Exocyclic N-Acyliminium Ion (NAI) Cyclization: Access to Fully Substituted Oxazoles and Furocoumarins

Article abstract of DOI:10.1021/acs.joc.9b00096

A concise, one-pot route to oxazoles and furocoumarins has been reported. The key step in this transformation involves in situ generation of N-acyliminium ion (NAI) precursor under catalyst and solvent-free conditions and their further transformations promoted by superacid in the same pot. We have also presented the experimental evidence for the involvement of proto-solvated novel exocyclic N-acyliminium ion. Further, the UV-visible and fluorescence studies revealed that few of the compounds reported here exhibited emission of blue light upon irradiation in EtOH in the region of 404-422 nm.

Full text of DOI:10.1021/acs.joc.9b00096

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Article
An Exocyclic N-Acyliminium ion (NAI) Cyclization:
Access to Fully Substituted Oxazoles and Furocoumarins
Venkata Nagarjuna Babu, Arumugavel Murugan,
Narenderreddy Katta, Suman Devatha, and Duddu S. Sharada
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 13 May 2019
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An Exocyclic N-Acyliminium ion (NAI) Cyclization: Access to Fully
Substituted Oxazoles and Furocoumarins
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Venkata Nagarjuna Babu, Arumugavel Murugan, Narenderreddy Katta, Suman Devatha and
Duddu S. Sharada*
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Catalysis & Chemical Biology Laboratory, Department of Chemistry, Indian Institute of Technology Hyderabad,
Kandi – 502285, Sangareddy, Telangana, INDIA, Phone: (040) 2301 7058; Fax: (040) 2301 6032,
E-mail: sharada@iith.ac.in Web : http://drsharadagroup.wixsite.com/sharada
R2
O
R2
N
N
TfOH (5 equiv)
N
O
1,2-DCE, 130 oC,
2-3 h
R1
O
X
H
O
18 examples
R1
up to 93% yield
O
80 oC
Neat condition
R1
N
H
O
OH
NAI precursor
OH
N
O
O
O
X
O
R2
N
X = C, O
O
O
TfOH (5 equiv)
1,2-DCE, 90 oC,
1-2 h
O
R2
R1
8 examples
up to 91% yield
Abstract: A concise, one-pot route to Oxazoles and Furocoumarins has been reported. The key step in this
transformation involves insitu generation of N-acyliminium ion (NAI) precursor under catalyst and solvent-
free conditions, and their further transformations promoted by superacid in the same pot. We have also
presented the experimental evidence for the involvement of proto-solvated novel exocyclic N-acyliminium
ion. Further, the UV-visible and fluorescence studies revealed that few of the compounds reported here
exhibited emission of blue light upon irradiation in EtOH in the region of 404-422 nm.
Introduction
N-acyliminium ions (NAIs) are well recognized as potent or highly reactive intermediates in C-C
and C-heteroatom bond forming reactions, and extensively explored for the synthesis of diverse natural-
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products and bioactive molecules1 due to their highly electrophilic nature. Chemists have developed N-acyl
iminium ion based biomimetic approaches for the synthesis of various alkaloids inspired by nature’s design
principles.2 Owing to their significant importance, chemists have been paid substantial attention to the
development of a variety of NAI precursors. Among them, pyrrolidine based NAI ion precursors3 have
obtained a dominant position for enabling powerful access to the generation of cyclic NAIs particularly
endo-cyclic (Figure 1) by the treatment of Brønsted acid or Lewis acid, and which are mainly limited to
intramolecular cyclization reactions.4 However, the synthesis of these NAI precursors often required
multistep syntheses.3 Amedeo Omodei-Sale et al. in 1983 have studied N-Phenacyloxycarbamates and other
systems containing a CH2-0-N= framework, in the presence of bases, undergo new type of [1,2] anionic C-
O-N to O-C-N rearrangement leading to the formation of NAI precursors.3c The development of a direct
route to access NAI precursors and their further transformations toward diverse scaffolds in a single pot is
a daunting challenge. The reason is the formation of NAI ion species prerequisite is a good leaving group
at the α-position to the nitrogen atom. In order to bring leaving groups at the desired position in substrates
involves multistep syntheses and which are highly difficult to operate in single pot. These challenges led
us to examine a direct synthetic route to access NAI precursors and their further efficient transformations
through a cascade process. The acid catalyzed reactions of NAI salts well explored in the literature, these
transformations mainly involved the generation of cationic NAI ions in the presence of excess strong acid.
As per the literature survey,5, 3 these type of conditions lead to the formation of dicationic species are called
super electrophiles, which can be explored in further transformations with suitable nucleophiles.3a
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Recently, we have developed an iminium induced one-pot double annulation cascade strategy for
the synthesis of dihydroisoquinolinium salts.6 Inspired by this work and our continuing interest in the
development of metal-free and green strategies for the synthesis of biologically important heterocyclic
compounds,7 herein, we report a novel super-acid-promoted tandem cyclization strategy to synthesize
diversified fully substituted Oxazoles and Furocoumarins from readily available starting materials via
insituly generated exocyclic NAI precursor in one pot. The development of a straightforward method to
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access the above mentioned privileged scaffolds via insitu generation of NAI precursors would be of great
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importance.
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O
O
N
N
O
N
N
H
N
H
O
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O
R
O
R
O
R
Designed Unknown
exo cyclic NAI intermediate
Known
Figure 1. Literature known NAIs and our designed NAI
R
O
N
N
O
O
O
O
O
O
selective
reduction
O
5
O
H
N
HN
2a
N
N
O
O
O
OH
A
1a
3aa
O
NAI precursor
O
N
O
O
6
Scheme 1. Designed Strategy for the Synthesis of NAI, Oxazoles and Furocoumarins
Results and Discussion:
At first, we envisaged to design NAI precursor by cross dehydrogenative coupling (CDC) of amines
and phenylglyoxals, followed by selective reduction (Scheme 1). Accordingly, we carried out the reaction
with phenylglyoxal 1a and 2-pyrrolidinone 2a for the synthesis of α-ketoamide 3aa under conditions
developed in our previous CDC strategy.7f Surprisingly, we isolated our desired α-hydroxyl β-keto amide
A (NAI precursor) instead of α-ketoamide 3aa after prolonged reaction time, albeit in very poor yield 15%
(Table 1, entry 1). This interesting result motivated us to improve the yield of the desired product. Then we
carried out the reactions at various temperatures, which resulted no much improvements in the yield of
product A. We have also screened other metal catalysts instead of Iodine. Unfortunately, all these reactions
led to the formation of mixture of products 3aa & A (Table 1, entries 5-12). Without losing hope, we have
checked the reaction under catalyst free conditions, surprisingly it furnished the desired compound A in
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40% yield (Table 1, entry 13). When we performed the reaction in the absence of catalyst, base and solvent,
to our delight, the desired product obtained with excellent yield i.e. 98% within minutes (Table 1, entry 14).
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Table 1. Optimization of the reaction conditions for NAI precursor Aa
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O
O
O
O
O
N
O
solvent, base
O
HN
N
O
OH
H
catalyst, temparature
3aa
A
1a
2a
Temp (oC)
Time (h) yield (%)b yield (%)b
solvent
entry
catalyst (equiv.) base (equiv.)
3aa
A
24
24
1
2
Iodine (1.5)
Iodine (1.5)
Iodine (1.5)
Iodine (1.5)
CuBr2 (0.2)
FeBr2 (0.2)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
-
Toluene
Toluene
Toluene
DMF
rt
0
0
15
22
-
60
80
80
rt
24
3
-
24
4
-
-
24
5
Toluene
DCE
30
20
10
20
32
40
50
60
-
10
20
22
30
36
42
32
20
40
98
24
6
rt
CuI (0.2)
24
7
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
rt
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
24
8
50
60
70
70
80
80
80
24
9
24
10
11
12
13
14
24
Cu(OAc)2 (0.2)
24
Cu(OAc)2 (0.2)
-
24
-
10 min
0
a Reaction conditions: 1a (1.0 equiv), 2a (1.1 equiv). b Isolated yields after column chromatography.
Having this catalyst and solvent-free conditions for NAI precursor A in hand, our attention was
turned towards the utilization of it for the synthesis of Biologically active molecules.
Recently, Jiang et al. have developed an efficient approach to Butenolides and Oxazoles via Metal-
Catalyzed [2 + 3] Cyclization from α-Hydroxyl Ketones and Arylacetonitriles (Scheme 2).8a Taylor et al.
Prepared Substituted Oxazoles by Ritter Reactions of α-Oxo Tosylates.8b An-Xin Wu et al. developed acid-
promoted synthesis of Fully Substituted Oxazoles via Robinson−Gabriel reaction annulation sequence8c.
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Keeping this in mind firstly we hypothesized to synthesize fully substituted Oxazole derivatives by using
nitriles through 3+2 cycloaddition under Metal-free conditions.
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Due to Oxazole derivatives found in a wide range of pharmaceuticals,9 natural products,10 and
agrochemicals.10 Among these Oxazole derivatives serve as an important chiral sources or ligands in
asymmetric transformations.10
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Scheme 2. Previous Work
R1
Ar
R3
O
R2
CuI/NaOH
R2, R3 =/ H
R3
OH
R1
Ar
R2
O
O
R1
R2
Ar
N
CN
CuI/NaOH
R3 = H
O
Accordingly, to test our hypothesis, first we generated the NAI precursor A by the reaction of
phenylglyoxal 1a with 2-pyrrolidinone 2a under standard conditions, which could subsequently use as the
model substrate without isolation.
Then the model reaction was performed by the addition of CH3CN 3a in the presence of Brønsted
acid (methyl sulfonic acid MsOH), afforded the expected product 4a albeit in 40% yield along with by-
product bisamide 5a in 20% yield (Table 2, entry 1). The formation of by-product might be due to the
release of H2O in the reaction. Encouraged by this preliminary result, we further screened with various
Brønsted and Lewis acids at different temperatures in DCE as a solvent and the results were summarized
in Table 2. From the results we understand that the nature of acid and temperature had a significant effect
on the outcome of the reaction. Among the various Brønsted acids screened, only triflic acid effectively
promoted the desired product (Table 2, entries 1-11). In order to evaluate the effects of acidity we screened
with different equivalents of triflic acid under various temperatures, finally, 5.0 equiv of triflic acid was
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found to be effective at 130 °C to afford the desired product 4a in excellent yield 91%. (Table 2, entry 11).
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The results revealed that the employment of Lewis acids was not useful (Table 2, entries 16 to 20).
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Table 2. Optimization studies for the synthesis of Oxazole 4aa
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O
3a
N
O
O
O
O
N
NH
O
TfOH (5 equiv)
HN
DCE, 130 o
O
C
N
N
O
H
O
5a
4a
1a
2a
N
O
OH
A
NAI precursor
entry
acid (equiv)
solvent
temp
isolated yield (%)
4a
5a
1
2
3
4
5
6
7
8
MsOH (5.0)
MsOH (5.0)
MsOH (5.0)
MsOH (5.0)
MsOH (5.0)
MsOH (5.0)
MsOH (5.0)
TfOH (5.0)
TfOH (4.0)
TfOH (5.0)
TfOH (6.0)
HCl (5.0)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
rt
rt
40
30
48
55
71
61
75
81
75
91
85
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
20
47
80 °C
9
100 °C
120 °C
120 °C
130 °C
120 °C
130 °C
130 °C
130 °C
130 °C
130 °C
130 °C
130 °C
130 °C
130 °C
130 °C
130 °C
4
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
10
11
12
13
14
15
16
17
18
19
20
H2SO4 (5.0)
CH3COOH (5.0) DCE
FeCl3 (0.2)
AlCl3 (0.2)
InCl3 (0.2)
DCE
DCE
DCE
DCE
DCE
Sc(Otf)3 (0.2)
Bf3OEt2 (0.2)
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aReaction conditions: 1st step: 1a (1.0 mmol), 2a (1.1 mmol), 80 °C, 10 min, 2nd step: DCE dry solvent (0.25 M), 3a (1.1 mmol),
TfOH (5 mmol), 130 °C, 2 h. bIsolated yields after column chromatography, Nd = not detected.
5
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9
After having the optimized conditions in hand, we have explored the substrate scope of the present
protocol (Table 3). Arylglyoxals bearing electron-neutral (4a, 4b & 4c), electron-rich (4d) and electron-
deficient (4e-4k) substituents were smoothly converted to the corresponding oxazoles with moderate to
very good yields. Interestingly, halo-substituted (4j-4n) arylglyoxals were also found to furnish the desired
products with good yields (66-86%), which would provide possibilities for further functionalization.
Pleasingly, 2-oxazolidinone in place of 2-pyrrolidinone were also found to furnish the desired products with
very good yields (4g, 4h, 4m & 4n).
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Table 3. Scope of the synthesis of various fully substituted oxazolesa
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R2
N
N
R2
3
O
O
O
TfOH (5 equiv)
O
DCE, 130 o
O
C
HN
X
R1
R1
N
H
O
X
N
2
1
X
4
R1
O
X= C,O
O
OH
A
Br
CH3
N
Br
O
O
O
O
CHO
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O
N
N
N
O
O
N
N
N
N
O
O
N
O
N
O
NO2
4a,
91%
4c,
88%
4d,
78%
4b,
73%
4e,
76%
Br
CH3
N
Br
O
CH3
N
O
O
O
O
O
N
N
N
N
N
O
N
N
N
O
O
O
F
O
NO2
4g,
O
NO2
4h,
NO2
4f,
O
NO2
73%
O
4j,
86%
86%
O
4i,
70%
81%
Br
Br
O
Br
O
O
O
O
N
O
N
N
N
N
H3C
F
H3C
F
H3C
N
N
O
O
N
N
O
N
Br
N
O
O
F
O
O
4o,
4m,
68%
4k,
4l,
83%
83%
4n,
66%
75%
CH3
F
F
F3C
CH3
N
O
O
O
O
N
O
O
N
O
HN
N
N
N
N
N
N
N
N
N
O
O2N
O
O
O2N
O
4r,
O
4q,
4s,
4s',
26%
38%
4p,
88%
73%
92%
O
O
O
HN
N
O
N
N
O
O2N
O2N
4t,
4t',
36%
32%
aReaction conditions: 1st step: 1a (1.0 mmol), 2a (1.1 mmol), 80 °C, 10-20 min, 2nd step: DCE dry solvent (0.25 M), 3a (1.1
mmol), TfOH (5 mmol), 130 °C, for 2-3 h. b Isolated yields, after column chromatography.
Next we checked the reactivity of strong electron withdrawing group (-NO2) in the 4th position of
arylglyoxal unit (Table 3, 4s & 4t), unfortunately in both the examples we got the both oxazole and bisamide
products, after prolonged reaction hours also we didn’t observe the complete conversion of bisamide to
oxazole products. We achieved the less oxazole product yields in both 4s & 4t cases (26% & 32%).
In order to expand the molecular library of polyfunctional oxazole derivatives, we extended it to
the heteroaryl nitriles, like 2-cyanopyridines, for the synthesis of valuable bis-hetero cycles those are pyrid-
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oxazoles skeletons as shown in table 3. In this transformations, 2-cyanopyridine is reacted smoothly with
NAI intermediates generated from arylglyoxals and 2-oxazolidinone or 2-pyrrolidinone to afford the
desired products from good to excellent yields (Table 3, 4o-4r).
9
After successfully synthesis of fully substituted Oxazoles, further our attention was turned towards
the synthesis of Furocoumarins, owing to the wide spectrum of biological activities, agrochemicals and
synthetic applications,11 have triggered substantial interest for their synthesis. Accordingly, the new
protocol was further demonstrated by using 4-hydroxy-2H-chromen-2-one as carbon-nucleophile (Table
4). Arylglyoxals with electron-neutral (7a & 7g), electron rich (7d & 7e) and electron-deficient (7b, 7h, 7f
& 7c) substituents were smoothly transformed into the corresponding privileged Furocoumarine under the
optimized conditions with very good yields (Table 4).
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Table 4. Scope of the Synthesis of Furocoumarins
R2
OH
O
O
R2
O
O
O
O
O
O
HN
N
6
R1
R1
H
O
TfOH (5 equiv)
1,2 DCE, 80 oC,
1-2 h
O
O
OH
A
R1
2
1
N
NAI precursor
7
O
O
O
O
O
O
O
O
H3C
F
H3CO
O
O
O
O
O
O
O
O
N
N
N
N
H3CO
F
7d,
82%
7c,
83%
7a,
85%
7b,
81%
OMe
OMe
O
O
O
O
O
O
O
O
H3C
O
O
O
O
O
O
O
O
N
N
N
N
MeO
F3C
F
7h,
86%
7f,
85%
7g,
75%
7e,
78%
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aReaction conditions: 1st step: 1 (1.0 mmol), 2 (1.1 mmol), 80 °C, 10-20 min, 2nd step: DCE dry solvent (0.25 M), 6 (1.1
mmol), TfOH (5 mmol), 80 °C, 1-2 h. b Isolated yields, after column chromatography.
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To gain insight into the reaction mechanism, preliminary control experiments were conducted.
When the reaction was performed in the absence of acid, no desired product was formed, indicating that
the presence of acid is crucial for this reaction (Scheme 3a). Since the present reaction requires excess acid
to effect the transformations (standard conditions), we hypothesized that the reaction might be proceed
through proto-solvation of N-acyliminium ion B (Scheme 3b). Accordingly, we have performed the reaction
with weak nucleophile i.e. benzene instead of acetonitrile 3a. To our delight, we could have isolated the
benzene trapped product C with 80% yield.
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This result suggested that a proto-solvated iminium intermediate B was most likely involved in this
reaction. To know further possible intermediates as per our observations during optimization of reaction
conditions (Table 2, entry1 and 3), we assumed that either bisamide or nitrelium ion may be the reaction
intermediates after attacking of nitrile 3a to intermediate B to afford the oxazole 4a. Accordingly, we have
subjected the bisamide 5a to standard conditions, which resulted in oxazole 4a with excellent yield as we
expected (Scheme 3c).
Scheme 3. Mechanistic Experiments.
O
O
standard condition
absence of acid
N
N
N
(a)
O
3a
N
OH
O
A
4a, 0%
O
H
O
H
O
N
standard condition
benzene
N
O
N
O
(b)
(c)
O
OH
A
C
B
proto solvated
iminium intermediate
O
O
H
O
N
N
standard condition
N
O
N
O
5a
4a, 92%
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Based on the above observed products and previous literature reports,3a, 4 a plausible mechanism
was proposed for the present reaction (Scheme 4). Initially the NAI precursor A would form the iminium
intermediate B under acidic conditions. Then cyclization was occur by two conceivable paths: In path a,
acetonitrile would attack proto solvated iminium intermediate B to afford nitrilium ion I, which then would
neutralized by the adjacent carbonyl oxygen to furnish the final product 4a. In path b, the nitrilium ion I
would be neutralized by the water molecule to form the bisamide 5a, which would further undergo
dehydration -cyclization to furnish the final product 4a.
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Scheme 4. Plausible reaction mechanism for 4a.
O
N
a
Path
H
N
N
O
O
O
O
I
O
O
N
N
N
H
HN
H2O
O
O
N
O
O
OH
O
2a
1a
A
B
N
O
4a
O
HN
5a
b
Path
Scheme 5. Gram Scale Synthesis
O
O
O
O
N
TfOH
DCE, 120 oC
HN
N
N
O
H
4a
3.1 g, 86%
1a
3a
2a
2 g
very good yield
robust method
clean reaction
After having successfully developed super acid promoted a one-pot strategy for the synthesis of
fully substituted oxazoles and furocoumarin scaffolds. We envisaged to examine the scalability of the
process. Consequently, we have performed the reaction on the 2g scale and isolated the product 4a as a
white solid with very good yield (86%) after column purification (Scheme 5). The scalability of our protocol
should prove industrially applicable.
Photophysical Properties of Pyrid-oxazoles and Furocoumarins:
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After having synthesized compounds in hand, we were keen to study the UV-visible and
fluorescence characteristics of chosen Pyrid-oxazoles and Furocoumarins. The UV-visible spectra of
compounds 4r, 4p, 4q & 4o in ethanol (EtOH) exhibited maximum absorption wavelength (λmax) at 320 nm
and the data are summarized in Table 5 and Figure 2.
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Figure 2. Fluorescence (a) and Absorption (b) spectra of Pyrid-oxazoles 4o-4r in ethanol at room
temperature.
Table 5. UV-Vis Absorption and Fluorescence Emission Properties of Compounds 4o-4ra,b
B λmax (abs) in nma C λmax (abs) in nma
entry compound A λmax (abs) in nma
λem in nmb
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4r
4p
4q
4o
206
262
225
226
227
320
320
320
320
464
420
414
422
205
206
205
b
aUV-visible absorption wavelengths, emission wavelengths at room temperature at concentration of
1x10-3 M in EtOH.
The fluorescence spectra of Pyrid-oxazole compounds showed emission wavelength (λem) at 414-
464 nm (Table 5). The presence of more electronegative atom (Fluorine) and strong electron withdrawing
group (trifluoromethyl group) in the para position of the aromatic ring in compounds 4r, 4p & 4q showed
the less fluorescence intensity (Figure 2).
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Figure 3. Fluorescence (c) and Absorption (d) spectra of Furocoumarins 7a-7h in ethanol at room
temperature.
Similarly, we have also recorded the UV-visible and fluorescence spectra of Furocoumarins (7a-7h) in
EtOH. The UV-visible spectra of compounds 7a-7h (Figure 3d) exhibited maximum absorption
wavelengths at 205-210 nm (Table 6). The absorption bands shift values indicated that there was no
significance difference with regardless of substituents presence in the aromatic rings, and an increase in
absorption intensity in the compounds 7f, 7e and 7a was observed. The fluorescence properties of the
compounds 7a-7h (Figure 3c) displayed emission wavelength (λem) at 396-449 nm (Table 6). Among all
the compounds, 7g, 7h and 7f showed an increase in fluorescence intensity along with an increase of the
electron with drawing properties of the substituent in aromatic ring were also observed.
Table 6. UV-Vis Absorption and Fluorescence Emission Properties of Compounds 7a-7ha,b
B λmax (abs) in nma C λmax (abs) in nma
entry compound A λmax (abs) in nma
λem (nm)b
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2
3
4
5
6
7
8
7a
7b
7d
7c
7g
210
300
294
314
300
302
301
286
301
328
330
340
329
338
337
345
328
412
415
449
417
404
408
436
396
207
208
208
205
205
7h
7e
7f
211
210
b
aUV-visible absorption wavelengths, emission wavelengths at room temperature at concentration of
1x10-3 M in EtOH.
CONCLUSIONS
In summary, we have described a concise, one-pot route to Oxazoles and Furocoumarins through
N-acyliminium ion as a key intermediate. The key step in this transformation involves insitu generation of
NAI precursor under catalyst and solvent free conditions, and their further transformations promoted by
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superacid in the same pot. The experimental evidence for the involvement of proto-solvated novel exocyclic
N-acyliminium ion in superacid promoted reaction has been presented. We have also investigated the
photophysical properties of Furocoumarins and Pyrid-oxazole derivatives, and these studies reveal that
possible applications for the discovery of highly fluorescent probes.
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Experimental Section
General Considerations
1
IR spectra were recorded on a FTIR spectrophotometer. H NMR spectra were recorded on 400
MHz spectrometer at 295 K in CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are reported in
standard fashion with reference to either internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or
CHCl3 (δH = 7.25 ppm). 13C NMR spectra were recorded on 100 MHz spectrometer at 25 °C in CDCl3;
chemical shifts (δ ppm) are reported relative to CHCl3 [δC = 77.00 ppm (central line of triplet)]. In the
1HNMR, the following abbreviations were used throughout: s = singlet, d = doublet, t = triplet, q = quartet,
qui = quintet, dd = doublet of doublets, m = multiplet and br s. = broad singlet. The assignment of signals
was confirmed by 1H, 13C CPD, and DEPT spectra. High-resolution mass spectra (HR-MS) were recorded
using Q-TOF multimode source. Melting points were determined on an electrothermal melting point
apparatus and are uncorrected. Other reagents were purchased as reagent grade and used without further
purification. All dry solvents were used. DCE and DCM was dried over CaH2.
Reactions were monitored by TLC on silica gel using a combination of petroleum ether and ethyl
acetate as eluents. All reactions were performed under air atmosphere in standard glassware, heated at 80
°C for 3 h before use. Solvents were distilled prior to use; petroleum ether with a boiling range of 40 to 60
˚C was used. Organic solutions were concentrated by rotary evaporation under vacuum. Acme’s silica gel
(60–120 mesh) was used for column chromatography (approximately 20 g per one gram of crude material).
1. General procedure (GP-I) for the synthesis of Phenylglyoxals (1a to 1h): All the Phenylglyoxals were
synthesized according to the literature procedures,12 to a 50 mL two-neck round bottom flask SeO2 (4.99 g,
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45.0 mmol), H2O (0.76g, 42.5 mmol) and 1,4-dioxane (25.0 ml) were added and fixed a condenser. Then
the mixture was heated to reflux with stirring until the solid was dissolved. Then, substituted aryl ketones
(25.0 mmol) was added to the solution. The reaction mixture was allowed to reflux for 2 to 6 h. After the
reaction was completed (monitoring by TLC), the reaction mixture was cooled to room temperature and
filtered through a Celite pad. The Celite pad was washed several times with diethyl ether. The combined
filtrate was evaporated on a rotary evaporator to afford the crude product. The crude residue was purified
through a silica gel column using petroleum ether/ethyl acetate (8:2) as eluent.
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2. General procedure (GP-II) for the synthesis of Oxazoles (4a to 4r): Phenylglyoxal 1a (1 mmol) was
taken in a dried 10 mL round bottom flask, and 2-pyrrolidinone 2a (1.1 mmol) was added and the reaction
mixture was stirred under neat conditions at 80oC temperature for 10 min to 20 min. After the formation of
intermediate A (confirmed by TLC), then added DCE (2 mL) and nitrile partner 3a (1.1 mmol), followed
by addition of Triflic acid (5 mmol) then the reaction flask was connected to a condenser circulating with
cold water and kept at 130 oC in oil bath. The progress of the reaction was monitored by TLC till the reaction
is completed (2-3 h). The reaction mixture was quenched by addition of saturated solution of NaHCO3 and
extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo. The residue was purified
through a silica gel column using petroleum ether/ethyl acetate (8:2) as eluent. All the compounds (4a to
4r) were confirmed by FTIR, 1H NMR, 13C NMR and HR-MS spectral analyses.
3. Large Scale procedure for the synthesis of Oxazole (4a): Phenylglyoxal 1a (14.91 mmol, 2g) was
taken in a dried 100 mL round bottom flask, and 2-pyrrolidinone 2a (16.40 mmol, 1.395g) was added and
the reaction mixture was stirred under neat conditions at 80 oC temperature for 10 min to 20 min, after the
formation of intermediate A (confirmed by TLC), then added DCE 40mL and triflicacid (74.55 mmol,
11.18g) was added and RB connected to the condenser circulating with cold water then the reaction setup
was shifted to 130 oC, oil bath after 2h, after completion of the reaction confirmed by TLC then the reaction
mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate, dried
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over MgSO4, and concentrated in vacuo. The residue was purified through a silica gel column using
petroleum ether/ethyl acetate (8:2) as eluent. Final compound was isolated with 86% yield, 3.1g.
7
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4. General procedure (GP-III) for the synthesis of Furocoumarins (7a to 7h):
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Phenyl glyoxal 1a (1 mmol) was taken in a dried 10 mL round bottom flask, and 2-pyrrolidinone 2a (1.1
mmol) was added and the reaction mixture was stirred under neat conditions at 80 oC temperature for 10
min to 20 min. After the formation of intermediate 3aa (confirmed by TLC), then added DCE (2 mL) and
4-Hydroxycoumarin partner 6, followed by addition of Triflic acid (5 mmol) then the reaction was kept at
80 oC. The progress of the reaction was monitored by TLC till the reaction is completed (1-2 h). The reaction
mixture was quenched by addition of saturated solution of NaHCO3 and extracted with ethyl acetate, dried
over MgSO4, and concentrated in vacuo. The residue was purified through a silica gel column using
1
petroleum ether/ethyl acetate (8:2) as eluent. All the compounds 7a to 7h were confirmed by FTIR, H
NMR, 13C NMR and HR-MS spectral analysis.
Spectroscopic data of all compounds (4a to 7h):
1-(2-methyl-5-phenyloxazol-4-yl)pyrrolidin-2-one (4a): white solid; (50 mg, 91%); mp 85-87˚C. IR (MIR-
ATR, 4000–600 cm-1) νmax = 3054, 2926, 1706, 1628, 1585, 1494, 1412, 1262, 1225, 1018, 913, 835, 729,
692, 591, 546; 1H NMR (400 MHz, CDCl3): δ 7.58 - 7.51 (m, 2H), 7.43 - 7.37 (m, 2H), 7.34 - 7.28 (m, 1H),
3.80 (t, J = 7.1 Hz, 2H), 2.59 (t, J = 8.1 Hz, 2H), 2.50 (s, 3 H), 2.24 (quin, J = 7.6 Hz, 2H); 13C{1H}NMR
(100 MHz, CDCl3): δ 175.2, 159.2, 143.0, 130.5, 128.7, 128.3, 127.5, 124.9, 48.8, 31.1, 19.0, 14.3. HR-
MS (ESI-TOF) m/z: [M+H]+ calcd for [C14H15N2O2]+ 243.1128; Found 243.1129.
1-(2-benzyl-5-phenyloxazol-4-yl)pyrrolidin-2-one (4b): Light yellow solid; (53 mg, 73%); mp 87-89 ˚C.
IR (MIR-ATR, 4000–600 cm-1) νmax = 3465, 3060, 3030, 2923, 1706, 1625, 1572, 1493, 1451, 1409, 1256,
1222, 1170, 1070, 1020, 912, 835, 766, 729, 692, 549; 1H NMR (400 MHz, CDCl3):δ 7.53 - 7.48 (m, 2 H),
7.40 - 7.32 (m, 6 H), 7.32 - 7.23 (m, 2 H), 4.12 (s, 2 H), 3.83 - 3.77 (m, 2 H), 2.56 (t, J = 8.1 Hz, 2 H), 2.21
(quin, J = 7.6 Hz, 2 H); 13C{1H}NMR(100 MHz, CDCl3): δ 175.0, 160.5, 143.3, 135.0, 130.7, 128.9, 128.8,
128.7, 128.4, 127.5, 127.2, 125.0, 77.5, 77.4, 77.2, 76.8, 48.8, 35.0, 31.2, 19.0. HR-MS (ESI-TOF) m/z:
[M+H]+ calcd for [C20H19N2O2]+ 319.1441; Found 319.1442.
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1-(2-(3-bromopropyl)-5-phenyloxazol-4-yl)pyrrolidin-2-one (4c): white solid; (48 mg, 88%); mp 138-
140˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3059, 2961, 1709, 1628, 1600, 1578, 1445, 1261, 1227, 1178,
1021, 915, 836, 767, 692; 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.3 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H),
7.35 - 7.29 (m, 1H), 3.81 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.59 (t, J =
8.1 Hz, 2H), 2.37 (quin, J = 6.8 Hz, 2H), 2.25 (quin, J = 7.6 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ
175.2, 160.9, 143.1, 130.5, 128.7, 128.5, 128.4, 127.4, 125.0, 48.8, 32.4, 31.1, 29.5, 26.9, 18.9. HR-MS
(ESI-TOF) m/z: [M+H]+ calcd for [C16H18BrN2O2]+ 349.0546; Found 349.0547.
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1-(2-(bromomethyl)-5-(3,4-dimethoxyphenyl)oxazol-4-yl)pyrrolidin-2-one (4d): Pale yellow solid; (76
mg, 78%); mp 150-151˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3046, 2936, 2836, 1703, 1601, 1513,
1
1460, 1416, 1262, 1235, 1212, 1171, 1140, 1020, 924, 860, 810, 765,731,698,623,582; H NMR (400 MHz,
CDCl3): δ 7.12 (s, 1H), 7.1 (d, J = 2 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 4.4 (s, 2H), 3.88 (s, 6H), 3.8 (t, J =
7.1, 2H), 2.5 (t, J = 8.3 Hz, 2H), 2.2 (q, J = 7.6, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 175.0, 155.7,
149.7, 149.0, 144.7, 130.1, 119.7, 118.7, 111.3, 108.7, 55.9, 48.8, 31.1, 20.5, 19.0. HR-MS (ESI-TOF) m/z:
[M+H]+ calcd for [C16H18BrN2O4]+ 381.0444; Found 381.0447.
2-(5-(3-nitrophenyl)-4-(2-oxopyrrolidin-1-yl)oxazol-2-yl)benzaldehyde (4e): white solid; (79 mg, 76%);
mp 234-237˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3078, 2922, 2852, 1701, 1605, 1526, 1410, 1348,
1259, 1204, 1166, 1097, 1015, 835, 804, 739,721, 693; 1H NMR (400 MHz, CDCl3): δ 10.02 (s, 1 H), 8.37
(t, J = 2.0 Hz, 1 H), 8.22 - 8.16 (m, J = 8.3 Hz, 2 H), 8.11 (ddd, J = 1.0, 2.0, 8.3 Hz, 1 H), 7.98 - 7.90 (m, 2
H), 7.85 (td, J = 1.3, 8.1 Hz, 1 H), 7.55 (t, J = 8.1 Hz, 1 H), 3.98 (t, J = 7.1 Hz, 2 H), 2.66 - 2.55 (m, 2 H),
2.30 (quin, J = 7.6 Hz, 2 H) 13C{1H}NMR (100 MHz, CDCl3) : δ 191.4, 174.5, 158.2, 148.4, 140.8, 137.7,
134.5, 131.4, 130.9, 130.2, 129.7, 129.1, 127.0, 122.9, 120.3, 77.4, 77.0, 76.7, 48.6, 31.2, 19.0. HR-MS
(ESI-TOF) m/z: [M+H]+ calcd for [C20H16N3O5]+378.1084; Found: 378.1093.
1-(2-(bromomethyl)-5-(3-nitrophenyl)oxazol-4-yl)pyrrolidin-2-one (4f): Light yellow solid; (83 mg,
81%); mp 128 ˚C; IR (MIR-ATR, 4000–600 cm-1) νmax = 3041, 2984, 2888, 1709, 1611, 1524, 1405, 1348,
1324, 1255, 1207, 1109, 920, 816, 766, 739, 720, 674, 588; 1H NMR (400 MHz, CDCl3) : δ 8.36 (s, 1H),
8.18 (dd, J = 1.2, 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 4.48 (s, 2H), 3.97 (t, J =
13
7.1 Hz, 2H), 2.63 (t, J = 8.1 Hz, 2H), 2.32 (quin, J = 7.5 Hz, 2H); C{1H} NMR (100 MHz, CDCl3): δ
174.3, 157.4, 148.3, 141.1, 133.1, 130.9, 129.6, 128.9, 123.0, 120.4, 48.5, 31.1, 19.9, 19.0. HR-MS (ESI-
TOF) m/z: [M+H]+ calcd for [C14H13BrN3O4]+366.0084; Found 366.0090.
3-(2-methyl-5-(3-nitrophenyl)oxazol-4-yl)oxazolidin-2-one (4g): Yellow solid; (55 mg, 86%); mp 126-
127˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3648, 3087, 2923, 2854, 1754, 1632, 1582, 1526, 1481, 1415,
1
1385, 1347, 1311, 1253, 1211, 1183, 1117, 1054, 1034, 983, 945, 898, 869, 807, 761, 731, 678, 597; H
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NMR (400 MHz, CDCl3) : δ 8.45 (t, J = 1.7 Hz, 1H), 8.22 - 8.10 (m, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.60 (t,
J = 8.1 Hz, 1H), 4.62 (t, J = 8.1 Hz, 2H), 4.13 (t, J = 7.8 Hz, 2H), 2.55 (s, 3H); 13C{1H}NMR (100 MHz,
CDCl3): δ 160.2, 155.8, 148.4, 140.2, 131.9, 130.7, 129.8, 129.0, 122.7, 119.9, 63.1, 45.8, 14.3. HR-MS
(ESI-TOF) m/z: [M+ Na]+ calcd for [C13H11N3NaO5]+ 312.0591; Found 312.0593.
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3-(2-(2-bromoethyl)-5-(3-nitrophenyl)oxazol-4-yl)oxazolidin-2-one (4h): Light yellow solid; (77 mg,
73%); mp 132-134˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3086, 2980, 2920, 1757, 1631, 1577, 1529,
1482, 1416, 1348, 1252, 1213, 1114, 1032, 983, 945, 808, 732, 678, 560; 1H NMR (400 MHz, CDCl3): δ
8.45 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 4.63 (t, J = 7.8 Hz,
2H), 4.16 (t, J = 7.8 Hz, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.43 (t, J = 6.8 Hz, 2H); 13C{1H}NMR (100 MHz,
CDCl3) : δ 160.1, 155.6, 148.4, 140.4, 132.1, 130.9, 129.8, 128.8, 122.9, 120.1, 63.2, 45.7, 32.0, 26.6. HR-
MS (ESI-TOF) m/z: [M+ H]+ calcd for [C14H13BrN3O5]+ 382.0033; Found: 382.0040.
3-(2-benzyl-5-(3-nitrophenyl)oxazol-4-yl)oxazolidin-2-one (4i): Light brown solid; (48 mg, 70%); mp
148-151˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3062, 2986, 2918, 1756, 1630, 1573, 1527, 1481, 1413,
1347, 1252, 1211, 1183, 1116, 1052, 1032, 982, 945, 898, 869, 806, 728, 696, 566; 1H NMR (400 MHz,
CDCl3): δ 8.41 (t, J = 1.7 Hz, 1H), 8.14 (dd, J = 1.0, 8.3 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 8.1
Hz, 1H), 7.40 - 7.34 (m, 4 H), 7.33 - 7.28 (m, 1H), 4.60 (t, J = 8.1 Hz, 2H), 4.16 (s, 2H), 4.15 - 4.10 (m,
2H); 13C{1H}NMR (100 MHz, CDCl3): δ 161.6, 155.6, 148.4, 140.3, 134.4, 132.1, 130.8, 129.7, 128.9,
128.9, 127.5, 122.8, 120.0, 63.1, 45.7, 34.9. HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for [C19H16N3O5]+
366.1084; Found 366.1087.
1-(5-(4-fluorophenyl)-2-methyloxazol-4-yl)pyrrolidin-2-one (4j): White solid; (46 mg, 86%); mp 78-
80˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3747, 3066, 2926, 2891, 1703, 1631, 1589, 1509, 1411, 1299,
1260, 1225, 1158, 1092, 1036, 1010, 957, 915, 836, 728, 606, 579; 1H NMR (400 MHz, CDCl3) δ : 7.54 -
7.47 (m, 2H), 7.12 - 7.05 (m, 2H), 3.80 (t, J = 7.1 Hz, 2H), 2.58 (t, J = 8.3 Hz, 2H), 2.48 (s, 3H), 2.28 - 2.18
(m, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 175.1, 162.4 (d, J = 247 Hz), 159.1, 142.1, 130.2, 127.0,
126.9 (d, J = 8 Hz), 123.9 (d, J = 4), 115.9 (d, J = 22 Hz), 48.8, 31.1, 19.0, 14.2. HR-MS (ESI-TOF) m/z:
[M+H]+ calcd for [C14H14FN2O2]+ 261.1034; Found: 261.1035.
3-(5-(4-bromophenyl)-2-(3-bromopropyl)oxazol-4-yl)oxazolidin-2-one (4k): Light yellow solid; (79 mg,
83%); mp 128-131˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3059, 2921, 2851, 1710, 1628, 1580, 1490,
1414, 1260, 1072, 1007, 913, 827, 728; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.8 Hz, 2H), 7.39 (d, J
= 8.3 Hz, 2H), 3.83 (t, J = 6.8 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 7.3 Hz, 2H), 2.59 (t, J = 8.1 Hz,
2H), 2.37 (quin, J = 6.8 Hz, 2H), 2.25 (quin, J = 7.6 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 174.9,
161.2, 141.9, 131.9, 131.0, 126.5, 126.4, 122.4, 48.7, 32.3, 31.2, 29.4, 26.8, 18.9. HR-MS (ESI-TOF) m/z:
[M+ Na]+ calcd for [C16H16Br2N2NaO2]+ 448.9471; Found 448.9464.
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methyl 2-(5-(4-fluoro-3-methylphenyl)-4-(2-oxopyrrolidin-1-yl)oxazol-2-yl)acetate (4l): Yellow solid;
(82 mg, 83%); mp 126-128˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 2956, 2893, 1744, 1706, 1630, 1586,
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1501, 1413, 1350, 1254, 1119, 1010, 887, 824, 731, 702, 635, 549; H NMR (400 MHz, CDCl3): δ 7.4 (dd,
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J = 7.1, 1.7 Hz, 1H), 7.32 (ddd, J = 7.9, 5, 2.2 Hz, 1H), 7.03 (t, J = 8.8 Hz, 1H), 3.87 (s, 2H), 3.83 (t, J =
7.3 Hz, 2H), 3.77 (s, 3H), 2.57 (t, J = 8.1 Hz, 2H), 2.29 (s, 3H), 2.28-2.20 (m, 2H); 13C{1H}NMR (100
MHz, CDCl3): δ 174.9, 167.5, 161.2 (d, J = 247 Hz), 154.5, 143.3, 130.3, 128.61 (d, J = 5.9 Hz), 125.3 (d,
J = 18 Hz), 124.7, (d, J = 9 Hz), 123.28 (d, J = 3.7 Hz), 115.55 (d, J = 24 Hz), 52.7, 48.7, 34.6, 31.1, 18.9,
14.65 (d, J = 3.7 Hz). HR-MS (ESI-TOF) m/z: [M+Na]+ calcd for [C17H17FN2O4]+ 355.1065; Found
355.1066.
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3-(2-benzyl-5-(4-fluoro-3-methylphenyl)oxazol-4-yl)oxazolidin-2-one (4m): white solid; (67 mg, 68%);
mp 96-98˚C.IR (MIR-ATR, 4000–600 cm-1) νmax = 3060, 2985, 2922, 1757, 1682, 1574, 1501, 1423, 1258,
1228, 1171, 1120, 1054, 1033, 982, 948, 795, 757, 716, 640; 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, J =
1.7, 7.6 Hz, 1H), 7.40 - 7.37 (m, 1H), 7.37 - 7.33 (m, 4H), 7.32 - 7.25 (m, 1H), 7.03 (t, J = 9.0 Hz, 1H),
4.53 (t, J = 7.8 Hz, 2H), 4.12 (s, 2H), 4.02 (dd, J = 7.3, 8.8 Hz, 2H), 2.29 (d, J = 1.5 Hz, 3H); 13C{1H}NMR
(100 MHz, CDCl3): δ 161.02 (d, J = 246 Hz), 160.4, 156.3, 143.2, 134.8, 129.4, 128.9, 128.8, 128.6, 128.5,
127.3, 125.5 (d, J = 17.6 Hz), 124.7 (d, J = 9 Hz), 123.0 (d, J = 3.7 Hz), 115.5 (d, J = 24 Hz), 62.9, 46.0,
34.9, 14.7 (d, J = 3.7 Hz). HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for [C20H18FN2O3]+ 353.1296; Found
353.1303.
3-(2-(3-bromopropyl)-5-(4-fluoro-3-methylphenyl)oxazol-4-yl)oxazolidin-2-one (4n): white solid; (65
mg, 66%); mp 118-121˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 2967, 2921, 1755, 1639, 1580, 1502,
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1423, 1256, 1229, 1170, 1119, 1034, 980, 946, 877, 821, 733, 630, 559; H NMR (400 MHz, CDCl3): δ
7.45 (dd, J = 1.5, 7.3 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.05 (t, J = 8.8 Hz, 1H), 4.56 (dd, J = 7.3, 8.8 Hz, 2H),
4.02 (dd, J = 7.3, 8.8 Hz, 2H), 3.55 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 7.3 Hz, 2H), 2.41 - 2.32 (m, 2H), 2.31
(d, J = 1.5 Hz, 3H) 13C{1H}NMR (100 MHz, CDCl3): δ 161.33 (d, J = 247 Hz), 160.7, 156.4, 143.0, 129.3,
128.5 (d, J = 6 Hz), 125.7, 125.5, 124.7 (d, J = 8 Hz), 123.0 (d, J = 4 Hz), 115.59 (d, J = 4 Hz), 62.9, 46.0,
32.3, 29.4, 26.8, 14.7 (d, J = 4 Hz), HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for [C16H17BrFN2O3]+383.0401;
Found 383.0396.
3-(5-(4-bromophenyl)-2-(pyridin-2-yl)oxazol-4-yl)oxazolidin-2-one (4o): Light green solid; (63 mg,
75%); mp 212-216˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3564, 3364, 2259, 2131, 1746, 1734, 1698,
1649, 1557, 1540, 1521, 1256, 1045, 1023, 989, 826, 763, 666, 632, 574, 548; 1H NMR (400 MHz, DMSO-
D6): δ 8.77 (d, J = 4.4 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.03 (dt, J = 1.5, 7.8 Hz, 1H), 7.71 (q, J = 8.8 Hz,
4H), 7.59 (dd, J = 4.9, 6.8 Hz, 1H), 4.63 (t, J = 7.8 Hz, 2H), 4.13 (t, J = 8.1 Hz, 2H); 13C{1H}NMR (100
MHz, DMSO-D6): δ 157.1, 155.4, 150.1, 144.5, 142.0, 137.7, 132.4, 131.9, 127.1, 125.8, 125.7, 122.3,
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122.2, 63.3, 45.6. HR-MS (ESI-TOF) m/z: [M+ Na]+ calcd for [C17H12BrN3NaO3]+ 407.9954; Found
407.9974.
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1-(5-(4-fluorophenyl)-2-(pyridin-2-yl)oxazol-4-yl)pyrrolidin-2-one (4p): white solid; (122 mg, 88%); mp
188-191˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3054, 2983, 2891, 1702, 1617, 1587, 1508, 1459, 1411,
1332, 1258, 1222, 1157, 1111, 1045, 1012, 838, 793, 738, 623, 601; 1H NMR (400 MHz, CDCl3): δ 8.82 -
8.74 (m, 1H), 8.16 - 8.09 (m, 1H), 7.84 (dt, J = 2.0, 7.8 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.39 (ddd, J = 1.0,
4.8, 7.5 Hz, 1H), 7.17 - 7.11 (m, 2H), 3.97 (t, J = 7.1 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 2.29 (quin, J = 7.5
Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 175.0, 161.5 (d, J = 249 Hz), 150.3, 145.5, 143.5, 137.0,
127.7 (d, J = 8 Hz), 123.6 (d, J = 4 Hz), 122.1, 116.0 (d, J = 22 Hz), 48.9, 31.2, 19.0. HR-MS (ESI-TOF)
m/z: [M+ H]+ calcd for [C18H15FN3O2]+ 324.1143; Found 324.1144.
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1-(2-(pyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)oxazol-4-yl)pyrrolidin-2-one (4q): white solid; (85 mg,
92%); mp 202-205˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3055, 2986, 2895, 1710, 1616, 1460, 1411,
1323, 1259, 1165, 1117, 1067, 1013, 843, 795, 740, 707, 619; 1H NMR (400 MHz, CDCl3): δ 8.85 - 8.72
(m, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.86 (dt, J = 1.5, 7.8 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.73 - 7.65 (m, 2H),
7.42 (ddd, J = 1.0, 4.9, 7.8 Hz, 1H), 4.03 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 8.1 Hz, 2H), 2.32 (quin, J = 7.5
Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 174.7, 158.0, 150.4, 145.3, 142.3, 137.1, 133.9, 130.7 (q, J =
261 Hz), 125.7, 125.6 (q, J = 3.7 Hz), 125.3, 125.2, 122.3, 48.8, 31.3, 19.0. HR-MS (ESI-TOF) m/z: [M+H]+
calcd for [C19H15F3N3O2]+ 374.1111; Found 374.1118.
1-(5-(4-fluoro-3-methylphenyl)-2-(pyridin-2-yl)oxazol-4-yl)pyrrolidin-2-one (4r): white solid; (72 mg,
73%); mp 162-164˚C; IR (MIR-ATR, 4000–600 cm-1) νmax = 3055, 2991, 2920, 1756, 1627, 1589, 1502,
1423, 1331, 1227, 1120, 1032, 949, 795, 757, 716, 640; 1H NMR (400 MHz, CDCl3):δ 8.75 (d, J = 4.9 Hz,
1H), 8.17 (d, J = 7.8 Hz, 1H), 8.02 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.64 - 7.51 (m, 2H), 7.30
(t, J = 9.0 Hz, 1H), 4.62 (t, J = 7.8 Hz, 2H), 4.10 (t, J = 7.8 Hz, 2H), 2.33 (s, 3H); 13C{1H}NMR (100 MHz,
CDCl3 & DMSO-D6): δ 160.81 (d, J = 245 Hz), 156.7, 155.7, 150.0, 144.5, 142.8, 137.7, 131.4, 128.5 (d,
J = 5 Hz), 125.6, 125.3, 125.1 (d, J = 8 Hz), 125.0, 122.8 (d, J = 6 Hz), 122.2, 122.1, 118.9, 115.8 (d, J =
23 Hz), 63.2, 45.7, 14.13 (d, J = 3 Hz). HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for [C18H15FN3O3]+
340.1092; Found: 340.1093.
1-(2-methyl-5-(4-nitrophenyl)oxazol-4-yl)pyrrolidin-2-one (4s): Light yellow solid; (15 mg, 26%); mp
166-168˚C; IR (MIR-ATR, 4000–600 cm-1) νmax = 3258, 3049, 2923, 2883, 2513, 1670, 1526, 1407, 1347,
1322, 1265, 1220, 1185, 1133, 877, 821, 790, 679, 611; 1H NMR (400 MHz, CDCl3):δ 8.38 - 8.27 (m, 2H),
8.26 - 8.11 (m, 2H), 7.33 (1H, d, J = 6.8 Hz), 6.80 (1H, d, J = 6.8 Hz), 3.50 (1H, dt, Ja = 6.4 and Jb = 8.6
Hz), 3.39 (1H, dt, Ja = 5.9 and Jb = 8.8 Hz), 2.36 - 2.26 (m, 2H), 2.12 (s, 3H), 2.09 - 1.91 (m, 3H);
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13C{1H}NMR (100 MHz, CDCl3): δ 191.6, 175.5, 170.2, 150.7, 138.6, 129.7, 123.9, 60.6, 44.6, 30.3, 23.0,
18.3.
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(2-(4-nitrophenyl)-2-oxo-1-(2-oxopyrrolidin-1-yl)ethyl)acetamide (4s’): white solid; (21 mg, 38%); mp
184-186˚C; IR (MIR-ATR, 4000–600 cm-1) νmax = 3111, 2924, 2898, 1696, 1598, 1577, 1512, 1416, 1326,
1267, 1222, 1175, 1036, 852, 689, 644; 1H NMR (400 MHz, CDCl3): δ 8.18 - 8.34 (m, 2H) 7.56 - 7.71 (m,
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2H) 3.82 - 4.00 (m, 2H) 2.56 - 2.72 (m, 2H) 2.54 (s, 3H) 2.19 - 2.37 (m, 2H); C{1H}NMR (100 MHz,
CDCl3): δ 174.4, 160.7, 146.6, 140.0, 133.7, 125.4, 123.9, 48.6, 31.2, 19.0, 14.3.
1-(2-(tert-butyl)-5-(4-nitrophenyl)oxazol-4-yl)pyrrolidin-2-one (4t): Yellow solid; (20 mg, 32%); mp 168-
170˚C; IR (MIR-ATR, 4000–600 cm-1) νmax = 3215, 2975, 2940, 1520, 1661, 1523, 1345, 1284, 1198, 810,
780, 729, 690; 1H NMR (400 MHz, CDCl3):δ 8.28 - 8.38 (m, 2H) 8.19 - 8.27 (m, 2H) 7.39 (1H, d, Ja = 6.36
Hz) 6.78 (1H, d, Ja = 6.36 Hz) 3.24 - 3.45 (m, 2H) 2.23 - 2.44 (m, 2H) 1.91 - 2.09 (m, 2H) 1.23 (s, 9H);
13C{1H}NMR (100 MHz, CDCl3): δ 191.8, 178.5, 175.6, 150.8, 138.5, 129.8, 123.9, 60.7, 44.3, 39.0, 30.4,
27.6, 27.4, 18.3;
N-(2-(4-nitrophenyl)-2-oxo-1-(2-oxopyrrolidin-1-yl)ethyl)pivalamide (4t’): Viscous liquid; (22mg, 36%);
IR (MIR-ATR, 4000–600 cm-1) νmax = 3111, 2974, 2932, 1709, 1599, 1514, 1413, 1337, 1265, 1194, 1110,
1021, 853, 756, 634; 1H NMR (400 MHz, CDCl3): δ 8.28 - 8.21 (m, 2H), 7.68 - 7.58 (m, 2H), 3.96 (2H, t,
J = 7.1 Hz), 2.67 - 2.57 (m, 2H), 2.29 (2H, quin, J = 7.6 Hz), 1.44 (s, 9H); 13C{1H}NMR (100 MHz, CDCl3):
δ 174.2, 170.3, 146.5, 139.4, 134.0, 133.5, 125.4, 123.9, 48.6, 34.1, 31.3, 28.5, 18.8.
1-(4-oxo-2-phenyl-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7a): white solid; (67 mg, 85%); mp
222-225˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3057, 2957, 1737, 1702, 1633, 1495, 1401, 1255, 1161,
1116, 1095, 958, 834, 756, 731, 690; 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 1.0, 7.8 Hz, 1H), 7.82 -
7.76 (m, 2H), 7.56 - 7.33 (m, 6H), 3.86 (br. s., 2H), 2.66 (t, J = 8.1 Hz, 2H), 2.32 (quin, J = 7.5 Hz, 2H);
13C{1H}NMR (100 MHz, CDCl3): δ 176.5, 156.8, 156.0, 152.8, 150.9, 131.1, 129.5, 129.0, 128.2, 125.4,
124.7, 120.7, 118.2, 117.4, 112.5, 109.3, 49.8, 30.9, 19.4. HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for
[C21H16NO4]+ 346.1074; Found 346.1065.
1-(2-(4-fluoro-3-methylphenyl)-4-oxo-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7b): white solid;
(60 mg, 81%); mp 270-273 ˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3055, 2923, 2889, 1739, 1698, 1635,
1506, 1438, 1413, 1262, 1238, 1119, 1042, 963, 897, 816, 760, 721, 635; 1H NMR (400 MHz, CDCl3): δ
7.94 (dd, J = 1.0, 7.8 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.59 - 7.51 (m, 2H), 7.47 - 7.42 (m, 1H), 7.41 - 7.34 (m,
1H), 3.86 (br. s., 2H), 2.77 - 2.51 (m, 2H), 2.40 - 2.34 (m, 3H), 2.34 - 2.21 (m, 2H); C{1H}NMR (100
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MHz, CDCl3): δ 176.5, 161.8 (d, J = 248 Hz), 156.8, 155.9, 152.7, 150.4, 131.1, 128.9 (d, J = 6 Hz), 125.9
(d, J = 18), 124.9 (d, J = 8 Hz), 124.7, 124.2 (d, J = 3 Hz), 120.6, 117.6, 117.4, 116.0, 115.7 (d, J = 23 Hz),
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112.5, 109.3, 49.8, 30.9, 19.4, 14.8 (d, J = 3 Hz),. HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for [C22H17FNO4]+
= 378.1136; Found 378.1128.
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1-(2-(4-fluorophenyl)-4-oxo-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7c): Light yellow solid; (64
mg, 83%); mp 268-271˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3067, 2889, 1730, 1629, 1604, 1503,
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1440, 1406, 1322, 1257, 1225, 1159, 1115, 1029, 959, 894, 833, 756, 724, 682, 622, 565, 516; H NMR
(400 MHz, CDCl3): δ 7.92 (dd, J = 1.5, 7.8 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.54 (ddd, J = 1.5, 7.2, 8.4 Hz,
1H), 7.43 (d, J = 7.8 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.21 - 7.11 (m, 2H), 3.86 (br. s., 2H), 2.75 - 2.56 (m,
2H), 2.32 (quin, J = 7.5 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 176.6, 163.18 (d, J = 249 Hz), 156.8,
156.0, 152.8, 150.1, 131.2, 127.6 (d, J = 9 Hz), 124.8, 124.5 (d, J = 4 Hz), 120.6, 117.9, 117.4, 116.4 (d, J
= 22 Hz), 112.4, 109.2, 49.9, 30.8, 19.4. HR-MS (ESI-TOF) m/z: [M+H]+ calcd for [C21H15FNO4]+
364.0980; Found 364.0976.
1-(2-(3,4-dimethoxyphenyl)-4-oxo-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7d): Light brown
solid; (59 mg, 82%); mp 253-255˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3747, 3673, 3614, 3055, 2308,
2134, 1741, 1701, 1649, 1540, 1515, 1458, 1419, 1263, 1144, 1026, 965, 896, 730, 702, 559; 1H NMR (400
MHz, CDCl3): δ 7.95 (dd, J = 1.5, 7.8 Hz, 1 H), 7.54 (dt, J = 1.5, 7.8 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H),
7.41 - 7.35 (m, 2 H), 7.34 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 1 H), 3.95 (d, J = 3.9 Hz, 7 H), 2.66 (br.
s., 2 H), 2.31 (br. s., 2 H), 1.66 (br. s., 2 H); 13C{1H}NMR (100 MHz, CDCl3): δ 176.5, 156.9, 155.6, 152.7,
151.2, 150.2, 149.2, 130.9, 124.7, 120.9, 120.6, 119.0, 117.4, 116.8, 112.6, 111.5, 109.4, 108.7, 56.0, 56.0,
49.9, 30.9, 19.5. HR-MS (ESI-TOF) m/z: [M+ H]+ calcd for [C23H20NO6]+ 406.1285; Found 406.1286.
1-(2-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7e): Light yellow solid;
(89 mg, 78%); mp 253-255˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 2961, 2840, 1738, 1706, 1609, 1570,
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1511, 1440, 1401, 1305, 1255, 1176, 1117, 1034, 959, 835, 757, 687; H NMR (400 MHz, CDCl3):δ 7.92
(dd, J = 1.5, 7.8 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.53 (ddd, J = 2.0, 7.1, 8.6 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H),
7.40 - 7.33 (m, 1H), 7.03 - 6.94 (m, 2H), 4.00 - 3.70 (m, 5H), 2.65 (t, J = 7.8 Hz, 2H), 2.31 (t, J = 7.3 Hz,
2H); 13C{1H}NMR (100 MHz, CDCl3): δ 160.5, 155.5, 152.7, 151.2, 130.8, 127.1, 124.7, 120.9, 120.5,
117.4, 116.6, 114.5, 112.7, 109.4, 55.4, 49.9, 30.9, 19.4. HR-MS (ESI-TOF) m/z: [M+Na]+ calcd for
[C22H17NO5Na]+ 398.0999; Found: 398.1002.
1-(4-oxo-2-(4-(trifluoromethyl)phenyl)-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7f): white solid;
(79 mg, 85%); mp 238-241˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 2889, 1976, 1740, 1703, 1625, 1506,
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1442, 1409, 1319, 1253, 1164, 1115, 1066, 1022, 956, 893, 843, 756, 690, 596; H NMR (400 MHz,
CDCl3): δ 7.96 (dd, J = 1.0, 7.8 Hz, 1H), 7.93 - 7.87 (m, J = 8.3 Hz, 2H), 7.78 - 7.69 (m, J = 8.3 Hz, 2H),
7.63 - 7.52 (m, 1H), 7.49 - 7.33 (m, 2H), 3.90 (br. s., 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.35 (quin, J = 7.5 Hz,
2H); 13C{1H}NMR (100 MHz, CDCl3): δ 176.4, 156.7, 156.6, 152.9, 149.2, 131.6 (q, J = 273 Hz), 130.7,
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126.0 (q, J = 3.7 Hz), 125.1, 124.9, 122.4, 120.8, 120.1, 117.5, 112.3, 109.3, 49.8, 30.8, 19.5. HR-MS (ESI-
TOF) m/z: [M+Na]+ calcd for [C22H14F3NNaO4]+ 436.0767; Found 436.0765.
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1-(7-methoxy-4-oxo-2-phenyl-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2-one (7g): White solid; (64 mg,
75%); mp 190-193˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3061, 2934, 2846, 1735, 1633, 1603, 1495,
1460, 1408, 1372, 1330, 1256, 1198, 1160, 1121, 1027, 969, 946, 838, 766, 693, 634, 570; 1H NMR (400
MHz, CDCl3): δ 7.83 (d, J = 8.3 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.50 - 7.44 (m, 2 H), 7.42 - 7.36 (m, 1H),
6.99 - 6.92 (m, 2H), 3.89 (s, 3H), 3.89 - 3.70 (m, 2H), 2.71 - 2.61 (m, 2 H), 2.32 (t, J = 7.6 Hz, 2H);
13C{1H}NMR (100 MHz, CDCl3): δ 176.5, 162.3, 157.1, 156.8, 154.6, 149.9, 129.2, 129.0, 128.3, 125.3,
121.7, 118.0, 113.1, 106.8, 106.0, 101.4, 55.8, 49.8, 30.9, 19.4. HR-MS (ESI-TOF) m/z: [M+H]+ calcd for
[C22H18NO5]+ 376.1179; Found 376.1178.
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1-(2-(4-fluoro-3-methylphenyl)-7-methoxy-4-oxo-4H-furo[3,2-c]chromen-3-yl)pyrrolidin-2one
(7h):
white solid; (78 mg, 86%); mp 204-207˚C. IR (MIR-ATR, 4000–600 cm-1) νmax = 3633, 2933, 2886, 1734,
1699, 1635, 1608, 1503, 1460, 1420, 1337, 1249, 1161, 1114, 1026, 973, 945, 835, 766, 720, 696, 623,
552; 1H NMR (400 MHz, CDCl3):δ 7.82 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 1.5, 7.3 Hz, 1H), 7.57 - 7.50 (m,
1H), 7.08 (t, J = 8.8 Hz, 1H), 6.98 - 6.91 (m, 2H), 3.89 (s, 3H), 3.88 - 3.79 (m, 2H), 2.74 - 2.49 (m, 2H),
2.34 (d, J = 1.5 Hz, 3H), 2.33 - 2.26 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ 176.4, 162.9, 161.38 (d,
J = 248 Hz) 157.1, 156.6, 154.6, 149.4, 128.7 (d, J = 5 Hz), 125.8, 125.7, 124.8 (d, J = 8 Hz), 124.3 (d, J =
3 Hz), 121.2, 117.5, 115.9 (d, J = 23 Hz), 113.1, 106.8, 105.9, 101.4, 55.8, 49.8, 30.9, 19.4, 14.8, 14.7. HR-
MS (ESI-TOF) m/z: [M+H]+ calcd for [C23H19FNO5]+ 408.1242; Found 408.1247.
1-(1-hydroxy-2-oxo-2-phenylethyl)pyrrolidin-2-one (A): White solid; (78 mg, 96%); mp 98-101˚C. IR
(MIR-ATR, 4000–600 cm-1) νmax = 3225, 3074, 2959, 2883, 1692, 1668, 1594, 1491, 1417, 1352, 1265,
1233, 1177, 1116, 1024, 1000, 963, 850, 798, 756, 683, 616, 567, 535; 1H NMR (400 MHz, CDCl3):δ 8.13
- 8.05 (m, 2H), 7.69 - 7.62 (m, 1H), 7.55 - 7.47 (m, 2H), 6.69 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 6.8 Hz, 1H),
3.48 (dt, J = 6.1, 8.9 Hz, 1H), 2.86 (dt, J = 5.1, 8.9 Hz, 1H), 2.45 (ddd, J = 7.1, 9.7, 17.0 Hz, 1H), 2.39 -
2.26 (m, 1H), 2.08 - 1.95 (m, 1H), 1.92 - 1.78 (m, 1H); 13C{1H}NMR (100 MHz, CDCl3): δ 195.9, 175.4,
135.0, 131.9, 129.1, 129.0, 77.4, 77.1, 76.7, 73.3, 41.3, 30.9, 17.8. HR-MS (ESI-TOF) m/z: [M+ H]+ calcd
for [C12H14NO3]+ 220.0968; Found 220.0969.
1-(2-oxo-1,2-diphenylethyl)pyrrolidin-2-one (C): White solid; (64 mg, 95%); mp 104-106˚C. IR (MIR-
ATR, 4000–600 cm-1) νmax = 3747, 3689, 3673, 3649, 3614, 3565, 3061, 2978, 2891, 1676, 1596, 1579,
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1520, 1450, 1416, 1362, 1268, 1206, 1100, 1076, 1030, 934, 854, 794, 762, 743, 697, 635, 590, 555; H
NMR (400 MHz, CDCl3):δ 7.96 - 7.87 (m, 2 H), 7.52 - 7.45 (m, 1 H), 7.41 - 7.31 (m, 5 H), 7.30 - 7.24 (m,
2 H), 6.84 (s, 1 H), 3.81 (dt, J = 5.9, 8.8 Hz, 1 H), 2.92 (dt, J = 5.4, 9.0 Hz, 1 H), 2.57 - 2.36 (m, 2 H), 2.16
- 2.03 (m, 1 H), 1.97 - 1.83 (m, 1 H); 13C{1H}NMR (100 MHz, CDCl3): δ 196.5, 175.2, 135.0, 134.5, 133.4,
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129.4, 129.2, 129.0, 128.6, 77.4, 77.1, 76.7, 60.7, 45.2, 31.1, 18.3. HR-MS (ESI-TOF) m/z: [M+ H]+ calcd
for [C18H18NO2]+ 280.1332; Found: 280.1326.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website. NMR spectra of
synthesized compounds, single crystal X-ray structure data and CIF file of compound 4d.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: sharada@iith.ac.in
ORCID
Duddu S. Sharada: 0000-0001-5861-4126
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
We gratefully acknowledge the Council of Scientific and Industrial Research (02(0297)/17/EMR-II) New
Delhi, India and Indian Institute of Technology Hyderabad (IITH) for financial support. V.N.B. and M.A
thanks UGC, NRK thanks DST-SERB and SD thanks to N-PDF SERB, New Delhi, India for the award of
research fellowship.
References:
1. (a) Vinogradov, M. G.; Turova, O. V.; Zlotin, S. G. The progress in the chemistry of N-acyliminium
ions and their use in stereoselective organic synthesis. Russ. Chem. Rev., 2017, 86, 1-17. (b)
Estibalez, U. M.; SanJuan, A. G.; Calvo, O. G.; Aranzamendi, E.; Lete, E.; Sotomayor. N.
Strategies Based on Aryllithium and N-Acyliminium Ion Cyclizations for the Stereocontrolled
Synthesis of Alkaloids and Related Systems. Eur. J. Org. Chem. 2011, 3610-3633. (c) Maryanoff,
B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Cyclizations of N-acyliminium
ions. Chem. Rev. 2004, 104, 1431-1628. (d) Royer, J.; Bonin, M.; Micouin, L. Chiral Heterocycles
by Iminium Ion Cyclization. Chem. Rev. 2004, 104, 2311-2352.
2. (a) Chris, J.; Reyes, P.; Romo, D. Bioinspired Total Synthesis of Agelastatin A. Angew. Chem.
2012, 124, 6976-6979 and references cited therein. (b) Wang, Y.; Zhu, L.; Zhang, Y.; Hong, R.
Bioinspired and Concise Synthesis of Stemoamide. Angew. Chem. 2011, 123, 2839-2842. (c)
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Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
Movassaghi, M.; Siegel, D. S.; Han, S. Total synthesis of all (-)-agelastatin alkaloids. Chem. Sci.,
2010, 1, 561–566.
6
7
8
9
3. (a) Zhang, Y.; DeSchepper, D. J.; Gilbert, T. M.; Kumar, K. S.; Sai.; Klumpp, D. A. Superacid
promoted reactions of N-acyliminium salts and evidence for the involvement of superelectrophiles.
Chem. Commun., 2007, 0, 4032–4034. (b) Indukuri, K.; Unnava, R.; Deka, M. J.; Saikia, A. K.
Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-
Ritter/Friedel-Crafts Type Reaction of Endocyclic N-Acyliminium Ions. J. Org. Chem. 2013, 78,
10629-10641 and references cited therein. (c) Consonni, P.; Favara, D.; Omodei-Salé, A.; Bartolini,
G.; Ricci, A. Reactivity of N-phenacyloxycarbamates and related systems in the presence of bases:
study of a new [1,2] anionic rearrangement. J. Chem. Soc., Perkin Trans. 2, 1983, 0, 967-973.
4. Saikia, A. K.; Indukuri, K.; Das, J. Stereoselective synthesis of O-tosyl azabicyclic derivatives via
aza Prins reaction of endocyclic N-acyliminium ions: application to the total synthesis of (±)-epi-
indolizidine 167B and 209D. Org. Biomol. Chem., 2014, 12, 7026–7035.
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11
12
13
14
15
16
17
18
19
20
21
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5. Mangalaraj, S.; Ramanathan, C. R. Construction of tetrahydro-b-carboline skeletons via Brønsted
acid activation of imide carbonyl group: syntheses of indole alkaloids (±)-harmicine and (±)-10-
desbromoarborescidine-A. RSC Adv., 2012, 2, 12665-12669.
6. Sagar, A.; Babu, V. N.; Shinde, A. H.; Sharada. D. S. A metal-free cyclic iminium induced one-pot
double annulation cascade: access to dihydroisoquinolinium (DHIQ) salts. Org. Biomol.
Chem. 2016, 14, 10366-10370.
7. a) Sagar, A.; Babu, V. N.; Polu, A.; Sharada. D. S. PIDA/TBAB‐Promoted Oxidative Geminal
Dibromofunctionalization of Alkynes: Direct Synthesis of Geminal Diazides. Eur. J. Org. Chem.
2018, 41, 5700-5705. b) Sagar, A.; Babu, V. N.; Bakthadoss, M.; Sharada. D. S. A Direct
Cycloaminative Approach to Imidazole Derivatives via Dual C–H Functionalization. Org. Lett.
2017, 19, 5014−5017.
8. a) Qi, C.; Peng, Y.; Wang, L.; Ren, Y.; Jiang, H. Copper-Catalyzed [2 + 3] Cyclization of
α-Hydroxyl Ketones and Arylacetonitriles: Access to Multisubstituted Butenolides and Oxazoles.
J. Org. Chem. 2018, 83, 11926-11935. b) Lai, P. S.; Taylor, M. S. Preparation of Substituted
Oxazoles by Ritter Reactions of α-Oxo Tosylates. Synthesis, 2010, 9, 1449-1452. c) Zhou, R. R.;
Cai, Q.; Li, D. K.; Zhuang, S. Y.; Wu, Y. D.; Wu, A. X. Acid-Promoted Multicomponent Tandem
Cyclization to Synthesize Fully Substituted Oxazoles via Robinson–Gabriel-Type Reaction. J.
Org. Chem., 2017, 82, 6450-6456.
9. See, for example: (a) Zhang H. Z.; Zhao Z. L.; Zhou, C. H. Recent advance in oxazole-based
medicinal chemistry. Eur J Med Chem. 2018, 144, 444-492. (b) Dalvie, D. K.; Kalgutkar, A. S.;
Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell. J. P. Biotransformation Reactions of Five-
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Membered Aromatic Heterocyclic Rings. Chem. Res. Toxicol. 2002, 15 (3), 269-299. (c) Ibrar, A.;
Khan, I.; Abbas, N.; Farooq, U.; Khan, A. Transition-metal-free synthesis of oxazoles: valuable
structural fragments in drug discovery. RSC Adv., 2016, 6, 93016-93047.
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8
9
10. For selected reviews on oxazole derivatives, see: (a) Wipf, P. Synthetic Studies of Biologically
Active Marine Cyclopeptides. Chem. Rev. 1995, 95, 2115. (b) Jin, Z. Muscarine, imidazole, oxazole
and thiazole alkaloids. Nat. Prod. Rep. 2006, 23, 464. (c) Riego, E.; Hernandez, D.; Albericio, F.;
Alvarez, M. Directly Linked Polyazoles: Important Moieties in Natural Products. Synthesis 2005,
12, 1907.
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11. (a) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa, H.; Takahashi, D.;
Koshimizu, K.; Ohigashi, H. 1,1-Dimethylallylcoumarins potently supress both
lipopolysaccharide- and interferon-γ-induced nitric oxide generation in mouse macrophage RAW
264.7 cells. Bioorg. Med. Chem. Lett. 2000, 10, 59; (b) Itoigawa, M.; Ito, C.; Tan, H. T. W.;
Kuchide, M.; Tokuda, H.; Nishino, H.; Furukawa, H. Cancer chemopreventive agents, 4-
phenylcoumarins from Calophyllum inophyllum. Cancer Lett. 2001, 169, 15; (c) AlSehemi, A. G.;
El-Gogary, S. R. Synthesis and Photooxygenation of Furo[3,2‐c]coumarin Derivatives as
Antibacterial and DNA Intercalating Agent. Chin. J. Chem. 2012, 30, 316;
12. (a) Riley, H. A.; Gray, A. R.; phenylglyoxal. Org. Synth. Coll. 1943, 2, 509; (b) Mupparapu, N.;
Khan, S.; Battula, S.; Kushwaha, M.; Gupta, A. P.; Ahmed, Q. N.; Vishwakarma, R. A. Metal-
Free Oxidative Amidation of 2-Oxoaldehydes: A Facile Access to α-Ketoamides. Org.
Lett. 2014, 16, 1152-1155; (c) Khan, S.; Ahmed, Q. N. 2-Oxo-Driven Coupling Reactions of 2-
Oxo Aldehydes/2-Oxo Iminium Ions and Hydroperoxides at Room Temperature. Eur. J. Org.
Chem. 2016, 5377–5385.
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