Modular and Chemoselective Strategy for the Direct Access to α-Fluoroepoxides and Aziridines via the Addition of Fluoroiodomethyllithium to Carbonyl-Like Compounds

Article abstract of DOI:10.1021/acs.orglett.8b04001

An expeditious, high-yielding synthesis of rare α-fluoroepoxides and α-fluoroaziridines through the addition of the unkown fluoroiodomethyllithium (LiCHIF) - formed via deprotonation the commercially available fluoroiodomethane with a lithium amide base -

Full text of DOI:10.1021/acs.orglett.8b04001

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Modular and Chemoselective Strategy for the Direct Access to
α‑Fluoroepoxides and Aziridines via the Addition of
Fluoroiodomethyllithium to Carbonyl-Like Compounds
Serena Monticelli,† Marco Colella,‡ Veronica Pillari,† Arianna Tota,‡ Thierry Langer,†
Wolfgang Holzer,† Leonardo Degennaro,‡ Renzo Luisi,*,‡ and Vittorio Pace*,†
†University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse, 14, A-1090 Vienna, Austria
‡Department of Pharmacy - Drug Sciences, University of Bari “A. Moro”, Via E. Orabona 4, Bari 70125, Italy
S
* Supporting Information
ABSTRACT: An expeditious, high-yielding synthesis of rare α-fluoroepoxides and α-fluoroaziridines through the addition of
the unkown fluoroiodomethyllithium (LiCHIF)formed via deprotonation the commercially available fluoroiodomethane with
a lithium amide baseto carbonyl-like compounds is documented. The ring-closure reactions, leading to α-fluorinated three-
membered heterocycles, rely on the diversely reactive C−I and C−F bonds. Excellent chemoselectivity was observed in the
presence of highly sensitive functionalitiesaldehyde, ketone, nitrile, alkenewhich remained untouched during the
homologation sequence.
luorine-containing chemicals are unique entities whose
behavior is dominated by the particular features of this
S, N, P), the transformation proved to be not compatible with
carbon species.8 In 2017 our group documented the first
straightforward generation and preparative use of fluorome-
thyllithium (LiCH2F; Scheme 1c).9 Despite its pronounced
chemical instability,10 the fine-tuning of the reaction
conditions allowed us to employ it in direct transfers of the
CH2F unit to a wide range of carbon electrophiles. Pivotal for
accomplishing such a challenging task was individuating the
commercially available fluoroiodomethane (ICH2F, bp 52
°C)11 as a convenient and versatile precursor for the carbenoid
which could be generated via iodine−lithium exchange
reaction. We reasoned that switching the carbenoid formation
event from the I/Li exchange to a deprotonation process12
would form a more complex and bivalent fluoroiodomethyl
carbanion suitable for introducing the CHIF fragment into an
organic electrophile (Scheme 1c). At the outset of our
investigations, we envisioned the potential of designing a
concerted carbonyl homologation/ring closure by taking
advantage of the constitutive different reactivity of the C−I
and C−F bonds. In fact, the selective involvement of the C−I
F
halogen which finely modulates their physicochemical
parameters.1 These properties are advantageously exploited
for designing valuable scaffolds attracting wide interest within
the pharmaco-biological, material, or agricultural commun-
ities.2 From a synthetic perspective the elaboration of fluoro-
containing skeletons is a highly significant challenge.3 Although
a series of conceptually different tactics became available for
the efficient introduction of this halogen, the use of fluorinated
carbanions remained for a long time elusive and problematic.4
Unfortunately, their intrinsic instability caused by the α-
elimination (even at −130 °C)5 dramatically limited the innate
potential of simple and well-established nucleophilic−electro-
philic transfer operations (Scheme 1a). Overcoming degrada-
tive issues was achieved through the installation on the
putative carbanion of stabilizing groupsusually strongly
electron-withdrawing6 or silicon-containing5,7 functional-
itieswhich required appropriate removal at the end of the
synthetic sequence (Scheme 1b).6b Arguably, the introduction
and the subsequent removal of such stabilizing groups could
make unsuitable the tactic for routine and extensive
applications. Although significant advancements have been
realized in radical monofluoromethylation of heteroatoms (O,
Received: December 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04001
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Scheme 1. Fluoro Homologations: State-of-the-Art
Scheme 2. Model Reaction: Optimization
low yields were observed likely for the difficult manipulation it
required (bp 19 °C), thus making fluoroiodomethane as the
ideal carbenoid precursor for this transformation. With the
optimized conditions in hand, the scope of the reaction was
explored (Scheme 3). A series of diaryl-ketones smoothly
underwent the homologation−ring closure sequence providing
the corresponding α-fluoroepoxides in excellent yields and
moderate to very good diastereoselectivity.
Accordingly, the protocol could be applied to variously
substituted systems decorated with a plethora of substituents
ranging from aromatic (3−4) to halogen-containing ones
bond, and its inherent excellent leaving group capability, would
have led to rather uncommon α-fluoroepoxides. Interestingly,
trisubstituted α-fluoroepoxides have not been previously
synthesized, and to the best of our knowledge, representative
examples of this motif are limited to the fully substituted
analogues (i.e., tetrasubstituted) accessible via protected
fluorinated carbanions,5,7,13 via the epoxidation of fluoroal-
kenes14 or through ring closure of fluorohalohydrins.15
Cognizant of the difficulties for preparing α-fluoroaziridines,16
we thought that this approach would have been adaptable for
facing this challenge, as well. The transfer of fluorocarbene to
imines first introduced by Seyferth in 1973 represented the
only available strategy for a long time:17 however, the presence
of elemental lead,18 and the poor efficiency, severely limited its
widespread application.19 To date, the protocol developed by
Verniest and De Kimpe involving the use of halofluoroamines
followed by ring closure represents a reliable methodology to
prepare N-alkyl analogues.20 Herein, we document a
conceptually simple homologation method for rapidly
assembling trisubstituted fluoro-epoxides and aziridines
starting from widely available carbonyl-like precursors and
fluoroiodomethyllithium.
Scheme 3. Scope of the Reaction: Synthesis of α-
b
Fluoroepoxides
Benzophenone 1 was selected as a model electrophile for
ascertaining the feasibility of the process and optimization.
Crucial for the generation of the unknown carbenoid LiCHIF
was identifying suitable reaction conditions in terms of solvent
and lithium amide base. An extensive optimization study was
conducted using Barbier-type conditions at −78 °C, and
several lithium amides were screened, as well as different
solvents (see Table S1, Supporting Information). Gratifingly,
the best results for the sequential homologation−ring closure
were achieved using lithium i-propyl-cyclohexyl amide (3
equiv) in a 1:1 (v/v) mixture of THF/Et2O as the reaction’s
solvent and 3 equiv of fluoroiodomethane (Scheme 2). Under
these conditions, fluoroepoxide 2 was isolated in an excellent
95% yield upon chromatography on basic alumina (Brock-
mann grade 2).21
Negligible differences were observed when the lithium
amide was generated with different alkyllithiums, whereas the
change to a magnesium base resulted in complete recovery of
the starting material (Table S1). Although BrCH2F was
amenable of deprotonation and could be used for preparing 2,
a
b
Reaction run on 1.5 mmol gave 88% yield (62:38 dr). Otherwise
indicated: isolated yields. Diasteromeric ratio (dr) determined by 19F
NMR analysis.
B
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including bromine (5), iodine (6), chlorine (7−8), fluorine
(9−11), or trifluoromethyl (12). Notably, the reaction leading
to 5 could be scaled up to 1.5 mmol with comparable chemo-
and stereocontrol. The X-ray analysis of fluoroepoxide 10
unambigously confirmed the structure for this previously
unknown motif.22 Ketones bearing an electron-donating group
(OMe, 13) on the aromatic ring or heterocycles (2-pyridyl 14
and 2-furyl 15) were found to be fully compatible. The
chemoselectivity toward the addition to a diarylketone
functionality was superb as showcased with the formyl-
substituted derivative (16) or the acyl-substituted epoxide
17.23 Moreover, selective transfer of the CHIF unit was also
observed in the case of a nitrile (18) or unsaturated moieties
such as an olefin (19) and an alkyne (20). The employment of
aryl-alkyl ketones allowed us to assemble fluoroepoxides with
uniformly higher dr values (up to 95:5) compared to those of
diarylketones: the presence of sterical elements on the
aromatic ring of aryl-alkylketones could rationalize this
behavior. Some additional points merit mention: (1) The
presence of an activated chloroalkyl substituent does not
interfere with the targeted delivery of the CHIF unit to the
carbonyl (22−25). (2) Dialkyl-ketones undergo the trans-
formation, though in some instance with limited efficiency
(26). However, a biologically relevant steroidic analogue was
amenable for the transformation, giving fluoroepoxide 27 in
excellent yield. The substantial reactivity analogy between
ketones and imines prompted us to extend the methodology
toward the synthesis of rare α-fluoroaziridines. We conceived
that our strategy could serve as a platform for forming the new
C−C bond through the addition of the mixed fluoroiodo-
carbenoid to an imine, followed by the ring closure. Pleasingly,
under our optimized conditions N-activated imines were
susceptible to the attack of LiCHIF, giving the corresponding
β-fluoroiodoamines in very high to excellent yields (Scheme
4). Similarly to the previously mentioned ketones, aromatic
substituents such as fluorine (29), chlorine (30), iodine (31),
and methoxy (32) were allowed. Again, running the process at
higher scale allowed us to completely preserve the efficiency
(28). The chemoselective transfer of LiCHIF was further
confirmed in the presence of a nitrile (33), olefin (34), or
alkyne (35). It is worth mentioning that also an aldimine (36)
could be employed in this process.
Significantly, the low propensity of lithiated fluoroiodoa-
mides to undergo intramolecular cyclization allowed isolating
highly functionalized β-fluoroiodoamines. Remarkably, the ring
closure could be triggered in the presence of NaH in DMF:
pleasingly, this two-step procedure showed a general
applicability, giving access to challenging α-fluoroaziridines
with high efficiency (Scheme 5). In the case of 37scalable
Scheme 5. Synthesis of α-Fluoroaziridines
Scheme 4. Synthesis of α-Fluoroiodoamines
a
b
Reaction run on 1.35 mmol gave 94% yield. Otherwise indicated:
isolated yields. Diasteromeric ratio (dr) determined by 19F NMR
analysis.
also at the 1.34 mmol scalesingle-crystal X-ray analysis
confirmed the beauty of this unusual molecular motif.22 N-
Sulfonyl-protected ketimine underwent a very smooth
homologation ring closure, giving compound 45 in an excellent
90% yield (Scheme 5).
In order to acquire additional insights into the reactivity of
the new synthesized compounds, we succeeded in realizing a
sequential homologation−ring closure concerted with the 1,2-
fluorine migration previously developed by Hu in the case of
fully substituted α-fluoroepoxides (Scheme 6a).13b It should be
observed that the herein studied trisubstituted α-fluoroepoxide
resulted in the formation of the quaternary fully substituted α-
fluoroaldehyde 47. The presence of a reactive halogen on the
aromatic ring of both α-fluoroepoxide (5) and α-fluoroazir-
idine (40) could be advantageously exploited for accomplish-
ing the recently described Feringa’s palladium-catalyzed cross-
coupling with organolithiums (Scheme 6b,c).24 Accordingly,
the polyaromatic systems 48 and 49 were rapidly assembled
a
b
Reaction run on 1.5 mmol gave 90% yield. Diasteromeric ratio
c
determined by 19F NMR analysis. Otherwise indicated: isolated
yields. Diasteromeric ratio (dr) was determined by 1H NMR analysis.
C
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Letter
ORCID
Scheme 6. Manipulation of α-Fluoroepoxides and Aziridines
Thierry Langer: 0000-0002-5242-1240
Leonardo Degennaro: 0000-0002-2187-9419
Renzo Luisi: 0000-0002-9882-7908
Vittorio Pace: 0000-0003-3037-5930
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the University of Vienna and Bari for
financial support. This research was supported by the project
Laboratorio Sistema code PONa300369 financed by MIUR,
MISE, Horizon 2020 − PON 2014/2020 FARMIDIAB “code
338”. S.M. acknowledges the University of Vienna for a
Unidocs fellowship. We thank A. Roller and D. Dobusch
(University of Vienna) for X-ray analysis and HRMS
measurements, respectively. The authors are indebted to
Albemarle Corporation and ABCR Germany for generous gifts
of organolithiums and fluoroiodomethane.
a
b
Isolated yields. Diasteromeric ratio determined by 19F NMR
c
analysis. Otherwise indicated: isolated yields. Diasteromeric ratio
(dr) determined by 19F-NMR analysis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04001.
■
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Experimental procedure, NMR spectra, and analytical
data for all the compounds (PDF)
Accession Codes
CCDC 1879398−1879399 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: vittorio.pace@univie.ac.at.
*E-mail: renzo.luisi@uniba.it.
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