Polyfluoroarylation of oxazolones: Access to non-natural fluorinated amino acids

Article abstract of DOI:10.1039/c7cc01606a

Herein, conditions are provided for the formation and use of the oxazolone enolate for the nucleophilic substitution of highly fluorinated (hetero)arenes, which after unmasking yield highly fluorinated non-natural amino acids and derivatives. In addition, the properties and chemical behavior of this new class of amino acids are explored. The utility is demonstrated in the one pot synthesis of medicinally relevant 2-aminohydantoins.

Full text of DOI:10.1039/c7cc01606a

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Polyfluoroarylation of oxazolones: access
to non-natural fluorinated amino acids†
Cite this:DOI: 10.1039/c7cc01606a
Kip A. Teegardin and Jimmie D. Weaver
*
Received 3rd March 2017,
Accepted 17th March 2017
DOI: 10.1039/c7cc01606a
rsc.li/chemcomm
Herein, conditions are provided for the formation and use of the
oxazolone enolate for the nucleophilic substitution of highly fluorinated
(hetero)arenes, which after unmasking yield highly fluorinated non-
natural amino acids and derivatives. In addition, the properties and
chemical behavior of this new class of amino acids are explored.
The utility is demonstrated in the one pot synthesis of medicinally
relevant 2-aminohydantoins.
Multifluorinated arenes and heteroarenes represent an important
motif, owing to the ability of fluorine to substantially alter the
performance of molecules in various applications (Scheme 1A).
However, in sharp contrast to their importance, there is a relative
dearth of methods that rapidly yield multifluorinated arenes, and
thus, there is a need for methods to access multifluorinated
(hetero)arenes.
Selective installation of fluorine is possible, but often is
lengthy and requires a unique strategy for every fluorination
pattern on every arene (Scheme 1B, right),1 making it less than
ideal for discovery chemistry, which demands the ability to
rapidly synthesize analogs. Alternatively, C–F functionalization
of highly fluorinated or perfluorinated (hetero)arenes is an
attractive approach, since perfluorinated arenes are relatively
inexpensive and already possess the difficult to install fluorines
in the desired locations (Scheme 1B, left). The potential advantage
of the C–F functionalization approach has been recognized by
Scheme 1 Multifluorinated arenes, defluorination as
arylation of oxazolones.
a strategy, and
others, and inroads are being made.2 Taken in conjunction addition through inductive effects.1 However, despite the feasibility
with recently developed photocatalytic C–F functionalization,3 and the potential for enhancing the pool of fluorinated aryl
considerable access to these important motifs can be realized. building blocks, many of these potential reactions remain
Perfluoroarenes are particularly well suited for nucleophilic undeveloped.
aromatic substitution, since the difficult step in such a reaction
Amino acids and derivatives are indispensable building blocks
is typically nucleophilic attack on the carbon by the incoming within mainstream organic chemistry. The addition of an oxazolone
nucleophile. The small size and the electronegative nature of enolate to an electrophile is a common strategy to elaborate the
the fluoride facilitates the addition step, and additional ring alpha amino acid motif.4 a-Arylation of the oxazolone enolate has
fluorination (except para-fluorination) further accelerates the been accomplished via Ag-mediated arylation with diaryliodonium
salts (Scheme 1C and eqn (1)),4d Pd-catalyzed cross-coupling of
aryl-bromides (eqn (2)),5 and pyridine addition via nucleophilic
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.
addition to N-tosylated pyridines.4a However, these methods do
E-mail: jimmie.weaver@okstate.edu
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc01606a little to access amino acids that possess highly fluorinated
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arenes, because the requisite fluorinated starting materials are halogenated solvents gave little to no conversion (entries 5–7).
not available. Additionally, while these methods proved useful To facilitate reaction scale up, we simultaneously reduced the
for accessing tertiary carbons, secondary carbons were never arene loading and concentrated the reaction to 1 M (entry 8)
obtained. We posited that the oxazolone enolate might undergo which smoothly proceeded to full conversion. Next, we evaluated a
uncatalyzed substitution of the perfluoroarenes, via nucleophilic less activated arene, octafluorotoluene (b), instead of pentafluoro-
aromatic substitution (SNAr), and because of the anticipated pyridine (entry 9), but unfortunately, it gave very low conversion
diminishment of nucleophilicity of the product, would cleanly under these conditions.
provide the product without over arylation. Importantly, if successful,
this would provide rapid and facile access to non-natural multi- (TMG-H+, pKa(MeCN) = 23.3 compared to B18.8 for DIPEA-H+).9
fluoroarylated amino acids.
However, upon switching to stronger base, tetramethyl guanidine
We observed complete conversion, even at À20 1C (entry 10).
The oxazolone is a versatile nucleophile which can conceivably Lower temperatures were necessary to avoid TMG addition to
undergo addition at C2, C4, and even the C5-oxygen bond.6 The the perfluoroarenes (not shown).
only example of SNAr-type reactions with oxazolones is the addition
Thus, with the use of tetramethylguanidine (TMG) at À20 1C, we
to 2-nitroarenes, which undergoes subsequent cyclization with the were able achieve full conversion of 1, using just 1.025 equivalents of
nitro functional group to give indazole products (eqn (3)).7 Though octafluorotoluene (b, entry 11). When we applied these reaction
the reaction leads to a different product, it suggests that oxazolone conditions to pentafluoropyridine (a, entry 12) we observed
enolate might be a competent nucleophile in the addition to quantitative conversion to the product by 19F NMR, suggesting
perfluoroarenes.
that the TMG conditions would have a broader scope.
We started our investigation using 2-phenyloxazol-5(4H)-one
With the optimal conditions in hand (entry 12), we were
(1, Table 1) derived from glycine with pentafluoropyridine and prepared to explore the scope. Typically, oxazolones are not
diisopropylamine (DIPEA) in acetonitrile which were optimal easily isolated due to their predisposition for ring opening, and
conditions in the analogous addition of Meldrum’s acid enolate.8 instead are usually derivatized immediately to a more stable
Initially, we ran the reaction at 45 1C (entry 1) but found the reaction molecule.4b This is easily accomplished under acidic conditions,
gave full conversion at room temperature, giving complete since the oxazolone behaves as an activated ester. We explored the
conversion to the C4-arylation product within just 20 min (entry ring opening of the oxazolone with alcohols to form perfluoroaryl
2). Owing to the relatively fast addition, we were able to lower N-benzoyl protected esters (Scheme 2). We found protonation of
the amount of the arene to 1.025 equiv. (entry 3) without any the oxazolone under anhydrous conditions was the key to high
detectable diminishment of conversion. Previously, we have yield and that this was best accomplished using catalytic amounts
observed DIPEA can undergo a slow N-substitution/dealkylation trifluoroacetic acid in dry alcohol.
sequence when subjected to highly electrophilic perfluoro-
The scope of the one pot perfluoroarylation and esterification
arenes at elevated temperatures.3d Consequently, by keeping of the oxazolone was explored (Scheme 2). Generally, the reaction
the amount of excess perfluoroarene low (0.025 equiv.) and scope was very good and worked well with many of the commercially
reactions at room temperature, the amine substituted product available perfluoroarenes. No undesired reactivity was observed
was not observed. A solvent screen (entries 2–7) revealed polar with esters (2a) or ketones (2b). Less activated octafluorotoluene,
aprotic solvents work best, while ethereal, hydrocarbon, and octafluoronapthalene, and decafluorobiphenyl all reacted to
give the expected product in excellent yields (2c, 2f, and 2g).
Table 1 Optimization of reaction conditionsa
Entry Conditions
Arene (equiv.) Amine (equiv.) T (1C) % conv.
1
2
3
4
5
6
7
8
0.3 M ACN
0.3 M ACN
0.3 M DMF
0.3 M DMSO a (2)
0.3 M THF
0.3 M Tol
a (2)
a (2)
a (2)
DIPEA (3)
DIPEA (3)
DIPEA (3)
DIPEA (3)
DIPEA (3)
DIPEA (3)
DIPEA (3)
DIPEA (3)
DIPEA (3)
TMG (2.4)
TMG (2.05)
TMG (2.05)
45
22
22
22
22
22
22
22
22
100
100
100
100
24
a (2)
a (2)
o5
0.3 M DCM a (2)
25
1 M ACN
1 M ACN
1 M ACN
1 M ACN
1 M ACN
a (1.025)
b (2)
b (2)
b (1.025)
a (1.025)
100
o5
100
100
100
9
10
11
12
À20
À20
À20
a
Conversion determined by 19F NMR after 30 min.
Scheme 2 Arylation and esterification of oxazolone.
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Both benzoxazoles (2h) and benzonitriles (2i) underwent arylation
and esterification in good yield. Comparison of pyridine products
2d and 2e revealed the preference for substitution of the 4-fluoro
over that of 3-chloro leaving group. This is consistent with a SNAr
reaction, and is expected, as fluorine is the preferred nucleofuge
and attack of the 4-position maximizes delocalization of the charge
in the Meisenheimer complex.
However, substitution of 4-chlorotetrafluoropyridine (see ESI†)
leads primarily to substitution of the chloride, rather than sub-
stituting at the 2-fluoro position, to give 2d as the major product.
This suggests, in this case, that the regioselectivity is primarily
dictated by the electronics of the arene rather than the nucleofuge.
Next, we explored the ring opening of oxazolones with water
which would provide direct access to non-natural N-benzoyl
protected amino acids in a rapid and facile manner (Scheme 3).
We were pleased to see that the perfluoroarylated oxazolone
intermediates could be efficiently hydrolyzed (3a–3e). However, since
facilitating access to more elaborate fluorinated building blocks is
our primary objective, we also developed chromatography-free
conditions that were amenable to scaling, and allowed us to
synthesize the amino acids derivatives on a gram scale with
minimal effort. After initial removal of MeCN, the crude acids were
extracted with CHCl3, washed with acidic brine, and stripped of
solvent in vacuo. Next, the acid was washed with hexanes and trace
dichloromethane to selectively extract the impurities and yield
pure acids. This process was applied successfully on a gram
scale for several substrates (3a–3c), suggesting the method may
be useful for making more sizeable quantities of the N-benzoyl
protected acids.
Next, we probed the deprotection of the N-benzoyl groups in
hopes of accessing the free amino acids. Unfortunately, in the
case of pyridine derived 3a, standard deprotection conditions
of refluxing in concentrated HCl led to the deprotected and
decarboxylated ammonium salts. The amino acid derivatives
apparently underwent a thermal decarboxylation, however it was
not clear whether debenzoylation occurred prior to or following
decarboxylation. Fortunately, after lowering the reaction temperature
to 60 1C, we found that the amino acids underwent smooth
debenzoylation, but did not undergo the decarboxylation.
Thus, by subjecting acids (3a–c, Scheme 4) to aqueous HCl
carefully heated to 60 1C, we acquired the unprotected amino
acids in quantitative yields. NMR doping experiments were
Scheme 4 Debenzoylation of amino acids and Schiff base mediated
decarboxylation.
performed, in which the isolated hydrochloride salts of amino
acids (4a–c) were added after prolonged heating in HCl (see
ESI†), and confirmed that debenzoylation occurs prior to
decarboxylation.
Alternatively, upon exposure to acetone the amino acid salts
(4a–c) undergo rapid and quantitative decarboxylative protonation.
Presumably, this takes place through a transiently formed Schiff
base, which facilitates the decarboxylation and then undergoes
hydrolysis to form (5a–c).10 Given the high yielding and facile nature
of each step, the addition of oxazolone to perfluoroarenes is an
attractive strategy to access highly fluorinated benzylic amine
derivatives such as 5a–c.
Having generated a strategy to access a novel class of fluorinated
amino acids and our own experience with the unexpected decarb-
oxylation of the amino acid derivatives, we thought it appropriate
to explore the thermal stability of several derivatives. Thus,
we performed thermal gravimetric analysis on several of the
products we had formed (Scheme 5). As expected the benzoyl
protected esters (2d) were thermally stable and gradually sub-
limed. However, the benzoyl protected acids 3a–c all underwent
decarboxylation at 108 1C, 132 1C, and 159 1C, respectively. The
differences in decarboxylation temperature seem to reflect the
stability of a benzylic anion, however, it may also correlate to
basicity of the amide motif. Comparison of 3b and 4b shows
that the HCl salts actually undergo a more facile thermal
decarboxylation than the N-benzoylated substrate, and is consistent
with our previous findings in Scheme 4. However, 4c failed to
undergo decarboxylation and instead gradually sublimed. It may be
Scheme 5 Thermal gravimetric analysis of a-multifluoroaryl amino acid
derivatives.
Scheme 3 Multifluoroaryl amino acids.
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In contrast, the guanidine serves in place of the activated carbon
and is attached to the C-terminus. To our knowledge, this
cyclization approach is novel and demonstrates the potential for
a one-pot, three component coupling that could be used to rapidly
explore the chemical space surrounding this important motif.
In summary, we have shown that the oxazolone enolate is
capable of nucleophilic aromatic substitution and can be utilized
to rapidly form non-natural fluorinated amino acid derivatives.
Importantly, the reaction is highly selective both in terms of C–F
and oxazolone regioselectivity. Furthermore, we have provided
conditions that allow transformation of the product to valuable
building blocks, namely, N-Bz esters, N-Bz acids, acid-HCl salts,
and by way of Schiff-base decarboxylation, the benzylic amines.
Furthermore, we have reported the behavior of these compounds
towards thermal decarboxylation, which indicate that the
compounds should be stable at room temperature. Finally, we
demonstrate the utility of the reaction and its product by
demonstrating its use in a 3-component reaction, which allows
rapid access 2-aminohydantoins, a biologically relevant motif.
Scheme 6 Fully substituted amino acid esters.
Notes and references
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Scheme 7 One pot multicomponent synthesis of 2-aminohydantoins.
possible that the 4c is sufficiently acidic that it instead sublimed
through a small equilibrium of neutral (or potentially zwitterionic)
amino acid.
Next, we evaluated the perfluoroarylations of substituted
oxazolones, which yield fully substituted, non-natural amino
acid derivatives (Scheme 6). Upon additional substitution of the
oxazolone, the carbonyl is permanently formed, which is prone
to opening by nucleophiles, including TMG. We were pleased to
see that even the substituted oxazolone enolate underwent
selective C4-addition to give the desired amino acids, rather
than C2-addition which has been observed for substituted
oxazolones.6,11 However, in order to be able to derivatize in the
second step, we found it necessary to utilize DIPEA as the base.
Perfluoroarylated amino acid esters were derived from alanine,
leucine, methionine, and phenylalanine in good yield (6a–d).
When we utilized TMG as the base, we found that after
arylation the TMG would undergo nucleophilic ring opening to
form N-acylated guanidines, which upon heating in HCl under-
went debenzoylation and cyclization with extrusion of dimethyl
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