Palladium Catalyzed Ring Expansion Reaction of Isoxazolones with Isocyanides: Synthesis of 1,3-Oxazin-6-One Derivatives

Article abstract of DOI:10.1002/adsc.202001200

A palladium catalyzed ring expansion reaction of isoxazolones with isocyanides was disclosed. In the reaction, a cascade process involving ring-opening/cyclization was suggested. The reaction features high atomic economy due to no elimination of CO₂ occurred. Moreover, products obtained demonstrate aggregation-induced emission properties with relatively high solid-state emission efficiencies. (Figure presented.).

Full text of DOI:10.1002/adsc.202001200

Title: Palladium catalyzed ring expansion reaction of isoxazolones with
isocyanides: synthesis of 1,3-oxazin-6-one derivatives
Authors: Yi-Ming Zhu, Wan Zhang, Hongkun Li, Xiaoping Xu, and
Shun-Jun Ji
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001200
Link to VoR: https://doi.org/10.1002/adsc.202001200

10.1002/adsc.202001200
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium catalyzed ring expansion reaction of isoxazolones
with isocyanides: synthesis of 1,3-oxazin-6-one derivatives
Yi-Ming Zhu,a Wan Zhang,b Hongkun Li,b,* Xiao-Ping Xua,* and Shun-Jun Jia,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou,
215123, P. R. China
Laboratory of Advanced Optoelectronic Materials, College of Chemistry, Chemical Engineering and Materials Science,
b
Soochow University, Suzhou 215123, China.
E-mail: hkli@suda.edu.cn; xuxp@suda.edu.cn; shunjun@suda.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
reaction was reported by Jurberg's group (Scheme
1c).[6] The combination of transition-metal-catalysis
and Marchesini's strategy not only improved the
efficiency of reaction, but also enriched the types of
products. Moreover, a Ag-catalyzed ring expansion
strategy was developed by Wei’s group, in which a
oxazineone intermediate was experienced, followed
by a Mumm-type rearrangement.[11a]
Abstract: A palladium catalyzed ring expansion reaction
of isoxazolones with isocyanides was disclosed. In the
reaction,
a
cascade
process
involving
ring-
opening/cyclization was suggested. The reaction features
high atomic economy due to no elimination of CO2
occurred. Moreover, products obtained demonstrate
aggregation-induced emission properties with relatively
high solid-state emission efficiencies.
Keywords: palladium, ring expansion, isoxazolone,
isocyanide, aggregation-induced emission
Introduction
The 1,3-oxazine-6-one skeleton often occurs in
natural products and drug molecules.[1] For example,
Discoipyrroles A, B, and D were proved to show
anticancer property,[1a] while Cetilistat ATL-962
could inhibit pancreatic lipase activity and be used as
an anti-obesity drug.[1d] The alkaloids Spinoxazine A
and B, which were separated and purified recently by
Kwon's group, also have oxazinone frameworks.[1b, 1c]
Over the past decades, organic chemists developed
many methods to construct the 1,3-oxazine-6-one
skeleton.[2-6] Meanwhile, isoxazolones, as a kind of
readily available starting material for the synthesis of
1,3-oxazin-6-ones, have attracted much attention in
synthetic community. In 1979, Vecchio et al.[2]
successfully constructed 1,3-oxazin-6-one derivatives
by using isoxazolones and aryl nitrile oxides.
However, the tedious work-up limited its application
(Scheme 1a). Moreover, the procedure was less atom-
economic since the loss of HNO2 and PhCN as by-
products. Marchesini's group[3] developed a new
pathway from isoxazolones to 1,3-oxazin-6-ones
through the ring-opening/cyclization cascade strategy
(Scheme 1b). However, the use of toxic reagents and
low reaction efficiency made the protocol less
practical. Recently, a Rh-catalyzed carbene insertion
Scheme 1. Strategies from isoxazolones to 1,3-oxazine-6-
ones.
Even so, more stable and versatile insertion
reagents anticipated to be explored to expand the
structural diversity of products. As a synthon with
similar property to carbene intermediate, isocyanide
is often stable, and has also been widespread used in
organic synthesis.[7]
Therefore, we wonder if isocyanide could serve as
insertion reagent in ring expansion reaction of
isoxazolone. Indeed, there were certain reactions
involving isocyanides and isoxazolones, which were
mainly initiated by nucleophilic attack from
methylene groups of isoxazolones[8] or carbon atoms
of isocyanides[9]. To the best of our knowledge,
elimination of CO2 often occurs in the reactions of
isoxazolones when meeting with transition-metal-
1
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10.1002/adsc.202001200
Advanced Synthesis & Catalysis
catalysts.[10] Reactions without the loss of CO2 are
rarely reported.[6, 11]
12
13
PdCl2 (10)
PdCl2 (10)
PhCOONa (1) DCE
83
81
PhCOONa
(0.5)
DCE
DCE
DCE
As an ongoing work about the palladium-catalyzed
8b]
isocyanide insertion reactions in our group,[12,
14
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PhCOONa
(0.2)
86
77
herein, we report an efficient Pd-catalyzed ring
expansion reaction of isoxazolones with isocyanides
for the synthesis of 1,3-oxazin-6-one derivatives.
15
PhCOONa
(0.1)
16
PhCOONa
(0.2)
Toluene 71
Results and Discussion
17
PhCOONa
(0.2)
DMSO
MeCN
TCE[c]
TCE
trace
At the setout of our investigation, isoxazolone 1a and
tert-butyl isocyanide 2a were chosen as reaction
partners, PdCl2 (5 mol %) as catalyst, NaOAc (1
equiv) as additive, and DCE (1,2-dichloroethane) as
solvent. The mixture was stirred at 85 oC for 12 h. To
our delight, target product 3aa could be isolated with
a yield of 47%. Structure of the product was
confirmed by NMR, HRMS, IR and single-crystal X-
ray diffraction. With this unambiguous result in hand,
we further optimized the reaction conditions, and the
results are summarized in Table 1.
First, several Pd catalysts and their dosages were
screened (Table 1, entry 1-7), and PdCl2 with a
loading of 10 mol % was found to be the best choice
giving a yield of 58% (Table 1, entry 6). After that,
additives were investigated (Table 1, entry 8-12).
Results showed that sodium benzoate could
efficiently increase the yield to 83% (Table 1, entry
12), which was further increased to 86% upon dosage
optimization (Table 1, entry 14). The screen of
solvents shown that chlorine-containing solvents
were better than others. Using TCE as solvent, a 95%
yield of product could be obtained (Table 1, entry 19).
Finally, reaction time and temperature were
investigated to determine the optimal reaction
condition (Table 1, entry 20): 1a (0.2 mmol), 2a (2.0
equiv), PdCl2 (10 mol %), PhCOONa (20 mol %),
TCE (2 mL), 85 oC, 6 h.
18
PhCOONa
(0.2)
36
95
95
86
41
19
PhCOONa
(0.2)
20[d]
21[e]
22[f]
PhCOONa
(0.2)
PhCOONa
(0.2)
TCE
PhCOONa
(0.2)
TCE
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
solvent (2 mL), 85 oC, 12 h. [b] Isolated yields. [c] TCE
means 1,1,2-Trichoroethane. [d] The reaction time was
[e]
[f]
6 h.
The reaction time was 4 h.
The reaction
temperature was 60 oC.
With optimal condition in hand, we investigated
the scope of the reaction partners. First, the generality
of isoxazolones were investigated, and the results
were summarized in Table 2. Substituents on the
benzene ring of isoxazolone were varied, and it
showed that both electron withdrawing and electron
donating groups could be well tolerated to give the
products with good yields (3aa-3ia). Furthermore,
when the benzene ring was replaced by heterocyclic
rings such as thiophene (3ka), furan (3la), pyridine
(3ma), the reactions proceeded smoothly to afford the
products in moderate to high yields. When a methyl
group (3na) other than benzene ring was introduced,
only trace amount of product was detected. After that,
compatibility of substituents at the 4-position of
isoxazolone was investigated, and it was found that
the desired products (3oa-3qa) could be isolated with
ideal yields.
It is worth noting that when there are no
substituents at 4-position of isoxazolones (3ra-3va),
the reactions could proceed smoothly as well,
providing the target products albeit in slightly lower
yields, which differs from those in our previous
work.[8b] It is suspected the property of different
additive might answer for it. If two hydrogen atoms
at 4-position of isoxazolone were substituted by two
methyl groups (3wa), no reaction could be observed.
Subsequently, isoxazolone 1a was used as a
template to investigate the universality of isocyanide
substrates. The results were summarized in Table 3.
It turned out that alkyl isocyanides with greater steric
Table 1. Optimization of the Reaction Conditions.[a]
Entry Catalyst
[mol %]
Additive
[equiv]
Solvent
Yield[b]
[%]
1
PdCl2 (5)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
DBU (1)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
47
2
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
Pd2(dba)3 (5)
PdCl2 (2.5)
PdCl2 (10)
PdCl2 (15)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
44
3
34
4
37
5
36
6
58
7
55
8
trace
25
9
Pyridine (1)
Cs2CO3 (1)
PivONa (1)
10
11
trace
59
2
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10.1002/adsc.202001200
Advanced Synthesis & Catalysis
hindrance gave better results (3aa, 3ac, 3ad). Those
with less steric hindrance such as n-butyl isocyanide
(3ae), could only give the product in 68% yield.
Reaction of functionalized isocyanide (3af) could
also run smoothly, and the yield could be maintained
at a moderate level. Attempts on aryl isocyanides
indicated that electron-rich one demonstrated higher
reactivity and produced target product (3ag) with
higher yield, while electron-deficient one showed
lower reactivity and only led to messy system.
To evaluate the potential application of this
protocol, a scale-up experiment was conducted
(amplified by 10 times). As shown in Scheme 2,
when 2 mmol of 1q was introduced into the reaction,
after 7 h stirring under standard conditions, 0.4952 g
of 3qa (87% yield) was obtained.
Table 2. Scope Study of isoxazolones.[a, b]
Scheme 2. Scale-up reaction.
To explore the reaction mechanism, some control
experiments were performed (Scheme 3). First, we
removed PdCl2 from the reaction system, and it was
found that the yield decreased significantly to 24%
(Scheme 3a). If sodium benzoate was removed as
well, the yield dramatically reduced to 13% (Scheme
3b). This indicated that both palladium species and
sodium benzoate could promote the reaction. A result
similar to the one obtained with substrate 1wa was
observed upon transformation of the N-methyl
substituted isoxazolone 4 (Scheme 3c). We suppose
that the isomerization of isoxazolone to enamine
format was crucial in this reaction.
[a]
Reaction conditions: 1a-1w (0.2 mmol), 2a (0.4 mmol),
PdCl2 (10 mol %), TCE (2 mL), PhCOONa (20 mol %), 85
oC, 6 h. [b] Isolated yields.
Scheme 3. Control experiments.
Table 3. Scope Study of isocyanides.[a, b]
[a]
Reaction conditions: 1a (0.2 mmol), 2a-2i (0.4 mmol),
PdCl2 (10 mol %), DCE (2 mL), PhCOONa (20 mol %),
Scheme 4. Plausible main path of reaction.
85 oC, 6 h. [b] Isolated yields.
3
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10.1002/adsc.202001200
Advanced Synthesis & Catalysis
Table 4. Photophysical properties of selected compounds.
Compound
3aa
λabs[a] (nm)
262/333
λem[b] (nm)
425
Ф[c]F,soln (%)
0.11
Ф[d]F,powder (%)
Τ[e] (ns)
5.22
2.79
3.39
50.17
39.92
31.73
33.64
23.43
69.48
3ca
283/334
282/313/338
256/336
258/335
260/340
407
0.18
3da
455
0.06
3ea
455
0
16.59
5.57
3ma
440
0.03
3qa
431
4.86
6.86/5.22[f]
[a]
[b]
Absorption wavelength (λabs) measured in DMSO at 50 μM.
Emission peaks (λem) measured in powder at room
[c], [d]
temperature.
Absolute fluorescence quantum yield (ФF) measured by a calibrated integrating sphere in DMSO
[e]
[f]
solution at 50 μM and powder respectively. Decaying lifetimes (τ) of these emitters in powder. Decaying lifetime (τ)
of 3qa in DMSO.
Based on above results and previous literatures,[3, 6] nearly non-emissive when molecularly dissolves.
a possible mechanism was proposed, which was However, its PL intensities increased rapidly when fw
shown in Scheme 4.[13] First, reaction of PdCl2 and is higher than 60%. Notably, it reached the highest
sodium benzoate produced Pd(PhCOO)2, and then the value at the fw of 90% which was about 500 times
Pd(II) species interact with the enamine-formatted higher than that in pure DMSO (Figure 1b). As water
isoxazolone 1a' to give intermediate A. After loss of is a poor solvent for 3aa, the aggregates were formed
benzoic acid, intermediate B was formed. With the in DMSO/water mixtures with higher fw. Their
coordination of isocyanide 2a to B, a cascade emissions are induced by aggregation, further proving
migration and insertion reaction occurred to afford their AIE properties.
intermediate C and D. After N-O bond cleavage of
the strained ring in D, intermediate E was thus formed.
600
(a) AIE-3aa
(b)
fw(vol%)
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
500
400
300
200
100
0
Accompanying with nucleophilic addition of oxygen
to diimine motif, F was generated. Then, protonolysis
of F by benzoic acid produced the final product 3aa,
as well as the re-generated Pd-catalyst. Hereto, we
suppose this cascade involving deprotonation/
coordination insertion/ ring-opening/ cyclization/
protonolysis would be a favored process when
compared to a direct insertion of Pd to N-O bond
because it often demonstrates elimination of CO2
while not in the present case.
400
450
500
550
600
650
700
750
0
20
40
60
80
100
Wavelength (nm)
Water fraction (vol%)
Although previous application of 1,3-oxazine-6-
one mainly focused on the bioactivity study, during
our experiments, we found that the 1,3-oxazine-6-one
derivatives exhibited intense fluorescence in solid
state under a 365 nm UV lamp (Figure 1c). To further
explore its potential application, we selected several
samples to investigate their photophysical properties.
As shown in Table 4, 1,3-oxazine-6-ones with
different functional groups, 3aa, 3ca, 3da, 3ea, 3ma
and 3qa showed similar absorption maxima in a range
of 333-340 nm in DMSO. The measured decaying
lifetimes were of nanosecond magnitude, indicating a
fluorescence rather than a phosphorescence decay
process. Comparing to their low quantum yields (ФF)
of 0-4.86% in solution, in powder state they emitted
in a range of 407-455 nm with much higher ФF of
23.43-69.48%, demonstrating AIE (aggregation-
induced emission) characteristics. It’s worth noting
that 3aa and 3qa showed higher ФF values of 50.17%
and 69.48%, respectively, in solid state. We then
systematically investigated their emission behaviors
in solution and aggregated states. Figure 1a showed
the photoluminescence (PL) spectra of 3aa in DMSO
and water mixtures with different water fractions (fw)
as an example. The PL curves of 3aa in DMSO and
DMSO/water mixtures with fw lower than 60% exhibit
flat lines parallel to the abscissa, indicating that it is
[a]
Figure 1.
Photoluminescence spectra of 3aa in
DMSO/water with different water fractions (fw); c = 50
μM, λex = 334 nm.
3aa in water/DMSO with di
Photo images of the selected samples under UV light
[b]
Variation in the PL intensity of
[c]
ff
erent water fractions.
(λex =365 nm).
Single crystal structure of 3aa (Figure S1a)
indicated a torsion angle between aromatic ring R1
and oxazinone ring. In dilute solution, the dynamic
rotations and vibrations of the aromatic rings and
oxazinone rings dissipate energy in a non-radiatively
manner, while in solid state the intermolecular C-
H···π interactions (Figure S1b) may restrict the
intramolecular motions, and thus resulted in an
enhancement in emission.[14,
Besides, bulky R2
15]
group as well as the twisted molecular conformation
could also contribute to the efficient fluorescence in
solid state by suppressing close packing.[14, 16]
Over the past years, a lot of AIE luminogens with
versatile functionalities have been developed.[17]
However, most of them were derived from silole,[18]
triphenylethene,[19] tetraphenylethene (TPE)[20] and
tetraphenyl-1,4-butadiene (TPBD).[21] Exploration of
AIE luminogens with new skeletons is thus highly
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001200
Advanced Synthesis & Catalysis
demanded.[14, 22] From this point of view, this work
provided a simple and efficient method to prepare a
type of AIE luminogens with high solid-state
emission efficiencies.
Procedure 2: A suspension of NH2OH·HCl (0.5291 g, 7.51
mmol) and NaOAc (0.6214 g, 7.57 mmol) in ethanol (20
mL) was stirred at room temperature for 5 minutes, and
then the product of last step was dissolved in ethanol and
added dropwise. The mixture was heated at 78 ℃ oil bath
overnight. After cooling to room temperature, the
suspension was concentrated in vacuo, and purified by
flash column chromatography over a short plug of silica gel.
Conclusion
Isocyanides were synthesized according to the published
methods with minor modifications.[24]
In summary, we reported a palladium-catalyzed ring
expansion reaction of isoxazolones with isocyanides
to synthesize 1,3-oxazin-6-one compounds, during
which no CO2 elimination was observed, and it
exhibited extremely high atom economy. Besides, this
protocol features relatively mild condition, wide
substrate scope, as well as excellent yield. For the
function of the product point of view, it provided a
new skeleton with AIE characters when compared to
conventional framework.
General procedure for synthesis of products:
Take 3aa as example, in a test tube loaded with 1a (0.2
mmol), PdCl2 (10 mol %), PhCOONa (20 mol %), 2 mL of
1,1,2-trichoroethane was added, followed by the injection
of 2a (2 equiv). Then the reaction system was sealed and
heated with oil bath at 85 ℃ for 6 h. After completion and
cooled to room temperature, solvent was removed under
vacuum. Product 3aa was obtained through purification by
flash column chromatography with petroleum ether and
ethyl acetate (VPE/VEA = 10/1), over a short plug of silica
gel.
Experimental Section
Procedure for gram scale synthesis of 3qa:
General Information
In a round bottom flask loaded with 1q (0.4021g, 2 mmol),
PdCl2 (0.0352g, 10 mol %), PhCOONa (0.0576g, 20
mol %), 20 mL of 1,1,2-trichoroethane was added,
followed by the injection of 2a (0.45 mL, 4 mmol). Then
the reaction system was sealed and heated with oil bath at
85 ℃ for 7 h. After completion and cooled to room
temperature, solvent was removed under vacuum. Product
3qa (0.4952g, 87% yield) was obtained as white solid
through purification by flash column chromatography with
petroleum ether and ethyl acetate (VPE/VEA = 10/1), over a
short plug of silica gel.
All commercially available compounds were used without
further purification, unless otherwise noted. Solvents for
chromatography were analytical grade and used without
further purification. Analytical thin-layer chromatography
(TLC) was performed on silica gel, visualized by
irradiation with UV light. 200-300 mesh silica gel was used
for column chromatography. 1H and 13C NMR spectra were
recorded on BRUKER 400 MHz spectrometer in CDCl3 or
DMSO-d6. Chemical shifts (δ) were reported according to
an internal tetramethylsilane (TMS) standard or the CDCl3
residual peak (δ 7.26) for 1H NMR (For DMSO-d6, peak at
δ 2.50 was used). Chemical shifts of 13C NMR were
reported relative to CDCl3 (δ 77.16) or DMSO-d6 (δ 39.52).
Data were reported in the following order: chemical shift (δ)
in ppm; multiplicities are indicated s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quartet), m (multiplet);
coupling constants (J) are in Hertz (Hz). IR spectra were
recorded on a BRUKER VERTEX 70 spectrophotometer
and are reported in terms of frequency of absorption (cm-1).
HRMS spectra were obtained by using BRUKER
micrOTOF-Q III instrument with ESI source. UV-vis
absorption spectra were obtained with Agilent Cary Series
UV-Vis-NIR Spectrophotometer at room temperature.
Photoluminescence spectra (PL) were measured by
Edinburgh FLS 980 fluorescence spectrometer at room
temperature. Absolute PL quantum yields (ΦF) were
measured by Edinburgh FLS 980 fluorescence
For spectra information of 1a,1c, 1e, 1f, 1g, 1o one can
refer to published document.[25] For spectra information of
1b, one can refer to published document.[10f] For spectra
information of 1n, one can refer to published document.[26]
For spectra information of 1p, one can refer to published
document.[27] For spectra information of 1r, 1s, 1t, 1u, 1v,
one can refer to published document.[8b] For spectra
information of 1w, one can refer to published document.[10d]
CCDC-2004329 (3aa) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
3-(benzo[d][1,3]dioxol-5-yl)-4-methylisoxazol-5(4H)-one
(1d) Yield: 71% (0.7734 g). White Solid. M.p. 177.8-
spectrometer with
Fluorescence lifetime was collected by Edinburgh LifeSpec
II L041.
a
calibrated integrating sphere.
1
179.1 ℃. H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H),
7.21 – 7.14 (m, 2H), 7.12 – 7.08 (m, 1H), 6.13 (s, 2H), 1.87
(s, 3H) ppm. 13C{1H}NMR (100 MHz, DMSO-d6) δ 173.0,
160.7, 149.4, 148.0, 122.2, 121.5, 108.9, 107.3, 101.9, 93.6,
Preparation of Starting Materials
+
7.4 ppm. HRMS (ESI) m/z: calcd for C11H10NO4 [M+H]+
220.0604, found: 220.0599. IR (neat, ν) = 3107, 2210,
Take 1a as example, 4-methyl-3-(p-tolyl)isoxazol-5(4H)-
one (1a) were synthesized according to the methods of
previous lectures without modifications.[23]
1690, 1590 cm-1.
3-(4-bromophenyl)-4-methylisoxazol-5(4H)-one
(1h)
Yield: 43% (0.5417 g). White Solid. M.p. 172.7-174.2 ℃.
1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.79 –
7.75 (m, 2H), 7.60 – 7.56 (m, 2H), 1.88 (s, 3H) ppm.
13C{1H}NMR (100 MHz, DMSO-d6) δ 172.6, 160.1, 160.0,
132.2, 129.4, 127.2, 124.4, 7.2 ppm. HRMS (ESI) m/z:
Procedure 1: To a suspension of NaH (0.5600 g, 23.3 mmol)
in toluene (20 mL) was added 1-(p-tolyl)propan-1-one
(0.75 mL, 5.00 mmol), the resulting mixture was stirred at
room temperature for 30 minutes. After that, (MeO)2CO
(0.85 mL, 10 mmol) was added when the mixture was
heated at 110 ℃ oil bath. After 12 hours, the reaction was
quenched with saturated NH4Cl solution and extracted with
ethyl acetate (3×20 mL). The combined organic layers
were dried over Na2SO4 and solvent was removed under
reduced pressure.
+
calcd for C10H8BrN NaO2 [M+Na]+ 275.9631, found:
275.9621. IR (neat, ν) = 3080, 2363, 2335, 1691, 1604 cm-1.
4-methyl-3-(4'-methyl-[1,1'-biphenyl]-4-yl)isoxazol-
5(4H)-one (1i) Yield: 46% (0.6053 g). White Solid. M.p.
150.8-152.5 ℃. 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001200
Advanced Synthesis & Catalysis
+
1H), 7.90 – 7.79 (m, 2H), 7.77 – 7.67 (m, 2H), 7.67 – 7.57 ppm. HRMS (ESI) m/z: calcd for C15H19N2O2 [M+H]+
(m, 2H), 7.36 – 7.21 (m, 2H), 2.35 (s, 3H), 1.94 (s, 3H) 259.1441, found: 259.1445. IR (neat, ν) = 3245, 3068,
ppm. 13C{1H}NMR (100 MHz, DMSO-d6) δ 173.0, 2970, 2927, 2362, 2340, 1712, 1605 cm-1.
160.6(0), 160.5(7), 160.5(5), 142.3, 137.7, 136.0, 129.7,
127.9, 127.0, 126.7, 20.7, 7.5 ppm. HRMS (ESI) m/z: calcd
2-(tert-butylamino)-4-(4-methoxyphenyl)-5-methyl-6H-
+
for C17H16NO2 [M+H]+ 266.1176, found: 266.1187. IR
1,3-oxazin-6-one (3ca) Yield: 84% (48.4 mg). White Solid.
(neat, ν) = 3021, 2810, 2363, 2349, 1666, 1597 cm-1
1
M.p. 165.8-167.4 ℃. H NMR (400 MHz, CDCl3) δ 7.66 –
7.37 (m, 2H), 7.04 – 6.82 (m, 2H), 5.27 (s, 1H), 3.84 (s,
3-(3-bromophenyl)-4-methylisoxazol-5(4H)-one
(1j) 3H), 2.07 (s, 3H), 1.43 (s, 9H) ppm. 13C{1H}NMR (100
Yield: 44% (0.5581 g). White Solid. M.p. 140.8-142.5 ℃. MHz, CDCl3) δ 162.6, 162.2, 160.6, 155.1, 130.7, 130.4,
1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.79 – 113.4, 102.2, 55.4, 52.0, 28.9, 13.0 ppm. HRMS (ESI) m/z:
7.77 (m, 1H), 7.76 – 7.72 (m, 1H), 7.66 – 7.63 (m, 1H), calcd for C16H20N2NaO3 [M+Na]+ 311.1366, found:
+
7.53 – 7.48 (m, 1H), 1.89 (s, 3H) ppm. 13C{1H}NMR (100 311.1356. IR (neat, ν) = 3250, 3065, 2961, 2926, 2871,
MHz, DMSO-d6) δ 172.5, 159.6, 152.6, 133.4, 131.2, 130.3, 2361, 2339, 1701, 1599 cm-1.
129.7, 126.6, 122.3, 7.2 ppm. HRMS (ESI) m/z: calcd for
C10H9BrNO2+ [M+H]+ 253.9811, found: 253.9817. IR (neat,
4-(benzo[d][1,3]dioxol-5-yl)-2-(tert-butylamino)-5-
ν) = 3039, 1689, 1610 cm-1.
methyl-6H-1,3-oxazin-6-one (3da) Yield: 92% (55.5 mg).
1
White Solid. M.p. 176.2-177.3 ℃. H NMR (400 MHz,
4-methyl-3-(thiophen-2-yl)isoxazol-5(4H)-one (1k) Yield: CDCl3) δ 7.18 – 7.03 (m, 2H), 6.92 – 6.75 (m, 1H), 5.99 (s,
76% (0.6924 g). Pale yellow Solid. M.p. 120.3-122.0 ℃. 1H 2H), 5.35 (s, 1H), 2.04 (s, 3H), 1.42 (s, 9H) ppm.
NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.97 – 7.88 13C{1H}NMR (100 MHz, CDCl3) δ 169.5, 162.5, 162.1,
(m, 1H), 7.61 – 7.55 (m, 1H), 7.33 – 7.26 (m, 1H), 1.94 (s, 148.6, 147.4, 131.9, 123.6, 109.4, 107.8, 102.5, 101.4, 52.0,
3H) ppm. 13C{1H}NMR (100 MHz, DMSO-d6) δ 172.6, 28.8, 13.0 ppm. HRMS (ESI) m/z: calcd for
+
155.9, 154.5, 130.4, 128.8, 128.4, 7.4 ppm. HRMS (ESI) C16H18N2NaO4 [M+Na]+ 325.1159, found: 325.1160. IR
m/z: calcd for C8H8NO2S+ [M+H]+ 182.0270, found: (neat, ν) = 3255, 3069, 2959, 2907, 2362, 2341, 1708, 1602
182.0269. IR (neat, ν) = 3039, 2925, 2848, 2362, 2340, cm-1.
1691, 1611 cm-1.
2-(tert-butylamino)-5-methyl-4-(4-
4-methyl-3-(5-methylfuran-2-yl)isoxazol-5(4H)-one (1l) (trifluoromethyl)phenyl)-6H-1,3-oxazin-6-one
(3ea)
Yield: 65% (0.5819 g). White Solid. M.p. 160.1 - 161.8 ℃. Yield: 91% (59.3 mg). White Solid. M.p. 198.2-199.5 ℃.
1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.11 – 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.61 (m, 4H), 5.38 (s,
6.81 (m, 1H), 6.56 – 6.20 (m, 1H), 2.38 (s, 3H), 1.91 (s, 3H) 1H), 2.02 (s, 3H), 1.44 (s, 9H) ppm. 13C{1H}NMR (100
ppm. 13C{1H}NMR (100 MHz, DMSO-d6) δ 172.8, 155.3, MHz, CDCl3) δ 162.1, 161.4, 161.3, 141.6, 131.2 (q, JC-F
=
=
151.9, 140.8, 114.8(8), 114.8(5), 108.8, 13.4, 7.2 ppm. 32.4 Hz), 129.2, 125.1 (q, JC-F = 3.8 Hz), 124.0 (q, JC-F
HRMS (ESI) m/z: calcd for C9H10NO3 [M+H]+ 180.0655, 270.5 Hz), 104.1, 52.3, 28.8, 12.6 ppm. HRMS (ESI) m/z:
+
+
found: 180.0660. IR (neat, ν) = 3083, 2363, 2360, 1092, calcd for C16H17F3N2NaO2 [M+Na]+ 349.1134, found:
1630 cm-1.
349.1138. IR (neat, ν) = 3268, 3069, 2975, 2926, 2361,
2340, 1709, 1603 cm-1.
1,4,5,6-tetrahydro-3H-benzo[6,7]cyclohepta[1,2-
c]isoxazol-3-one (1q) Yield: 70% (0.7038 g). White Solid. 2-(tert-butylamino)-4-(4-fluorophenyl)-5-methyl-6H-
1
M.p. 175.8-177.7 ℃. H NMR (400 MHz, DMSO-d6) δ 1,3-oxazin-6-one (3fa) Yield: 86% (47.4 mg). White Solid.
1
11.77 (s, 1H), 7.61 – 7.53 (m, 1H), 7.47 – 7.40 (m, 1H), M.p. 186.2-188.4 ℃. H NMR (400 MHz, CDCl3) δ 7.67 –
7.38 – 7.31 (m, 2H), 2.87 (t, 2H), 2.47 (t, J = 6.7 Hz, 2H), 7.45 (m, 2H), 7.21 – 7.01 (m, 2H), 5.28 (s, 1H), 2.03 (s,
1.90 (dt, J = 10.6, 6.6 Hz, 2H) ppm. 13C{1H}NMR (100 3H), 1.43 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
MHz, DMSO-d6) δ 173.1, 159.2, 143.6, 131.0, 130.2, 126.6, 163.3 (d, JC-F = 248.2 Hz), 162.4, 161.7, 155.3, 134.1 (d,
126.3, 125.8, 101.6, 34.5, 24.5(2), 24.4(5) ppm. HRMS JC-F = 3.3 Hz), 131.0 (d, JC-F = 8.4 Hz), 115.1 (d, JC-F
=
+
(ESI) m/z: calcd for C12H12NO2 [M+H]+ 202.0863, found: 21.6 Hz), 103.1, 52.2, 28.9, 12.8 ppm. HRMS (ESI) m/z:
+
202.0864. IR (neat, ν) = 3060, 2952, 2843, 2356, 2335, calcd for C15H18FN2O2 [M+H]+ 277.1347, found:
1687, 1613 cm-1.
277.1344. IR (neat, ν) = 3243, 3068, 2978, 2965, 2928,
2863, 2362, 2335, 1712, 1602 cm-1.
4-methyl-3-(pyridin-3-yl)isoxazol-5(4H)-one (1m) Yield:
1
53% (0.4665 g). White Solid. M.p. 126.6-128.5 ℃. H 2-(tert-butylamino)-4-(4-chlorophenyl)-5-methyl-6H-
NMR (400 MHz, DMSO-d6) δ 8.91 – 8.80 (m, 1H), 8.79 – 1,3-oxazin-6-one (3ga) Yield: 91% (53.2 mg). White Solid.
1
8.66 (m, 1H), 8.16 – 7.98 (m, 1H), 7.66 – 7.53 (m, 1H), M.p. 192.4-193.7 ℃. H NMR (400 MHz, CDCl3) δ 7.58 –
1.90 (s, 3H) ppm. 13C{1H}NMR (100 MHz, DMSO-d6) δ 7.46 (m, 2H), 7.45 – 7.34 (m, 2H), 5.18 (s, 1H), 2.02 (s,
172.5, 158.8(9), 158.8(7), 151.3, 147.9, 135.1, 124.7, 124.2, 3H), 1.43 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
+
7.1 ppm. HRMS (ESI) m/z: calcd for C9H9N2O2 [M+H]+ 165.1, 162.2, 161.5, 136.5, 135.5, 130.3, 128.4, 103.5, 52.2,
+
177.0659, found: 177.0661. IR (neat, ν) = 3336, 2060, 28.9, 12.8 ppm. HRMS (ESI) m/z: calcd for C15H18ClN2O2
2380, 2355, 1620 cm-1.
[M+H]+ 293.1051, found: 293.1049. IR (neat, ν) = 3244,
3067, 2970, 2927, 2362, 2340, 1712, 1604 cm-1.
2-(tert-butylamino)-5-methyl-4-(p-tolyl)-6H-1,3-oxazin-
6-one (3aa) Yield: 95% (51.7 mg). White Solid. M.p. 4-(4-bromophenyl)-2-(tert-butylamino)-5-methyl-6H-
183.8 - 185.3 ℃. 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.41 1,3-oxazin-6-one (3ha) Yield: 88% (59.1 mg). White Solid.
1
(m, 2H), 7.26 – 7.16 (m, 2H), 5.18 (s, 1H), 2.40 (s, 3H), M.p. 201.6-203.0 ℃. H NMR (400 MHz, CDCl3) δ 7.64 –
2.05 (s, 3H), 1.44 (s, 9H) ppm. 13C{1H}NMR (100 MHz, 7.52 (m, 2H), 7.50 – 7.35 (m, 2H), 5.21 (s, 1H), 2.02 (s,
CDCl3) δ 162.9, 162.8, 162.5, 139.6, 135.2, 128.9, 128.8, 3H), 1.43 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
102.9, 52.1, 28.9, 21.5, 12.8 ppm. HRMS (ESI) m/z: calcd 162.2, 161.6, 159.5, 136.9, 131.4, 130.6, 123.8, 103.5, 52.2,
+
for C16H20N2NaO2 [M+Na]+ 295.1417, found: 295.1411. 28.9, 12.8 ppm. HRMS (ESI) m/z: calcd for
+
IR (neat, ν) = 3255 (N-H), 3068, 2967, 2925, 2858, 2363, C15H17BrN2NaO2 [M+Na]+ 359.0366, found: 359.0371.
2338, 1704, 1600, 1563 cm-1.
IR (neat, ν) = 3243, 3062, 2971, 2957, 2926, 2361, 2341,
1711, 1606 cm-1.
2-(tert-butylamino)-5-methyl-4-phenyl-6H-1,3-oxazin-6-
one (3ba) Yield: 85% (43.8 mg). White Solid. M.p. 173.2- 2-(tert-butylamino)-5-methyl-4-(4'-methyl-[1,1'-
1
174.0 ℃. H NMR (400 MHz, CDCl3) δ 7.63 – 7.52 (m, biphenyl]-4-yl)-6H-1,3-oxazin-6-one (3ia) Yield: 89%
2H), 7.49 – 7.40 (m, 3H), 5.18 (s, 1H), 2.04 (s, 3H), 1.44 (s, (62.0 mg). White Solid. M.p. 210.5-212.1 ℃. 1H NMR (400
9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ 162.9, 162.4, MHz, CDCl3) δ 7.73 – 7.58 (m, 4H), 7.57 – 7.46 (m, 2H),
151.0, 138.1, 129.4, 128.9, 128.1, 103.3, 52.2, 28.9, 12.8 7.31 – 7.18 (m, 2H), 5.24 (s, 1H), 2.40 (s, 3H), 2.10 (s, 3H),
6
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10.1002/adsc.202001200
Advanced Synthesis & Catalysis
1.45 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ one (3qa) Yield: 91% (51.7 mg). White Solid. M.p. 174.5-
1
165.6, 162.5, 160.4, 142.2, 137.7, 137.6, 136.6, 129.7, 176.3 ℃. H NMR (400 MHz, CDCl3) δ 7.73 – 7.57 (m,
129.5, 127.1, 126.5, 103.2, 52.2, 28.9, 21.2, 12.9 ppm. 1H), 7.41 – 7.29 (m, 2H), 7.27 – 7.19 (m, 1H), 5.31 (s, 1H),
+
HRMS (ESI) m/z: calcd for C22H24N2NaO2 [M+Na]+ 2.64 (t, J = 7.0 Hz, 2H), 2.32 (t, J = 7.0 Hz, 2H), 2.19 (p, J
349.1911, found: 349.1918. IR (neat, ν) = 3264, 3070, = 6.8 Hz, 2H), 1.46 (s, 9H) ppm. 13C{1H}NMR (100 MHz,
2964, 2925, 2361, 2341, 1710, 1603 cm-1.
CDCl3) δ 164.3, 162.8, 161.4, 141.3, 138.2, 130.0, 129.2,
128.1, 126.5, 106.5, 52.3, 33.2, 32.1, 29.0, 21.5 ppm.
HRMS (ESI) m/z: calcd for C17H21N2O2+ [M+H]+ 285.1598,
found: 285.1601. IR (neat, ν) = 3314, 2968, 2931, 2361,
2341, 1711, 1659 cm-1.
4-(3-bromophenyl)-2-(tert-butylamino)-5-methyl-6H-
1,3-oxazin-6-one (3ja) Yield: 88% (59.2 mg). White Solid.
1
M.p. 142.3-144.0 ℃. H NMR (400 MHz, CDCl3) δ 7.72 –
7.65 (m, 1H), 7.57 – 7.50 (m, 1H), 7.50 – 7.43 (m, 1H),
7.33 – 7.27 (m, 1H), 5.23 (s, 1H), 2.01 (s, 3H), 1.43 (s, 9H) 2-(tert-butylamino)-4-phenyl-6H-1,3-oxazin-6-one (3ra)
ppm. 13C{1H}NMR (100 MHz, CDCl3) δ 162.1, 161.3, Yield: 73% (35.6 mg). White Solid. M.p. 158.0-159.6 ℃.
161.2, 140.1, 132.4, 131.8, 129.7, 127.5, 122.2, 103.8, 52.3, 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.91 (m, 2H), 7.50 –
28.9, 12.7 ppm. HRMS (ESI) m/z: calcd for 7.43 (m, 3H), 6.08 (s, 1H), 5.58 (s, 1H), 1.53 (s, 9H) ppm.
+
C15H17BrN2NaO2 [M+Na]+ 359.0366, found: 359.0375. 13C{1H}NMR (100 MHz, CDCl3) δ 165.7, 161.2, 161.1,
IR (neat, ν) = 3252, 3066, 2974, 2929, 2362, 2341, 1711, 135.9, 131.5, 128.8, 127.3, 91.9, 52.5, 28.9 ppm. HRMS
1606 cm-1.
(ESI) m/z: calcd for C14H17N2O2+ [M+H]+ 245.1285, found:
245.1294. IR (neat, ν) = 3232, 3070, 2970, 2361, 2339,
1723 cm-1.
2-(tert-butylamino)-5-methyl-4-(thiophen-2-yl)-6H-1,3-
oxazin-6-one (3ka) Yield: 95% (50.2 mg). Pale yellow
Solid. M.p. 170.4 - 172.1 ℃. 1H NMR (400 MHz, CDCl3) δ 2-(tert-butylamino)-4-(4-methoxyphenyl)-6H-1,3-
7.67 – 7.58 (m, 1H), 7.56 – 7.48 (m, 1H), 7.21 – 7.11 (m, oxazin-6-one (3sa) Yield: 58% (31.8 mg). White Solid.
1
1H), 5.38 (s, 1H), 2.26 (s, 3H), 1.49 (s, 9H) ppm. M.p. 155.6-157.2 ℃. H NMR (400 MHz, CDCl3) δ 8.13 –
13C{1H}NMR (100 MHz, CDCl3) δ 162.7, 154.3, 154.0, 7.76 (m, 2H), 7.07 – 6.82 (m, 2H), 5.99 (s, 1H), 5.65 (s,
143.2, 130.4, 128.4, 100.5, 52.1, 28.7, 12.6 ppm. HRMS 1H), 3.85 (s, 3H), 1.51 (s, 9H) ppm. 13C{1H}NMR (100
(ESI) m/z: calcd for C13H16N2NaO2S+ [M+Na]+ 287.0825, MHz, CDCl3) δ 165.3, 165.2, 162.4, 161.4, 129.1, 128.3,
found: 287.0829. IR (neat, ν) = 3252, 3068, 2969, 2929, 114.1, 90.1, 55.5, 52.4, 28.9 ppm. HRMS (ESI) m/z: calcd
2873, 2362, 2340, 1693, 1603 cm-1.
for C15H19N2O3 [M+H]+ 275.1390, found: 275.1380. IR
+
(neat, ν) = 3266, 3055, 2983, 2964, 2362, 2335, 1727 cm-1.
2-(tert-butylamino)-5-methyl-4-(5-methylfuran-2-yl)-
6H-1,3-oxazin-6-one (3la) Yield: 84% (44.0 mg). White 4-(4-(tert-butyl)phenyl)-2-(tert-butylamino)-6H-1,3-
Solid. M.p. 189.2 - 190.5 ℃. 1H NMR (400 MHz, CDCl3) δ oxazin-6-one (3ta) Yield: 65% (39.0 mg). White Solid.
1
7.16 – 6.96 (m, 1H), 6.31 – 6.04 (m, 1H), 5.11 (s, 1H), 2.38 M.p. 175.8-177.1 ℃. H NMR (400 MHz, CDCl3) δ 7.94 –
(s, 3H), 2.26 (s, 3H), 1.44 (s, 9H) ppm. 13C{1H}NMR (100 7.86 (m, 2H), 7.51 – 7.46 (m, 2H), 6.06 (s, 1H), 5.53 (s,
MHz, CDCl3) δ 162.9, 156.0, 151.4, 151.3, 150.1, 117.5, 1H), 1.52 (s, 9H), 1.35 (s, 9H) ppm. 13C{1H}NMR (100
108.6, 99.6, 52.0, 28.8, 14.2, 11.3 ppm. HRMS (ESI) m/z: MHz, CDCl3) δ 165.5, 161.3, 157.2, 155.1, 133.1, 127.2,
calcd for C14H19N2O3+ [M+H]+ 263.1390, found: 263.1396. 125.8, 91.3, 52.5, 35.1, 31.3, 28.9 ppm. HRMS (ESI) m/z:
+
IR (neat, ν) = 3250, 3072, 2980, 2962, 2925, 2361, 2339, calcd for C18H24N2NaO2 [M+Na]+ 323.1730, found:
1689, 1605 cm-1.
323.1728. IR (neat, ν) = 3254, 3054, 2966, 2930, 2905,
2868, 2361, 2340, 1712 cm-1.
2-(tert-butylamino)-5-methyl-4-(pyridin-3-yl)-6H-1,3-
oxazin-6-one (3ma) Yield: 70% (36.3 mg). White Solid. 2-(tert-butylamino)-4-(p-tolyl)-6H-1,3-oxazin-6-one
M.p. 182.6 - 184.1 ℃. 1H NMR (400 MHz, CDCl3) δ 8.91 – (3ua) Yield: 66% (34.1 mg). White Solid. M.p. 175.5-
1
8.78 (m, 1H), 8.69 – 8.59 (m, 1H), 7.94 – 7.81 (m, 1H), 178.0 ℃. H NMR (400 MHz, CDCl3) δ 7.96 – 7.74 (m,
7.43 – 7.32 (m, 1H), 5.27 (s, 1H), 2.05 (s, 3H), 1.44 (s, 9H) 2H), 7.31 – 7.18 (m, 2H), 6.04 (s, 1H), 5.65 (s, 1H), 2.41 (s,
ppm. 13C{1H}NMR (100 MHz, CDCl3) δ 162.4, 161.9, 3H), 1.52 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
159.8, 150.3, 149.9, 136.2, 133.9, 123.0, 104.3, 52.3, 28.9, 165.7, 161.3, 159.7, 142.0, 133.1, 129.5, 127.3, 91.2, 52.4,
+
12.6 ppm. HRMS (ESI) m/z: calcd for C14H18N3O2
28.9, 21.6 ppm. HRMS (ESI) m/z: calcd for
[M+H]+ 260.1394, found: 260.1398. IR (neat, ν) = 3251, C15H18N2NaO2 [M+Na]+ 281.1260, found: 281.1259. IR
+
3072, 2974, 2360, 2340, 1721, 1604 cm-1.
(neat, ν) = 3232, 3064, 2971, 2361, 2341, 1720 cm-1.
2-(tert-butylamino)-5-ethyl-4-phenyl-6H-1,3-oxazin-6-
2-(tert-butylamino)-4-(3-(trifluoromethyl)phenyl)-6H-
one (3oa) Yield: 84% (45.7 mg). White Solid. M.p. 113.8 - 1,3-oxazin-6-one (3va) Yield: 59% (36.8 mg). White Solid.
1
1
114.2 ℃. H NMR (400 MHz, CDCl3) δ 7.57 – 7.48 (m, M.p. 130.4-131.9 ℃. H NMR (400 MHz, CDCl3) δ 8.25 –
2H), 7.45 – 7.40 (m, 3H), 5.19 (s, 1H), 2.42 (q, J = 7.3 Hz, 8.18 (m, 1H), 8.15 – 8.04 (m, 1H), 7.77 – 7.70 (m, 1H),
2H), 1.43 (s, 9H), 1.15 (t, J = 7.4 Hz, 3H) ppm. 7.63 – 7.54 (m, 1H), 6.10 (s, 1H), 5.88 (s, 1H), 1.53 (s, 9H)
13C{1H}NMR (100 MHz, CDCl3) δ 163.3(3), 163.2(8), ppm. 13C{1H}NMR (100 MHz, CDCl3) δ 164.2, 160.9,
161.7, 138.3, 129.3, 128.2, 109.5, 52.2, 29.0, 20.2, 13.9 157.5, 136.8, 131.3 (q, JC-F = 32.5 Hz), 130.3, 129.3, 127.8
ppm. HRMS (ESI) m/z: calcd for C16H22N2NaO2+ [M+Na]+ (q, JC-F = 3.6 Hz), 124.2 (q, JC-F = 3.9 Hz), 124.0 (q, JC-F
=
295.1417, found: 295.1423. IR (neat, ν) = 3263, 3066, 270.0 Hz), 92.6, 52.7, 28.8 ppm. HRMS (ESI) m/z: calcd
2968, 2928, 2872, 2362, 2338, 1709, 1602 cm-1.
for C15H15F3N2NaO2+ [M+Na]+ 355.0978, found: 335.0977.
IR (neat, ν) = 3238, 3067, 2976, 2939, 2361, 2341, 1724,
1590 cm-1.
2-(tert-butylamino)-5,6-dihydro-4H-naphtho[1,2-
d][1,3]oxazin-4-one (3pa) Yield: 91% (49.2 mg). White
1
Solid. M.p. 166.5-168.1 ℃. H NMR (400 MHz, CDCl3) δ 5-methyl-4-(p-tolyl)-2-((2,4,4-trimethylpentan-2-
8.15 – 7.95 (m, 1H), 7.43 – 7.27 (m, 2H), 7.25 – 7.14 (m, yl)amino)-6H-1,3-oxazin-6-one (3ab) Yield: 57% (37.4
1H), 5.49 (s, 1H), 2.90 (t, J = 7.8 Hz, 2H), 2.70 (t, J = 7.7 mg). White Solid. M.p. 149.3-151.2 ℃. 1H NMR (400 MHz,
Hz, 2H), 1.52 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ 7.62 – 7.39 (m, 2H), 7.26 – 7.20 (m, 2H), 5.06 (s,
CDCl3) δ 161.3, 158.1, 156.4, 139.6, 132.1, 131.0, 127.9, 1H), 2.40 (s, 3H), 2.05 (s, 3H), 1.82 (s, 2H), 1.48 (s, 6H),
126.8, 126.0, 102.4, 52.1, 28.8, 27.6, 19.6 ppm. HRMS 1.01 (s, 9H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ 162.8,
+
(ESI) m/z: calcd for C16H18N2NaO2 [M+Na]+ 293.1260, 162.6, 139.6, 135.2, 129.0, 128.8, 102.8, 55.9, 51.5, 31.8,
found: 293.1262. IR (neat, ν) = 3249, 3073, 2964, 2926, 31.6, 29.4, 21.5, 12.9 ppm. HRMS (ESI) m/z: calcd for
2362, 2340, 1709, 1604 cm-1.
C20H28N2NaO2 [M+Na]+ 351.2043, found: 351.2043. IR
(neat, ν) = 3257, 3071, 2977, 2947, 2928, 2893, 2864, 2361,
2340, 1693, 1603 cm-1.
+
2-(tert-butylamino)-6,7-
dihydrobenzo[6,7]cyclohepta[1,2-d][1,3]oxazin-4(5H)-
7
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10.1002/adsc.202001200
Advanced Synthesis & Catalysis
2-(adamantan-1-ylamino)-5-methyl-4-(p-tolyl)-6H-1,3-
oxazin-6-one (3ac) Yield: 96% (67.2 mg). White Solid.
1339; b) M. C. Kim, J. H. Lee, B. Shin, L. Subedi, J. W.
Cha, J. S. Park, D. C. Oh, S. Y. Kim, H. C. Kwon, Org.
Lett. 2015, 17, 5024-5027; c) P. Fu, S. La, J. B.
MacMillan, J. Nat. Prod. 2016, 79, 455-462; d) Y.
Yamada, T. Kato, H. Ogino, S. Ashina, K. Kato, Horm
Metab Res. 2008, 40, 539-543; e) R. L. Jarvest, M. J.
Parratt, C. M. Debouck, J. G. Gorniak, L. J. Jennings, H.
T. Serafinowska, J. E. Strickler, Bioorg. Med. Chem.
Lett. 1996, 6, 2463-2466; f) M. Giitschow, U. Neumann,
Bioorg. Med. Chem. 1997, 5, 1935-1942; g) U.
Neumann, N. M. Schechter, M. Gütschow, Bioorg. Med.
Chem. 2001, 9, 947-954.
1
M.p. 205.7-207.2 ℃. H NMR (400 MHz, CDCl3) δ 7.56 –
7.38 (m, 2H), 7.26 – 7.19 (m, 2H), 4.99 (s, 1H), 2.40 (s,
3H), 2.14 – 2.08 (m, 3H), 2.06 (d, J = 3.8 Hz, 9H), 1.68 (t,
J = 3.0 Hz, 6H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
162.9, 162.5(2), 162.4(8), 139.6, 135.2, 129.0, 128.8, 102.8,
52.6, 41.7, 36.3, 29.5, 21.5, 12.9 ppm. HRMS (ESI) m/z:
calcd for C22H27N2O2+ [M+H]+ 351.2067, found: 351.2067.
IR (neat, ν) = 3244, 3070, 2904, 2845, 2360, 2334, 1711,
1604 cm-1.
2-(cyclohexylamino)-5-methyl-4-(p-tolyl)-6H-1,3-oxazin-
6-one (3ad) Yield: 98% (58.4 mg). White Solid. M.p.
1
152.0-153.5 ℃. H NMR (400 MHz, CDCl3) δ 7.55 – 7.37
(m, 2H), 7.27 – 7.18 (m, 2H), 5.34 (s, 1H), 3.73 (s, 1H),
2.39 (s, 3H), 2.04 (s, 3H), 1.97 (s, 2H), 1.70 (dt, J = 13.7,
4.1 Hz, 2H), 1.60 (dt, J = 12.6, 4.0 Hz, 1H), 1.41 – 1.29 (m,
2H), 1.18 (s, 3H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
163.5, 162.4, 139.7, 135.1, 128.8, 128.5, 102.4, 50.3, 32.8,
25.4, 24.7, 21.5, 12.8 ppm. HRMS (ESI) m/z: calcd for
[2] F. Risitano, G. Grassi, F. Foti, F. Caruso, G. Lo
Vecchio, J. Chem. Soc. Perkin Trans. 1, 1979, 24,
1522-1524.
[3] a) E. M. Beccalli, C. L. Rosa, A. Marchesini, J. Org.
Chem. 1984, 49, 4287-4290; b) E. M. Beccalli, A.
Marchesini, H. Molinari, Tetrahedron Lett. 1986, 27,
627-630; c) E. M. Beccalli, A. Marchesini, M. L.
Gelmi, T. Pilati, J. Org. Chem. 1987, 52, 1666-1669; d)
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Marchesini, Synthesis, 1988, 8, 630-631.
+
C18H22N2NaO2 [M+Na]+ 321.1573, found: 321.1580. IR
(neat, ν) = 3251, 3956, 2926, 2892, 2361, 2340, 1703, 1598
cm-1.
2-(butylamino)-5-methyl-4-(p-tolyl)-6H-1,3-oxazin-6-
one (3ae) Yield: 68% (37.0 mg). White Solid. M.p. 90.2-
92.1 ℃. 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.36 (m, 2H),
7.29 – 7.19 (m, 2H), 5.33 (s, 1H), 3.66 – 2.80 (m, 2H), 2.39
(s, 3H), 2.02 (s, 3H), 1.65 – 1.40 (m, 2H), 1.38 – 1.24 (m,
2H), 0.92 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}NMR (100 MHz,
CDCl3) δ 171.0, 163.6, 139.7, 135.1, 130.0, 128.9, 128.7,
41.1, 31.5, 21.5, 19.9, 13.8, 12.8. ppm. HRMS (ESI) m/z:
[4] a) R. Giri, J. K. Lam, J.-Q. Yu, J. Am. Chem. Soc. 2010,
132, 686-693; b) M. Chen, Z.-H. Ren, Y.-Y. Wang, Z.-
H. Guan, Angew. Chem. Int. Ed. 2013, 52, 14196-
14199; c) K. Liu, M.-Z. Zou, A.-W. Lei, J. Org. Chem.
2016, 81, 7088-7092.
+
calcd for C16H20N2NaO2 [M+Na]+ 273.1598, found:
273.1607. IR (neat, ν) = 3253, 2957, 2930, 2870, 2363,
2336, 1703, 1607 cm-1.
ethyl
(5-methyl-6-oxo-4-(p-tolyl)-6H-1,3-oxazin-2-
[5] B. Niu, B. Jiang, L.-Z. Yu, M. Shi, Org. Chem. Front.
2018, 5, 1267-1271.
yl)glycinate (3af) Yield: 67% (40.4 mg). White Solid. M.p.
1
120.4-122.2 ℃. H NMR (400 MHz, CDCl3) δ 7.52 – 7.29
(m, 2H), 7.25 – 7.17 (m, 2H), 5.97 (s, 1H), 4.21 (q, J = 7.1
Hz, 2H), 4.08 (br, 2H), 2.39 (s, 3H), 2.01 (s, 3H), 1.28 (t, J
= 7.1 Hz, 3H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
169.3, 162.6, 155.8, 139.9, 134.6, 128.9, 128.8, 61.7, 42.8,
21.5, 14.2, 12.8 ppm. HRMS (ESI) m/z: calcd for
C16H19N2O4+ [M+H]+ 303.1339, found: 303.1338. IR (neat,
ν) = 3389, 2987, 2955, 2924,2362, 2340, 1721, 1604 cm-1.
[6] I. D. Jurberg, H. M. L. Davies, Org. Lett. 2017, 19,
5158-5161.
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Ji, Org. Chem. Front. 2015, 2, 1338-1341; d) C.-G. Liu,
Z.-Y. Gu, H.-W. Bai, S.-Y. Wang, S.-J. Ji, Org. Chem.
Front. 2016, 3, 1299-1303; e) W.-G. Hu, J.-W. Li, Y.-
L. Xu, J.-X. Li, W.-Q. Wu, H.-Y. Liu, H.-F. Jiang, Org.
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5580; h) J.-Q. Liu, X.-Y. Shen, Y.-H. Wang, X.-S.
Wang, X.-H. Bi, Org. Lett. 2018, 20, 6930-6933; i) F.
Wang, T.-Q. Wei, P. Xu, S.-Y. Wang, S.-J. Ji, Chinese
Chemical Letters, 2019, 30, 379-382; j) Y. Fang, C.
Liu, F. Wang, R. Ding, S.-Y. Wang, S.-J. Ji, Org.
Chem. Front. 2019, 6, 660-663; k) Y. Fang, J.-M.
Yang, R. Zhang, S.-Y. Wang, S.-J. Ji, Org. Chem.
Front. 2019, 6, 3383-3386; l) P. Xu, Y.-M. Zhu, X.-Y.
Liu, X.-Z. Zhou, S.-Y. Wang, S.-J. Ji, Chinese
Chemical Letters, 2019, 10.1016/j.cclet.2020.03.023;
m) Z. Wang, X.-H. Meng, P. Liu, W.-Y. Hu, Y.-L.
Zhao, Org. Chem. Front. 2020, 7, 126-130.
2-((4-methoxyphenyl)amino)-5-methyl-4-(p-tolyl)-6H-
1,3-oxazin-6-one (3ag) Yield: 87% (56.1 mg). White Solid.
M.p. 188.4-189.6 ℃. 1H NMR (400 MHz, CDCl3) δ 7.57 (s,
1H), 7.53 – 7.50 (m, 2H), 7.50 – 7.39 (m, 2H), 7.27 – 7.24
(m, 2H), 6.90 – 6.83 (m, 2H), 3.79 (s, 3H), 2.41 (s, 3H),
2.11 (s, 3H) ppm. 13C{1H}NMR (100 MHz, CDCl3) δ
162.8, 162.2, 156.6, 153.7, 140.0, 134.8, 129.9, 129.0(4),
128.9(7), 122.0, 114.4, 104.8, 55.6, 21.6, 13.1 ppm. HRMS
(ESI) m/z: calcd for C19H19N2O3+ [M+H]+ 323.1390, found:
323.1399. IR (neat, ν) = 3273, 2362, 2336, 1709, 1604 cm-1.
Acknowledgements
In celebration of 20th anniversary of Shun-Jun Ji's research
group. We gratefully acknowledge the National Natural Science
Foundation of China (No. 21772138 and 21672157), the project
of scientific and technologic infrastructure of Suzhou (SZS201708)
and PAPD. We should thank Hua-Wei Liu in this group for
reproducing the result of 3aa, 3da, 3ka and 3ag.
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10.1002/adsc.202001200
Advanced Synthesis & Catalysis
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[13] According to one of the reviewer’s suggestion,
reactions using stoichiometric amount of PhCOONa
without Pd catalyst were conducted. As shown below,
when 1 equiv. PhCOONa was introduced, 3aa could be
isolated in 55% yield. Further increase the amount to
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reaction ran under our conditions mainly promoted by
Pd catalyst.
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9
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Advanced Synthesis & Catalysis
FULL PAPER
Palladium catalyzed ring expansion reaction of
isoxazolones with isocyanides: synthesis of 1,3-
oxazin-6-one derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Yi-Ming Zhu,a Wan Zhang,b HongKun Li,b,* Xiao-
Ping Xua,* and Shun-Jun Jia,*
10
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