A Difluoromethylene Linchpin/Synthon: Application in Conjunction with Anion Relay Chemistry (ARC) Permits Ready Access to Diverse Difluoromethylene Scaffolds

Article abstract of DOI:10.1021/acs.orglett.0c03508

Organodifluorine synthons, in conjuction with three-component diastereoselective anion relay chemistry (ARC), permit ready access to diverse difluoromethylene scaffolds. Initiated via [1,2]-addition of an organolithium reagent to a β-difluoromethylene silyl aldehyde, an alkoxide intermediate is formed, which is capable of undergoing a [1,4]-Brook rearrangement to generate a stabilized α-difluoromethylene carbanion, which, upon electrophile capture, affords a three-component adduct. This three component synthetic tactic represents a novel one-pot divergent strategy for the construction of diverse organodifluorine containing compounds.

Full text of DOI:10.1021/acs.orglett.0c03508

pubs.acs.org/OrgLett
Letter
A Difluoromethylene Linchpin/Synthon: Application in Conjunction
with Anion Relay Chemistry (ARC) Permits Ready Access to Diverse
Difluoromethylene Scaffolds
Kevin T. O’Brien, Jonathan W. Nadraws, and Amos B. Smith, III*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03508
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ABSTRACT: Organodifluorine synthons, in conjuction with
three-component diastereoselective anion relay chemistry (ARC),
permit ready access to diverse difluoromethylene scaffolds.
Initiated via [1,2]-addition of an organolithium reagent to a β-
difluoromethylene silyl aldehyde, an alkoxide intermediate is
formed, which is capable of undergoing a [1,4]-Brook rearrangement to generate a stabilized α-difluoromethylene carbanion,
which, upon electrophile capture, affords a three-component adduct. This three component synthetic tactic represents a novel one-
pot divergent strategy for the construction of diverse organodifluorine containing compounds.
rganofluorine compounds are ubiquitous in modern
Osociety, with polytetrafluoroethylene (PTFE) polymers
and hydrofluorocarbon (HFC) refrigerants seeing widespread
use.1 Over the last several decades, the role of fluorine in small
molecule therapeutics has gained significant attention, with
∼20% of approved active pharmaceutical ingredients and 35%
agrochemicals containing at least one F atom.2 The strong
polarization of the C−F bond, in conjunction with the short
bond length and small van der Waals radius of the F atom,
results in a variety of useful properties.3 In medicinal
chemistry, these properties manifest in a myriad of ways,
permitting fluorine to serve as a bioisostere,4 to modify the
basicity and acidity of adjacent functional groups,5 to effect the
solubility of compounds,6 to alter metabolism,7 and/or to
Figure 1. (a) Fluorination synthons; (b) prior coupling tactic
employing a dianion synthon; and (c) fluoro-organic synthon and
three-component coupling tactic via Type II anion relay chemistry
(ARC).
control the conformation of structures,8 among other
attributes.
Accordingly, numerous methods for the incorporation of F
atoms into organic compounds have been developed, which
which the anionic carbon is stabilized by geminal fluorine
utilize either direct or indirect fluorination tactics, either
substituents, in a tactic comprising [1,2]-addition of an
adding a single F atom (for instance, employing DAST or
organolithium reagent to aldehyde linchpin 1 to afford an
SelectFluor) or an activated organofluorine reagent, such as the
alkoxide intermediate (2). Subsequent [1,4]-Brook rearrange-
Ruppert−Prakash reagent (TMS-CF3).9 However, most
ment of alkoxide 2 with electrophile capture could then afford
existing fluorination methods employ monovalent synthons,
a three-component adduct (3), with the relative stereo-
which generally permit only linear syntheses (Figure 1a).
Ideally, fluorination could be performed as a convergent
synthetic step, permitting the reaction to serve as a point of
diversification, which is often desirable from the perspective of
chemistry of the anion relay chemistry (ARC) adduct under
Felkin−Anh stereocontrol.11 Such a method would hold great
promise if (a) the scope of each component is broad, (b) the
the medicinal chemist. Recently, Dilman has exploited divalent
Received: October 21, 2020
difluoromethylene synthons for use in multicomponent
coupling tactics (Figure 1b).10 While highly effective, this
method lacks a broad scope of coupling partners and requires
multiple steps to achieve.
We reasoned that a one-pot three-component union (Figure
1c) could be achieved by employing an ambiphilic linchpin in
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diastereoselectivity is high, (c) the reaction is performed in a
single pot, and (d) the linchpin is readily constructed.
expected 1:1 mixture of diastereomers at the benzylic position.
Having demonstrated the proof-of-concept via a two-pot ARC
sequence utilizing 9a, we next turned our attention to
validation of the one-pot, three-component coupling ARC
tactic. To this end, employing the defined conditions, three-
component adduct 10 was observed as the major product from
the one-pot sequence in 64% yield.
Having validated the ARC sequence, we turned to explore
the electrophile scope. Reactions were performed using n-BuLi
as the nucleophile and linchpin 8, with a variety of
electrophiles (Scheme 2). Evaluation of (E)-cinnamaldehyde
We first set out to validate a synthetic route to access diverse
difluoro-linchpins (1), which would be amenable to varied
substitution at the α-position. Drawing inspiration from the
work of Mikami and co-workers,12 we sought to construct β-
difluoro-linchpins via a direct α-silyldifluoromethylation of an
oxazolidinone-derived lithium enolate. Initially, oxazolidinone
4 was acylated with an acid chloride to afford 5 (Scheme 1).
Scheme 1. Linchpin Synthesis
a
Scheme 2. Electrophile Scope
Next, the lithium enolate of 5 was generated with LiHMDS
and subsequently α-silyldifluoro-methylated, to furnish 6 as a
single diastereomer. The absolute stereochemistry of 6 was
determined unambiguously using X-ray crystallography (see
the Supporting Information). The desired linchpin was then
obtained via reduction of oxazolidinone 6 with LiAlH4 to
provide 7, followed by oxidation with Dess−Martin period-
inane (DMP) to afford 8 in good yield.
With the desired linchpin 8 in hand, we next sought to
validate the proposed reaction sequence (see Figure 2). High
a
Conditions: n-BuLi (1.0 equiv), linchpin (1.0 equiv), electrophile
b
(2.0 equiv), TBAF deprotection of crude product. Diastereomeric
ratio pertains to the α-position of amine. Absolute configuration
c
assigned by the transition-state model (see the Supporting
Information).
as an electrophile demonstrated that α,β-unsaturated aldehyde
electrophiles are amendable to the ARC sequence to provide
allyl alcohol 11a. Next, a series of alkyl halide electrophiles
were employed with MeI, affording 11b in good yield, and with
benzyl and allyl bromide, affording three-component adducts
11c and 11d in modest yield. Pleasingly, enantioenriched
sulfonyl imine electrophiles also served as successful electro-
philes in the ARC sequence, providing β-difluoroamine
substrates as three-component adducts as single diastereomers;
both (S)- and (R)-phenyl sulfonyl amine furnished ARC
adducts 11e and 11f with high diastereoselectivity in moderate
yield. In addition, employing the (R)-α,β-unsaturated sulfonyl
imine of cinnamaldehyde permitted access to β-difluoro-allyl
amine 11g in 62% yield. Thus, this ARC tactic holds the
promise of a viable method for the construction of
enantioenriched β-difluoroamines, for which limited methods
are currently available.14
At first glance, it may appear that the three-component
adducts obtained from aldehyde electrophiles are less than
ideal, as there is no diastereoselectivity in the second [1,2]-
addition. However, such diol products can be used to access
difluorocyclopentyl ketals (see Scheme 3). Similar pseudo-
pentose structural motifs are found in many bioactive
compounds, such as the approved drug Gemcitabine
(Gemzar). For example, benzylic oxidation of 10 with MnO2
spontaneously leads to ketal formation to arrive at 12, as a 4:1
Figure 2. Stepwise evaluation of ARC sequence.
diastereoselectivity of the initial [1,2]-addition was deemed
critical for the utility of this transformation. Therefore, we first
performed the initial [1,2]-addition of n-BuLi to linchpin 8 at
−78 °C in Et2O, with subsequent reaction with HCl in Et2O to
arrive at alcohols 9a and 9b as separable diastereomers. High
1
diastereoselectivity was observed (9:1 by H NMR analysis),
with the absolute configuration of 9a determined by Mosher
ester analysis, demonstrating that Felkin−Anh diastereoselec-
tivity was operative.13 Next, deprotonation of 9a was achieved
with n-BuLi at −78 °C in Et2O, and benzaldehyde was added.
The envisioned [1,4]-Brook rearrangement was then triggered
via the use of the polar additive HMPA. Pleasingly,
tricomponent adduct 10 was obtained in 72% yield as an
B
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Scheme 3. Difluorocyclopentyl Ketal Synthesis
mixture of diastereomers in excellent yield. A similar strategy
may be adapted to permit the synthesis of other
difluorocyclopentyl ketals from the corresponding aldehyde
adducts.
Next, our attention turned to the scope of organolithium
reagents that could be employed as initiating nucleophiles in
this ARC sequence. Standard reaction conditions were
employed, utilizing linchpin 8 to evaluate a variety of
organolithium reagents (Figure 3). Having demonstrated that
Figure 4. Scope of linchpin substrates. [Conditions: n-BuLi (1.0
equiv), linchpin (1.0 equiv), MeI (2.0 equiv), and TBAF deprotection
of crude product; linchpins: R = Et (8a), allyl (8b), vinyl (8c), Ph
(8d), and Me (8).]
demonstrates that this ARC methodology is amenable to both
epimers of the linchpins.
Many synthetic methods are predicated on the manipulation
of difluoromethyl radicals.15 The σ-withdrawing, π-donating
properties of the F atom permit access to difluoromethyl
radicals, anions,16 and carbenes.17 Mechanistic studies were
performed to provide support in this case for an anionic
reaction mechanism for the [1,4]-Brook rearrangement with
alkylation (Scheme 4). Here, the principle concern was the
Scheme 4. Mechanistic Studies
Figure 3. Nucleophile scope. [Conditions: Nu-Li (1.0 equiv),
linchpin (1.0 equiv), MeI (2.0 equiv), TBAF deprotection of the
crude product.]
n-butyllithium with methyl iodide as the electrophile is
amenable to the ARC tactic, we attempted commercially
available PhLi. Accordingly, the three-component adduct 13a
was obtained as a single diastereomer in moderate yield. Vinyl
lithium and alkynyl lithium reagents were also successfully
employed to afford allyl and propargyl alcohols 13b and 13c in
moderate to good yield. Equally pleasingly, lithiated 1,3-
dithiane can be utilized successfully in the ARC sequence,
permitting the incorporation of this versatile functionality in
adduct 13d. Thus, alkyl, vinyl, alkynyl, aryl, and dithianyl
lithium reagents comprise viable nucleophiles in this three-
component ARC coupling tactic.
Another significant aspect of this coupling tactic would be
the tolerance on variability of the linchpin. At this juncture, we
had examined exclusively the viability of linchpin 8, bearing an
α-Me substitution. While this substitution is useful for
polyketide synthetic targets, larger substituents or functional
handles would serve to provide access to a more diverse pool
of difluoromethylene scaffolds. Therefore, we set out to
examine several linchpins with varied α-substitution. 9See
Figure 4.) For the evaluation of linchpins 8a−8d, standard
reaction conditions were employed, utilizing n-BuLi as the
nucleophile and MeI as the electrophile. Increasing the size of
the substituent from Me to Et had a slightly negative effect on
yield, arriving at the three-component adduct 14a in 63% yield.
Olefin moieties were well-tolerated at the α-position, affording
homoallyl and allyl products 14b and 14c. Pleasingly, Ph and
vinyl α-substitutions were also well-tolerated, despite the
expected increased acidity of the corresponding linchpins.
Furthermore, the synthesis of three-component adduct 14d
[1,4]-Brook rearrangement, rather than the [1,2]-carbonyl
addition. Thus, the ARC sequence was entered via the
deprotonation of alcohol 9a. Next, the [1,4]-Brook rearrange-
ment was triggered via the addition of a solution of
benzaldehyde in Et2O/HMPA, with or without an equivalent
of TEMPO. In both cases, three-component adduct 10 was
obtained in good yield. In addition, TEMPO adduct 15 was
not identified in the trapping experiment. Next, to offer
support for a [1,4]-Brook rearrangement, we demonstrated the
isolation of silyl ether ARC product 16. The labile nature of
TMS ethers led us to remove this group prior to purification
for simplicity. However, isolation of 16 here demonstrates that
C−Si to O−Si migration indeed occurs.
In summary, we disclose here a new ambiphilic organo-
difluoromethylene synthon that can be employed in a three-
component ARC coupling tactic to afford a variety of
difluoromethylene adducts with high diastereoselectivity.
Moreover, we have disclosed a synthetic route that permits
C
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α-substituent and absolute stereochemical configuration can be
readily achieved by selecting the appropriate acid chloride and
oxazolidione substrates, respectively, many of which are
commercially available. The value of this synthon and the
corresponding three-component coupling tactic is also
apparent in the great variety of nucleophiles, linchpins, and
electrophiles that can be employed. Thus, one can envision
numerous difluoromethylene scaffolds that can be prepared by
employing this tactic as a key disconnection, which may
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03508.
General experimental procedures; characterization data;
1H NMR/13C NMR/19F NMR spectra (PDF)
Accession Codes
CCDC 2040145 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Amos B. Smith, III − Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United
States; orcid.org/0000-0002-1712-8567;
Email: smithab@sas.upenn.edu
(11) (a) Cherest, M.; Felkin, H.; Prudent, N. Torsional Strain
Involving Partial Bonds. The Stereochemistry of Lithium Aluminum
Hydride Reduction of Simple Open-Chain Ketones. Tetrahedron Lett.
1968, 9 (18), 2199−2204. (b) Anh, N.; Lefour, J. M.; Dau, T.
Torsional Strain Involving Partial Bonds. The Stereochemistry of
Lithium Aluminum Hydride Reduction of Simple Open-Chain
Ketones. Tetrahedron Lett. 1968, 9 (18), 2199−2204.
Authors
Kevin T. O’Brien − Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United
States; orcid.org/0000-0002-9584-9589
Jonathan W. Nadraws − Department of Chemistry, University
of Pennsylvania, Philadelphia, Pennsylvania 19104, United
States
(12) Hashimoto, R.; Iida, T.; Aikawa, K. K.; Ito, S.; Mikami, K.
Direct α-Siladifluoromethylation of Lithium Enolates with Ruppert-
Prakash Reagent via C-F Bond Activation. Chem. - Eur. J. 2014, 20
(10), 2750−2754.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03508
(13) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Mosher ester analysis for
the determination of absolute configuration of stereogenic (chiral)
carbinol carbons. Nat. Protoc. 2007, 2, 2451−2458.
Notes
(14) Fadeyi, O. O.; Lindsley, C. W. Rapid, General Access to Chiral
β-Fluoroamines and β,β-Difluoroamines via Organocatalysis. Org.
Lett. 2009, 11 (4), 943−946.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) Heine, N. B.; Studer, A. Radical Difluoromethylation of Thiols
with (Difluoromethyl)triphenylphosphonium Bromide. Org. Lett.
2017, 19 (15), 4150−4153.
Financial support was provided by the National Institute of
Health National Cancer Institute, through Grant No. CA-
19033, and the National Foundation for Cancer Research.
Instrumentation supported by the NSF Major Research
Instrumentation Program (Award No. NSF CHE-1827457)
and Vagelos Institute for Energy Science and Technology were
used in this study. We thank Dr. C. Ross III at the University
of Pennsylvania for assistance with HRMS analysis.
(16) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Nucleophilic
Difluoromethylation of Primary Alkyl Halides Using Difluoromethyl
Phenyl Sulfone as a Difluoromethyl Anion Equivalent. Org. Lett. 2004,
6 (23), 4315−4317.
(17) Brahms, D. L. S.; Dailey, W. P. Fluorinated Carbenes. Chem.
Rev. 1996, 96 (5), 1585−1632.
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