Palladium-Catalyzed Cascade Difluoroalkylation/Cyclization of N-Propargylamides: Synthesis of Oxazoles and Oxazolines

Article abstract of DOI:10.1021/acs.joc.8b02111

A palladium-catalyzed process to construct oxazoles and oxazolines with broad functional-group tolerance has been developed, and the method introduces difluoromethyl groups into heterocycles in a one-pot fashion. This system uses a carbonyl oxygen as the acceptor for the addition of a vinylpalladium intermediate to achieve the cyclization. Oxazoline derivatives are generated as the Z-isomer with high stereoselectivity. Additionally, we validated the tentative mechanism of this reaction.

Full text of DOI:10.1021/acs.joc.8b02111

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Article
Palladium-Catalyzed Cascade Difluoroalkylation/Cyclization
of N-Propargylamides: Synthesis of Oxazoles and Oxazolines
Jun-Wei Ma, Qiang Wang, Xin-Gang Wang, and Yong-Min Liang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02111 • Publication Date (Web): 15 Oct 2018
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Palladium-Catalyzed Cascade Difluoroalkylation/Cyclization of
N-Propargylamides: Synthesis of Oxazoles and Oxazolines
Jun-Wei Ma, Qiang Wang, Xin-Gang Wang and Yong-Min Liang*
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State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
Abstract
A palladium-catalyzed process to construct oxazoles and oxazolines with broad
functional-group tolerance has been developed, and the method introduces difluoromethyl
groups into heterocycles in a one-pot fashion. This system uses a carbonyl oxygen as the
acceptor for the addition of a vinylpalladium intermediate to achieve the cyclization.
Oxazoline derivatives are generated as the Z-isomer with high stereoselectivity. Additionally,
we validated the tentative mechanism of this reaction.
Introduction
Difluoromethyl moieties, serve as isosteric and isopolar analogs of oxygen atoms as well
as lipophilic hydrogen-bond donors, and they endow molecular scaffolds with enhanced
biological activities, hydrophobicity, solubility, metabolic stability, and bulk properties
common to organic substances.1 At the same time, difluoromethyl groups have a significant
impact on the acidity, electronic properties, and reactivity of proximate functional groups.2
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Therefore, the development of novel methods to introduce difluorinated groups into
molecules, with concomitant constructing of useful scaffolds in adjacent positions, is of
fundamental interest to the field of fluorine chemistry.
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Alkyl halodifluoroacetates,3 recognized as appealing difluorinated reagents, are
frequently utilized in transition-metal catalysis4 and visible light photocatalysis5. In particular,
alkyne cascade difluoromethylation/cyclization progress5a, 6 with RfX (X = I and Br) is an
attractive and powerful method to generate difluorinated cycloadducts. This protocol starts
from the electrophilic radical addition of CF2CO2Et radical addition to alkynes with the
generation of carbon radical intermediates, which subsequently participate in intramolecular
cyclization reactions by trapping with aromatic rings or nucleophiles. Several successful cases
have been reported in recent years (Scheme 1 a-c). Such limited results can be largely
attributed to structural modifications of electron-rich substrates and challenges in designing
applicable oxidation systems. Further research on the versatility and efficiency of this
strategy is highly desired for the preparation of difluoroalkylated cycloadducts. According to
previous literature, the Nevado and Chaladaj groups as well as our group have developed a
palladium-catalyzed process to realize difluorofunctionalizations.7
A vinylpalladium
intermediate was invoked as an electrophilic coupling partner in the catalytic cycle, providing
insights into new synthetic routes involving tandem difluoroalkylation/cyclization reactions.
Oxazoles and oxazolines are ubiquitous in bioactive natural products,8 drugs,9 ligands,10
and functional materials11. Tremendous efforts have been devoted to accessing oxazole or
oxazoline backbones bearing diverse substituents, such as aryl, azide, sulfonyl, peroxy, acyl,
and halogens.12, 13 To the best of our knowledge, the carbonyl oxygen of N-propargylamides
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has been considered an applicable nucleophilic site due to its high resonance stabilization
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from the carbon-oxygen and nitrogen-carbon bonds. Therefore, we present
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palladium-catalyzed approach to forming difluoroalkylated oxazoles and oxazolines utilizing
readily prepared N-propargylamide.
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Accompanying the introduction of difluoroalkyl radicals into terminal propargyl amides,
a subsequent stereoselective cis-addition of the oxygen nucleophile generates the desired
difluoro-substituted heterocycles under Pd catalysis (Scheme 1). A difluoroalkyl unit
(CF2CH2-R or CF2-HC=CR1R2) and a new C-O bond are formed sequentially in one pot. Both
Z-oxazolines and oxazoles (through a base-induced tautomerization) could be obtained from
a variety of substrates. This protocol serves as an ideal method for generating difluorinated
derivatives and developing further functional group-selective reactions.
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Scheme 1 Intramolecular difluoroalkylation of alkynes.
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Results and Discussion
Our initial investigation commenced by utilizing N-propargylbenzamide as the standard
substrate. The formation of difluoroalkyl oxazole 2aa was observed in the presence of
Pd2(dba)3 (10 mol %), DavePhos (20 mol %) and excess ICF2COOEt (1.5 equiv.) at 60 °C in DCE
for 23 h. Further screening of the reaction conditions indicated that the catalyst and matched
ligand were the primary factors influencing the outcome of this reaction. Pd(OAc)2 proved to
be the most suitable catalyst as it gave product 2aa in a promising yield of 20% (Table 1,
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entry 3). A short survey on ligands revealed that t-BuDavePhos was superior to other ligands
as it provided a higher reaction efficiency (64%, entry 5). Better results were not observed
when using other bases (entries 8–11). Other solvents, such as 1,4-dioxane, ethyl acetate and
THF, led to lower yields of the product (entries 12–14). When the equivalents of ethyl
iododifluoroacetate was decreased from 1.5 equiv. to 1.0 equiv., the reaction still provided
an acceptable yield of 52% (entry 15). The yield became 33% when the catalyst loading was
lowered to 5 mol% (entry 16).
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Table 1 Optimization of the reaction conditions.a, e
Entry
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Catalyst
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ligand
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DavePhos
DavePhos
PPh3
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Cy-DPEPhos
L1
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t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
Additive
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
t-BuOLi
Cs2CO3
Et3N
TMEDA
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Yieldd (%)
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trace
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t
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DCE
DCE
DCE
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16c
1,4-dioxane
ethyl acetate
THF
DCE
DCE
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1aa (0.2 mmol), ethyl iododifluoroacetate (0.3 mmol), catalyst (10 mol %), ligand (20 mol %), additive
b
(0.3 mmol) in solvent (1.0 mL) at 60 °C for 23 h, unless noted otherwise. Ethyl iododifluoroacetate (0.2
mmol). Pd(OAc)2 (5 mol %), t-BuDavePhos (10 mol %). Yields of isolated products. 2aa could hardly
c
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be observed in the copper-catalyzed condition (shown in Scheme 1c).
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Scheme 2 Reaction scope for the synthesis of difluoromethylated oxazoles.a, b
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a 1aa (0.2 mmol), ethyl iododifluoroacetate (0.3 mmol), Pd(OAc)2 (10 mol %), t-BuDavePhos (20 mol %), 1.5 equiv.
of Na3PO4 (0.3 mmol) in DCE at 60 °C for 23 h. b Yields of the isolated products. c This reaction was performed at
80 °C.
With the optimized conditions in hand, the substrate scope of this transformation was
then evaluated. It can be seen from Scheme 2 that a series of ortho-, meta-, and
para-substituted aryl susbtrates were tolerated and gave the corresponding products
(2aa-2ao) in moderate to good yields. Substituents, such as halogen, methyl, methoxy,
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acetoxy, trifluoromethyl and chloromethyl groups, were compatible with this reaction.
Meta-substitution led to lower yields of the oxazole derivatives compared with
corresponding substituents in the ortho- and para- positions. The standard conditions were
also applied to multisubstituted terminal propargyl amides (2ap-2au). Notably, biologically
active perfluorophenyl oxazole (2as) was well suited for this transformation. Heteroaromatic
substrates (2av-2az) and a sterically hindered naphthyl substrate (2ba) were tolerated under
the standard reaction conditions as well. When an aliphatic substituted N-propargylamide
was used, the reaction provided the desired difluoroalkylation product (2bb) in 46% yield.
Table 2 Optimization of the reaction conditions.a
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Entry
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ligand
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Additive
Na3PO4
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K3PO4
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Solvent
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DCE
DCE
DCE
Yieldc (%)
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75
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t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
t-BuDavePhos
DCE
DCE
1,4-dioxane
ethyl acetate
THF
K3PO4
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3a (0.2 mmol), ethyl iododifluoroacetate (0.3 mmol), catalyst (10 mol %), ligand (20 mol %), additive
b
(0.3 mmol) in solvent (1.0 mL) at 80 °C for 23 h, unless noted otherwise. Reaction performed at 60 °C.
c Yields of isolated products.
Next, we optimized the reaction conditions for the synthesis of oxazoline products,
using α,α-disubstituted propynyl amides as the standard substrate. A series of optimization
experiments were performed with 3a under the Pd(OAc)2/t-BuDavePhos catalyst system. A
higher efficiency was achieved for this reaction by increasing the temperature from 60 °C to
80 °C, and the yield increased from 58% to 70% (Table 2, entries 1-2). Compared with Na3PO4,
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K3PO4 gave a superior yield of 4a (78%, entry 3). Subsequent adjustments of the additives
and solvents produced lower yields of the oxazoline products (entries 4-9).
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Scheme 3 Reaction scope for the synthesis of difluoromethylated oxazolines.a, b
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a 3a (0.2 mmol), ethyl iododifluoroacetate (0.3 mmol), Pd(OAc)2 (10 mol %), t-BuDavePhos (20 mol %), K3PO4 (0.3
mmol) in DCE at 80 °C for 23 h. b Yields of the isolated products.
Under the optimized conditions, we commenced our investigations and found that this
method could afford various oxazoline derivatives in satisfactory yields with complete
stereocontrol in favor of the Z isomer (Scheme 3). Only occasionally were trace amounts of
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E-products detected in this reaction system. Broad substrate scope and functional group
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tolerance were observed, and electron-poor and electron-rich substituted phenyl groups,
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alkyl chains, and (hetero)aromatics were all tolerated (4a-4l).
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spiro-fused
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N-propargylamide and α,β-unsaturated amide were also suitable for the transformation
providing 4b in 64% and 4k in 42% yield, respectively.
Moreover, further explorations of the synthetic utility and generality of this strategy
were conducted (Scheme 4). As a representative example, the aminodifluoroalkylation of 1aa
on a 6.28 mmol scale offered an efficient gram scale synthesis of 2aa in 49% yield. Notablly,
perfluoroalkyl iodide is an applicable fluoroalkyl source for this transformation as well. This
trend proved this method is an excellent platform for the synthesis of functionalized
perfluoroalkylated compounds. In the present literature, we found that difluoromethylated
product 2aa could be readily hydrolyzed to carboxylic acid 5 via K2CO3-promoted hydrolysis.
This reaction provides good opportunities for downstream transformations.14
Scheme 4. (1) Scaleup experiment. (2) Perfluoroalkylated compounds 2bc and 4m.
(3) Hydrolysis reaction.
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Scheme 5. Proposed pathways.
Scheme 6. Mechanistic Investigation.
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Three plausible routes for the formation of oxazoline products in the Z-configuration are
proposed as shown in Scheme 5: (1) a difluoromethyl-substituted N-propargylamide
intermediate is generated through Sonogashira coupling and then undergoes cyclization and
protonation to generate the desired product under the assistance of Pd (path A); (2) the
cyclization of the N-propargylamide initiated by palladium leads to a methylene-2-oxazoline,
and the following difluoromethylation would give Z-4a as the major product due to steric
effects; and (3) in the presence of Pd, the difluoromethyl radical reacts with
N-propargylamide to form the six-membered cyclic vinylpalladium intermediate,15 which
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afford Z-products via reductive elimination.
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To further elucidate the mechanism, we conducted a series of trapping experiments
and deuterium labeling experiments to account for this reaction (Scheme 6). The
radical-clock experiment was performed by using 1,1-diphenylethylene as a radical scavenger.
A mixture of 6 and 7 was obtained with yields of 24% and 34%, respectively, as determined
by GC-MS. The addition of TEMPO (1.0 equiv.) to the reaction mixture completely quenched
the reaction by forming the TEMPO–CF2CO2Et adduct in 57% yield. These trapping
experiments indicated that a difluoroalkyl radical is present in the catalytic system. Next, we
performed deuterium labeling studies with deuterated N-propargylamide 3a-d (D = 99%).
The standard reaction afforded product 4a-d with 61% D incorporation at the alkenyl
position. This result was incompatible with path A. A photocatalytic experiment confirmed
that the Z-configuration (8) is more favored in the addition of the ICF2COOEt to
α,α-disubstituted propynyl amides under radical processes (see the Supporting Information).
Then, we tested 8 under the standard conditions and synthesized 4a in moderate yield. The
desired product was obtained in low yield from control experiment (Scheme 6-f), therefore,
path B is unlikely to be the active mechanism of this reaction. Thus, we tend to favor path C.
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Scheme 7. Plausible Mechanism.
The tentative mechanistic proposal consistent with the aforementioned experimental
results is depicted in Scheme 7. Our proposal is based on the hypothesis that the
electrophilic difluoroalkyl radical is induced by a palladium-complex and then is trapped by
the alkene, producing vinyl radical A.7 The subsequent recombination with Pd(I)I would give
key Pd(II) species B via a single-electron transfer pathway (SET). Then, C is generated in the
presence of effective ligands on the metal.15 Assisted by phosphate, C is converted to D,
which undergoes reductive elimination to afford Z-product E with regeneration of Pd(0). F is
formed through a base-induced tautomerization when the methylene hydrogen exists in the
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4-position of the oxazoline. Additionally, the zero-valent palladium catalyst forms the new
reactive species that can participate in Pd-catalyst turnover.
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Conclusion
In summary, compared with previous protocols using electron-rich substrates to realize
cascade difluoroalkylation/cyclization reactions, this palladium-catalyzed strategy allowed facile
access to difluoromethyl oxazoles and oxazolines from readily accessible N-propargylamides , and
the method shows good functional-group compatibility, broad potential applicability, and high
regio- and stereoselectivity,. Perfluoroalkyl iodides were also suitable for the generation of
perfluoroalkyl heterocycles. Further studies to explore the derivative reactions as well as to
define the mechanism are currently underway in our laboratory.
Experimental Section
General Methods. For Column chromatography, 200-300 mesh silica gel was employed.
Analytical TLC was performed with silica gel GF254 plates. 1H NMR (400 MHz), 13C NMR (100 MHz)
and 19F NMR (376 MHz) were recorded in CDCl3 using TMS as internal standard. All products
were further characterized by high resolution mass spectra (HRMS); copies of their H NMR, 13C
1
NMR and 19F NMR spectra are provided. The HRMS was obtained using a Q-TOF instrument
equipped with ESI source. Data collections for crystal structure were performed at room
temperature (293 K) using Mo Kα radiation on a Bruker APEXII diffractometer. Unless otherwise
noted, reactions were carried out under an argon atmosphere. Commercially available reagents
were used without further purification. All solvents were dried under standard method.
General methods to prepare N-Propargylamides.16
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A propargylic amine was dissolved in a dry DCM solution of Et3N (1.0 equiv.), DMAP (0.05 equiv.),
and the acid chloride (1.0 equiv.) was added dropwise at 0 °C . The mixture was stirred overnight
at room temperature. After the reaction was completed, the mixture was quenched with water
and extracted with CH2Cl2. The combined organic layer was washed with brine and then dried
over anhydrous magnesium sulfate. The crude product was concentrated in vacuo and purified
by column chromatography on silica gel using ethyl acetate/n-hexane as the eluent to give the
corresponding N-Propargylamide.
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General Procedures for the Synthesis of 2.
In a 10 mL tube, N-propargylamide 1 (0.20 mmol), Na3PO4 (49.2 mg, 0.30 mmol, 1.5 equiv.),
Pd(OAc)2 (4.5mg, 10 mol %), t-BuDavePhos (13.7mg, 20 mol %) were added and charged with
argon more than three times. Then, ethyl difluoroiodoacetate (44 μL, 0.30 mmol) dissolved in
DCE (1.0 mL) was injected into the tube. The reaction mixture was stirring at 60 °C for 23 h. After
this time, the residue was purified with chromatography column on silica gel or preparative TLC
(PTLC) to afford the final product 2.
General Procedures for the Synthesis of the Products 4.
In a 10 mL tube, N-propargylamide 3 (0.20 mmol), K3PO4 (63.7 mg, 0.30 mmol, 1.5 equiv.),
Pd(OAc)2 (4.5mg, 10 mol %), t-BuDavePhos (13.7mg, 20 mol %) were added and charged with
argon more than three times. Then, ethyl difluoroiodoacetate (44 μL, 0.30 mmol) dissolved in
DCE (1.0 mL) was injected into the tube. The reaction mixture was stirring at 80 °C for 23 h. After
this time, the residue was purified with chromatography column on silica gel or preparative TLC
(PTLC) to afford the final product 4.
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Characterization Data of Products 2aa-2bc, 4a-4m, 5, 9 and deuterium labeling experiments.
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ethyl 2,2-difluoro-3-(2-phenyloxazol-5-yl)propanoate (2aa). Rf = 0.40 (hexane:ethyl acetate
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10:1) ; Colourless oil; 35.9 mg (64%) ; H NMR (400 MHz, Chloroform-d) δ 8.03 – 7.98 (m, 2H),
7.47 – 7.42 (m, 3H), 7.09 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.59 (t, J = 15.0 Hz, 2H), 1.30 (t, J = 7.2 Hz,
3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.31; 13C NMR (101 MHz, Chloroform-d) δ 163.0 (t, J
= 31.9 Hz), 162.0 , 142.3 (t, J = 5.5 Hz), 130.4 , 128.7 , 127.8 , 126.9 , 126.1 , 113.4 (t, J = 253.4 Hz),
63.2 , 31.7 (t, J = 26.4 Hz), 13.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H14F2NO3 282.0936;
Found 282.0932.
ethyl 2,2-difluoro-3-(2-(p-tolyl)oxazol-5-yl)propanoate (2ab). Rf = 0.60 (hexane:ethyl acetate
10:1) ; Yellow oil; 34.2 mg (58%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.2 Hz, 2H), 7.26
(d, J = 8.2 Hz, 2H), 7.06 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.58 (t, J = 15.0 Hz, 2H), 2.40 (s, 3H), 1.31 (t,
J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.29; 13C NMR (101 MHz, Chloroform-d) δ
163.1 (t, J = 31.9 Hz), 162.4 , 142.0 (t, J = 5.5 Hz), 140.8 , 129.5 , 127.8 , 126.2 , 124.4 , 113.5 (t, J =
252.4Hz), 63.2 , 31.9 (t, J = 26.5 Hz), 21. 5 , 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H16F2NO3 296.1093; Found 296.1091.
ethyl 2,2-difluoro-3-(2-(4-methoxyphenyl)oxazol-5-yl)propanoate (2ac). Rf
=
0.30
(hexane:ethyl acetate 10:1) ; Yellow oil; 34.3 mg (55%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.94
(d, J = 8.8 Hz, 2H), 7.04 (s, 1H), 7.00 – 6.92 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.58 (t, J =
15.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.31; 13C NMR (101
MHz, Chloroform-d) δ 163.1 (t, J = 32.1 Hz), 162.2 , 161.3 , 141.7 (t, J = 5.5 Hz), 127.9 , 127.6 ,
119.8 , 114.1 , 113.5 (t, J = 253.4 Hz), 63.3 , 55.3 , 31.8 (t, J = 26.5 Hz), 13.9 ; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C15H16F2NO4 312.1042; Found 312.1040.
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ethyl 2,2-difluoro-3-(2-(4-fluorophenyl)oxazol-5-yl)propanoate (2ad). Rf = 0.40 (hexane:ethyl
acetate 10:1); Yellow oil; 30.5 mg (51%) ; 1H NMR (400 MHz, Chloroform-d) δ 8.05 – 7.96 (m, 2H),
7.20 – 7.11 (m, 2H), 7.08 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.59 (t, J = 15.0 Hz, 2H), 1.32 (t, J = 7.1 Hz,
3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.30 , -109.12; 13C NMR (101 MHz, Chloroform-d) δ
164.1 (d, J = 251.2 Hz), 163.1 (t, J = 31.9 Hz), 161.4 , 142.5 (t, J = 5.4 Hz), 128.4 (d, J = 8.7 Hz),
127.9 , 123.5 (d, J = 3.3 Hz), 116.0 (d, J = 22.1 Hz), 113.5 (t, J = 253.6 Hz), 63.3 , 31.8 (t, J = 26.5 Hz),
13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13F3NO3 300.0842; Found 300.0840.
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ethyl 3-(2-(4-chlorophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2ae). Rf = 0.30 (hexane:ethyl
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acetate 10:1) ; Yellow oil; 34.0 mg (54%) ; H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 8.3 Hz,
2H), 7.43 (d, J = 8.3 Hz, 2H), 7.10 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.60 (t, J = 15.1 Hz, 2H), 1.32 (t, J
= 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.29; 13C NMR (101 MHz, Chloroform-d) δ
163.0 (t, J = 31.9 Hz), 161.3 , 142.7 (t, J = 5.2 Hz), 136.6 , 129.1 , 128.1 , 127.5 , 125.6 , 113.4 (t, J =
253.6 Hz), 63.3 , 31.8 (t, J = 26.5 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13ClF2NO3
316.0547; Found 316.0543.
ethyl 3-(2-(4-(chloromethyl)phenyl)oxazol-5-yl)-2,2-difluoropropanoate (2af). Rf = 0.30
(hexane:ethyl acetate 10:1) ; Brown oil; 34.1 mg (52%) ; 1H NMR (400 MHz, Chloroform-d) δ 8.00
(d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.10 (s, 1H), 4.62 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.60 (t,
J = 15.0 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.27; 13C NMR
(101 MHz, Chloroform-d) δ 163.1 (t, J = 32.0 Hz), 161.6 , 142.6 (t, J = 5.4 Hz), 139.7 , 129.0 , 128.0 ,
127.0 , 126.6 , 113.5 (t, J = 253.6 Hz), 63.3 , 45.6 , 31.9 (t, J = 26.4 Hz), 13.9; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C15H15ClF2NO3 330.0703; Found 330.0699.
methyl 4-(5-(3-ethoxy-2,2-difluoro-3-oxopropyl)oxazol-2-yl)benzoate (2ag). Rf
= 0.50
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(hexane:ethyl acetate 3:1) ; Brown solid; 40.0 mg (59%) ; mp 63-65 °C; H NMR (400 MHz,
Chloroform-d) δ 8.13 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.3 Hz, 2H), 7.15 (s, 1H), 4.35 (q, J = 7.1 Hz,
2H), 3.95 (s, 3H), 3.62 (t, J = 15.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz,
Chloroform-d) δ -104.24; 13C NMR (101 MHz, Chloroform-d) δ 166.3 , 163.0 (t, J = 32.1 Hz), 161.2 ,
143.3 (t, J = 5.5 Hz), 131.6 , 130.8 , 130.0 , 128.4 (t, J = 1.4 Hz), 126.1 , 114.7 (t, J = 252.6 Hz), 63.3 ,
52.3 , 31.8 (t, J = 26.5 Hz), 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H16F2NO5 340.0991;
Found 340.0990.
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ethyl 2,2-difluoro-3-(2-(m-tolyl)oxazol-5-yl)propanoate (2ah). Rf = 0.40 (hexane:ethyl acetate
10:1) ; Yellow oil; 25.4 mg (43%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.08 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.59 (t,
J = 15.0 Hz, 2H), 2.41 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.27;
13C NMR (101 MHz, Chloroform-d) δ 163.1 (t, J = 31.9 Hz), 162.3 , 142.2 (t, J = 5.5 Hz), 138.5 ,
131.3 , 128.7 , 127.8 , 126.9 , 126.8 , 123.3 , 113.5 (t, J = 253.4 Hz), 63.2 , 31.9 (t, J = 26.5 Hz),
21.3 , 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H16F2NO3 296.1093; Found 296.1091.
ethyl 3-(2-(3-bromophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2ai). Rf = 0.30 (hexane:ethyl
1
acetate 10:1) ; Yellow oil; 27.3 mg (38%) ; H NMR (400 MHz, Chloroform-d) δ 8.15 (t, J = 1.8 Hz,
1H), 7.98 – 7.88 (m, 1H), 7.62 – 7.54 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.11 (s, 1H), 4.35 (q, J = 7.1
Hz, 2H), 3.60 (t, J = 15.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ
-104.26; 13C NMR (101 MHz, Chloroform-d) δ 163.0 (t, J = 31.9 Hz), 160.7 , 143.0 (t, J = 5.3 Hz),
133.4 , 130.2 , 129.2 , 128.9 , 128.1 , 124.7 , 122.8 , 113.4 (t, J = 252.3 Hz), 63.3 , 31.8 (t, J = 26.5
Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13BrF2NO3 360.0041; Found 360.0039.
ethyl 2,2-difluoro-3-(2-(3-fluorophenyl)oxazol-5-yl)propanoate (2aj). Rf = 0.30 (hexane:ethyl
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acetate 10:1) ; Yellow oil; 20.9 mg (35%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.80 (dt, J = 7.8, 1.2
Hz, 1H), 7.73 – 7.67 (m, 1H), 7.44 (td, J = 8.1, 5.7 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.12 (s, 1H), 4.35 (q,
J = 7.2 Hz, 2H), 3.60 (td, J = 15, 0.8 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz,
Chloroform-d) δ -104.29 , -111.98; 13C NMR (101 MHz, Chloroform-d) δ 163.0 (t, J =32.0 Hz),
162.8 (d, J = 246.7 Hz), 161.0 (d, J = 3.4 Hz), 142.9 (t, J =5.5 Hz), 130.5 (d, J = 8.1 Hz), 129.0 (d, J =
8.7 Hz), 128.1 , 121.9 (d, J = 3.3 Hz), 117.5 (d, J = 21.1 Hz), 113.4(t, J =252.3 Hz) , 113.2 (d, J = 24.0
Hz), 63.3 , 31.8 (t, J = 26.4 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13F3NO3
300.0842; Found 300.0839.
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ethyl 2,2-difluoro-3-(2-(o-tolyl)oxazol-5-yl)propanoate (2ak). Rf = 0.30 (hexane:ethyl acetate
10:1) ; Yellow oil; 35.4 mg (60%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.31 – 7.23 (m, 1H), 7.08 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.59 (t, J
= 15.0 Hz, 2H), 2.41 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.27;
13C NMR (101 MHz, Chloroform-d) δ 163.1 (t, J = 32.0 Hz), 162.4 , 142.2 (t, J = 5.5 Hz), 138.5 ,
131.3 , 128.7 , 127.8 , 126.9 , 126.8 , 123.3 , 113.5 (t, J = 253.5 Hz), 63.3 , 31.9 (t, J = 26.5 Hz),
21.3 , 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H16F2NO3 296.1093; Found 296.1089.
ethyl 2,2-difluoro-3-(2-(2-methoxyphenyl)oxazol-5-yl)propanoate (2al). Rf
=
0.30
(hexane:ethyl acetate 10:1) ; Yellow oil; 31.1 mg (50%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.90
(dd, J = 8.0, 1.8 Hz, 1H), 7.46 – 7.41 (m, 1H), 7.14 (s, 1H), 7.08 – 7.00 (m, 2H), 4.33 (q, J = 7.2 Hz,
2H), 3.97 (s, 3H), 3.60 (td, J = 15.0, 0.9 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz,
Chloroform-d) δ -104.21; 13C NMR (101 MHz, Chloroform-d) δ 163.1 (t, J = 31.8Hz), 160.4 , 157.5 ,
141.7 (t, J = 5.6 Hz), 131.8 , 130.0 , 127.8 , 120.6 , 116.2 , 113.6 (t, J = 251.5 Hz), 111.9 , 63.2 ,
56.0 , 31.9 (t, J = 26.5 Hz), 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H16F2NO4 312.1042;
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Found 312.1042.
ethyl 3-(2-(2-bromophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2am). Rf
=
0.20
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(hexane:ethyl acetate 10:1) ; Yellow oil; 30.2 mg (42%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.90
(dd, J = 7.8, 1.7 Hz, 1H), 7.71 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (td, J = 7.6, 1.3 Hz, 1H), 7.30 (td, J = 8.9,
8.3, 1.5 Hz, 1H), 7.19 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.62 (t, J = 15.0 Hz, 2H), 1.32 (t, J = 7.2 Hz,
3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.18; 13C NMR (101 MHz, Chloroform-d) δ 163.0 (t, J
= 31.9 Hz), 160.5 , 142.9 (t, J = 5.5 Hz), 134.5 , 131.3 , 131.1 , 127.9 , 127.8 , 127.4 , 120.9 , 113.4
(t, J = 253.5 Hz), 63.3 , 31.8 (t, J = 26.6 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C14H13BrF2NO3 360.0041; Found 360.0043.
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ethyl 3-(2-(2-chlorophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2an). Rf = 0.30 (hexane:ethyl
acetate 10:1) ; Yellow oil; 29.0 mg (46%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.99 – 7.91 (m, 1H),
7.54 – 7.48 (m, 1H), 7.41 – 7.33 (m, 2H), 7.19 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.62 (t, J = 15.0 Hz,
2H), 1.32 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.20; 13C NMR (101 MHz,
Chloroform-d) δ 163.0 (t, J = 31.8 Hz), 156.0 , 142.9 (t, J = 5.5 Hz), 132.4 , 131.2 , 130.7 , 127.9 ,
127.8 , 126.8 , 125.9 , 113.4 (t, J = 253.5 Hz), 63.3 , 31.8 (t, J = 26.5 Hz), 13.8; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C14H13ClF2NO3 316.0547; Found 316.0546.
ethyl 2,2-difluoro-3-(2-(2-(trifluoromethyl)phenyl)oxazol-5-yl)propanoate (2ao). Rf = 0.30
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(hexane:ethyl acetate 10:1) ; Yellow oil; 34.2 mg (49%) ; H NMR (400 MHz, Chloroform-d) δ 8.02
– 7.96 (m, 1H), 7.82 (dd, J = 7.8, 1.3 Hz, 1H), 7.69 – 7.57 (m, 2H), 7.17 (s, 1H), 4.33 (q, J = 7.2 Hz,
2H), 3.61 (td, J = 15.0, 0.9 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ
-59.88 , -104.25; 13C NMR (101 MHz, Chloroform-d) δ 163.0 (t, J = 32.0 Hz), 160.0 , 143.8 (t, J =
5.5 Hz), 131.8 , 131.4 , 130.4 , 128.3 (q, J = 32.3 Hz), 128.0 , 126.9 (q, J = 5.6 Hz), 125.8 (q, J = 2.0
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Hz), 123.4 (q, J = 274.7 Hz), 113.4 (t, J = 253.5 Hz), 63.3 , 31.8 (t, J = 26.5 Hz), 13.8; HRMS (ESI-TOF)
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m/z: [M + H]+ Calcd for C15H13F5NO3 350.0810; Found 350.0808.
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(hexane:ethyl acetate 10:1) ; Yellow oil; 29.1 mg (47%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.63
(s, 2H), 7.09 (s, 1H), 7.07 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.59 (t, J = 15.2 Hz, 2H), 2.37 (s, 6H), 1.32
(t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.25; 13C NMR (101 MHz, Chloroform-d)
δ 163.1 (t, J = 31.9 Hz), 162.5 , 142.1 (t, J = 5.5 Hz), 138.4 , 132.2 , 127.7 , 126.9 , 124.0 , 113.5 (t, J
= 253.5 Hz), 63.2 , 31.9 (t, J = 26.5 Hz), 21.1 , 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H18F2NO3 310.1249; Found 310.1248.
ethyl 2,2-difluoro-3-(2-mesityloxazol-5-yl)propanoate (2aq). Rf = 0.60 (hexane:ethyl acetate
1
10:1) ; Yellow oil; 39.4 mg (61%) ; H NMR (400 MHz, Chloroform-d) δ 7.12 (s, 1H), 6.92 (s, 2H),
4.32 (q, J = 7.1 Hz, 2H), 3.57 (t, J = 15.0 Hz, 2H), 2.32 (s, 3H), 2.20 (s, 6H), 1.31 (t, J = 7.2 Hz, 3H) ;
19F NMR (376 MHz, Chloroform-d) δ -104.49; 13C NMR (101 MHz, Chloroform-d) δ 163.1 (t, J =
32.0 Hz), 162.1 , 142.1 (t, J = 5.5 Hz), 139.8 , 138.3 , 128.5 , 126.9 , 124.8 , 113.6 (t, J = 253.5 Hz),
63.2 , 31.8 (t, J = 26.4 Hz), 21.2 , 20.1 , 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H20F2NO3
324.1406; Found 324.1402.
ethyl 3-(2-(2,4-dichlorophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2ar). Rf
=
0.30
(hexane:ethyl acetate 10:1) ; Yellow oil; 31.4 mg (45%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.92
(d, J = 8.5 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 8.5, 2.1 Hz, 1H), 7.19 (s, 1H), 4.34 (q, J =
7.2 Hz, 2H), 3.62 (t, J = 15.0 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ
-104.21; 13C NMR (101 MHz, Chloroform-d) δ 162.9 (t, J = 31.9 Hz), 159.1 , 143.1 (t, J = 5.4 Hz),
136.6 , 133.0 , 131.4 , 131.0 , 128.0 , 127.3 , 124.3 , 113.3 (t, J = 253.6 Hz), 63.4 , 31.8 (t, J = 26.4
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Hz), 13.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H12Cl2F2NO3 350.0157; Found 350.0156.
ethyl 2,2-difluoro-3-(2-(perfluorophenyl)oxazol-5-yl)propanoate (2as). Rf = 0.20 (hexane:ethyl
acetate 10:1) ; Yellow oil; 27.5 mg (37%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.28 (d, J = 2.7 Hz,
1H), 4.36 (q, J = 7.1 Hz, 2H), 3.64 (td, J = 15.0, 0.9 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H) ; 19F NMR (376
MHz, Chloroform-d) δ -104.21 , -137.3 – -139.2 (m), -144.65 – -151.00 (m), -157.80 – -162.96 (m) ;
13C NMR (101 MHz, Chloroform-d) δ 162.8 (t, J = 31.9 Hz), 152.5 – 149.8 (m), 146.7 – 146.0 (m),
144.4 (t, J = 4.6 Hz), 144.0 – 143.3 (m), 141.5 – 140.7 (m), 139.6 – 138.7 (m), 137.2 – 136.4 (m),
128.4 , 113.2 (t, J = 253.7 Hz), 103.7 (td, J = 13.8, 3.9 Hz), 63.4 , 31.7 (t, J = 26.6 Hz), 13.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H9F7NO3 372.0465; Found 372.0459.
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ethyl 3-(2-(3,4-difluorophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2at). Rf
=
0.20
(hexane:ethyl acetate 10:1) ; Yellow oil; 29.2 mg (46%) ; H NMR (400 MHz, Chloroform-d) δ 7.86
7.74 (m, 2H), 7.31 – 7.21 (m, 1H), 7.10 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.60 (td, J = 15.1, 0.9 Hz,
2H), 1.34 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.33 , -133.88 (d, J = 21.4 Hz),
-136.30 (d, J = 21.3 Hz) ; 13C NMR (101 MHz, Chloroform-d) δ 163.0 (t, J = 32.0 Hz), 153.0 (d, J =
12.9 Hz), 151.7 (d, J = 13.4 Hz), 150.5 (d, J = 12.4 Hz), 149.2 (d, J = 13.0 Hz), 143.0 (t, J = 5.3 Hz),
128.2 , 124.2 (dd, J = 6.7, 3.8 Hz), 122.7 (dd, J = 6.7, 3.8 Hz), 117.9 (d, J = 17.9 Hz), 115.5 (d, J =
20.1 Hz), 113.4 (t, J = 253.6 Hz), 63.3 , 31.8 (t, J = 26.4 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C14H12F4NO3 318.0748; Found 318.0746.
ethyl 3-(2-(2,6-dichlorophenyl)oxazol-5-yl)-2,2-difluoropropanoate (2au). Rf
=
0.60
(hexane:ethyl acetate 3:1) ; Yellow oil; 33.5 mg (48%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.44 –
7.35 (m, 3H), 7.22 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.62 (t, J = 14.9 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H) ;
19F NMR (376 MHz, Chloroform-d) δ -104.27; 13C NMR (101 MHz, Chloroform-d) δ 162.9 (t, J =
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31.9 Hz), 157.0 , 143.6 (t, J = 5.5 Hz), 136.3 , 132.0 , 128.1 , 127.4 , 113.4 (t, J = 253.5 Hz), 63.3 ,
31.8 (t, J = 26.6 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H12Cl2F2NO3 350.0157;
Found 350.0158.
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ethyl 3-(2-(6-chloropyridin-3-yl)oxazol-5-yl)-2,2-difluoropropanoate (2av). Rf
=
0.20
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(hexane:ethyl acetate 10:1) ; Brown solid; 27.2 mg (43%) ; mp 60-63 °C; H NMR (400 MHz,
Chloroform-d) δ 9.01 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 8.4, 2.4 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.15
(s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.62 (t, J = 15.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz,
Chloroform-d) δ -104.26; 13C NMR (101 MHz, Chloroform-d) δ 162.9 (t, J = 32.0 Hz), 158.9 , 153.0 ,
147.4 , 143.6 (t, J = 5.1 Hz), 136.0 , 128.4 , 124.5 , 122.3 , 113.3 (t, J = 253.7 Hz), 63.4 , 31.8 (t, J =
26.4 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H12ClF2N2O3 317.0499; Found 317.0494.
ethyl 3-(2-(2-chloropyridin-3-yl)oxazol-5-yl)-2,2-difluoropropanoate (2aw). Rf
= 0.20
(hexane:ethyl acetate 10:1) ; Yellow oil; 34.1mg (54%) ; 1H NMR (400 MHz, Chloroform-d) δ 8.53 –
8.47 (m, 1H), 8.36 – 8.29 (m, 1H), 7.42 – 7.35 (m, 1H), 7.22 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.64 (t,
J = 15.0 Hz, 2H), 1.34 (td, J = 7.1, 1.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.17; 13C
NMR (101 MHz, Chloroform-d) δ 162.9 (t, J = 31.9 Hz), 158.2 , 150.5 , 148.5 , 143.9 (t, J = 5.3 Hz),
139.3 , 128.2 , 123.0 , 122.3 , 113.3 (t, J = 253.7 Hz), 63.4 , 31.8 (t, J = 26.4 Hz), 13.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H12ClF2N2O3 317.0499; Found 317.0497.
ethyl 2,2-difluoro-3-(2-(furan-2-yl)oxazol-5-yl)propanoate (2ax). Rf = 0.20 (hexane:ethyl
1
acetate 10:1) ; Yellow oil; 14.6 mg (27%) ; H NMR (400 MHz, Chloroform-d) δ 7.65 (dd, J = 3.7,
1.2 Hz, 1H), 7.44 (dd, J = 5.0, 1.2 Hz, 1H), 7.11 (dd, J = 5.1, 3.7 Hz, 1H), 7.04 (s, 1H), 4.35 (q, J = 7.2
Hz, 2H), 3.57 (t, J = 14.9 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ
-104.32; 13C NMR (101 MHz, Chloroform-d) δ 163.1 (t, J = 32.0 Hz), 158.3 , 141.9 (t, J = 5.5 Hz),
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129.6 , 128.5 , 127.9 , 127.8 , 127.8 , 113.4 (t, J = 252.1 Hz), 63.3 , 31.8 (t, J = 26.6 Hz), 13.9; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H12F2NO4 272.0729; Found 272.0727.
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acetate 10:1) ; Yellow oil; 19.5 mg (34%) ; 1H NMR (400 MHz, Chloroform-d) δ 7.58 – 7.53 (m, 1H),
7.08 (s, 1H), 7.01 (d, J = 3.5 Hz, 1H), 6.54 (dd, J = 3.5, 1.7 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.58 (t, J
= 14.9 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.32; 13C NMR (101
MHz, Chloroform-d) δ 163.0 (t, J = 31.7 Hz), 154.9 , 144.5 , 142.6 , 142.0 (t, J = 5.5 Hz), 127.8 ,
113.4 (t, J = 253.6 Hz), 111.8 , 111.6 , 63.3 , 31.8 (t, J =26.5 Hz), 13.9; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C12H12F2NO3S 288.0500; Found 288.0498.
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ethyl 3-(2-(5-chlorothiophen-2-yl)oxazol-5-yl)-2,2-difluoropropanoate (2az). Rf
= 0.20
1
(hexane:ethyl acetate 10:1) ; Yellow oil; 17.4 mg (27%) ; H NMR (400 MHz, Chloroform-d) δ 7.41
(d, J = 3.9 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J = 4.0 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.56 (td, J = 15.0,
0.9 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.32; 13C NMR (101
MHz, Chloroform-d) δ 163.0 (t, J = 31.9 Hz), 157.2 , 142.2 (t, J = 5.4 Hz), 133.5 , 128 , 127.9 , 127.2 ,
127.0 , 113.3 (t, J = 253.7 Hz), 63.4 , 31.7 (t, J = 26.5 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C12H11ClF2NO3S 322.0111; Found 322.0111.
ethyl 2,2-difluoro-3-(2-(naphthalen-1-yl)oxazol-5-yl)propanoate (2ba). Rf
=
0.30
(hexane:ethyl acetate 10:1); Yellow oil; 29.8 mg (45%) ; 1H NMR (400 MHz, Chloroform-d) δ 9.23 –
9.17 (m, 1H), 8.20 – 8.12 (m, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.68 – 7.62 (m, 1H),
7.59 – 7.52 (m, 2H), 7.24 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.66 (t, J = 15.0 Hz, 2H), 1.31 (t, J = 7.1 Hz,
3H) ; 19F NMR (376 MHz, Chloroform-d) δ -104.18; 13C NMR (101 MHz, Chloroform-d) δ 163.2 (t, J
= 31.9 Hz), 162.1 , 133.8 , 131.3 , 130.0 , 128.5 , 127.9 , 127.8 , 127.6 , 126.3 , 125.9 , 124.9 ,
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123.6 , 113.6 (t, J = 253.6 Hz), 63.3 , 31.9 (t, J = 26.5 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C18H16F2NO3 332.1093; Found 332.1088.
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ethyl 3-(2-((3r,5r,7r)-adamantan-1-yl)oxazol-5-yl)-2,2-difluoropropanoate (2bb). Rf = 0.20
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(hexane:ethyl acetate 10:1) ; Brown soild; 31.2 mg (46%) ; mp 54-57 °C; H NMR (400 MHz,
Chloroform-d) δ 6.86 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 14.9 Hz, 2H), 2.12 – 2.04 (m, 3H),
2.03 – 1.98 (m, 6H), 1.81 – 1.72 (m, 6H), 1.34 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d)
δ -104.44; 13C NMR (101 MHz, Chloroform-d) δ 171.4 , 163.2 (t, J = 32.2 Hz), 141.2 , 125.9 , 113.6
(t, J = 253.1 Hz), 63.2 , 40.1 , 36.4 , 35.5 , 31.8 (t, J = 26.5 Hz), 27.9 , 13.9; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C18H24F2NO3 340.1719; Found 340.1717.
5-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-2-phenyloxazole (2bc). Rf = 0.50 (hexane:ethyl acetate
10:1) ; Colorless oil; 20.4 mg (27%) ; 1H NMR (400 MHz, Chloroform-d) δ 8.12 – 7.98 (m, 2H), 7.52
– 7.42 (m, 3H), 7.18 (s, 1H), 3.60 (t, J = 17.3 Hz, 2H) ; 19F NMR (376 MHz, Chloroform-d) δ -80.98
(td, J = 9.5, 3.1 Hz), -108.63 – -115.20 (m), -123.90 (dt, J = 9.4, 4.2 Hz), -126.05 (dt, J = 12.4, 6.7
Hz) ; 13C NMR (101 MHz, Chloroform-d) δ 162.6 , 140.4 (t, J = 2.7 Hz), 130.7 , 128.8 , 128.8 , 127.0 ,
126.3 , 28.7 (t, J = 23.7 Hz) ; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H9F9NO 378.0535; Found
378.0534.
ethyl (Z)-3-(4,4-dimethyl-2-phenyloxazol-5(4H)-ylidene)-2,2-difluoropropanoate (4a). Rf
=
0.40 (hexane:ethyl acetate 3:1) ; Colorless oil; 48.2 mg (78%) ; 1H NMR (400 MHz, Chloroform-d) δ
8.00 – 7.95 (m, 2H), 7.57 – 7.53 (m, 1H), 7.49-7.45 (m, 2H), 5.04 (t, J = 10.4 Hz, 1H), 4.37 (q, J = 7.1
Hz, 2H), 1.49 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.34; 13C NMR
(101 MHz, Chloroform-d) δ 167.5 (t, J = 8.6 Hz), 163.9 (t, J = 34.5 Hz), 158.9 , 132.2 , 128.6 , 128.2 ,
125.6 , 112.0 (t, J = 245.9 Hz), 91.4 (t, J = 30.0 Hz), 71.3 , 62.9 , 28.9 (t, J = 2.2 Hz), 13.9; HRMS
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(ESI-TOF) m/z: [M + H]+ Calcd for C16H18F2NO3 310.1249; Found 310.1248.
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ethyl (Z)-2,2-difluoro-3-(2-phenyl-3-oxa-1-azaspiro[4.5]dec-1-en-4-ylidene)propanoate (4b).
Rf = 0.50 (hexane:ethyl acetate 3:1) ; Yellow oil; 44.7 mg (64%) ; 1H NMR (400 MHz, Chloroform-d)
δ 8.04 – 7.96 (m, 2H), 7.56 – 7.50 (m, 1H), 7.47 – 7.42 (m, 2H), 5.00 (t, J = 10.4 Hz, 1H), 4.35 (q, J =
7.1 Hz, 2H), 1.94 – 1.66 (m, 7H), 1.60 – 1.50 (m, 2H), 1.46 – 1.36 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H) ;
19F NMR (376 MHz, Chloroform-d) δ -95.89; 13C NMR (101 MHz, Chloroform-d) δ 168.0 (t, J = 8.7
Hz), 164.0 (t, J = 34.6 Hz), 158.1 , 131.9 , 128.5 , 128.2 , 126.1 , 112.2 (t, J = 245.6 Hz), 91.7 (t, J =
30.1 Hz), 74.4 , 62.8 , 38.5 (t, J = 2.2 Hz), 25.3 , 21.9 , 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H22F2NO3 350.1562; Found 350.1556.
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ethyl (Z)-3-(4,4-dimethyl-2-(p-tolyl)oxazol-5(4H)-ylidene)-2,2-difluoropropanoate (4c). Rf =
1
0.40 (hexane:ethyl acetate 3:1) ; Yellow oil; 46.5 mg (72%) ; H NMR (400 MHz, Chloroform-d) δ
7.85 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 5.02 (t, J = 10.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H),
2.41 (s, 3H), 1.48 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.21; 13C
NMR (101 MHz, Chloroform-d) δ 167.6 (t, J = 8.6 Hz), 163.9 (t, J = 34.5 Hz), 158.9 , 142. 8 , 129.3 ,
128.1 , 122.8 , 112.0 (t, J = 245.8 Hz), 91.3 (t, J = 30.0 Hz), 71.2 , 62.8 , 28.9 (t, J = 2.3 Hz), 21.6 ,
13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H20F2NO3 324.1406; Found 324.1402.
ethyl (Z)-3-(4,4-dimethyl-2-(perfluorophenyl)oxazol-5(4H)-ylidene)-2,2-difluoropropanoate
1
(4d). Rf = 0.50 (hexane:ethyl acetate 3:1) ; Yellow oil; 41.5 mg (52%) ; H NMR (400 MHz,
Chloroform-d) δ 5.09 (t, J = 10.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.53 (s, 6H), 1.35 (t, J = 7.2 Hz,
3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.99 , -134.67 – -136.58 (m), -145.96 – -148.51 (m),
-159.22 – -160.96 (m) ; 13C NMR (101 MHz, Chloroform-d) δ 166.0 (t, J = 8.1 Hz), 163.4 (t, J = 34.2
Hz), 149.9 – 149.4 (m), 147.5 – 146.4 (m), 144.9 – 143.7 (m), 142.6 – 141.5 (m), 139.7 – 138.5 (m),
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136.9 – 136.3 (m), 111.5 (t, J = 247.1 Hz), 103.3 – 102.7 (m), 93.8 – 91.6 (m), 72.0 , 63.0 (t, J =
15.0 Hz), 28.7 , 13.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H13F7NO3 400.0778; Found
400.0774.
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ethyl(Z)-3-(2-(3,5-dichlorophenyl)-4,4-dimethyloxazol-5(4H)-ylidene)-2,2- difluoropropanoate
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(4e). Rf = 0.60 (hexane:ethyl acetate 3:1) ; Yellow oil; 32.4 mg (48%) ; H NMR (400 MHz,
Chloroform-d) δ 7.85 (s, 2H), 7.52 (s, 1H), 5.06 (t, J = 10.9 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.48 (s,
6H), 1.37 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.70; 13C NMR (101 MHz,
Chloroform-d) δ 167.0 (t, J = 8.1 Hz), 163.8 (t, J = 34.3 Hz), 156.9 , 135.5 , 132.0 , 128.6 , 126.5 ,
111.8 (t, J = 247.1 Hz), 92.2 (t, J = 29.7 Hz), 71.7 , 63.1 , 28.8 (t, J = 2.2 Hz), 13.9; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C16H16Cl2F2NO3 378.0470; Found 378.0468.
ethyl (Z)-2,2-difluoro-3-(2-(4-methoxyphenyl)-4,4-dimethyloxazol-5(4H)-ylidene)propanoate
1
(4f). Rf = 0.40 (hexane:ethyl acetate 3:1) ; Yellow oil; 45.4 mg (67%) ; H NMR (400 MHz,
Chloroform-d) δ 7.91 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 5.02 (t, J = 10.4 Hz, 1H), 4.36 (q, J
= 7.2 Hz, 2H), 3.86 (s, 3H), 1.48 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d)
δ -96.21; 13C NMR (101 MHz, Chloroform-d) δ 167.7 (t, J = 8.6 Hz), 163.9 (t, J = 34.5 Hz), 162.7 ,
158.7 , 130.0 , 117.9 , 113.9 , 112.1 (t, J = 245.7 Hz), 91.1 (t, J = 30.0 Hz), 71.2 , 62.9 , 55.3 , 28.9 (t,
J = 2.2 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H20F2NO4 340.1355; Found 340.1353.
ethyl (Z)-3-(2-(2-chloropyridin-3-yl)-4,4-dimethyloxazol-5(4H)-ylidene)-2,2-
difluoropropanoate (4g). Rf = 0.30 (hexane:ethyl acetate 3:1) ; Yellow oil; 48.2 mg (70%) ; 1H
NMR (400 MHz, Chloroform-d) δ 8.55 (dd, J = 4.8, 2.0 Hz, 1H), 8.18 (dd, J = 7.7, 2.0 Hz, 1H), 7.39
(dd, J = 7.7, 4.8 Hz, 1H), 5.06 (t, J = 11.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.53 (s, 6H), 1.32 (t, J =
7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.85; 13C NMR (101 MHz, Chloroform-d) δ
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166.7 (t, J = 8.0 Hz), 163.7 (t, J = 34.3 Hz), 155.8 , 151.7 , 150.1 , 140.2 , 122.3 , 122.1 , 111.8 (t, J =
247.0 Hz), 91.9 (t, J = 29.6 Hz), 72.4 , 63.0 , 28.78 (t, J = 2.2 Hz), 13.9; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C15H16ClF2N2O3 345.0818; Found 345.0813.
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ethyl (Z)-3-(2-(6-chloropyridin-3-yl)-4,4-dimethyloxazol-5(4H)-ylidene)-2,2-
difluoropropanoate (4h). Rf = 0.20 (hexane:ethyl acetate 3:1) ; Brown solid; 36.5 mg (53%) ;
mp 66-68 °C; 1H NMR (400 MHz, Chloroform-d) δ 8.96 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 8.3, 2.4 Hz,
1H), 7.46 (d, J = 8.3 Hz, 1H), 5.07 (t, J = 10.9 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.50 (s, 6H), 1.34 (t, J
= 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.97; 13C NMR (101 MHz, Chloroform-d) δ
166.8 (t, J = 8.0 Hz), 163.7 (t, J = 34.5 Hz), 156.3 , 154.9 , 149.5 , 138.0 , 124.3 , 121.1 , 111.8 (t, J =
247.1 Hz), 92.3 (t, J = 29.6 Hz), 71.8 , 63.0 , 28.8 (t, J = 2.2 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H16ClF2N2O3 345.0818; Found 345.0815.
ethyl (Z)-3-(4,4-dimethyl-2-(thiophen-2-yl)oxazol-5(4H)-ylidene)-2,2-difluoropropanoate (4i).
Rf = 0.30 (hexane:ethyl acetate 3:1) ; Yellow oil; 34.7 mg (55%) ; 1H NMR (400 MHz, Chloroform-d)
δ 7.68 (dd, J = 3.6, 1.2 Hz, 1H), 7.55 (dd, J = 5.0, 1.2 Hz, 1H), 7.13 (dd, J = 5.0, 3.6 Hz, 1H), 5.02 (t, J
= 10.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.48 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H) ; 19F NMR (376 MHz,
Chloroform-d) δ -96.25; 13C NMR (101 MHz, Chloroform-d) δ 167.2 (t, J = 8.5 Hz), 163.8 (t, J = 34.3
Hz), 154.7 , 131.7 , 131.1 , 128.0 , 127.9 , 111.9 (t, J = 246.0 Hz), 91.5 (t, J = 30.0 Hz), 71.5 , 63.0 ,
28.9 (t, J = 2.2 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H16F2NO3S 316.0813; Found
316.0807.
ethyl
(Z)-3-(4,4-dimethyl-2-(naphthalen-1-yl)oxazol-5(4H)-ylidene)-2,2-difluoropropanoate
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(4j). Rf = 0.50 (hexane:ethyl acetate 3:1) ; Yellow oil; 36.6 mg (51%) ; H NMR (400 MHz,
Chloroform-d) δ 9.24 (d, J = 8.6 Hz, 1H), 8.15 (dd, J = 7.3, 1.2 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.90
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(d, J = 8.1 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.59 – 7.50 (m, 2H), 5.06 (t, J = 10.4 Hz, 1H), 4.33 (q, J = 7.1
Hz, 2H), 1.58 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.08; 13C NMR
(101 MHz, Chloroform-d) δ 166.8 (t, J = 8.5 Hz), 164.0 (t, J = 34.4 Hz), 158.2 , 133.6 , 133.0 , 130.8 ,
129.8 , 128.6 , 127.9 , 126.4 , 126.0 , 124.6 , 121.8 , 112.2 (t, J = 245.8 Hz), 90.9 (t, J = 30.0 Hz),
72.4 , 63.0 , 29.1 (t, J = 2.3 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20F2NO3
360.1406; Found 360.1404.
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ethyl (Z)-3-(4,4-dimethyl-2-((E)-styryl)oxazol-5(4H)-ylidene)-2,2-difluoropropanoate (4k). Rf =
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0.30 (hexane:ethyl acetate 3:1) ; Yellow oil; 28.1 mg (42%) ; H NMR (400 MHz, Chloroform-d) δ
7.54 – 7.50 (m, 2H), 7.45 (d, J = 16.3 Hz, 1H),7.42 – 7.39 (m, 3H), 6.61 (d, J = 16.3 Hz, 1H).4.98 (t, J
= 10.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.45(s, 6H), 1.35 (t, J = 7.1 Hz, 3H) ; 19F NMR (376 MHz,
Chloroform-d) δ -96.33; 13C NMR (101 MHz, Chloroform-d) δ 167.3 (t, J = 8.3 Hz), 163.9 (t, J = 34.5
Hz), 158.7 , 142.1 , 134.5 , 130.1 , 128.9 , 127.7 , 112.9 , 112.0 (t, J = 246.0 Hz), 91.0 (t, J = 29.7 Hz),
71.1 , 62.9 , 28.9 (t, J = 2.2 Hz), 13.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H20F2NO3
336.1406; Found 336.1400.
ethyl (Z)-3-(4,4-dimethyl-2-propyloxazol-5(4H)-ylidene)-2,2-difluoropropanoate (4l). Rf = 0.30
(hexane:ethyl acetate 3:1) ; Yellow oil; 22.6 mg (41%) ; 1H NMR (400 MHz, Chloroform-d) δ 4.88 (t,
J = 10.6 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 1.70 (h, J = 7.4 Hz, 2H), 1.37 (s, 6H),
1.36 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H) ; 19F NMR (376 MHz, Chloroform-d) δ -96.24; 13C
NMR (101 MHz, Chloroform-d) δ 167.8 (t, J = 8.4 Hz), 163.9 (t, J = 34.3 Hz), 162.7 , 112.0 (t, J =
245.8 Hz), 90.5 (t, J = 29.8 Hz), 70.7 , 62.9 , 29.5 , 28.8 (t, J = 2.3 Hz), 18.8 , 13.9 , 13.4; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H20F2NO3 276.1406; Found 276.1407.
(Z)-4,4-dimethyl-5-(2,2,3,3,4,4,5,5,5-nonafluoropentylidene)-2-phenyl-4,5-dihydrooxazole
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