Synthesis of β-Fluoro-α,β-Unsaturated Amides from the Fragmentation of Morpholine 3,3,3-trifluoropropanamide by grignard reagents

Article abstract of DOI:10.1021/acs.orglett.0c00599

Fluoroalkenes serve as bioisosteres to peptide bonds and are resistant to hydrolytic enzymes in vivo. Currently, α-fluoro-α,β-unsaturated carbonyl compounds are readily accessible via general synthetic methods; however, β-fluoro-α,β-unsaturated carbonyl groups are more challenging to construct. To address this need, we have designed a reagent, morpholine 3,3,3-trifluoropropanamide, that creates (E)-β-fluoro-α,β-unsaturated amides upon the addition of many commonly used Grignard reagents. Reactions with this reagent enable a high level of stereocontrol in the fluoroalkene product.

Full text of DOI:10.1021/acs.orglett.0c00599

pubs.acs.org/OrgLett
Letter
Synthesis of β‑Fluoro-α,β-Unsaturated Amides from the
Fragmentation of Morpholine 3,3,3-Trifluoropropanamide by
Grignard Reagents
Amna T. Adam, Frank R. Fronczek, and David A. Colby*
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ABSTRACT: Fluoroalkenes serve as bioisosteres to peptide bonds
and are resistant to hydrolytic enzymes in vivo. Currently, α-fluoro-
α,β-unsaturated carbonyl compounds are readily accessible via general
synthetic methods; however, β-fluoro-α,β-unsaturated carbonyl
groups are more challenging to construct. To address this need, we
have designed a reagent, morpholine 3,3,3-trifluoropropanamide, that
creates (E)-β-fluoro-α,β-unsaturated amides upon the addition of
many commonly used Grignard reagents. Reactions with this reagent
enable a high level of stereocontrol in the fluoroalkene product.
he incorporation of fluorine into organic molecules can
produce unique effects during drug discovery, such as
pounds, and most are limited by low yields and poor
stereoselectivities.14−16 Notable recent exceptions are the
hydrofluorination of alkynes using gold catalysts that provide
access to (Z)-β-fluoro-α,β-unsaturated carbonyl compounds17
and the chromium-mediated reductive coupling of CBrF2-
containing compounds with aldehydes to give (E)-β-fluoro-
α,β-unsaturated amides18 (Scheme 1). The two shortcomings
of the latter transformation are the stoichiometric amounts of
chromium and the need of CBrF2-containing compounds,
which are difficult to access. Herein, we report the design of a
reagent that allows the creation of (E)-β-fluoro-α,β-unsatu-
T
reducing metabolism, enhancing distribution, and increasing
bioavailability.1 Fluoroalkenes are particularly valuable in the
discovery process, because they can serve as bioisosteres of
peptide bonds.2 Also, fluoroalkenes are resistant to the
hydrolytic enzymes that easily cleave the amide bonds in
many peptides. Fluoroalkenes have been used as surrogates for
amide bonds in drug discovery, and, for example, Pannecoucke
and co-workers created a fluoroalkene analogue of the
antihypertensive agent, enalapril (see Figure 1).3 Other recent
Scheme 1. Two Recent Approaches to the Synthesis of β-
Fluoro-α,β-Unsaturated Amides
Figure 1. Enalapril and fluorinated analogue displaying a vinyl
fluorine as a bioisostere of the amide bond.
examples of this strategy have been reported by Altman et al.,4
Augustyns and co-workers,5 Welch and co-workers,6 Hollen-
stein and Leumann,7 and Fujii and co-workers.8 Most of these
cases also demonstrated the application of innovative synthetic
methods to create the requisite fluoroalkene.9,10
Currently, there are general methods to synthesize α-fluoro-
α,β-unsaturated carbonyl compounds,9,10 such as the Julia
olefination,11 the Peterson olefination,12 the Horner−Wads-
worth−Emmons reaction,3 and a Reformatsky addition/
elimination process.13 Unfortunately, fewer methods exist for
the preparation of β-fluoro-α,β-unsaturated carbonyl com-
Received: February 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00599
© XXXX American Chemical Society
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Letter
rated amides in a single step, using commercially available
Grignard reagents.
Initially, our plan was to synthesize a 3,3,3-trifluoropropa-
namide from N,O-dimethylhydroxylamine in order to create a
Weinreb amide. Unfortunately, the coupling of 3,3,3-
trifluoropropanoic acid with N,O-dimethylhydroxylamine
produced low and inconsistent yields, varying from 0 to
33%. Although Weinreb amides are versatile synthetic
intermediates, morpholine amides also participate in similar
functional group transformations.19,20 Accordingly, morpholine
3,3,3-trifluoropropanamide (1) became the target and is
synthesized in quantitative yield from morpholine and 3,3,3-
trifluoropropanoic acid using EDCI, HOBT, and triethylamine
(Figure 2). This preparation of 1 is an alternative to the
Figure 2. Preparation of morpholine 3,3,3-trifluoropropanamide (1).
previously reported syntheses that require N-pentafluoropropyl
morpholines as starting materials.21,22 The morpholine 3,3,3-
trifluoropropanamide (1) is a stable, anhydrous solid that can
Figure 3. Synthesis of β-fluoro-α,β-unsaturated amides 2−13 using
reagent 1 and Grignard reagents. Isolated yields are shown; see the
Supporting Information for details.
1
be freely weighed in the air. It was characterized by H, 13C,
and 19F NMR spectroscopy, mass spectrometry, combustion
analysis, and X-ray crystallography.23 Crystals of 1 from a 1:1
solution of hexanes and cyclohexanes were used for X-ray
analysis, and data were collected at T = 90 K, using Mo Kα
radiation on a Bruker Kappa Apex-II DUO diffractometer.
Also, 1 displays high solubility in common organic solvents,
such as tetrahydrofuran (THF), diethyl ether (Et2O), ethyl
acetate (EtOAc), acetonitrile (CH3CN), benzene, toluene, and
dichloromethane (CH2Cl2), which makes it an ideal reagent
for the subsequent production of fluoroalkenes.
Reagent 1 was treated with 2 equiv of phenyl magnesium
bromide in 1:1 THF/Et2O at −78 °C, and after 4 h, the (E)-
product 2 is obtained in 73% isolated yield (Figure 3). The
stereochemical assignment was determined by the character-
istic coupling constant between the vinyl proton and vinyl
fluoride. In the case of 2, the JHF(cis) is 19.3 Hz, which
establishes the (E)-product.23,24 Other common phenyl
Grignard reagents, such as tolyl, p-chlorophenyl, p-fluorophen-
yl, p-methoxyphenyl, and naphthyl, participate in a similar
fashion and give (E)-products 3, 4, 5, 6, and 7, respectively, in
yields of 50%−59%. Lithium salts (i.e., lithium chloride or
lithium bromide) were added to the Grignard reagents to
improve the isolated yields of products 3, 5, 6, and 7. Knochel
has previously reported the beneficial role of lithium salts in
the reactivity of Grignard reagents,25 and an increase in yield
was observed during optimization for this process. Although
methyl magnesium chloride, ethyl magnesium bromide, vinyl
magnesium bromide, and ethynyl magnesium bromide were
also added to 1, only low yields of volatile products (12%, 10%,
9%, and 11%, respectively) were isolated. The isopropyl,
cyclohexyl, and butyl Grignard reagents give products 8−10
with the expected (E)-stereoisomer as the major product in
yields at 62%−71%. The 1,3-dioxan-2-ylethyl magnesium
bromide affords 11 in the yield of 73% and enabled the
acquisition of its X-ray structure, confirming the (E)-
fluoroalkene. The o-methylthiophenyl and 2-thienyl Grignard
reagents give products 12 and 13, respectively, displaying
compatibility with ortho-substituents and heteroaromatic rings.
The ortho-product 12 was isolated as an inseparable 8:1
mixture of E/Z isomers. Lithium salts were added during the
optimization of products, 8, 11, and 12. Overall, both alkyl and
aryl Grignard reagents add to reagent 1 to create the (E)-
fluoroalkenes in modest to good yields.
We conducted a brief mechanistic analysis to gain insight
into the transformation of reagent 1 in the presence of the
Grignard reagents.23 Reagent 1 was treated with 1 equiv of
isopropyl magnesium chloride in THF-d8 and observed by 19F
NMR (Scheme 2). The β,β-difluoroacrylamide intermediate
was observed by the presence of the diagnostic signals at −76.0
and −71.2 ppm. This intermediate is similar to that proposed
during the preparation of the CBrF2-containing compound
depicted in Scheme 1.26 Following the addition of the second
equivalent of isopropyl magnesium chloride, the (E)-
fluoroalkene 8 is observed. The enolate intermediate is not
observed by 19F NMR, suggesting that the elimination of
fluoride is instantaneous. The stereochemical outcome of the
addition of nucleophiles to gem-difluoroalkenes is known in the
literature to provide the (E)-isomer with high selectivity.27
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In summary, morpholine 3,3,3-trifluoropropanamide (1),
now commercially available,28 provides access to (E)-β-fluoro-
α,β-unsaturated amides upon the addition of 2 equiv of
common alkyl, aryl, and heteroaryl Grignard reagents. It avoids
the use of toxic metals such as chromium. This one-pot
transformation provides good yields and a high level of
stereocontrol for the (E)-fluoroalkene. 19F NMR experiments
demonstrate the formation of the β,β-difluoroacrylamide as the
likely mechanistic intermediate. Also, the addition of an
organolithium reagent provides the (Z)-β-fluoro-α,β-unsatu-
rated ketone. The transformation of the morpholine amides
into other functional groups is demonstrated. Overall, reagent
1 offers a simple process for accessing fluoroalkenes, which
have a growing role in medicinal chemistry and drug design.
Scheme 2. Proposed Mechanism for the Formation (E)-β-
Fluoro-α,β-Unsaturated Amide 8 from Reagent 1 and 2
equiv of i-PrMgCl
a
a
In this scheme, 19F NMR data for the β,β-difluoroacrylamide
intermediate were obtained in THF-d8 at 471 Hz at room temperature
(rt).
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00599.
These results apply to this case, because the electronic
repulsion of the F atoms control the transition state prior to
the elimination and produce the (E)-fluoroalkene.
Morpholine amides are versatile groups that can be easily
transformed to other functional groups.19,20 Usually, they
provide access to ketones following the addition of a suitable
nucleophile. Accordingly, reagent 1 was treated with 2 equiv of
phenyl lithium in the presence of TMEDA, and the double
addition product 12 was produced in a good yield (75%) (see
reaction 1).
1
Full experimental details, characterization data, and H,
13C, and 19F NMR spectra for all new compounds
(PDF)
Accession Codes
CCDC 1948771 and 1948772 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
The ketone (14) was isolated exclusively as the (Z)-
fluoroalkene; TMEDA improved the selectivity and yields.
The characteristic JHF(trans) is 34.2 Hz, and all characterization
data for (Z)-14 matched the reported values.14 These data
suggest that the transformation of the morpholine amide to a
ketone occurs with inversion of the stereochemistry of the
fluoroalkene. These results broaden the potential utility of
reagent 1 in the stereoselective synthesis of fluoroalkenes and
are currently under investigation. Morpholine amides 2 and 7
were transformed to amine 15 and methyl ester 16,
respectively (see reactions 2 and 3).
AUTHOR INFORMATION
■
Corresponding Author
David A. Colby − Department of BioMolecular Sciences,
University of Mississippi, University, Mississippi 38677, United
States; orcid.org/0000-0002-5434-1690;
Email: dacolby@olemiss.edu
Authors
Amna T. Adam − Department of BioMolecular Sciences,
University of Mississippi, University, Mississippi 38677, United
States
Frank R. Fronczek − Department of Chemistry, Louisiana State
University, Baton Rouge, Louisiana 70803, United States;
orcid.org/0000-0001-5544-2779
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00599
Author Contributions
A.T.A. conducted the experiments and acquired the analytical
data. D.A.C. and A.T.A. wrote the manuscript and designed the
experimental approach. F.R.F. gathered and interpreted the X-
ray crystallographic data.
The conversion of morpholine amide 2 to amine 15 is
accomplished by activation with trimethyloxonium tetrafluor-
oborate in the presence of 2,6-di-tert-butylpyridine, followed
by the addition of NaBH4 (see reaction 2), which are similar to
the conditions reported by Toste and workers.17 Morpholine
amide 7 was also activated with trimethyloxonium tetrafluor-
oborate and then treated with water to produce the methyl
ester 16 (see reaction 3). Both of these reactions occur with
complete retention of the (E)-fluoroalkene and demonstrate
the potential uses of the products obtained from 1.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of Mississippi and
the National Institute of Drug Abuse (No. R15DA046795).
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Synthesis of (E)-α,β-Unsaturated Amides, Ketones, Aldehydes, and
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