentioning that the use of
Barbier-type conditions not only compromised the chemo-
selectivity but also constituted a conditio sine qua non to enable
reactivity, in analogy to the highly unstable monofluorome-
thylating agent LiCH2F we introduced in 2017.17 In fact, when
the nucleophile was generated prior to the acylation event (3
min, i.e., non-Barbier conditions) compound 2 was formed in
only <10% yield.
With the optimized conditions in hand, we then studied the
scope of the reaction (Scheme 2). Unsaturated Weinreb
amides smoothly undergo the homologative difluoromethyla-
tion, providing the resulting ketones (3−8) in excellent yields
(>91%). Interestingly, substitution across the cinnamoyl core
(both on the aromatic ringwith functionalities of diverse
electronic behavioror on the exocyclic olefin) are perfectly
tolerated, thus affording interesting products, including the
unprecedented ketone 6 presenting two different fluorine-
containing substituents (sp2 C−F) and (sp3 CHF2) at the α
and α′-position, respectively. Moreover, incorporating a triple
bond into the Weinreb amide core maintains untouched the
efficiency (9). The excellent yields observed in the case of
aromatic Weinreb amides, delivering difluoroketones (10−33),
accounts for the robustness and versatility of the process.
Substitution on the aromatic nuclei is uniformly permitted
by our group, these amides act as highly competent acylating
agents for α-substituted methyl-type carbanions,16 including
the unprecedented lithium monofluoromethyl nucleophile
(LiCH2F).17 Additionally, structural limitations, e.g., needing
aromatic or bulky groups, pointed out by Dilman in the case of
using difluorinated phosphorus ylides could be advantageously
circumvented.18
We selected the optically active Weinreb amide 119 as the
model substrate for gaining insight into both chemical
reactivity and preservation of the stereochemical information
(Table 1). Cognizant of the requirement of activating
TMSCHF2, we screened a set of conditions for generating
the formal CHF2-transfer nucleophilic agent. Nonoptimal
efficiency was noticed by using TBAT (tetrabutylammonium
difluorotriphenylsilicate) or an alkaline metal fluoride in DMF,
accompanied by minor but still noticeable racemization
(entries 1−3). Moreover, the use of the amidic solvent DMF
is responsible for self-difluoromethylation phenomena, as
indicated by 1H NMR analysis of reaction crudes. The process
manifested a strong solvent-activating agent dependence, as
deducted by the complete lack of reactivity when switching
coeteris paribusfrom DMF to THF (entry 4). Activating the
pronucleophile Me3SiCHF2 with a stoichiometric amount of a
low nucleophilic alkoxide in THF (potassium tert-butoxide)
allowed us to produce in satisfying yield the desired
difluoroketone 2, albeit with minor epimerization (entry 5).
Changing to a commercially available THF solution of t-BuOK
had a positive effect on the yield, although epimerization could
not be fully avoided (entry 6). Pleasingly, the activation of
TMSCHF2 with a commercially available solution of the more
sterically hindered potassium tert-pentoxide (i.e., amylate, 0.9
M in cyclohexane)20 resulted in an excellent 91% yield of the
targeted ketone with full preservation of the optical purity
(entry 7). Some additional points merits mention: (a) Despite
B
DOI: 10.1021/acs.orglett.9b03024
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such as nitrile (25), nitro (26), ketone (27), ester (28), or a
pyrrolidinyl amide (29) remain completely untouched during
the transformation, presumably due to the excellent perform-
ance of Weinreb amides in reaction with α-functionalized
carbanions. Additionally, a bis-Weinreb amide is amenable for
mono- or bis-difluoromethylation by simply tuning the
stoichiometry: in the case of using 1.0 equiv of nucleophile
and cooling the mixture at −20 °C, it is possible to introduce a
single CHF2 group, leaving untouched the remaining Weinreb
amide site (30). Alternatively, by increasing the nucleophile
loading up to 3.0 equiv, both Weinreb amides undergo the
difluoromethylation, affording the symmetric bis-difluoroke-
tone 31 in an excellent 90% yield through a single operation. A
synthetically useful boronate estera benchmark for further
chemistryis analogously tolerated (32), pointing out the
unique characteristics of the CHF2 nucleophile compared to
different CHHal2 carbenoids whose addition to boronate esters
follows a Matteson-type homologation pathway.22 Moreover,
polyaromatic (33) or thiophene (34) Weinreb amides can be
employed, further highlighting the stability of a sensitive TMS
group on the furan ring (35). Finally, additional aliphatic
Weinreb amides including the highly sterically demanding
adamantyl substituted (37) or the one generated from the
nonsteroidal anti-inflammatory drug naproxen could be
conveniently employed for preparing the targeted scaffolds in
very high yield.
Scheme 2. Scope of the Reaction: Synthesis of
Difluoromethylketones
The availability of a highly efficient preparative procedure
for tertiary difluoroketones spurred us to undertake a survey on
their use in chemical synthesis. By simply selecting the reaction
conditions, high chemoselective processes with strong
nucleophiles can be designed (Scheme 3). The Feringa Pd-
catalyzed cross-coupling of p-iodoketone 17 with PhLi gave the
corresponding p-phenyl derivative 39 in very high yield
without touching the sensitive difluorocarbonyl unit.23 Also,
a selective Wittig reaction on the ketone functionality of 24
conducted to the difluoroallyl compound 40. The carbonyl of
23 undergoes the attack of the carbenoid iodomethyllithium
(LiCH2I)24 to prepare in a single operation the extremely rare
α-difluoromethyl epoxide core25 (41). Moreover, the pendant
vinyl substituent of 12 could be used to construct a
difluoromethyl cyclopropane,26 furnishing the unknown ketone
42, featuring contemporaneously two different difluoromethyl
fragments. Finally, the tetrahedral hemiaminal generated by the
addition of the CHF2 unit to a Weinreb amide could be
trapped and fully characterized according to our previous
established procedure.27 It is worth noting that analogous
stable tetrahedral adducts derived from difluoromethyl ketones
are relevant for enzymatic inhibition studies of potential
pharmacological interest.7a
In summary, we have disclosed a conceptually intuitive and
smooth access to difluoromethyl ketones via the straightfor-
ward homologation with a formal CHF2-type carbanion
equivalent of variously functionalized Weinreb amides. The
methodology paves on the activation of the commercially
available reagent TMSCHF2 in the presence of potassium tert-
amylate in THF. Particularly attractive characteristics of this
uniformly high-yielding and general methodology are (1) the
excellent tolerance of sensitive functionalities (including
challenging ketone, ester, amide, nitro, nitrile groups, inter
alia), (2) the perfect flexibility to Weinreb amides of diverse
electronic behavior; (3) the negligible effect of sterically
demanding elements positioned on the acylating partner; and
with both electron-donating (10, 11, 21−24) and electron-
withdrawing substituents (13−20). Significantly, positioning
the substituent on delicate sites (ortho, 11, 13) does not
influence the yield. In analogy to the compatibility of the
reaction conditions with the presence of unsaturated C−C
bonds seen above, a vinyl fragment (12) does not suffer any
modification during the generation of the carbene-like species.
Scaling-up the process (15 mmol, compound 12) resulted in
comparable efficiency, thus making it of potential interest for
nonacademic audiences. We anticipate these mild conditions
enable further elaboration of the scaffold upon tuning of the
difluoromethylation methodology en route to difluorocyclo-
propanes (vide infra). The whole set of halogens (13−20) can
be placed on the aromatic ring as well as ether (21, 22), acetal
(23), or thioether (24) functionalities, thus adding reliability
to the technique. The compatibility of the procedure with
highly sensitive groups to the nucleophilic environment is
undoubtedly one of the main advantages of the method-
ology.21 In fact, susceptible electrophilic decorating elements
C
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Scheme 3. Synthetic Versatility of α,α-
Difluoromethylketones
ACKNOWLEDGMENTS
■
We thank the University of Vienna for financial support. A.C.
acknowledges the University of Messina for a predoctoral
mobility grant.
DEDICATION
■
Dedicated to Professor Norbert Haider in the occasion of his
retirement.
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ASSOCIATED CONTENT
* Supporting Information
■
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Experimental procedure, NMR spectra, HPLC traces,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: vittorio.pace@univie.ac.at. Web: https://
drugsynthesis.univie.ac.at/. Twitter: @LabPace.
ORCID
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Am. Chem. Soc. 2018, 140, 2036−2040. See also: Stephens, T. C.;
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Nicola Micale: 0000-0002-9294-6033
Vittorio Pace: 0000-0003-3037-5930
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§M.M. and A.C contributed equally.
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The authors declare no competing financial interest.
D
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