Alkali-Induced Ring-Opening of 2-Amidodihydrofuran and Manganese-Catalyzed Aerobic Dehydrogenation Annulation: Access to Functionalized Oxazole

Article abstract of DOI:10.1021/acs.joc.7b00112

A novel and efficient synthesis of functionalized oxazoles from 2-amidodihydrofurans has been achieved by alkali-induced intramolecular C-O bond cleavage and formation using air as a green oxidant. Moreover, these functionalized oxazoles could be readily transformed into the corresponding oxazole-substituted pyrazoles and 2H-azirines.

Full text of DOI:10.1021/acs.joc.7b00112

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Article
Alkali-induced Ring-Opening of 2-Amidodihydrofuran
and Manganese Catalyzed Aerobic Dehydrogenation
Annulation: An Access to Functionalized Oxazole
Pan Li, Jingjing Zhao, Xinjian Li, and Fuwei Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00112 • Publication Date (Web): 06 Apr 2017
Downloaded from http://pubs.acs.org on April 6, 2017
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Alkali-induced Ring-Opening of 2-Amidodihydrofuran and Manganese Catalyzed Aerobic
Dehydrogenation Annulation: An Access to Functionalized Oxazole
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Pan Li, Jingjing Zhao, Xinjian Li and Fuwei Li*
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State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China.
fuweili@licp.cas.cn
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Table of content graphic
Abstract
A novel and efficient synthesis of functionalized oxazoles from 2ꢀamidodihydrofurans has been achieved by alkaliꢀinduced
intramolecular C–O bond cleavage and formation using air as a green oxidant. Moreover, these functionalized oxazoles could
be readily transformed into the corresponding oxazole substituted pyrazoles and 2Hꢀazirines.
Introduction
The cleavage and construction of chemical bonds are basic elements in catalysis and organic synthesis, their realizations
via an efficient, selective and highly atom economic manner are the long term goal for sustainable chemistry. C–O Bonds
widely exist in oxygenꢀcontaining heterocycles and functional compounds such as alcohol and ether, their catalytic cleavages
and transformations between different types for the advanced synthesis have attracted enormous interests in recent times.1
Therefore, it is highly desirable and interesting if these C–O bond breakings and formations would catalytically occur in the
diverse conversion of oxygenꢀcontaining heterocycle into another heterocyclic skeleton compound,2 especially when such
transformation simultaneously generates functional moiety for further transformations.
Oxazole skeleton is widely existed in natural products and pharmaceutical compounds,3 extensive efforts have been
devoted to the synthesis and functionalization of oxazoles.4 In particular, the asꢀprepared or in situ generated enamides are
active substrates or intermediates to yield oxazoles mainly via the following two pathways: first, intramolecular vinylation of
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the amide as indicated in the path A of Scheme 1, and these specific enamides usually need a leaving group (LG) in the
βꢀvinylic position;5 second, direct cyclization of enamide with the neighbouring olefin through oxidative C−H
functionalization,6 nevertheless, such atomꢀeconomic transformation requires strong oxidants, such as K2S2O8, PhI(OAc)2,
copper salts (Scheme 1, Path B). Compared with these two routes, the C–O bond formation of oxazole enabled by the
catalytic aerobic oxidation represents a more challenging and greener way in view of the natural and environmentally benign
character of air.7 Herein, we develop a novel nonprecious metalꢀcatalyzed procedure to synthesize the oxazole skeleton via
the oxidative cyclization of enamide with the in situ generated allene moiety8 using air as a green oxidant. In addition, the
functional substituents could also be generated onto the oxazole ring due to the uniqueness of this procedure.
Scheme 1. Reported Synthesis of Oxazoles from Enamines.
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Besides taking as a nucleophile for the annulation to yield oxazole, the amide group of 2ꢀamidodihydrofuran is also herein
proposed to be an assisting function to facilitate the ring opening of dihydrofuran via C−O bond cleavage in the presence of
base,9 which is then experimentally verified by replacing the amide with representative Ph or H, without any reaction
observed as indicated in Scheme 2. However, the 2ꢀaminodihydrofuran afforded the ring opening product 5a with a mixture
of E and Z isomer was obtained in total 44% yield with one isomer structurally confirmed by XRD (CCDC 1401603) under
the same reaction condition, which showed that ring opening of 1a indeed happened with the help of a base along with its
catalyzed decarbonylation resulting in the loss of an acetyl moiety.
Scheme 2. Investigation on the Role of Amide Substitutent for the Ring-Opening of Dihydrofurans.
Taking such unique advantage, it is hypothesized as illustrated in Scheme 3 that the 2ꢀamidodihydrofuran could go through
C−O bond cleavage to generate γꢀdicarbonyl enamide which thereafter undergoes an oxidative dehydrogenation process to
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generate the allene intermediate,8 eventually, from which the oxazoles bearing a 1,3ꢀdicarbonyl moiety would be formed via
an intramolecular nucleophilic annulation.
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Scheme 3. Our Proposed Strategy for the Synthesis of Functionalized Oxazoles from 2-Amidodihydrofurans.
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Results and Discussion
With the above assumption in mind, we started the investigation by the catalytic transformation of 1a (Table 1). Considering
that copper catalysts play a crucial role in the aerobic oxidation,10 a series of copper salts were initially selected as the
oxidation catalysts with the presence of Cs2CO3 to initiate the cyclic C−O cleavage under an air atmosphere. The expected
oxazole 2a was obtained in moderate yields (entries 1−6). Manganese catalyst, also a good singleꢀelectron oxidant,11 can
possibly facilitate the oxidization of the in situ generated 1,3ꢀdicarbonyl anion species via C–O bond cleavage of 1a to
produce corresponding alkyl radical intermediate,12 which would be easily trapped by O2 to forward the oxidative
dehydrogenation.13 Within the screened manganese catalysts, Mn(OAc)3 displayed higher efficiency (entries 7−9).
Interestingly, the transformation of 1a to 2a could also proceed in the absence of metal catalyst but only giving 24% yield
(entry 10), and no reaction occurred without base (entry 11), indicating the in situ generated 1,3ꢀdicarbonyl anion
intermediate could slowly react with O2 without a metal catalyst although which could accelerate such process.14 Present
transformation was found to be very sensitive to solvent, it proceeded smoothly in DMF and DMSO (entries 12 and 13),
however, only gave 10% yield of 2a in toluene or DCE (entries 14 and 15). K2CO3 showed the best assisting activity among
the screened bases (entries 16–18), giving 2a in 73% yield. As mentioned in Scheme 2, 5a was observed instead of 2a when
the reaction was conducted under an argon atmosphere, suggesting oxygen was expectedly involved in the oxidation step
(entry 19). However, only 47% yield of 2a was obtained in 1 atm oxygen owning to the 2a will further oxidized in an excess
of oxygen (entry 20). In addition, the yield dramatically decreased as the temperature declined, probably indicating one step
among C–O cleavage, oxidative dehydrogenation and/or annulation is significantly temperature sensitive (entries 21 and 22).
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To our delight, 78% yield of 2a could be achieved even using 0.5 equiv. of K2CO3 (entries 23 and 24). However, only 45%
yield of 2a was obtained when using 0.25 equiv. of K2CO3, and the 1a was still observed (entry 25).
Table 1. Reaction optimizationa
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entry
1
catalyst (10 mol%)
CuBr
base (equiv)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
yield (%)
45
2
CuI
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3
CuCl2
51
4
CuF2
44
5
Cu(TFA)2
Cu(OAc)2
MnCl2.4H2O
Mn(OAc)2.4H2O
Mn(OAc)3.2H2O
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19b
20c
21d
22e
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25f
24
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
Mn(OAc)3.2H2O
0
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
K2CO3 (3)
K3PO4 (3)
CsF (3)
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DMSO
DCE
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10
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
73
57
10
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
K2CO3 (1)
K2CO3 (0.5)
K2CO3 (0.25)
N. D.
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35
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a All reactions were carried out on a 0.2 mmol scale in 2 mL of solvent in a 35 mL sealed tube (total volume 50 mL) in
100 oC for 18 h. b Under argon. c Under 1 atm O2. d 90 oC. e 80 oC. f 36 h.
Having identified the optimized reaction conditions (Table 1, entry 23), we turned to examining the scope of this catalytic
transformation (Scheme 4). 2ꢀAcetamidedihydrofurans derived from various aromatic enamides (R3 = Me, with different Ar)
were initially investigated, substrates with electronꢀdonating groups (R = Me or OMe) and electronꢀwithdrawing groups (R =
F, Br, I, or NO2) were all suitable for this transformation, affording the desired oxazoles in 42% to 75% yields, respectively
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(2b–2h). Besides, other representative aromatic substrates, such as thiophene and naphthalene groups, were also well
tolerated (2i–2l). Subsequently, 2ꢀacetamideꢀdihydrofurans derived from various 1,3ꢀdicarbonyl compounds (different R1, R2)
were examined, the unsymmetrical 1,3ꢀdicarbonyl derived substrates gave the corresponding products in 40% to 75% yields,
respectively (2m–2o, 2u and 2v). These 2ꢀacetamidedihydrofurans derived from symmetrical 1,3ꢀdicarbonyl compounds
afforded desirable products in moderate to excellent yields (2p–2t), and the cyclic 2ꢀamidodihydrofurans displayed higher
activity in this transformation (2r–2t).
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Scheme 4. Catalytic Tandem Synthesis of Functionalized Oxazoles from 2-Amidodihydrofurans.
The structure of the representative oxazole 2u is further confirmed by Xꢀray single crystal diffraction (XRD, CCDC
1401540). The C5–C12 bond length is 1.368 Å indicating its C=C character, and the hydrogen atom attached to O2 suggests
the presence of alcoholic group. Moreover, it is worthy to note that a high chemical shift HNMR peak (13–18 ppm)
belonging to product 2 (except for 2r–2t) was observed which revealed the intramolecular O–H…O hydrogen bond between
the hydroxyl and ketone group is stably present in the solution condition, this interesting observation is significantly different
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with the reported structures of aryl substituted 1,3ꢀdicarbonyl compounds which are ketoꢀ or ketoꢀenol mixture in solution,[15]
these functionalized oxazoles prepared by present method display exclusive enolic form in either liquid or solid condition.
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Moreover, the amide substituent of dihydrofuran could also be smoothly changed (2w). Surprisingly, dihydrofuran 1x
derived from 1,3ꢀdiphenylpropanedione (R1 = R2 = Ph, R3 = Me, Ar = Ph) gave the pyrrole (2x) instead of oxazole in 86%
yield via an another plausible process. It's worth noting that a little of pyrroles were detected in the transformation from
dihydrofurans (1p and 1q) to oxazoles (2p and 2q) owing to losing the acetyl group. As shown in Scheme 5, the
2ꢀamidodihydrofuran 1x undergoes alkaliꢀinduced ring opening to form carbanion A. Then A experiences an intramolecular
annulation to generate a fiveꢀmembered ring B, followed by further intramolecular annulation to generate C. Eventually, the
product 2x would be generated from C via a ringꢀopening along with benzoate leaving. And the benzoic acid was detected by
GCꢀMS.
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Scheme 5. A Plausible Mechanism to Generate 2x.
With the hydroxyl enone as a synthetic moiety, the above funtionalized oxazoles could be further transformed into other
interesting oxazole substituted heterocyclic compounds as representatively shown in Scheme 6. The hydroxyl enone
substituent of 2p could react with hydrazine hydrate to obtain corresponding pyrazole 3 in 90% yield.16 Besides, the oxazole
substituted 2Hꢀazirine 4 could be synthesized in 65% yield via a twoꢀstep reaction.17
Scheme 6. Further Transformations.
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To understand the mechanism about this transformation, a series of control experiments were carried out (Scheme 7). Only
trace amount of 2a was detected in the presence of 1,1ꢀdiphenylethylene indicating present transformation appeared to
undergo a radical process (Scheme 7a). Compared with the tranfomation from 2a to 5a, 1r would transform into the
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corresponding enamide 5r in 95% yield at 100 C under argon without any side decarbonylation reaction observed possibly
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because the steric hinderance of the cyclohexone substitutent is much higher than previous actyl group (Scheme 7b). Note
o
that the conversion of 1r into 5r was difficult to happen at 80 C (Scheme 4c), but the resultant enamide 5r could
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catalytically convert to the expected oxazole 2r through oxidative cyclization in very high yield even at 50 C (Scheme 4d).
These results not only showed that the enamide generated from the ring opening of 2ꢀamidodihydrofuran was the
intermediate of such transformation, but also indicated that the C–O cleavage involved ring opening step need higher
temperature than the aerobic dehydrogenation and the subsequent annulation.
Scheme 7. Control Experiments.
O
.
Mn(OAc)3 2H2O (10 mol%)
Me
O
Me
OH
K2CO3 (0.5 equiv)
HN
1,1-Diphenylethylene (2 equiv)
Ph
O
O
Me
Me
Me
MeCN, Air, 100 oC, 18 h
(a)
(b)
OEt
N
CO2Et
Ph
(trace)
1a
2a
O
Me
O
O
HN
O
NH
Ph
K2CO3 (2 equiv)
Ph
MeCN, Ar, 100 oC, 18 h
O
O
5r
(95% yield)
1r
O
O
Me
O
NH
HN
Ph
O
K2CO3 (2 equiv)
Me
(c)
(d)
MeCN, Ar, 80 oC, 18 h
Ph
O
5r
(trace)
O
1r
.
O
O
Mn(OAc)3 2H2O (10 mol%)
O
K2CO3 (0.5 equiv)
NH
Me
O
N
MeCN, Air, 50 oC, 18 h
Me
O
Ph
Ph
O
5r
2r
(95% yield)
In order to further understand the mechanism, Electron Paramagnetic Resonance (EPR) experiments were performed using
2ꢀmethylꢀ2ꢀnitrosopropane (MNP) as a spin trapping reagent (Figure 1).18 A mixture of 1a, Mn(OAc)3, K2CO3 and MNP was
o
stirred under argon at 100 C for one hour. Then the mixture was detected by EPR spectroscopy, and a strong signal with
three Lorentzian lines (g = 2.0060, a (14N) = 15.70 G) was clearly detected indicating the alkyl radical B possibly originated
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from the in situ generating γꢀdicarbonyl enamide was trapped by MNP (Figure 1a). The above signal could also be detected
when the reaction was conducted in air at 100 oC for one hour, more interestingly, another signal (g = 2.0055, a (14N) = 27.03
G) derived from the trapping of peroxy radical C with MNP was also observed (Figure 1b). Notably, no signal was detected
without manganese catalyst might indicate that carbanion A generated from the ring opening of 1a would transform into
corresponding alkyl radical B via single electron transfer process in the presence of manganese catalyst.11
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Figure 1. EPR Studies of the Model Reaction under Ar and Air
Based on the above control experiments and EPR studies, a proposed mechanism is drawn in Scheme 8. Initially, the
2ꢀamidodihydrofuran undergoes alkaliꢀinduced ring opening to form carbanion A which further converts to the alkyl radical
B in the presence of MnIII catalyst.11 The radical B reacts with O2 to produce a peroxy radical C,12 both of them could be
trapped with MNP and observed by EPR. The resultant MnII could be oxidized by C to regenerate MnIII catalytic species with
giving the peroxide anion intermediate D (Scheme 8, Path A).19 As observed in previous catalyst optimization (Table 1, entry
10), D might be alternatively produced with much slower reaction rate from the reaction of A with O2 (Scheme 8, Path B).14
Then D captures a proton like a base from 2ꢀamidodihydrofuran to form a peroxide E with the regeneration of A.
Subsequently, E is transformed into an allene intermediate F possibly induced by heat or base,13 and eventually converts to
the oxazole 2 via an intramolecular annulation process.20
Scheme 8. A Plausiblem Mechanism.
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Conclusions
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In summary, we have developed a novel and efficient methodology to synthesize functionalized oxazoles from easily
available 2ꢀamidodihydrofurans. This highly atomꢀeconomic transformation employs inexpensive Mn(OAc)3 as the catalyst
and air as the oxidant. The control experiments and EPR studies reveal that present cascade catalytic transformation appears
to involve γꢀdicarbonyl enamide and allene intermediates through a series of base promoting ringꢀopening, manganese
catalyzed aerobic oxidative dehydrogenation and annulation process. In addition, these functionalized oxazoles could be
readily transformed into the corresponding oxazole substituted pyrazoles and 2Hꢀazirines. Present cascade catalytic
procedure would inspire new designs on the synthesis of heterocyclic skeletons via intramolecular C–O bond cleavage and
formation.
Experimental Section
General Considerations. The 1H and 13C NMR spectra were recorded with 400 MHz spectrometers as solutions in CDCl3 or
1
MeOD. Chemical shifts are expressed in parts per million (ppm) and are referenced to CHCl3 (δ = 7.26 ppm for H and δ =
77.0 ppm for 13C) or MeOD (δ = 3.34 ppm for 1H and δ = 49.9 ppm for 13C) as an internal standard.
General procedure to prepare 2-amidodihydrofurans 1.9b To a 50 mL Schlenk tube with a stir bar was added enamides
.
(1 mmol), 1,3ꢀdicarbonyl compounds (2 mmol), Mn(OAc)3 2H2O (804 mg, 3 mmol) and 10 mL of MeCN. The mixture was
stirred under argon at 80 ºC for 6 h, cooled to room temperature, poured into brine and extracted with EtOAc. The combined
extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (PE/EA = 2:1)
to afford the desired 2ꢀamidodihydrofurans 1.
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Ethyl 5-acetamido-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate (1a)9b: 1H NMR (400 MHz, CDCl3) δ 7.45–7.31 (m,
5 H), 6.44 (bs, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.67 (d, J = 15.3 Hz, 1 H), 3.11 (d, J = 15.3 Hz, 1 H), 2.33 (s, 3 H), 1.99 (s, 3
H), 1.24 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.5, 165.7, 165.5, 142.9, 128.7, 128.4, 124.5, 101.6, 95.2,
59.5, 42.9, 24.0, 14.3, 13.9.
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Ethyl 5-acetamido-2-methyl-5-(p-tolyl)-4,5-dihydrofuran-3-carboxylate (1b)9b: H NMR (400 MHz, CDCl3) δ 7.32 (d, J =
8.0 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 6.48 (br, 1 H), 4.11 (q, J = 7.0 Hz, 2 H), 3.61 (t, J = 15.2 Hz, 1 H), 3.08 (d, J = 15.3
Hz, 1 H), 2.34 (s, 3 H), 2.31 (s, 3 H), 1.97 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.6,
165.7, 165.6, 140.0, 138.3, 129.3, 124.4, 101.6, 95.3, 59.5, 42.8, 24.0, 21.0, 14.3, 13.88.
Ethyl 5-acetamido-5-(4-methoxyphenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (1c)9b: H NMR (400 MHz, CDCl3) δ
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7.38 (d, J = 8.7 Hz, 2 H), 6.95–6.87 (m, 2 H), 6.20 (bs, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 3.69 (d, J = 15.3 Hz, 1
H), 3.12 (dd, J = 15.3, 1.7 Hz, 1 H), 2.32 (s, 2 H), 2.01 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ
169.5, 165.6, 159.5, 135.0, 125.9, 114.0, 101.7, 95.2, 59.5, 55.3, 42.7, 24.0, 14.3, 13.9.
Ethyl 5-acetamido-5-(4-fluorophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (1d)9b: 1H NMR (400 MHz, CDCl3) δ 7.39
(dd, J = 8.7, 5.2 Hz, 2 H), 7.03 (t, J = 8.5 Hz, 2 H), 6.66 (br, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.55 (d, J = 15.3 Hz, 1 H), 3.04
(d, J = 15.1 Hz, 1 H), 2.29 (s, 3H), 1.94 (s, 2 H), 1.23 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.7, 165.6,
165.4, 162.4 (1J CF = 247.1 Hz), 138.61, 126.5 (3J CF = 8.2 Hz), 115.4 (2J CF = 22.0 Hz), 101.5, 94.8, 59.6, 43.4, 23.8, 14.3,
13.9.
Ethyl 5-acetamido-5-(4-bromophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (1e)9b: 1H NMR (400 MHz, CDCl3) δ 7.50
(d, J = 8.3 Hz, 2 H), 7.31 (d, J = 8.3 Hz, 2 H), 6.38 (br, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 3.55 (d, J = 15.4 Hz, 1 H), 3.07 (d, J =
15.5 Hz, 1 H), 2.31 (s, 3 H), 1.99 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.4, 165.6, 165.3,
141.7, 131.8, 126.4, 122.5, 101.6, 94.8, 59.7, 43.5, 24.0, 14.4, 14.0.
Ethyl 5-acetamido-5-(4-iodophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (1f)9a: H NMR (400 MHz, CDCl3) δ 7.69
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(d, J = 8.4 Hz, 2 H), 7.18–7.16 (m, 2 H), 6.58 (s, 1 H), 4.12 (q, 7.1 Hz, 2 H), 3.51 (d, J = 15.4 Hz, 1 H), 3.04 (dd, J = 15.4,
1.7 Hz, 1 H), 2.30 (s, 3 H), 1.96 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.6, 165.7, 165.3,
142.4, 137.7, 126.5, 101.4, 94.8, 94.1, 59.7, 43.5, 23.9, 14.3, 13.9.
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Ethyl 5-acetamido-2-methyl-5-(4-nitrophenyl)-4,5-dihydrofuran-3-carboxylate (1g): H NMR (400 MHz, CDCl3) δ 8.21
(d, J = 8.7 Hz, 2 H), 7.59 (d, J = 8.8 Hz, 2 H), 6.89 (s, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 3.38 (d, J = 15.7 Hz, 1 H), 3.05 (dd, J =
15.7, 1.7 Hz, 1 H), 2.34 (s, 3 H), 1.99 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.7, 165.9,
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165.1, 149.2, 147.4, 125.6, 123.9, 101.1, 94.2, 59.9, 44.5, 23.7, 14.3, 14.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C16H18N2NaO6 357.1057, found 357.1060.
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Ethyl 5-acetamido-2-methyl-5-(3-nitrophenyl)-4,5-dihydrofuran-3-carboxylate (1h)9b: H NMR (400 MHz, CDCl3) δ 8.27
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(t, J = 1.7 Hz, 1 H), 8.17 (d, J = 8.1 Hz, 1 H), 7.81–7.76 (m, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 6.77 (bs, 1 H), 4.15 (q, J = 7.1
Hz, 2 H), 3.42 (d, J = 15.6 Hz, 1 H), 3.10 (dd, J = 15.7, 1.8 Hz, 1 H), 2.35 (s, 3 H), 2.01 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H);
13C{1H}NMR (100 MHz, CDCl3) δ 169. 7, 165.9, 165.1, 148.4, 144.5, 130.9, 129.7, 123.1, 120.0, 101.3, 94.1, 60.0, 44.5,
23.8, 14.3, 14.1.
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Ethyl 5-acetamido-2-methyl-5-(thiophen-2-yl)-4,5-dihydrofuran-3-carboxylate (1i)9b: H NMR (400 MHz, CDCl3) δ 7.28
(d, J = 4.2 Hz, 1 H), 7.13 (d, J = 2.9 Hz, 1 H), 6.99 (dd, J = 5.1, 3.6 Hz, 1 H), 6.41 (bs, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 3.76
(d, J = 15.3 Hz, 1 H), 3.28 (dq, J = 15.4, 1.6 Hz, 1 H), 2.27 (s, 3 H), 2.04–1.96 (m, 3 H), 1.25 (t, J = 7.1 Hz, 3 H);
13C{1H}NMR (100 MHz, CDCl3) δ 169.2, 165.4, 165.0, 146.5, 127.1, 125.7, 124.2, 102.2, 93.6, 59.7, 42.8, 24.0, 14.4, 13.8.
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N-(4-acetyl-5-methyl-2-(thiophen-2-yl)-2,3-dihydrofuran-2-yl)acetamide (1j)9b: H NMR (400 MHz, CDCl3) δ 7.30–7.25
(m, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 6.97 (dd, J = 5.0, 3.6 Hz, 1 H), 6.76 (bs, 1 H), 3.82 (d, J = 15.0 Hz, 1 H), 3.29 (dd, J =
15.1, 1.6 Hz, 1 H), 2.27 (s, 3 H), 2.16 (s, 3 H), 2.03–1.95 (m, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 194.3, 169.5, 164.6,
146.3, 127.1, 125.7, 124.2, 111.9, 93.6, 43.4, 29.4, 23.9, 14.7.
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Ethyl 5-acetamido-2-methyl-5-(naphthalen-2-yl)-4,5-dihydrofuran-3-carboxylate (1k): H NMR (400 MHz, CDCl3) δ
8.00–7.73 (m, 4 H), 7.51–7.49 (m, 3 H), 6.54 (s, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.72 (d, J = 15.3 Hz, 1 H), 3.18 (d, J = 15.5
Hz, 1 H), 2.39 (s, 3 H), 1.99 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.6, 165.8, 165.5, 139.9,
133.0, 132.9, 128.9, 128.4, 127.6, 126.6 (two carbons overlap), 123.4, 122.4, 101.7, 95.3, 59.6, 42.9, 24.0, 14.3, 14.0. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C20H21NNaO4 362.1363, found 362.1369.
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N-(4-acetyl-5-methyl-2-(naphthalen-2-yl)-2,3-dihydrofuran-2-yl)acetamide (1l): H NMR (400 MHz, CDCl3) δ 7.91–7.83
(m, 4 H), 7.52–7.50 (m, 3 H), 6.50 (s, 1 H), 3.84 (d, J = 14.8 Hz, 1 H), 3.24 (d, J = 14.8 Hz, 1 H), 2.40 (s, 3 H), 2.18 (s, 3 H),
2.02 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 194.2, 169.9, 165.5, 139.7, 132.9, 132.8, 128.8, 128.3, 127.5, 126.5 (two
carbons overlap), 123.3, 122.3, 111.6, 95.3, 43.4, 29.3, 23.8, 14.8. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C19H19NNaO3 332.1257, found 332.1264.
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Methyl 5-acetamido-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate (1m)9b: H NMR (400 MHz, CDCl3) δ 7.47–7.29
(m, 5 H), 6.45 (bs, 1 H), 3.67 (d, J = 15.2 Hz, 1 H), 3.65 (s, 3 H), 3.09 (dd, J = 15.2, 1.5 Hz, 1 H), 2.32 (s, 3 H), 1.97 (s, 3 H);
13C{1H}NMR (100 MHz, CDCl3) δ 169.6, 166.0, 165.9, 142.9, 128.7, 128.5, 124.4, 101.3, 95.3, 50.8, 42.8, 24.0, 13.9.
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Tert-butyl 5-acetamido-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate (1n)9b: 1H NMR (400 MHz, CDCl3) δ
7.48–7.29 (m, 5 H), 6.38 (bs, 1 H), 3.58 (d, J = 15.4 Hz, 1 H), 3.06 (dd, J = 15.4, 1.7 Hz, 1 H), 2.29 (s, 3 H), 1.98 (s, 3 H),
1.45 (s, 9 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.6, 165.0, 164.6, 142.9, 128.6, 128.2, 124.5, 102.8, 94.8, 79.7, 43.5,
28.3, 23.9, 13.9.
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Benzyl 5-acetamido-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate (1o): H NMR (400 MHz, CDCl3) δ 7.47 (d, J =
8.4 Hz, 2 H), 7.36–7.23 (m, 7 H), 6.69 (s, 1 H), 5.11 (s, 2 H), 3.52 (d, J = 15.3 Hz, 1 H), 3.05 (dd, J = 15.4, 1.6 Hz, 1 H), 2.31
(s, 3 H), 1.92 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.7, 166.4, 165.0, 141.6, 136.2, 131.7, 128.4, 128.0 (two
carbons overlap), 126.3, 122.3, 101.1, 94.9, 65.5, 43.4, 23.8, 14.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H21NNaO4 374.1363, found 374.1365.
N-(4-acetyl-5-methyl-2-phenyl-2,3-dihydrofuran-2-yl)acetamide (1p)9b: 1H NMR (400 MHz, CDCl3) δ 7.53–7.30 (m, 5 H),
6.56 (br, 1 H), 3.75 (d, J = 14.8 Hz, 1 H), 3.13 (d, J = 14.8 Hz, 1 H), 2.34 (s, 3 H), 2.16 (s, 3 H), 1.99 (s, 3 H); 13C{1H}NMR
(100 MHz, CDCl3) δ 194.2, 169.7, 165.3, 142.8, 128.8, 128.6, 124.4, 111.8, 95.2, 43.4, 29.4, 24.0, 14.8.
N-(5-ethyl-2-phenyl-4-propionyl-2,3-dihydrofuran-2-yl)acetamide (1q): 1H NMR (400 MHz, CDCl3) δ 7.61–7.29 (m, 5 H),
6.39 (s, 1 H), 3.81 (d, J = 14.6 Hz, 1 H), 3.15 (dd, J = 14.9, 1.6 Hz, 1 H), 2.46–2.39 (m, 2 H), 2.37 (s, 3 H), 2.24 (q, J = 7.3
Hz, 2 H), 1.13 (t, J = 7.5 Hz, 3 H), 1.05 (t, J = 7.2 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 197.3, 173.2, 164.8, 143.0,
128.8, 128.5, 124.4, 110.7, 95.2, 43.1, 34.6, 29.9, 14.7, 9.1, 7.7. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H21NNaO3
310.1414, found 310.1417.
N-(4-oxo-2-phenyl-2,3,4,5,6,7-hexahydrobenzofuran-2-yl)acetamide (1r)9b: 1H NMR (400 MHz, CDCl3) δ 7.43–7.33 (m, 5
H), 6.80 (bs, 1 H), 3.52 (d, J = 14.8 Hz, 1 H), 3.00 (d, J = 14.8 Hz, 1 H), 2.57–2.51 (m, 2 H), 2.42–2.24 (m, 2 H), 2.13–2.03
(m, 2 H), 1.98 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 195.3, 175.4, 169.8, 142.4, 128.8, 128.6, 124.4, 112.4, 98.6, 39.6,
36.3, 23.9, 23.6, 21.6.
N-(2-(4-fluorophenyl)-4-oxo-2,3,4,5,6,7-hexahydrobenzofuran-2-yl)acetamide (1s): 1H NMR (400 MHz, CDCl3) δ 7.61 (s,
1 H), 7.40–7.28 (m, 2 H), 7.06–6.95 (m, 2 H), 3.37 (d, J = 15.1 Hz, 1 H), 2.85 (d, J = 15.1 Hz, 1 H), 2.54–2.51 (m, 2 H),
2.32–2.24 (m, 2 H), 2.10–2.01 (m, 2 H), 1.91 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 195.5, 175.9, 170.3, 162.3 (d, 1J CF
= 247.6 Hz), 138.1, 126.3 (3J CF = 8.2 Hz), 115.4 (2J CF = 21.8 Hz), 111.9, 98.2, 40.2, 36.2, 23.5 (two carbons overlap), 21.4.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H16FNNaO3 312.1006, found 312.1010.
N-(6,6-dimethyl-4-oxo-2-phenyl-2,3,4,5,6,7-hexahydrobenzofuran-2-yl)acetamide (1t): 1H NMR (400 MHz, CDCl3) δ
7.60–7.28 (m, 5 H), 6.55 (s, 1 H), 3.58 (d, J = 14.9 Hz, 1 H), 3.03 (d, J = 14.9 Hz, 1 H), 2.49–2.36 (m, 2 H), 2.28–2.16 (m, 2
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H), 2.00 (s, 3 H), 1.18 (s, 3 H), 1.11 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 194.6, 174.1, 169.6, 142.6, 128.9, 128.8,
124.3, 111.1, 98.7, 50.8, 39.3, 37.4, 34.2, 28.9, 28.4, 24.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H21NNaO3
322.1414, found 322.1412.
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Tert-butyl 5-acetamido-5-(4-bromophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (1u): H NMR (400 MHz, CDCl3) δ
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7.46 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.6 Hz, 2 H), 6.61 (s, 1 H), 3.43 (d, J = 15.6 Hz, 1 H), 3.00 (dd, J = 15.4, 1.3 Hz, 1 H),
2.27 (s, 3 H), 1.96 (s, 3 H), 1.45 (s, 9 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.5, 164.8, 164.6, 141.8, 131.7, 126.4, 122.2,
102.8, 94.4, 80.0, 44.1, 28.3, 23.9, 14.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H22BrNNaO4 417.0546, found
417.0552.
Benzyl 5-acetamido-5-(4-bromophenyl)-2-methyl-4,5-dihydrofuran-3-carboxylate (1v): 1H NMR (400 MHz, CDCl3) δ 7.47
(d, J = 8.4 Hz, 2 H), 7.36–7.23 (m, 7 H), 6.69 (s, 1 H), 5.11 (s, 2 H), 3.52 (d, J = 15.3 Hz, 1 H), 3.05 (dd, J = 15.4, 1.6 Hz, 1
H), 2.31 (s, 3 H), 1.92 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 169.7, 166.4, 165.0, 141.6, 136.2, 131.7, 128.4, 128.0
(two carbons overlap), 126.3, 122.3, 101.1, 94.9, 65.5, 43.4, 23.8, 14.0. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H20BrNNaO4 452.0468, found 452.0476.
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Ethyl 2-methyl-5-phenyl-5-propionamido-4,5-dihydrofuran-3-carboxylate (1w): H NMR (400 MHz, CDCl3) δ 7.44–7.27
(m, 5 H), 6.61 (s, 1 H), 4.09 (q, J = 7.1 Hz, 2 H), 3.62 (d, J = 15.2 Hz, 1 H), 3.05 (d, J = 15.2 Hz, 1 H), 2.31 (s, 3 H), 2.18 (q,
J = 7.4 Hz, 2 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.08 (t, J = 7.4 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 173.3, 165.7, 165.5,
143.0, 128.6, 128.3, 124.3, 101.4, 95.1, 59.5, 43.0, 29.7, 14.3, 13.9, 9.01. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C17H19NNaO5 340.1155, found 340.1159.
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N-(4-benzoyl-2,5-diphenyl-2,3-dihydrofuran-2-yl)acetamide (1x)9a: H NMR (400 MHz, CDCl3) δ 7.59–7.48 (m, 4 H),
7.44–7.34 (m, 3 H), 7.31 (d, J = 7.4 Hz, 2 H), 7.25–7.16 (m, 2 H), 7.10–7.07 (m, 4 H), 6.67 (bs, 1 H), 4.01 (d, J = 15.8 Hz, 1
H), 3.57 (d, J = 15.9 Hz, 1 H), 2.05 (s, 3 H)；13C{1H}NMR (100 MHz, CDCl3) δ 193.4, 169.7, 163.2, 143.1, 139.0, 131.2,
129.9, 129.7, 129.3, 129.0, 128.9, 128.7, 127.7, 127.6, 124.6, 111.7, 94.9, 45.5, 24.1.
General procedure to prepare oxazole 2 from 2-amidodihydrofurans 1. To a 35 mL tube (total volume 50 mL) with a
.
stir bar was added 2ꢀamidodihydrofuran (0.2 mmol), Mn(OAc)3 2H2O (0.02 mmol, 5.4 mg), K2CO3 (0.1 mmol, 14 mg) and 2
mL of MeCN. The mixture was stirred at 100 ºC for 18 h, cooled to room temperature, poured into brine and extracted with
EtOAc. The combined extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by column
chromatography (PE/EA = 6:1) to afford the desired oxazoles 2.
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Ethyl 3-hydroxy-2-(2-methyl-4-phenyloxazol-5-yl)but-2-enoate (2a): 45 mg of 2a was obtained from 1a (57.8 mg, 0.2
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mmol). Purified by column chromatography (6:1 PE/EA), yield 78%; Rf = 0.20 (6:1 PE/EA); slightly yellow oil; H NMR
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(400 MHz, CDCl3) δ 13.49 (s, 1 H), 7.66–7.64 (m, 2 H), 7.39–7.32 (m, 2 H), 7.30–7.22 (m, 1 H), 4.16 (q, J = 7.1 Hz, 2 H),
2.51 (s, 3 H), 1.88 (s, 3 H), 1.08 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.3, 171.8, 160.8, 139.7, 137.2,
132.0, 128.5, 127.5, 125.9, 93.0, 61.1, 19.9, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H18NO4 288.1230,
found 288.1229.
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Ethyl 3-hydroxy-2-(2-methyl-4-(p-tolyl)oxazol-5-yl)but-2-enoate (2b): 32 mg of 2b was obtained from 1b (60.6 mg, 0.2
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mmol). Purified by column chromatography (6:1 PE/EA), yield 53%; Rf = 0.34 (6:1 PE/EA); yellow solid; m.p. 59 ºC; H
NMR (400 MHz, CDCl3) δ 13.48 (s, 1 H), 7.54 (d, J=8.2 Hz, 2 H), 7.16 (d, J=8.0 Hz, 2 H), 4.16 (q, J = 7.1 Hz, 2 H), 2.50 (s,
3 H), 2.34 (s, 3 H), 1.86 (s, 3 H), 1.10 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.2, 171.9, 160.7, 139.2,
137.2, 137.2, 129.2, 129.1, 125.8, 93.1, 61.1, 21.2, 19.8, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H20NO4
302.1387, found 302.1383.
Ethyl 3-hydroxy-2-(4-(4-methoxyphenyl)-2-methyloxazol-5-yl)but-2-enoate (2c): 41 mg of 2c was obtained from 1c (63.8
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mg, 0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 65%; Rf = 0.22 (6:1 PE/EA); slightly yellow oil; H
NMR (400 MHz, CDCl3) δ 13.47 (s, 1 H), 7.58 (d, J = 8.9 Hz, 2 H), 6.89 (d, J = 8.9 Hz, 2 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.81
(s, 3 H), 2.49 (s, 3 H), 1.86 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.3, 171.9, 160.6, 159.0,
138.6, 137.0, 127.2, 124.6, 113.9, 93.0, 61.1, 55.2, 19.9, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H20NO5
318.1336, found 318.1320.
Ethyl 2-(4-(4-fluorophenyl)-2-methyloxazol-5-yl)-3-hydroxybut-2-enoate (2d): 37 mg of 2d was obtained from 1d (61.4
1
mg, 0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 60%; Rf = 0.37 (6:1 PE/EA); slightly yellow oil; H
NMR (400 MHz, CDCl3) δ 13.49 (s, 1 H), 7.78–7.40 (m, 2 H), 7.15–6.88 (m, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 2.49 (s, 3 H),
1.87 (s, 3 H), 1.08 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.4, 171.7, 162.2 (d, 1J CF = 247.2 Hz), 160.8,
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139.4 (d, J = 1.5 Hz), 136.4, 128.2 (d, J = 3.3 Hz), 127.7 (d, J = 8.0 Hz), 115.5 (d, J = 21.6 Hz), 92.8, 61.1,
CF
CF
CF
CF
19.9, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H17FNO4 306.1136, found 306.1126.
Ethyl 2-(4-(4-bromophenyl)-2-methyloxazol-5-yl)-3-hydroxybut-2-enoate (2e): 46 mg of 2e was obtained from 1e (73.6
mg, 0.2 mmol). Purified by column chromatography (4:1 PE/EA), yield 63%; Rf = 0.29 (4:1 PE/EA); yellow solid; m.p. 73
ºC; 1H NMR (400 MHz, CDCl3) δ 13.49 (s, 1 H), 7.55–7.50 (m, 2 H), 7.48–7.43 (m, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 2.49 (s, 3
H), 1.87 (s, 3 H), 1.09 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.4, 171.5, 160.9, 140.0, 136.3, 131.6,
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131.0, 127.5, 121.4, 92.7, 61.2, 19.9, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H17BrNO4 366.0335, found
366.0301.
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Ethyl 3-hydroxy-2-(4-(4-iodophenyl)-2-methyloxazol-5-yl)but-2-enoate (2f): 62 mg of 2f was obtained from 1f (83 mg, 0.2
1
mmol). Purified by column chromatography (4:1 PE/EA), yield 75%; Rf = 0.34 (4:1 PE/EA); white solid; m.p. 69 ºC; H
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NMR (400 MHz, CDCl3) δ 13.49 (s, 1 H), 7.68–7.66 (d, J = 8.6 Hz, 2 H), 7.50–7.32 (m, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 2.50
(s, 3 H), 1.87 (s, 3 H), 1.09 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.4, 171.5, 160.9, 140.2, 137.6, 136.3,
131.5, 127.6, 93.0, 92.7, 61.2, 19.9, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H17INO4 414.0197, found
414.0193.
Ethyl 3-hydroxy-2-(2-methyl-4-(4-nitrophenyl)oxazol-5-yl)but-2-enoate (2g): 28 mg of 2g was obtained from 1g (66.8 mg,
0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 42%; Rf = 0.24 (6:1 PE/EA); yellow solid; m.p. 108 ºC;
1H NMR (400 MHz, CDCl3) δ 13.56 (s, 1 H), 8.32–8.16 (m, 2 H), 7.92–7.70 (m, 2 H), 2.53 (s, 3 H), 1.91 (s, 3 H), 1.07 (t, J =
7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.8, 171.2, 161.4, 146.7, 142.2, 138.5, 135.5, 126.4, 123.9, 92.5, 61.4,
20.0, 14.04, 13.98; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H17N2NaO6 355.0901, found 355.0904.
Ethyl 3-hydroxy-2-(2-methyl-4-(3-nitrophenyl)oxazol-5-yl)but-2-enoate (2h): 29 mg of 2h was obtained from 1h (66.8 mg,
0.2 mmol). Purified by column chromatography (4:1 PE/EA), yield 43%; Rf = 0.28 (4:1 PE/EA); slightly yellow solid; m.p.
1
113 ºC; H NMR (400 MHz, CDCl3) δ 13.56 (s, 1 H), 8.55 (t, J = 1.9 Hz, 1 H), 8.11 (ddd, J = 8.2, 2.2, 0.7 Hz, 1 H),
7.96–7.88 (m, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 2.53 (s, 3 H), 1.90 (s, 3 H), 1.07 (t, J =
7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.9, 171.3, 161.3, 148.6, 141.2, 135.4, 133.9, 131.4, 129.4, 122.1, 120.9,
92.3, 61.3, 20.0, 14.04, 13.97; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H17N2O6 333.1081, found 333.1097.
Ethyl 3-hydroxy-2-(2-methyl-4-(thiophen-2-yl)oxazol-5-yl)but-2-enoate (2i): 30 mg of 2i was obtained from 1i (59 mg, 0.2
mmol). Purified by column chromatography (6:1 PE/EA), yield 51%; Rf = 0.40 (6:1 PE/EA); brown oil; 1H NMR (400 MHz,
CDCl3) 1H NMR (400 MHz, CDCl3) δ 13.60 (s, 1 H), 7.27–7.23 (m, 2 H), 7.03 (dd, J = 5.1, 3.6 Hz, 1 H), 4.18 (q, J = 7.1 Hz,
2 H), 2.50 (s, 3 H), 1.93 (s, 3 H), 1.14 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 180.1, 171.7, 161.1, 138.7,
134.4, 133.7, 127.5, 125.0, 124.0, 92.0, 61.2, 19.8, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C14H16NO4S
294.0795, found 294.0807.
4-Hydroxy-3-(2-methyl-4-(thiophen-2-yl)oxazol-5-yl)pent-3-en-2-one (2j): 25 mg of 2j was obtained from 1j (53 mg, 0.2
1
mmol). Purified by column chromatography (6:1 PE/EA), yield 47%; Rf = 0.28 (6:1 PE/EA); yellow solid; m.p. 102 ºC; H
NMR (400 MHz, CDCl3) δ 17.04 (s, 1 H), 7.29 (dd, J = 3.6, 1.1 Hz, 1 H), 7.28–7.26 (m, 1 H), 7.05 (dd, J = 5.1, 3.6 Hz, 1 H),
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2.53 (s, 3 H), 1.99 (s, 6 H); 13C{1H}NMR (100 MHz, CDCl3) δ 194.1, 161.7, 139.9, 134.1, 133.8, 127.7, 125.4, 124.2, 102.0,
23.6, 14.1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C13H14NO3S 264.0689, found 264.0686.
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Ethyl 3-hydroxy-2-(2-methyl-4-(naphthalen-2-yl)oxazol-5-yl)but-2-enoate (2k): 44 mg of 2k was obtained from 1k (67.8
1
mg, 0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 66%; Rf = 0.32 (6:1 PE/EA); slightly yellow oil; H
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NMR (400 MHz, CDCl3) δ 13.56 (s, 1 H), 8.23 (s, 1 H), 7.90–7.83 (m, 1 H), 7.83–7.78 (m, 2 H), 7.72 (dd, J = 8.6, 1.7 Hz, 1
H), 7.51–7.42 (m, 2 H), 4.18 (q, J = 7.1 Hz, 2 H), 2.56 (s, 3 H), 1.90 (s, 3 H), 1.08 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100
MHz, CDCl3) δ 179.4, 171.8, 160.9, 140.1, 137.2, 133.4, 132.6, 129.4, 128.3, 128.1, 127.6, 126.2, 126.0, 125.0, 123.6, 93.1,
61.2, 19.9, 14.1, 14.0; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C20H20NO4 338.1387, found 338.1392.
4-Hydroxy-3-(2-methyl-4-(naphthalen-2-yl)oxazol-5-yl)pent-3-en-2-one (2l): 44 mg of 2l was obtained from 1l (61.8 mg,
0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 71%; Rf = 0.28 (6:1 PE/EA); slightly yellow solid; m.p.
92 ºC; 1H NMR (400 MHz, CDCl3) δ 17.06 (s, 1 H), 8.26 (d, J = 0.8 Hz, 1 H), 7.89–7.85 (m, 1 H), 7.85–7.77 (m, 2 H), 7.73
(dd, J = 8.6, 1.7 Hz, 1 H), 7.52–7.43 (m, 2 H), 2.58 (s, 3 H), 2.00 (s, 6 H); 13C{1H}NMR (100 MHz, CDCl3) δ 193.8, 161.5,
141.4, 137.4, 133.5, 132.8, 128.8, 128.5, 128.3, 127.6, 126.4, 126.3, 125.1, 123.2, 103.3, 23.8, 14.1; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C19H17NNaO3 330.1101, found 330.1100.
Methyl 3-hydroxy-2-(2-methyl-4-phenyloxazol-5-yl)but-2-enoate (2m): 41 mg of 2m was obtained from 1m (55 mg, 0.2
mmol). Purified by column chromatography (6:1 PE/EA), yield 75%; Rf = 0.24 (6:1 PE/EA); slightly yellow solid; m.p. 72
ºC; 1H NMR (400 MHz, CDCl3) δ 13.38 (s, 1 H), 7.67–7.65 (m, 2 H), 7.37–7.33 (m, 2 H), 7.28–7.24 (m, 1 H), 3.70 (s, 3 H),
2.51 (s, 3 H), 1.85 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.4, 172.2, 160.9, 139.5, 137.2, 131.8, 128.6, 127.5, 125.8,
92.7, 52.1, 19.8, 14.1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H16NO4 274.1074, found 274.1064.
Tert-butyl 3-hydroxy-2-(2-methyl-4-phenyloxazol-5-yl)but-2-enoate (2n): 25 mg of 2n was obtained from 1n (63.4 mg, 0.2
mmol). Purified by column chromatography (6:1 PE/EA), yield 40%; Rf = 0.44 (6:1 PE/EA); yellow oil; 1H NMR (400 MHz,
CDCl3) δ 13.67 (s, 1 H), 7.66–7.64 (m, 2 H), 7.37–7.33 (m, 2 H), 7.27–7.25 (m, 1 H), 2.50 (s, 3 H), 1.90 (s, 3 H), 1.27 (s, 9
H); 13C{1H}NMR (100 MHz, CDCl3) δ 178.7, 171.3, 160.4, 140.3, 136.8, 132.3, 128.4, 127.3, 126.0, 94.1, 82.3, 27.9, 20.0,
14.1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C18H22NO4 316.1543, found 316.1541.
Benzyl 3-hydroxy-2-(2-methyl-4-phenyloxazol-5-yl)but-2-enoate (2o): 50 mg of 2o was obtained from 1o (70.2 mg, 0.2
mmol). Purified by column chromatography (6:1 PE/EA), yield 72%; Rf = 0.28 (6:1 PE/EA); slightly yellow solid; m.p. 72
ºC; 1H NMR (400 MHz, CDCl3) δ 13.35 (s, 1 H), 7.69–7.59 (m, 2 H), 7.37–7.30 (m, 2 H), 7.30–7.20 (m, 4 H), 7.09–7.06 (m,
2 H), 5.15 (s, 2 H), 2.50 (s, 3 H), 1.89 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.8, 171.5, 160.9, 139.5, 137.4, 135.4,
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131.8, 128.6, 128.4, 128.0, 127.6, 127.4, 126.0, 92.9, 66.4, 19.9, 14.1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H19NNaO4 372.1206, found 372.1208.
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4-Hydroxy-3-(2-methyl-4-phenyloxazol-5-yl)pent-3-en-2-one (2p): 35 mg of 2p was obtained from 1p (51.8 mg, 0.2 mmol).
Purified by column chromatography (4:1 PE/EA), yield 68%; Rf = 0.29 (4:1 PE/EA); brown solid; m.p. 46 ºC; 1H NMR (400
MHz, CDCl3) δ 16.98 (s, 1 H), 7.69–7.67 (m, 2 H), 7.41–7.33 (m, 2 H), 7.31–7.25 (m, 1 H), 2.53 (s, 3 H), 1.96 (s, 6 H);
13C{1H}NMR (100 MHz, CDCl3) δ 193.7, 161.3, 141.0, 137.4, 131.4, 128.8, 127.9, 125.7, 103.2, 23.7, 14.1; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C15H16NO3 258.1125, found 258.1128.
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5-Hydroxy-4-(2-methyl-4-phenyloxazol-5-yl)hept-4-en-3-one (2q): 30 mg of 2q was obtained from 1q (57.4 mg, 0.2
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mmol). Purified by column chromatography (6:1 PE/EA), yield 53%; Rf = 0.50 (6:1 PE/EA); slightly yellow oil; H NMR
(400 MHz, CDCl3) δ 17.02 (s, 1 H), 7.71–7.69 (m, 2 H), 7.41–7.33 (m, 2 H), 7.30–7.26 (m, 1 H), 2.85 (q, J = 7.6 Hz, 2 H),
2.42–2.10 (m, 2 H), 1.94 (s, 3 H), 1.39 (t, J = 7.6 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ
198.4, 192.1, 165.6, 140.7, 137.2, 131.5, 128.7, 127.8, 125.7, 102.6, 30.1, 23.2, 21.9, 11.3, 8.9; HRMS (ESIꢀTOF) m/z: [M +
H]+ Calcd for C17H20NO3 286.1438, found 286.1440.
2-(2-Methyl-4-phenyloxazol-5-yl)cyclohexane-1,3-dione (2r): 50 mg of 2r was obtained from 1r (54.2 mg, 0.2 mmol).
Purified by column chromatography (19:1 DCM/MeOH), yield 93%; Rf = 0.21 (1:1 DCM/MeOH); slightly yellow solid; m.p.
196 ºC; 1H NMR (400 MHz, MeOD) δ 7.56–7.54 (m, 2 H), 7.37–7.30 (m, 2 H), 7.26–7.22 (m, 1 H), 2.58 (t, J = 6.4 Hz, 4 H),
2.48 (s, 3 H), 2.14–2.04 (m, 2 H); 13C{1H}NMR (100 MHz, MeOD) δ 193.8, 162.5, 142.6, 137.5, 133.7, 129.2, 128.1, 127.1,
106.4, 35.6, 22.0, 13.8; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H16NO3 270.1125, found 270.1100.
2-(4-(4-Fluorophenyl)-2-methyloxazol-5-yl)cyclohexane-1,3-dione (2s): 55 mg of 2s was obtained from 1s (57.8 mg, 0.2
mmol). Purified by column chromatography (19:1 DCM/MeOH), yield 96%; Rf = 0.17 (1:1 DCM/MeOH); slightly yellow
solid; m.p. 212 ºC; 1H NMR (400 MHz, MeOD) δ 7.62–7.55 (m, 2 H), 7.10–6.99 (m, 2 H), 2.53 (t, J = 6.4 Hz, 4 H), 2.46 (s,
3 H), 2.09–2.03 (m, 2 H); 13C{1H}NMR (100 MHz, MeOD) δ 192.5, 163.5 (1J CF = 245.1 Hz), 162.9, 141.2, 137.3, 130.0 (4J
2
CF = 3.2 Hz), 129.1 (d, 3J CF = 8.0 Hz), 116.0 (d, J CF = 21.8 Hz), 106.7, 34.9, 21.8, 13.7; HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C16H14FNNaO3 310.0850, found 310.0853.
5,5-Dimethyl-2-(2-methyl-4-phenyloxazol-5-yl)cyclohexane-1,3-dione (2t): 54 mg of 2t was obtained from 1t (59.8 mg, 0.2
mmol). Purified by column chromatography (15:1 DCM/MeOH), yield 91%; Rf = 0.24 (15:1 DCM/MeOH); slightly yellow
solid; m.p. 191 ºC; 1H NMR (400 MHz, MeOD) δ 7.55–7.53 (m, 2 H), 7.35–7.29 (m, 2 H), 7.28–7.20 (m, 1 H), 2.48 (s, 3 H),
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2.47 (s, 4 H), 1.16 (s, 6 H); 13C{1H}NMR (100 MHz, MeOD) δ 190.0, 163.3, 139.8, 138.9, 133.2, 129.4, 128.6, 127.4, 106.3,
47.9, 32.9, 28.5, 13.7; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H19NNaO3 320.1257, found 320.1255.
Tert-butyl 2-(4-(4-bromophenyl)-2-methyloxazol-5-yl)-3-hydroxybut-2-enoate (2u): 39 mg of 2u was obtained from 1u
(79.2 mg, 0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 49%; Rf = 0.28 (6:1 PE/EA); slightly yellow
solid; m.p. 78 ºC; 1H NMR (400 MHz, CDCl3) δ 13.66 (s, 1 H), 7.55–7.51 (m, 2 H), 7.49–7.46 (m, 2 H), 2.49 (s, 3 H), 1.89
(s, 3 H), 1.28 (s, 9 H); 13C{1H}NMR (100 MHz, CDCl3) δ 178.9, 171.1, 160.6, 140.7, 135.9, 131.6, 131.3, 127.5, 121.2, 93.8,
82.5, 27.9, 20.0, 14.0; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H20BrNO4 416.0468, found 416.0465.
Benzyl 2-(4-(4-bromophenyl)-2-methyloxazol-5-yl)-3-hydroxybut-2-enoate (2v): 54 mg of 2v was obtained from 1v (86 mg,
0.2 mmol). Purified by column chromatography (6:1 PE/EA), yield 63%; Rf = 0.28 (6:1 PE/EA); slightly yellow solid; m.p.
96 ºC; 1H NMR (400 MHz, CDCl3) δ 13.37 (s, 1 H), 7.51–7.46 (m, 2 H), 7.44–7.38 (m, 2 H), 7.28–7.20 (m, 3 H), 7.09–7.03
(m, 2 H), 5.14 (s, 2 H), 2.49 (s, 3 H), 1.90 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 179.9, 171.2, 161.0, 139.8, 136.5,
135.3, 131.7, 130.8, 128.4, 128.1, 127.6, 127.5, 121.5, 92.7, 66.5, 20.0, 14.1; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H18BrNNaO4 450.0311, found 450.0333.
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Ethyl 2-(2-ethyl-4-phenyloxazol-5-yl)-3-hydroxybut-2-enoate (2w): 39 mg of 2w was obtained from 1w (60.6 mg, 0.2
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mmol). Purified by column chromatography (6:1 PE/EA), yield 65%; Rf = 0.45 (6:1 PE/EA); slightly yellow oil; H NMR
(400 MHz, CDCl3) δ 13.48 (s, 1 H), 7.67–7.65 (m, 2 H), 7.37–7.33 (m, 2 H), 7.27–7.23 (m, 1H), 4.15 (q, J = 7.1 Hz, 2 H),
2.84 (q, J = 7.6 Hz, 2 H), 1.87 (s, 3 H), 1.38 (t, J = 7.6 Hz, 3 H), 1.08 (t, J = 7.1 Hz, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ
179.1, 171.8, 165.1, 139.5, 136.9, 132.1, 128.5, 127.4, 126.0, 93.1, 61.0, 21.9, 19.9, 13.9, 11.3; HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C17H19NNaO4 324.1206, found 324.1201.
(2-Methyl-5-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (2x): 45 mg of 2x was obtained from 1x (76.6 mg, 0.2 mmol).
1
Purified by column chromatography (4:1 PE/EA), yield 86%; Rf = 0.36 (4:1 PE/EA); slightly yellow solid; m.p. 206 ºC; H
NMR (400 MHz, CDCl3) δ 8.93 (s, 1 H), 7.89–7.81 (m, 2 H), 7.56–7.52 (m, 1 H), 7.50–7.41 (m, 4 H), 7.37–7.33 (m, 2 H),
7.24–7.19 (m, 1 H), 6.68 (d, J = 2.8 Hz, 1 H), 2.62 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 192.5, 140.4, 137.5, 131.6,
131.3, 129.7, 129.02, 128.96, 128.1, 126.7, 123.8, 121.2, 109.2, 13.9; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H15NO
284.1046, found 284.1051.
General procedure for further transformations.
5-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-methyl-4-phenyloxazole (3): To a 15 mL tube with a stir bar was added 2p (51 mg, 0.2
mmol) and hydrazine hydrate (40 mg, 0.8 mmol) and THF (2 mL). Then the mixture was stirred at 70 ºC for 12 h, cooled to
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room temperature, poured into brine and extracted with EtOAc. The combined extracts were dried over MgSO4, filtered, and
evaporated. The residue was purified by column chromatography to afford the corresponding pyrazole 3 (45 mg, 90% yield).
1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1 H), 7.60–7.55 (m, 2 H), 7.30 (t, J = 7.4 Hz, 2 H), 7.25–7.21 (t, J = 7.3 Hz, 1 H),
2.54 (s, 3 H), 2.13 (s, 6 H); 13C{1H}NMR (100 MHz, CDCl3) δ 160.9, 144.3, 138.9, 136.1, 132.1, 128.4, 127.4, 126.1, 107.1,
14.1, 11.5; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H15N3O 276.1107, found 276.1106.
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1-(3-Methyl-2-(2-methyl-4-phenyloxazol-5-yl)-2H-azirin-2-yl)ethanone (4): 2p (51 mg, 0.2 mmol) and ammonium formate
(50 mg, 0.8 mmol) and EtOH (4 mL) were introduced into a 15 mL tube with a stir bar, and the mixture was stirred at 90 ºC
for 12 h. After the reaction was completed, it was cooled to room temperature, poured into brine and extracted with EtOAc.
The combined extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by column
chromatography to give the corresponding enamine. Then the enamine and DCE (2 mL) was added to a 15 mL tube with a
stir bar. The mixture was cooled to 0 ºC, followed by the PhI(OAc)2 (77 mg, 0.24 mmol). Then the mixture was stirred at
room temperature for 6 h, poured into brine and extracted with EtOAc. The combined extracts were dried over MgSO4,
filtered, and evaporated. The residue was purified by column chromatography to provide the corresponding 2Hꢀazirine 4 (33
mg, 65% yield). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.3 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.36–7.32 (m, 1 H), 2.50
(s, 3 H), 2.45 (s, 3 H), 2.10 (s, 3 H); 13C{1H}NMR (100 MHz, CDCl3) δ 203.8, 161.1, 157.8, 143.0, 139.6, 131.0, 128.8,
128.5, 126.9, 39.4, 28.0, 14.1, 12.4; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H15N2O2 255.1128, found 255.1125.
General procedure to prepare 5a from 1a: To a 50 mL Schlenk tube with a stir bar was added 2ꢀamidodihydrofuran 1a
(58 mg, 0.2 mmol), K2CO3 (55 mg, 0.4 mmol) and 2 mL of MeCN. The mixture was stirred under argon at 100 ºC for 18 h.
After the reaction was completed, it was cooled to room temperature, then poured into brine and extracted with EtOAc. The
combined extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography
(PE/EA = 2:1) to afford the enamine 5a (22 mg, 44% yield). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.41–7.27 (m, 6
H), 5.94 (t, J = 7.1 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 3.18 (d, J = 7.1 Hz, 2 H), 2.13 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H);
13C{1H}NMR (100 MHz, CDCl3) δ 171.9, 168.3, 137.2, 136.4, 128.4, 128.3, 125.9, 116.0, 61.0, 34.0, 23.4, 14.2; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C14H18NO3 248.1281, found 248.1282. One isomer was confirmed by XRD, CCDC
1401603.
General procedure to prepare 5r from 1r: To a 100 mL Schlenk tube with a stir bar was added 2ꢀamidodihydrofuran 1r
(271 mg, 1 mmol), K2CO3 (276 mg, 2 mmol) and 10 mL of MeCN. The mixture was stirred under argon at 100 ºC for 18 h,
cooled to room temperature, poured into brine and extracted with EtOAc. The combined extracts were dried over MgSO4,
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filtered, and evaporated. The residue was purified by column chromatography (PE/EA) to afford the enamine 5r (257 mg,
1
95% yield). N-(2-(2,6-dioxocyclohexyl)-1-phenylvinyl)acetamide: H NMR (400 MHz, MeOD) δ 7.49 (d, J = 7.5 Hz, 2 H),
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7.25 (t, J = 7.6 Hz, 2 H), 7.15 (t, J = 7.3 Hz, 1 H), 6.44 (s, 1 H), 2.44 (t, J = 6.3 Hz, 4 H), 2.01 (s, 3 H), 1.93 (t, J = 6.2 Hz, 2
H); 13C{1H}NMR (100 MHz, MeOD) δ 194.1, 170.7, 140.5, 133.1, 128.9, 127.5, 126.8, 117.0, 61.5, 36.8, 23.2, 22.2; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C16H18NO3 272.1281, found 272.1283.
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Acknowledgment
We gratefully acknowledge the Chinese Academy of Sciences and the National Natural Science Foundation of China
(21133011, 21373246, and 21522309) for generous financial support. We also thank Prof. Longmin Wu of Lanzhou
University for his generous help on EPR experiment.
Supporting Information
Full 1H and 13C{1H} NMR spectra of the new starting materials 1g, 1k, 1l, 1o, 1q, 1s, 1t, 1u, 1v and 1w and final products
2, 3, 4, 5 and Xꢀray crystallographic data for 2u and 5a. This material is available free of charge via the Internet at
http://pubs.acs.org.
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