Rapid Access to Benzimidazo[1,2- a]quinoline-Fused Isoxazoles via Pd(II)-Catalyzed Intramolecular Cross Dehydrogenative Coupling: Synthetic Versatility and Photophysical Studies

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Rapid Access to Benzimidazo[1,2‑a]quinoline-Fused Isoxazoles via

Pd(II)-Catalyzed Intramolecular Cross Dehydrogenative Coupling:

Synthetic Versatility and Photophysical Studies

Subrata Sahoo and Shantanu Pal*

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ABSTRACT: An eﬃcient and atom-economical palladium-catalyzed intramolecular cross dehydrogenative coupling (CDC)

reaction has been developed for the construction of highly π-conjugated benzimidazo[1,2-a]quinoline-fused isoxazole scaﬀolds using

molecular oxygen as sole oxidant. The approach portrayed wide substrate scope with good functional group tolerance and depicted a

useful tool for the generation of ﬂuorescence active compounds with high quantum yield. Synthetic versatility of the method via Fe-

catalyzed reductive isoxazole ring cleavage toward pyridine, pyrimidine, pyrazole fused heteropolycyclic compounds has been

showcase.

quinoline synthesis,⁶while Peng’s research group in 2019

reported π-conjugated benzimidazole-fused quinoline via

INTRODUCTION

■

Fused heteropolycyclic aromatic compounds are an important

class of π-conjugated molecules, which have been extensively

palladium-catalyzed sequential Heck and oxidative amination

reactions.⁷Most recently, Li and co-workers disclosed a C−H

used in the ﬁeld of pharmaceuticals, organic electronics, and

materials sciences.¹In particular, benzimidazo[1,2-a]-

activation cascade reaction from imidamides and anthranils

toward benzimidazo[1,2-a]quinolines using a rhodium(III)

catalyst.⁸However, those methods for the synthesis of the

benzimidazole-fused quinoline skeleton mostly involved

prefunctionalization of the starting materials, and its synthetic

application is limited because of the required overall multistep

transformations. Although few approaches have been docu-

mented in the literature for benzimidazole-fused quinoline, no

such reports are available for the synthesis of benzimidazole-

quinoline-fused isoxazole to the best of our knowledge.

Notably, the synthesis of fused polycyclic compounds

containing benzimidazole, quinoline, and isoxazole has not

been explored, thus limiting the biological evaluation of such

quinolines are reported to have a variety of biological activities,

such as antiviral, antifungal, antibacterial, etc.²(Figure 1). In

addition, 1,2-disubstituted (hetero) aryl-fused imidazole or

benzimidazole scaﬀolds and their metal complexes have been

signiﬁcantly explored as organic light-emitting diodes

(OLEDs), organic solar cells, organic ﬁeld-eﬀect transistors

(OFETs), etc.³On the other hand, isoxazoles are pervasive

scaﬀolds that are found in a variety of life-saving drugs and

pharmaceuticals as well as biologically active natural products.⁴

The design and synthesis of new molecules by combining

diﬀerent pharmacophores are fascinating topics in drug

discovery. Benzoimidazo[1,2-a]isoxazolo[4,3-c]quinoline with

a fused cyclic ring system comprises benzimidazole, quinoline,

and isoxazole components, which belong to a captivating

family of structurally unique heterocycles having an interesting

biological proﬁle⁵(Figure 1). Consequently, there have been

signiﬁcant interests in developing novel methodologies for the

construction of such kinds of fused polycyclic skeletons as

represented in Scheme 1. In 2012, Chen and co-workers

conveyed the rhodium(III)-catalyzed benzimidazole-fused

Received: December 12, 2020

Published: February 24, 2021

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coupling reactions, methods for developing the intramolecular

CDC reaction to construct heteropolycyclic skeletons are still

rare¹²and stimulating the ongoing research. Herein, we

disclosed the ﬁrst synthesis of benzimidazoquinoline-fused

isoxazole compounds via the palladium-catalyzed intramolec-

ular cross-dehydrogenative coupling reaction under base-free,

Co-catalyst-free, and metallic oxidant-free conditions,^13a−c

using molecular oxygen as the sole oxidant. Substrate scope,

functional group diversity, and photophysical studies of the

products are unveiled. Moreover, the synthesized product was

diversiﬁed to pyridine-, pyrimidine-, pyrazole-fused hetero-

polycyclic compounds, among others, via Fe-catalyzed

reductive isoxazole ring cleavage. In addition, the isoxazole-

cleaved product was converted to the derivatives of

pharmacologically potent benzo[4,5]imidazo[1,2-a]quinoline.

Notably, in this developed synthetic avenue, the C4

functionalization of isoxazole has been accomplished, which

is otherwise diﬃcult to achieve without a cocatalyst such as

Ag(I).^13c

RESULTS AND DISCUSSION

■

Our expedition commenced with the preparation of biheter-

ocyclic scaﬀolds 2 through 1,3-dipolar cycloaddition between

oxime 1a and phenyl acetylene 1b highlighted in Scheme 2.

Figure 1. Designing of novel 1-henylbenzo[4,5]imidazo[1,2-a]-

isoxazolo[4,3-c]quinoline and an example of biologically active

benzimidazo-quinoline derivatives.

Scheme 1. Previously Reported Approaches and Present

Approach

Scheme 2. Synthesis of the Biheterocyclic Scaﬀold

First, oxime 1a was subjected to the dipolar cycloaddition

reaction as per reported literature^13dprecedent, which was

found to be not suitable for this substrate because of the very

low yield. Therefore, we started screening the reaction

conditions using a diﬀerent solvent, reagent, base, and

temperature to get scaﬀold 2a in the best yield. N-

Bromosuccinimide along with triethyl ammine in DMF as a

solvent at 50 °C was found to be the best condition for this

reaction.

With the desired starting precursor, 2a, we started

optimization of the reaction conditions. At the beginning,

the reaction was performed with PdCl₂(10 mol %) as a

catalyst and Cu(OAc)₂(1.2 equiv) as an oxidant in xylene as a

solvent at 120 °C (Table 1, entry 1). However, no desired

product was formed with the recovery of starting material 2a.

Upon changing the catalyst from PdCl₂to Pd(OAc)₂, the

desired coupling product 3a was formed in 44% yield (Table 1,

entry 2). The product yield was improved to 65% upon the

addition of Piv−OH as an additive (Table 1, entry 3),

indicating the crucial role of Piv−OH. No improvement in the

yield was observed upon the addition of a base (Table 1, entry

4) and changing the palladium sources, such as Pd(PPh₃)₄,

PdCl₂(MeCN)₂, and Pd(PPh₃)₂Cl₂(Table 1, entries 5−7).

compounds. Therefore, an atom-economical and step-

economical method is highly desirable.

From the past few years, transition-metal-catalyzed cross-

dehydrogenative coupling (CDC) reactions,⁹forming carbon−

carbon bonds by directly connecting two C−H bonds. This

method is favorable in terms of the atom and step economy

since prefunctionalization of the starting materials is not

required. Although impressive attention has been given toward

intermolecular¹⁰and intramolecular¹¹cross-dehydrogenative

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a

Table 1. Optimization of the Reaction Conditions

b

entry

catalyst (10 mol %)

oxidant (1.2 equiv)

solvent 6

::

additives 1

yield (%)

1

2

3

4

5

6

7

8

PdCl₂

Cu(OAc)₂

CuI

O₂

air

O₂

xylene

acetonitrile

DMF

THF

1,4-dioxane

DCE

xylene

:

nd

44

65

42

nd

trace

nd

84

67

50

trace

35

<30

trace

40

trace

nd

Pd(OAc)₂

Pd(PPh₃)₄

PdCl₂(MeCN)₂

Pd(PPh₃)₂Cl₂

PdCl₂

Piv−OH

K₂CO₃

Piv−OH

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

Pd(OAc)₂

Piv−OH

CH₃CO₂H

CF₃CO₂H

Ag₂CO₃

AgOAc

AgNO₃

K₂S₂O₈

BQ

nd

31

O₂

a

b

General conditions: 2a (1.0 mmol), Pd(OAc)₂(0.1 equiv), solvent/PivOH 6:1 v/v, O₂balloon, 12 h. Isolated yield.

The reaction did not work in the absence of a palladium

catalyst (Table 1, entry 9), indicating the essential role of

palladium. In addition, lowering the temperature from 120 to

100 °C led to an increase in reaction time and a decrease in the

yield of the reaction. Fortunately, product 3a was formed in a

maximum yield of 84% when the reaction was performed

under an oxygen atmosphere using an oxygen balloon (Table

1, entry 11), without an external oxidant. In the absence of

pivalic acid, the yield of the reaction was decreased to 67%

(Table 1, entry 12). In open air, product 3a was formed in 50%

yield (Table 1, entry 13), and the reaction took a longer time

for completion. When Cu(OAc)₂was used as an oxidant, the

yield of the reaction was low. However, when the same

reaction was performed in the presence of CuI (Table 1, entry

10), no desired coupling product was observed, and the

starting material was consumed. This may be due to the

formation of some copper complexes that led to the decrease

in the yield of the reaction. Furthermore, the screening of

diﬀerent solvents (such as toluene, acetonitrile, DMF, THF,

1,4-dioxane, N,N-dimethylacetamide, and DCE), oxidants

(such as Ag₂CO₃, AgOAc, AgNO₃, K₂S₂O₈, and BQ), and

diﬀerent additives did not give improved results (Table 1,

entries 14−25).

After having optimized the reaction conditions (10 mol %

Pd(OAc)₂, 6:1 xylene/pivalic acid, oxygen atmosphere) to

check the substrate diversity of the present CDC reaction, a

wide range of benzimidazole-based biheterocyclic scaﬀolds

2a−t have been synthesized by the cycloaddition reaction

between oxime 1a and substituted phenyl acetylene 1b as

represented in Scheme 3.

The substrates with electron-donating groups reacted

slightly faster compared to those with electron-withdrawing

groups in the CDC reaction (Scheme 4). Substrates, having

para-substitution of the aryl ring with methoxy 2b, pentyl 2i,

chloro 2k, methyl 2m, and N,N-dimethyl 2n underwent the

CDC reaction smoothly to give the corresponding heteropoly-

cycles in 61−84% yields. 2-Bromo compound 2l did not give

the desired coupling product with complex TLC; however, the

starting material was consumed completely. In the case of

meta-substituted compound 2c and 3,4-disubstituted com-

pound 2d, the CDC reaction proceeded smoothly to yield the

corresponding coupling products 3c and 3d in 72% and 68%

yields, respectively. Conversely, substrate 2p, having 2,4-

disubstitution, was converted to the coupling product in 72%

yield. Sterically hindered 1,3,5-trisubstituted compound 2q was

converted to the corresponding coupling product 3q in 68%

yield. 2-Chloro compound 2r, 2-methoxy compound 2s, and

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Scheme 3. Cycloaddition Reaction for the Synthesis of

Scheme 4. Substrate Scope of the CDC Reaction

Biheterocyclic Scaﬀolds

3,5-dimethoxy compound 2t underwent the CDC reaction

smoothly to give the corresponding coupling products in 83%,

77%, and 70% yields, respectively.

To see the substituent eﬀect in the benzimidazole ring,

compounds 2u−2zc were prepared by using the same

procedure describe in Scheme 2. The symmetrically sub-

stituted benzimidazole ring containing starting material 2u

proceeded with the smooth CDC reaction to give the

corresponding coupling product 3u in a good yield. However,

during the synthesis of aldehyde type 1, unsymmetrical

substituted benzimidazole yielded an inseparable mixture of

two regio isomers; e.g., 5-methyl, 5-methoxy, 5- carboxylate,

and 5-nitro benzimidazole provided a mixture of both 5- and 6-

substituted aldehydes. With this inseparable mixture of

aldehyde type 1, biheterocyclic scaﬀolds of type 2 were

prepared, which was also found to be an inseparable mixture.

In order to check the feasibility of the reaction, with this

inseparable mixture of starting material, the CDC reaction was

performed and found that both electron-donating and

electron-withdrawing group substitution on the benzimidazole

ring underwent the smooth CDC reaction to give the

corresponding coupling product in a good yield (Scheme 5).

Substrates containing a nitro group in the benzimidazole ring

(2zb and 2zc) were futile to give the corresponding coupling

product.

In order to know which C−H bond between C2 of

benzimidazole and C4 of isoxazole is being activated ﬁrst, the

compound 2a was treated with highly reactive coupling

partners such as stilbene, diphenyl acetylene, iodobenzene,

etc. in an intermolecular fashion (Scheme 6). Unfortunately, all

of the reactions were futile to give the intermolecular CDC

product; rather, the intramolecular coupling product was

isolated. This is probably because of the steric environment,

which did not allow coupling partners to come closer to either

C2 of benzimidazole or C4 of isoxazole.

Toward the kinetic isotopic experiment, compound 2a was

n

treated with BuLi and D₂O to get deuterated compound 2a-

C₂D. Initially, the hydrogen present at the C2 position of

benzimidazole was replaced by deuterium within 1.5 h. Further

rotation of the reaction mixture for 3 h resulted in the

replacement of C4 hydrogen of isoxazole also. After 12 h,

complete conversion to the product 2a-C₂D-C₄D was

observed. This observation indicated that the benzimidazole

C₂−H bond is more acidic than the isoxazole C₄−H bond. The

reported pK_avalues for the hydrogen at the C2 position of the

benzimidazole are 32.5 and 34.0 for the C4 position of

isoxazole.^14aFrom this, it can be stated that palladium was

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Scheme 5. Substituent Eﬀect in the Benzimidazole Ring for the CDC Reaction

incorporated at the C2 position of benzimidazole prior to C4

of isoxazole. Compound 2a-C₄D was prepared via the

cycloaddition reaction between 2a and deuterated phenyl

acetylene in DMF.

The β-amino α,β-unsaturated ketone 4, under basic

conditions in the presence of acetone, delivered substituted

pyridine-fused heteropolycyclic compound 5a in 82% yield

(Scheme 8).^15aThe corresponding purine-fused compound 5b

was obtained (93% yield) from compound 4 in the presence of

urea under heating conditions (Scheme 8).^15bMoreover, the

thermal cycloaddition of compound 4 with ethyl propiolate

aﬀorded 5c in 91% yield (Scheme 8). The hydrazine

cyclization of 4 with hydrazine hydrate furnished correspond-

ing pyrazole-fused product 5d in 78% yield (Scheme 8).^15c

Furthermore, the −NH₂group in compound 4 was substituted

by chloride under treatment with NaNO₂in HCl and aﬀorded

compound 5e in 85% yield, which underwent Pd-catalyzed

hydrodehalogenation to furnish 5f in 73% yield and NaBH₄

reduction to give alcohol 5g in 95% yield (Scheme 8).

Photophysical Studies. Photophysical properties of the

synthesized compounds have been shown in Table 2. The

ﬂuorescence emission spectra of benzoimidazo[1,2-a]-

isoxazolo[4,3-c]quinolines were measured in CHCl₃as

shown in Figure 2.

UV−vis studies displayed that the absorption band of

compounds 3a−q covers from 275 to 425 nm, involving two to

three absorption peaks, which are attributed to π−π* and

n−π* charge transfer transition, respectively. The nature of

substituents in aryl ring plays a crucial role in absorption

wavelength and ﬂuorescent quantum yield. The compounds

3a−q showed blue ﬂuorescent emission with a moderate to

high quantum yield (Φ_F), 0.24−0.86. The products 3b and 3g

bearing p-methoxy aryl ring and extended π-conjugated ring,

respectively, have displayed a longer absorption wavelength

and comparatively high Φ_Fwith respect to 3a. Compound 3j,

having cyclopropyl ring substitution, showed the lowest

absorption wavelength as compared to the rest with a quantum

yield of 0.24.

Furthermore, the KIE was determined to be 1.01 for the

parallel reaction using 2a and 2a-C₂D and 1.17 for the reaction

using 2a and 2a-C₄D. These values indicated that the C−H

activation step is not involved in the rate-limiting step. As the

C−H activation step is not the rate-limiting step for both the

transformations, therefore, it is quite possible that the

carbometalation could be the rate-limiting step in this reaction.

Based on control experiments, H/D exchange, kinetic studies,

and previous literature reports, a possible catalytic cycle for the

palladium-catalyzed CDC reaction has been represented in

Scheme 7.

First, palladium was coordinated to the nitrogen atom of

benzimidazole, and then, it was shifted to the C-2 position of

the benzimidazole ring via metallotropism-triggered^14bactiva-

tion to form intermediate I. Subsequently, an intramolecular

C−H bond cleavage happened via a concerted metalation

deprotonation (CMD) pathway to generate intermediate II.

Finally, reductive elimination provided product 3a and

regenerated palladium(0), which was oxidized in the presence

of oxygen to its active form palladium(II).

Synthetic Versatility. To further explore the potential of

synthesized compounds, 1-phenylbenzo[4,5]imidazo[1,2-a]-

isoxazolo[4,3-c]quinoline was subjected to diﬀerent isoxazole

ring cleavage reaction conditions to generate potential

intermediate β-amino α,β-unsaturated ketone. Fortunately,

treatment of 3a with Fe-powder in acetic acid under reﬂux

conditions provided β-amino α, β-unsaturated ketone inter-

mediate 4, which is a versatile intermediate and converted to

pyridine-, pyrimidine-, and pyrazole-fused heteropolycyclic

compounds as well as functionalized benzimidazoquinoline-

fused compounds in good yields (Scheme 8).

Notably, compound 3n exhibited maximum absorption

wavelength and maximum quantum yield (Φ_F0.86) in this

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Scheme 6. Control Experiments, H/D Exchange, and Kinetic Studies

archive. The compound 3p having methoxy- and methyl-

substituted aryl rings has shown strong UV absorption (log ε =

5.77) with a quantum yield of 0.68.

EXPERIMENTAL SECTION

■

General Information. Unless otherwise noted, all chemicals were

purchased from commercial suppliers and used without further

puriﬁcation. Column chromatography puriﬁcations were performed

using 100−200 mesh silica gel. Commercial grade solvents and

reagents were used without further puriﬁcation. Experiments involving

moisture-senstive and/or air-sensitive components were performed in

oven-dried glassware under a positive pressure of nitrogen/argon

using freshly distilled solvents. Analytical thin-layer chromatography

(TLC) was performed using Merck 60 F₂₅₄precoated silica gel plates

(0.2 mm thickness). Subsequent to elution, plates were visualized

using UV radiation (254 nm) on Spectroline Model ENF-24061/F

254 nm. Flash chromatography was performed using 100−200 mesh

silica gel with the indicated solvent system. Columns were typically

packed as slurry and equilibrated with the appropriate solvent system

prior to use. High-resolution mass spectral analysis (HRMS) was

performed on a Bruker Daltonics MicroTOF-Q-II mass spectrometer

and Thermoscintiﬁc Exactive Plus ORBITRAP mass spectrometer

using MeOH as a solvent with an electrospray ionization (ESI)

positive method. ¹H NMR and ¹³C NMR spectra were recorded on a

Bruker 400 NMR spectrometer (400 MHz for ¹H, 100 MHz for ¹³C).

Chemical shifts for ¹H NMR spectra are reported as δ in units of parts

per million (ppm) relative to the signal of chloroform-d (δ 7.28,

singlet). Multiplicities were given as s (singlet); d (doublet); t

(triplet); q (quartet); dd (doublets of doublet); dt (doublets of

triplet); or m (multiplet). The number of protons (n) for a given

CONCLUSIONS

■

To conclude, we have reported the ﬁrst synthesis of

benzoimidazo[1,2-a]isoxazolo[4,3-c]quinoline compounds

using a palladium-catalyzed intramolecular cross-dehydrogen-

ative coupling reaction. Diverse heteropolycyclic compounds

have been synthesized with a good yield and functional group

tolerance. The kinetic isotope experiments suggested that the

C−H activation step was not involved in the rate-determining

step. The synthetic utility of the product toward other fused N-

heteropolycyclic compounds (pyridine, pyrimidine, and

pyrazole) has also been explored via Fe-catalyzed isoxazole

ring cleavage. Moreover, the isoxazole-cleaved product was

converted to the derivatives of pharmacologically potent

benzo[4,5]imidazo[1,2-a]quinoline. The photophysical studies

displayed a strong blue ﬂuorescence emission of the

compounds with a high quantum yield. The results presented

here may have considerable interest in medicinal and materials

sciences.

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Scheme 7. Proposed Mechanism

Scheme 8. Synthetic Versatility

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2-(1H-Benzo[d]imidazol-1-yl)benzaldehyde Oxime (1a). The

compound 1a was synthesized by the procedure as described above

and obtained as a white solid: 87% yield (2.06 g); R_f= 0.4 (40%

Table 2. Photophysical Properties of the Products

a

b

c

compounds

λ_abs,max(nm)

λ_em,max(nm)

log ε

Φ_F

1

EtOAc + pet ether); H NMR (400 MHz, DMSO-d₆) δ 11.55 (1H,

3a

3b

3g

3i

314

343

324

346

290

341

342

395

305

341

451

450

451

450

451

450

451

5.25

5.23

5.25

5.70

5.00

5.14

5.15

5.53

5.77

0.52

0.74

0.76

0.24

0.41

0.52

0.56

0.86

0.68

0.56

s), 8.44 (1H, s), 8.08−7.96 (1H, m), 7.88−7.74 (1H, m), 7.70−7.60

(2H, m), 7.60−7.52 (1H, m), 7.51 (1H, s), 7.37−7.24 (2H, m),

7.17−7.10 (1H, m); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 144.8,

143.8, 143.4, 135.4, 134.1, 131.1, 130.1, 130.0, 128.8, 127.1, 124.0,

122.8, 120.3, 110.7; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd

for C₁₄H₁₂N₃O 238.0975, found 238.0976.

General Procedure for the Synthesis of Isoxazoles (2a−t).

To an oven-dried round-bottom ﬂask were added aldoxime of type 1a

(1 mmol), N-bromosuccinimide (1.2 mmol), 5 mL of DMF, and

allowed to rotate 1 h at rt. Then triethyl ammine (1.2 mmol) was

added dropwise, followed by the dropwise addition of substituted

acetylene (1.1 mmol). The reaction mixture was allowed to rotate at

50 °C (using an oil bath) until the completion of the reaction

(conﬁrmed by TLC). After completion of the reaction, DMF was

evaporated under a high vacuum and extracted with ethyl acetate (10

mL) and water (10 mL). The organic layer was separated, and the

aqueous layer was extracted with ethyl acetate (3 × 10 mL). The

combined organic layer was washed with 10 mL of brine solution,

dried over anhydrous Na₂SO₄, and concentrated in vacuo. The

residue was puriﬁed by column chromatography using 100−200 silica

gel to get the desired product 2.

3j

3k

3m

3n

3p

3q

a

b

Absorption maxima in CHCl₃(1 × 10⁻⁶mol/L). Emission maxima

c

in CHCl₃(1 × 10⁻⁶mol/L). Fluorescence quantum yield,

determined by quinine sulfate (Φ_F= 0.546 in H₂SO₄).

Characterization Data for the Products (2a−t). 3-(2-(1H-

Benzo[d]imidazol-1-yl)phenyl)-5-phenylisoxazole (2a). The com-

pound 2a was synthesized by the procedure as described above and

obtained as a yellow liquid: 72% yield (239 mg); R_f= 0.5 (40%

EtOAc + pet ether); ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (1H, s),

8.05−7.98 (1H, m), 7.83−7.76 (2H, m), 7.76−7.70 (2H, m), 7.67−

7.63 (2H, m), 7.48 (3H, dd, J = 5.1, 1.9 Hz), 7.26−7.16 (2H, m), 7.09

(1H, dd, J = 7.0, 1.6 Hz), 6.66 (1H, s); ¹³C{¹H} NMR (100 MHz,

DMSO-d₆) δ 169.6, 160.9, 144.6, 143.4, 134.9, 134.1, 132.0, 131.1,

130.2, 129.7, 129.3, 126.9, 126.7, 125.8, 123.7, 122.6, 120.1, 110.6,

100.2, 39.9; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₂H₁₆N₃O 338.1288, found 338.1296.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(4-methoxyphenyl)-

isoxazole (2b). The compound 2b was synthesized by the procedure

as described above and obtained as a yellow liquid: 71% yield (260

mg); R_f= 0.5 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.13−8.09 (1H, m), 7.96 (1H, s), 7.90 (1H, d, J = 8.0 Hz),

7.72−7.66 (2H, m), 7.59−7.55 (1H, m), 7.44−7.40 (2H, d, J = 8.0

Hz), 7.37−7.29 (2H, m), 7.25 (1H, m), 6.91−6.85 (2H, d, J = 8.0

Hz), 5.38 (1H, s), 3.83 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

170.6, 161.1, 160.0, 143.2, 143.0, 134.7, 133.9, 131.0, 130.7, 129.6,

128.1, 127.4, 127.4, 123.9, 122.9, 120.4, 119.6, 114.2, 110.3, 96.8,

55.3; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₃H₁₈N₃O₂

368.1394, found 368.1406.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(3-methoxyphenyl)-

isoxazole (2c). The compound 2c was synthesized by the procedure

as described above and obtained as a yellow liquid: 72% yield (264

mg); R_f= 0.6 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.14−8.08 (1H, m), 7.96 (1H, s), 7.93−7.87 (1H, m),

7.72−7.68 (2H, m), 7.60−7.56 (1H, m), 7.37−7.30 (2H, m), 7.28−

7.22 (2H, m), 7.06−7.02 (2H, m), 6.92 (1H, ddd, J = 8.3, 2.5, 0.9

Hz), 5.50 (1H, s), 3.81 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

170.4, 160.1, 159.8, 143.2, 143.0, 134.7, 133.9, 131.1, 130.7, 130.0,

129.7, 128.2, 127.9, 127.3, 124.0, 122.9, 120.4, 118.3, 116.4, 110.7,

110.3, 98.4, 55.3; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₃H₁₈N₃O₂368.1394, found 368.1404.

Figure 2. Emission spectra of 3a, 3b, 3g, 3i, 3j, 3k, 3m, 3n, 3p, and

3q in CHCl₃(1 × 10⁻⁶mol/L).

resonance is indicated by nH. Coupling constants are reported as a J

value in hertz. Carbon nuclear magnetic resonance spectra (¹³C

NMR) are reported as δ in units of parts per million (ppm) downﬁeld

from TMS (δ 0.0) and relative to the signal of chloroform-d (δ 77.0,

triplet).

Procedure for the Synthesis of Aldehyde (1).¹⁶To a 25 mL

round-bottom ﬂask, 2-ﬂuorobenzaldehydes (2.0 equiv, 13.6 mmol),

benzo[d]imidazoles (1.0 equiv, 6.8 mmol), and K₂CO₃(2.0 equiv,

13.6 mmol) in DMF (5.0 mL) were added, and the reaction was

stirred at 90 °C for 10 h. Upon the completion of the reaction

(conﬁrm by TLC), the solvent was removed under reduced pressure,

and the residue was dissolved in EtOAc (150 mL). The organic layer

was washed with H₂O (3 × 40 mL), dried over anhydrous Na₂SO₄,

and removed under the reduced pressure. The crude was puriﬁed with

silica gel column chromatography to aﬀord the target compound 1.

Procedure for the Synthesis of Oxime (1a). Et₃N (1.2 equiv)

was added to the stirring solution of 1 (1.0 equiv, 10 mmol) and

NH₂OH·HCl (1.2 equiv) in 20 mL of methanol. The resulting

solution was allowed to stir at room temperature, and the progress of

the reaction was monitored by TLC until completion. Upon

completion of the reaction, the reaction mixture was concentrated

under reduced pressure by removing the solvent. The residue was

extracted with DCM (25 mL) and water (25 mL). The organic layer

was separated, and the aqueous layer was extracted with DCM (3 ×

25 mL). The organic extract was washed with brine 25 mL and dried

over anhydrous Na₂SO₄, ﬁltered, and concentrated under reduced

pressure. The crude product was puriﬁed by column chromatography

using silica gel 100−200 to get desired product 1a.

3 - ( 2 - ( 1 H - B e n z o [ d ] i m i d a z o l - 1 - y l ) p h e n y l ) - 5 - ( 3 , 4 -

dimethoxyphenyl)isoxazole (2d). The compound 2d was synthesized

by the procedure as described above and obtained as a yellow liquid:

1

75% yield (296 mg); R_f= 0.6 (40% EtOAc + pet ether); H NMR

(400 MHz, CDCl₃) δ 8.13−8.08 (1H, m), 7.96 (1H, s), 7.89 (1H,

m), 7.71−7.66 (2H, m), 7.60−7.55 (1H, m), 7.36−7.28 (2H, m),

7.25 (1H, m), 7.06−6.97 (2H, m), 6.82 (1H, d, J = 8.3 Hz), 5.38 (1H,

s), 3.89 (3H, s), 3.88 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

170.5, 160.0, 150.7, 149.1, 143.2, 143.1, 134.7, 133.9, 131.1, 130.7,

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129.7, 128.2, 127.4, 124.0, 122.9, 120.3, 119.7, 119.1, 111.1, 110.4,

108.5, 97.1, 55.9; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₄H₂₀N₃O₃398.1499, found 398.1499.

(100 MHz, CDCl₃) δ 175.5, 159.6, 143.1, 134.6, 133.8, 130.8, 129.5,

128.0, 127.5, 123.8, 122.8, 120.4, 110.4, 97.6, 8.4, 7.9; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₁₉H₁₆N₃O 302.1288, found

302.1285.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(thiophen-2-yl)-

isoxazole (2e). The compound 2e was synthesized by the procedure

as described above and obtained as a yellow liquid: 68% yield (233

mg); R_f= 0.5 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.12−8.08 (1H, m), 7.94 (1H, s), 7.89 (1H, dd, J = 4.8, 3.7

Hz), 7.71−7.67 (2H, m), 7.59−7.54 (2H, m), 7.39−7.29 (3H, m),

7.28−7.22 (1H, m), 7.10 (1H, dd, J = 5.1, 1.2 Hz), 5.37 (1H, s);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.7, 159.9, 143.2, 143.0,

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(4-chlorophenyl)-

isoxazole (2k). The compound 2k was synthesized by the procedure

as described above and obtained as a yellow liquid: 67% yield (249

mg); R_f= 0.5 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.13−8.08 (1H, m), 7.96 (1H, s), 7.90 (1H, d, J = 7.9 Hz),

7.76−7.65 (2H, m), 7.62−7.53 (1H, m), 7.44−7.37 (2H, m), 7.37−

7.30 (3H, m), 7.26 (2H, m), 5.48 (1H, s); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 170.6, 160.1, 143.0, 133.9, 132.1, 131.1, 130.7, 130.3, 129.7,

128.8, 128.2, 127.3, 127.2, 126.8, 125.7, 124.0, 122.9, 120.5, 110.3,

98.2; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₂H₁₅ClN₃O 372.0898, found 372.0896.

134.7, 133.9, 131.1, 130.8, 129.6, 128.2, 127.2, 126.9, 125.2, 124.6,

124.0, 122.9, 120.4, 110.3, 97.9, 77.3; HRMS (ESI-ORBITRAP) m/z

[M + H]⁺calcd for C₂₀H₁₄N₃OS 344.0852, found 344.0862.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(4-ﬂuorophenyl)-

isoxazole) (2f). The compound 2f was synthesized by the procedure

as described above and obtained as a yellow liquid: 65% yield (231

mg); R_f= 0.5 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.12−8.08 (1H, m), 7.98 (1H, s), 7.94−7.89 (1H, m),

7.72−7.68 (2H, m), 7.59−7.55 (1H, m) 7.50−7.44 (2H, m), 7.38−

7.29 (2H, m), 7.28−7.22 (1H, m), 7.09−7.03 (2H, m), 5.44 (1H, s);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 169.4, 160.1, 143.0, 135.54 (d, J

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(2-bromophenyl)-

isoxazole (2l). The compound 2l was synthesized by the procedure as

described above and obtained as a yellow liquid: 76% yield (316 mg);

1

R_f= 0.5 (40% EtOAc + pet ether); H NMR (400 MHz, CDCl₃) δ

8.21−8.13 (1H, m), 7.99 (1H, s), 7.88 (1H, d, J = 7.8 Hz), 7.70 (3H,

m), 7.60−7.54 (2H, m), 7.41−7.29 (3H, m), 7.27−7.16 (2H, m),

5.93 (1H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 168.2, 159.6,

142.8, 134.8, 134.0, 133.9, 131.2, 131.0, 130.6, 129.8, 129.8, 128.8,

128.5, 127.7, 127.5, 127.4, 124.0, 122.9, 121.2, 120.5, 110.4, 103.2;

HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₅BrN₃O

416.0393, found 416.0394.

= 176 Hz), 133.9, 131.2, 130.7, 129.7, 129.2, 128.2, 127.0, 125.2,

124.0, 123.0, 120.4, 110.3, 98.5; HRMS (ESI-ORBITRAP) m/z [M +

H]⁺calcd for C₂₂H₁₅FN₃O 356.1194, found 356.1204.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(naphthalen-1-yl)-

isoxazole (2g). The compound 2g was synthesized by the procedure

as described above and obtained as a yellow liquid: 78% yield (302

mg); R_f= 0.7 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.24−8.19 (1H, m), 8.06 (1H, s), 7.99 (1H, d, J = 8.1 Hz),

7.89 (1H, d, J = 8.2 Hz), 7.87−7.82 (1H, m), 7.76−7.70 (2H, m),

7.63−7.58 (1H, m), 7.57 (1H, dd, J = 7.2, 1.2 Hz), 7.53−7.43 (3H,

m), 7.42−7.35 (2H, m), 7.33−7.24 (2H, m), 5.50 (1H, s); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 170.1, 159.8, 143.3, 142.9, 134.6, 134.0,

133.5, 131.2, 130.9, 130.7, 130.0, 129.8, 128.4, 128.2, 127.4, 127.3,

126.3, 124.9, 124.4, 124.1, 123.0, 120.5, 110.5, 102.5; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₆H₁₈N₃O 388.1444, found

388.1439.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(p-tolyl)isoxazole

(2m). The compound 2m was synthesized by the procedure as

described above and obtained as a yellow liquid: 73% yield (256 mg);

1

R_f= 0.6 (40% EtOAc + pet ether); H NMR (400 MHz, CDCl₃) δ

8.14−8.08 (1H, m), 7.96 (1H, s), 7.90 (1H, d, J = 7.8 Hz), 7.72−7.64

(2H, m), 7.58−7.54 (1H, m), 7.37 (2H, d, J = 8.2 Hz), 7.36−7.29

(1H, m), 7.28−7.22 (2H, m), 7.16 (2H, d, J = 8.0 Hz), 5.46 (1H, s),

2.35 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.8, 160.0,

143.2, 143.0, 140.6, 134.7, 133.9, 131.9, 130.7, 129.6, 129.5, 128.1,

127.4, 125.7, 124.1, 123.9, 122.9, 120.4, 110.3, 97.6, 21.4; HRMS

(ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₃H₁₈N₃O 352.1444,

found 352.1442.

4-(3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)isoxazol-5-yl)-N,N-di-

methylaniline (2n). The compound 2n was synthesized by the

procedure as described above and obtained as a yellow liquid: 78%

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(2-ﬂuorophenyl)-

isoxazole (2h). The compound 2h was synthesized by the procedure

as described above and obtained as a yellow liquid: 77% yield (273

mg); R_f= 0.5 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.13−8.04 (1H, m), 7.95 (1H, s), 7.89 (1H, d, J = 7.8),

7.82 (1H, td, J = 7.6, 1.6 Hz), 7.75−7.66 (2H, m), 7.62−7.55 (1H,

m), 7.42−7.30 (3H, m), 7.27−7.18 (2H, m), 7.12−7.03 (1H, m),

5.82 (1H, d, J = 3.4 Hz); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.4,

160.4, 158.9 (d, J = 253 Hz), 143.0, 134.7, 131.8, 131.7, 131.1, 130.8,

129.6, 128.3, 127.5, 127.3, 124.5, 124.5, 123.9, 122.8, 120.5, 116.3,

116.1, 110.2, 102.5, 102.4; HRMS (ESI-ORBITRAP) m/z [M + H]⁺

calcd for C₂₂H₁₅FN₃O 356.1194, found 356.1198.

1

yield (296 mg); R_f= 0.5 (40% EtOAc + pet ether); H NMR (400

MHz, CDCl₃) δ 8.14−8.07 (1H, m), 7.99 (1H, s), 7.90 (1H, d, J =

7.7 Hz), 7.72−7.63 (2H, m), 7.62−7.51 (1H, m), 7.36−7.29 (3H, m),

7.28−7.21 (2H, m), 6.63 (2H, d, J = 9.0 Hz), 5.32 (1H, s), 2.98 (6H,

s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 177.1, 171.4, 159.8, 151.4,

143.1, 134.7, 133.8, 130.8, 130.7, 129.5, 128.1, 127.7, 127.0, 123.9,

122.8, 120.4, 114.7, 111.6, 110.4, 95.3, 40.1; HRMS (ESI-ORBI-

TRAP) m/z [M + H]⁺calcd for C₂₄H₂₁N₄O 381.1710, found

381.1707.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(3, 4, 5-

triﬂuorophenyl)isoxazole (2o). The compound 2o was synthesized

by the procedure as described above and obtained as a yellow liquid:

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(4-pentylphenyl)-

isoxazole (2i). The compound 2i was synthesized by the procedure as

described above and obtained as a yellow liquid: 73% yield (297 mg);

1

58% yield (226 mg); R_f= 0.5 (40% EtOAc + pet ether); H NMR

R_f= 0.7 (40% EtOAc + pet ether); H NMR (400 MHz, CDCl₃) δ

(400 MHz, CDCl₃) δ 8.13−8.05 (1H, m), 7.94 (1H, s), 7.91 (1H, d, J

= 7.9 Hz), 7.72 (2H, m), 7.62−7.56 (1H, m), 7.39−7.29 (2H, m),

7.23 (1H, d, J = 7.7 Hz), 7.11 (2H, dd, J = 7.7, 6.4 Hz), 5.44 (1H, s);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 167.3 (d, J = 2.5 Hz), 160.4 (s),

152.7 (dd, J = 10.4, 4.0 Hz), 150.2 (dd, J = 10.4, 4.1 Hz), 143.2 (s),

142.9 (s), 142.2 (t, J = 15.3 Hz), 139.6 (t, J = 15.2 Hz), 134.6 (s),

133.9 (s), 131.5 (s), 130.7 (s), 129.8 (s), 128.2 (s), 126.7 (s), 124.1

(s), 123.1 (s), 120.6 (s), 110.5−110.0 (m), 99.4 (s); HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₃F₃N₃O 392.1005, found

392.1000.

8.13−8.08 (1H, m), 7.96 (1H, s), 7.90 (1H, dd, J = 4.8, 3.7 Hz),

7.73−7.63 (2H, m), 7.58−7.53 (1H, m), 7.43−7.36 (2H, m), 7.36−

7.29 (1H, m), 7.29−7.21 (2H, m), 7.17 (2H, d, J = 8.3), 5.46 (1H, s),

2.86−2.44 (2H, m), 1.60 (2H, dt, J = 15.0, 7.6 Hz), 1.45−1.20 (4H,

m), 0.89 (3H, t, J = 7.0 Hz); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

170.8, 160.0, 145.6, 143.2, 143.0, 134.7, 133.9, 131.0, 130.7, 129.6,

128.9, 128.1, 127.4, 125.7, 124.3, 123.9, 122.9, 120.4, 110.3, 97.6,

35.7, 31.3, 30.8, 22.4, 13.9; HRMS (ESI-ORBITRAP) m/z [M + H]⁺

calcd for C₂₇H₂₆N₃O 408.2070, found 408.2066.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-cyclopropylisoxazole

(2j). The compound 2j was synthesized by the procedure as described

above and obtained as a redish solid: 74% yield (222 mg); R_f= 0.6

(40% EtOAc + pet ether); ¹H NMR (400 MHz, CDCl₃) δ 8.04−7.99

(1H, m), 7.93−7.86 (2H, m), 7.71−7.60 (2H, m), 7.56−7.50 (1H,

m), 7.38−7.25 (2H, m), 7.23−7.17 (1H, m), 4.88 (1H, s), 1.97−1.49

(1H, m), 1.13−0.82 (2H, m), 0.82−0.60 (2H, m); ¹³C{¹H} NMR

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(4-methoxy-2-

methylphenyl)isoxazole (2p). The compound 2p was synthesized by

the procedure as described above and obtained as a yellow liquid:

1

74% yield (282 mg); R_f= 0.6 (40% EtOAc + pet ether); H NMR

(400 MHz, CDCl₃) δ 8.19−8.13 (1H, m), 7.97 (1H, s), 7.91−7.86

(1H, m), 7.73−7.67 (2H, m), 7.60−7.54 (1H, m), 7.44 (1H, d, J =

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8.6 Hz), 7.36−7.20 (3H, m), 6.74 (1H, dd, J = 8.6, 2.6 Hz), 6.68 (1H,

d, J = 2.6 Hz), 5.18 (1H, s), 3.80 (3H, s), 1.93 (3H, s); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 170.3, 160.7, 159.6, 143.2, 142.9, 138.0,

134.8, 133.8, 131.0, 130.5, 129.8, 129.7, 128.3, 127.7, 124.0, 122.9,

120.4, 119.2, 116.5, 111.5, 110.4, 100.3, 55.2, 21.1; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₄H₂₀N₃O₂382.1550, found

382.1544.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-mesitylisoxazole (2q).

The compound 2q was synthesized by the procedure as described

above and obtained as a yellow liquid: 77% yield (292 mg); R_f= 0.6

(40% EtOAc + pet ether); ¹H NMR (400 MHz, CDCl₃) δ 8.20−8.13

(1H, m), 8.02 (1H, s), 7.84 (1H, d, J = 7.9 Hz), 7.73−7.67 (2H, m),

7.58−7.52 (1H, m), 7.32−7.16 (3H, m), 6.82 (2H, s), 5.16 (1H, s),

2.26 (3H, s), 1.79 (6H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

170.5, 159.5, 143.2, 142.5, 139.9, 137.8, 134.5, 134.0, 131.1, 130.7,

129.7, 128.3, 128.1, 127.5, 124.0, 123.9, 122.9, 120.5, 110.4, 103.0,

21.1, 19.7; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₅H₂₂N₃O 380.1757, found 380.1754.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(3-chlorophenyl)-

isoxazole (2r). The compound 2r was synthesized by the procedure

as described above and obtained as a yellow liquid: 71% yield (263

mg); R_f= 0.5 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.13−8.08 (1H, m), 7.95 (1H, s), 7.93−7.88 (1H, m),

7.75−7.66 (2H, m), 7.60−7.56 (1H, m), 7.49 (1H, t, J = 1.6 Hz),

7.38−7.29 (5H, m), 7.24 (1H, m), 5.52 (1H, s); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 169.1, 160.2, 143.2, 142.9, 134.9, 134.6, 133.9, 131.3,

130.8, 130.3, 130.2, 129.7, 128.3, 128.2, 127.0, 125.7, 124.0, 123.9,

123.0, 120.5, 110.3, 99.0; HRMS (ESI-ORBITRAP) m/z [M + H]⁺

calcd for C₂₂H₁₅ClN₃O 372.0898, found 372.0894.

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-(2-methoxyphenyl)-

isoxazole (2s). The compound 2s was synthesized by the procedure

as described above and obtained as a yellow liquid: 70% yield (257

mg); R_f= 0.6 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.24−8.17 (1H, m), 7.94 (1H, s), 7.91 (1H, d, J = 7.8 Hz),

7.86 (1H, d, J = 7.8 Hz), 7.74−7.65 (2H, m), 7.60−7.52 (1H, m),

7.41−7.23 (4H, m), 7.01 (1H, t, J = 7.6 Hz), 6.86 (1H, d, J = 8.4 Hz),

5.70 (1H, s), 3.60 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

166.6, 159.9, 156.1, 143.3, 143.1, 135.0, 133.8, 131.2, 130.8, 130.5,

129.8, 128.5, 128.0, 127.3, 123.8, 122.7, 120.6, 120.3, 115.9, 111.1,

110.4, 102.2, 55.0; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₃H₁₈N₃O₂368.1394, found 368.1397.

mg); R_f= 0.6 (10% EtOAc + pet ether); mp 183−185 °C; ¹H NMR

(400 MHz, CDCl₃) δ 9.11−9.03 (2H, m), 8.57−8.47 (2H, m), 8.30−

8.21 (1H, m), 8.08−7.97 (1H, m), 7.84−7.77 (1H, m), 7.73−7.59

(3H, m), 7.55−7.47 (3H, m); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

167.9, 155.8, 144.3, 142.5, 136.1, 131.9, 131.6, 131.5, 128.9, 128.6,

126.9, 125.6, 125.0, 123.9, 123.9, 120.8, 116.0, 114.3, 113.2, 103.2;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₂H₁₄N₃O 336.1131,

found 336.1131.

1-(4-Methoxyphenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3b). The compound 3b was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 77%

yield (281 mg); R_f= 0.6 (10% EtOAc + pet ether); mp 178−180 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.12−9.09 (1H, m), 8.42 (1H, dd, J =

7.8 Hz, 1.5), 8.33 (1H, d, J = 8.5 Hz), 8.31−8.25 (1H, m), 8.14−8.07

(1H, m), 7.84−7.76 (1H, m), 7.74−7.68 (1H, m), 7.54−7.35 (4H,

m), 7.14−7.10 (1H, m), 4.05 (3H, s); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 167.7, 159.8, 155.6, 144.0, 142.4, 135.9, 131.7, 131.4, 129.7,

127.9, 125.5, 124.9, 123.8, 120.5, 120.2, 118.7, 115.9, 114.2, 113.2,

103.1, 55.7; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₃H₁₆N₃O₂

336.1237, found 336.1237.

1-(3-Methoxyphenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3c). The compound 3c was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 72%

yield (263 mg); R_f= 0.6 (10% EtOAc + pet ether); mp 175−180 °C;

¹H NMR (400 MHz, CDCl₃) δ 8.56 (1H, dd, J = 7.8, 1.5 Hz), 8.53

(1H, d, J = 8.4 Hz), 8.31−8.25 (1H, m), 8.19 (1H, dd, J = 7.7, 1.7

Hz), 7.94−7.89 (1H, m), 7.84−7.78 (1H, m), 7.65−7.59 (1H, m),

7.57−7.42 (3H, m), 7.24 (1H, td, J = 7.5, 0.9 Hz), 7.18 (1H, d, J = 8.4

Hz), 4.10 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.8, 158.1,

155.1, 144.8, 142.5, 136.3, 133.1, 131.7, 131.7, 131.5, 125.9, 125.7,

124.9, 123.7, 123.6, 120.8, 120.5, 116.1, 114.6, 113.1, 111.9, 105.0,

55.8; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₃H₁₆N₃O₂

336.1237, found 336.1237.

1-(3,4-Dimethoxyphenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-

c]quinoline (3d). The compound 3d was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 68%

yield (268 mg); R_f= 0.7 (10% EtOAc + pet ether); mp 238−241 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.30 (1H, d, J = 2.0 Hz), 8.55−8.49

(2H, m), 8.44 (1H, dd, J = 8.5 Hz, 2.1 Hz), 8.29−8.24 (1H, m),

7.93−7.87 (1H, m), 7.84−7.78 (1H, m), 7.56−7.46 (3H, m), 7.13

(1H, d, J = 8.6 Hz), 4.23 (3H, s), 4.04 (3H, s); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 168.2, 155.7, 151.6, 149.0, 144.2, 143.0, 136.1, 131.8,

131.6, 125.6, 125.0, 123.8, 121.7, 120.4, 119.8, 116.0, 114.5, 113.3,

112.4, 111.0, 102.0, 56.4, 56.0; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₂₄H₁₈N₃O₃396.1343, found 396.1343.

3 - ( 2 - ( 1 H - B e n z o [ d ] i m i d a z o l - 1 - y l ) p h e n y l ) - 5 - ( 3 , 5 -

dimethoxyphenyl)isoxazole (2t). The compound 2t was synthesized

by the procedure as described above and obtained as a yellow liquid:

1

81% yield (321 mg); R_f= 0.6 (40% EtOAc + pet ether); H NMR

(400 MHz, CDCl₃) δ 8.13−8.06 (1H, m), 7.95 (1H, s), 7.89 (1H, d, J

= 7.9 Hz), 7.70 (2H, d, J = 7.8 Hz), 7.61−7.56 (1H, m), 7.38−7.20

(3H, m), 6.62 (2H, d, J = 2.0 Hz), 6.48 (1H, s), 5.48 (1H, s), 3.79

(6H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.4, 161.0, 160.0,

143.2, 143.0, 134.7, 133.9, 131.1, 130.7, 129.6, 128.4, 128.2, 127.3,

124.0, 122.9, 120.4, 110.3, 103.8, 102.7, 98.6, 55.4; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₄H₂₀N₃O₃398.1499, found

398.1497.

General Procedure for the Palladium-Catalyzed Cross-

Dehydrogenative Coupling Reaction. To an oven-dried 50 mL

Schlenk tube ﬁtted with an oxygen balloon were added 1 mmol

cycloaddition product 2, 10 mol % Pd(OAc)₂, 1.2 mL of xylene, and

0.2 mL of pivalic acid, and the mixture was allowed to rotate at 120

°C in an oil bath for 12−24 h. After completion (conﬁrmed by TLC),

the reaction mixture was extracted with ethyl acetate (10 mL) and

water (10 mL). The organic layer was separated, and the aqueous

layer was extracted with ethyl acetate (3 × 10 mL). The combined

organic layer was washed with 10 mL of brine solution, dried over

anhydrous Na₂SO₄, and concentrated in vacuo. The residue was

puriﬁed by column chromatography using silica gel 100−200 to give

the desired product 3.

1-(Thiophen-3-yl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3e). The compound 3e was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 77%

yield (262 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 177−180 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.92 (1H, dd, J = 3.0 Hz, 1.2 Hz),

8.64−8.43 (2H, m), 8.31−8.25 (2H, m), 8.11−7.94 (1H, m), 7.85−

7.79 (1H, m), 7.64−7.44 (4H, m); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 164.1, 155.5, 144.5, 142.7, 136.2, 135.0, 131.9, 131.6, 131.4,

128.2, 126.6, 126.6, 125.7, 125.0, 123.9, 123.8, 120.7, 116.1, 114.4,

113.2; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₀H₁₂N₃OS

342.0696, found 342.0696.

1-(4-Fluorophenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3f). The compound 3f was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 53%

yield (187 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 208−210 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.17−9.10 (2H, m), 8.57−8.49 (2H,

m), 8.31−8.25 (1H, m), 8.05−7.99 (1H, m), 7.85−7.79 (1H, m),

7.58−7.47 (3H, m), 7.43−7.31 (2H, m); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 166.9, 164.6 (d, J = 252 Hz), 155.8, 144.2, 142.5, 136.1,

132.0, 131.6, 131.1, 131.0, 125.7, 125.1, 124.0, 123.3, 120.8, 116.2,

116.1, 114.3, 113.3, 103.0; HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₂₂H₁₃FN₃O 354.1037, found 354.1037.

Characterization Data of the Compounds (3a−zc). 1-

Phenylbenzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]quinoline (3a).

The compound 3a was synthesized by the general procedure

described above and obtained as an oﬀ-white solid: 84% yield (281

1-(Naphthalen-1-yl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3g). The compound 3g was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 81%

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yield (312 mg); R_f= 0.6 (10% EtOAc + pet ether); mp 255−258 °C;

¹H NMR (400 MHz, CDCl₃) δ 8.65−8.58 (2H, m), 8.55 (1H, d, J =

general procedure described above and obtained as an oﬀ-white solid:

67% yield (253 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 180−184

1

°C; H NMR (400 MHz, CDCl₃) δ 9.10−8.93 (2H, m), 8.60−8.44

8.5 Hz), 8.36−8.25 (2H, m), 8.16 (1H, d, J = 8.2 Hz), 8.05−7.97

(1H, m), 7.90−7.82 (2H, m), 7.78 (1H, dd, J = 8.0 Hz, 7.4 Hz),

7.63−7.54 (3H, m), 7.52−7.41 (2H, m); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 168.9, 155.5, 144.5, 142.3, 136.3, 133.9, 132.4, 132.0, 131.6,

130.9, 130.5, 128.6, 127.5, 126.5, 125.7, 125.1, 123.9, 123.8, 123.7,

121.0, 116.2, 114.4, 113.2, 105.3; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₂₆H₁₆N₃O 386.1288, found 386.1288.

(2H, m), 8.35−8.18 (1H, m), 8.14−7.95 (1H, m), 7.82−7.76 (1H,

m), 7.55−7.43 (3H, m), 7.00−6.87 (2H, m), 3.16 (6H, s); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 169.0, 155.7, 152.3, 144.5, 143.6, 136.2,

131.7, 131.5, 130.2, 125.6, 124.7, 123.6, 123.3, 120.5, 115.9, 114.8,

114.6, 113.1, 111.5, 100.7, 40.1; HRMS (ESI-ORBITRAP) m/z [M +

H]⁺calcd for C₂₄H₁₉N₄O 379.1553, found 379.1552.

1-(2-Fluorophenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3h). The compound 3h was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 68%

yield (240 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 193−195 °C;

¹H NMR (400 MHz, CDCl₃) δ 8.89 (1H, td, J = 7.6 Hz, 1.8 Hz), 8.58

1-(3,4,5-Triﬂuorophenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-

c]quinoline (3o). The compound 3o was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 47%

yield (182 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 251−255 °C;

¹H NMR (400 MHz, CDCl₃) δ 8.99−8.88 (2H, m), 8.50−8.42 (2H,

(1H, dd, J = 7.8 Hz, 1.5 Hz), 8.54 (1H, d, J = 8.5 Hz), 8.32−8.25

(1H, m), 8.01−7.94 (1H, m), 7.86−7.80 (1H, m), 7.68−7.60 (1H,

m), 7.58−7.45 (4H, m), 7.40−7.32 (1H, m); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 164.3, 160.1 (d, J = 256 Hz), 155.2, 144.5, 142.0,

136.2, 133.4, 132.0, 131.9, 131.6, 125.7, 125.1, 124.4, 123.9, 121.0,

116.8, 116.5, 116.1, 115.3, 114.3, 113.2, 105.2; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₃FN₃O 354.1037,

found 354.1036.

m), 8.28−8.17 (1H, m), 8.04−7.93 (1H, m), 7.80 (1H, m), 7.57−

7.45 (3H, m); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 164.53, 156.05,

152.83−152.61 (m), 150.22 (dd, J = 10.1, 4.0 Hz). 144.07, 141.68,

136.12, 132.27, 131.57, 125.75, 125.26, 124.43, 124.31, 122.71,

121.06, 116.16, 114.02, 113.35, 113.27, 113.10, 104.20; HRMS

(APCI-ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₁F₃N₃O

390.0849, found 390.0847.

1-(4-Methoxy-2-methylphenyl)benzo[4,5]imidazo[1,2-a]-

isoxazolo[4,3-c]quinoline (3p). The compound 3p was synthesized

by the general procedure described above and obtained as a white

solid: 73% yield (273 mg); R_f= 0.6 (10% EtOAc + pet ether); mp

198−200 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.30 (1H, s), 8.58−8.53

(2H, m), 8.44 (1H, dd, J = 8.5 Hz, 2.1 Hz), 8.27 (1H, m), 7.90 (1H,

m), 7.85−7.76 (1H, m), 7.56−7.45 (3H, m), 7.13 (1H, d, J = 8.6 Hz),

4.23 (3H, s), 4.04 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

168.0, 155.7, 151.6, 149.0, 144.2, 143.0, 136.1, 131.8, 131.6, 125.6,

125.0, 123.8, 123.8, 121.7, 120.4, 119.8, 116.0, 114.5, 113.3, 112.4,

111.0, 56.4, 56.0; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₄H₁₈N₃O₂380.1394, found 380.1395.

1-(4-Pentylphenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3i). The compound 3i was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 86%

yield (348 mg); R_f= 0.7 (10% EtOAc + pet ether). M.p.: 178−181

1

°C; H NMR (400 MHz, CDCl₃) δ 8.97 (2H, d, J = 8.2 Hz), 8.53

(2H, t, J = 8.5 Hz), 8.30−8.23 (1H, m), 8.07−7.98 (1H, m), 7.80

(1H, t, J = 7.9 Hz), 7.55−7.45 (5H, m), 2.76 (2H, t, J = 7.6 Hz),

1.86−1.68 (2H, m), 1.45−1.45 (4H, m), 0.95 (3H, t, J = 6.8 Hz);

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 168.3, 155.8, 147.1, 144.4,

142.8, 136.2, 131.8, 131.6, 129.0, 128.6, 125.6, 124.9, 124.4, 123.9,

123.8, 120.8, 116.0, 114.5, 113.2, 102.7, 36.1, 31.5, 30.8, 22.5, 14.0;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₇H₂₄N₃O 406.1914,

found 406.1914.

1-Mesitylbenzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]quinoline

(3q). The compound 3q was synthesized by the general procedure

described above and obtained as an oﬀ-white solid: 68% yield (256

mg); R_f= 0.6 (10% EtOAc + pet ether); R_f= 0.6 (10% EtOAc + pet

1-Cyclopropylbenzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]quinoline

(3j). The compound 3j was synthesized by the general procedure

described above and obtained as a reddish solid: 73% yield (218 mg);

1

ether); mp 222−225 °C; H NMR (400 MHz, CDCl₃) δ 8.62−8.52

1

R_f= 0.6 (10% EtOAc + pet ether); mp 177−180 °C; H NMR (400

(2H, m), 8.28 (1H, dd, J = 7.5 Hz, 1.0 Hz), 7.94−7.78 (1H, m),

7.87−7.81 (1H, m), 7.61−7.52 (1H, m), 7.51−7.40 (2H, m), 7.10

(2H, s), 2.44 (3H, s), 2.28 (6H, s); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 168.9, 155.0, 145.0, 142.1, 140.9, 138.6, 136.4, 131.9, 131.5,

128.8, 125.7, 125.0, 123.7, 123.3, 121.1, 116.2, 114.5, 113.1, 106.3,

21.4, 20.0; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₅H₂₀N₃O 378.1601, found 378.1603.

MHz, CDCl₃) δ 8.48 (1H, d, J = 8.5 Hz), 8.43 (1H, dd, J = 7.8 Hz,

1.5 Hz), 8.28−8.21 (1H, m), 8.00−7.93 (1H, m), 7.82−7.75 (1H, m),

7.53−7.42 (3H, m), 3.24−3.13 (1H, m), 1.61−1.55 (2H, m), 1.47−

1.40 (2H, m); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 174.1, 154.9,

144.8, 143.2, 136.4, 131.8, 131.4, 125.7, 124.9, 123.9, 123.4, 120.2,

116.2, 114.4, 113.1, 104.0, 10.7, 9.8; HRMS (ESI-TOF) m/z [M +

H]⁺calcd for C₁₉H₁₄N₃O 300.1131, found 300.1131.

1-(3-Chlorophenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3r). The compound 3r was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 83%

yield (360 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 206−208 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.06 (1H, s), 8.89 (1H, dd, J = 4.6

Hz, 1.5 Hz), 8.33 (2H, dd, J = 26.5 Hz, 8.1 Hz), 8.06 (1H, m), 7.91−

7.79 (1H, m), 7.69 (1H, t, J = 7.9 Hz), 7.54 (2H, m), 7.46−7.34 (3H,

m); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.9, 155.6, 144.0, 141.8,

135.8, 134.9, 131.8, 131.3, 131.2, 130.0, 128.3, 128.3, 126.4, 125.4,

124.9, 124.0, 123.9, 120.8, 115.8, 114.0, 113.1, 103.6; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₃ClN₃O [M + H]⁺

370.0742, found 370.0738.

1-(2-Methoxyphenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3s). The compound 3s was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 77%

yield (281 mg); R_f= 0.6 (10% EtOAc + pet ether); mp 185−188 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.06 (1H, s), 8.94−8.84 (1H, m),

8.33 (2H, dd, J = 26.5 Hz, 8.1 Hz), 8.10−8.02 (1H, m), 7.89−7.82

(1H, m), 7.69 (1H, t, J = 7.9), 7.58−7.49 (2H, m), 7.46−7.34 (3H,

m), 3.93 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.8, 158.1,

155.1, 144.8, 142.5, 136.3, 133.1, 131.7, 131.7, 131.5, 125.9, 125.7,

124.9, 123.7, 123.6, 120.8, 120.5, 116.1, 114.6, 113.1, 111.9, 105.0,

55.8; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₃H₁₆N₃O₂

336.1237, found 336.1239.

1-(4-Chlorophenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline (3k). The compound 3k was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 61%

yield (225 mg); R_f= 0.6 (10% EtOAc + pet ether); mp 258−260 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.10−9.03 (2H, m), 8.55−8.49 (2H,

m), 8.30−8.24 (1H, m), 8.04−7.98 (1H, m), 7.85−7.78 (1H, m),

7.67−7.63 (2H, m), 7.56−7.48 (3H, m); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 166.7, 155.9, 144.3, 142.3, 137.6, 136.1, 132.0, 131.6, 129.9,

129.2, 125.7, 125.4, 125.1, 124.0, 120.8, 116.1, 114.3, 113.3, 103.5;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₂H₁₃ClN₃O 370.0742,

found 370.0742.

1-(p-Tolyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]quinoline

(3m). The compound 3m was synthesized by the general procedure

described above and obtained as an oﬀ-white solid: 71% yield (248

1

mg); R_f= 0.6 (10% EtOAc + pet ether); mp 212−215 °C H NMR

(400 MHz, CDCl₃) δ 8.94 (2H, d, J = 8.3 Hz), 8.57−8.45 (2H, m),

8.29−8.23 (1H, m), 8.06−7.96 (1H, m), 7.83−7.77 (1H, m), 7.57−

7.43 (5H, m), 2.52 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

168.2, 155.7, 144.4, 142.8, 142.1, 136.1, 131.8, 131.6, 129.6, 128.6,

125.6, 124.9, 124.3, 123.9, 123.8, 120.8, 116.0, 114.5, 113.2, 102.8,

21.7; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₂₃H₁₆N₃O

350.1288, found 350.1288.

4-(Benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]quinolin-1-yl)-N,N-

dimethylaniline (3n). The compound 3n was synthesized by the

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1-(3,5-Dimethoxyphenyl)benzo[4,5]imidazo[1,2-a]isoxazolo[4,3-

c]quinoline (3t). The compound 3t was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 70%

yield (276 mg); R_f= 0.7 (10% EtOAc + pet ether); mp 190−192 °C;

¹H NMR (400 MHz, CDCl₃) δ 8.54 (1H, dd, J = 7.8 Hz, 1.5 Hz),

8.51 (1H, d, J = 8.5 Hz), 8.46 (2H, d, J = 2.3 Hz), 8.30−8.24 (1H,

m), 7.92−7.87 (1H, m), 7.81 (1H, ddd, J = 8.7 Hz, 7.4 Hz, 1.6 Hz),

7.56−7.46 (3H, m), 6.72 (1H, t, J = 2.3 Hz), 4.05 (6H, s); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 167.8, 161.0, 155.8, 144.2, 142.6, 136.1,

131.8, 131.5, 128.3, 125.6, 125.0, 124.0, 123.9, 120.6, 116.0, 114.4,

113.3, 106.1, 105.1, 103.4, 55.8; HRMS (ESI-ORBITRAP) m/z [M +

H]⁺calcd for C₂₄H₁₈N₃O₃396.1343, found 396.1346.

10,11-Dimethyl-1-phenylbenzo[4,5]imidazo[1,2-a]isoxazolo[4,3-

c]quinoline (3u). The compound 3u was synthesized by the general

procedure described above and obtained as an oﬀ-white solid: 78%

yield (283 mg); R_f= 0.6 (10% EtOAc + pet ether); mp 261−263 °C;

¹H NMR (400 MHz, CDCl₃) δ 9.06−9.01 (2H, m), 8.49 (1H, dd, J =

dropwise. After the addition of the n-butyllithium, the reaction

mixture was allowed to rotate at room temperature for 20 min. After

that, again the temperature of the reaction bath was lowered to −78

°C, and D₂O (1 mL) was added dropwise. The solution was then

slowly warmed to room temperature and allowed to rotate for 1.5 h.

The solvent was removed under reduced pressure. The residue was

puriﬁed by ﬂash column using ethyl acetate and pet ether as an eluent:

R_f= 0.5 (40% EtOAc + pet ether). The weight of the product is 252

mg (75% yield).

3-(2-(1H-Benzo[d]imidazol-1-yl-2-d)phenyl)-5-phenylisoxazole

1

(2a-C₂D): H NMR (400 MHz, CDCl₃) δ 8.14−8.08 (1H, m), 7.90

(1H, d, J = 7.9 Hz), 7.74−7.65 (2H, m), 7.59−7.54 (1H, m), 7.48

(2H, dt, J = 5.3, 2.1 Hz), 7.41−7.29 (5H, m), 7.30−7.26 (1H, m),

5.52 (1H, s).

(b) Deuteration at the C2 and C4 position of the benzimidazole

ring

7.8, 1.4 Hz), 8.43 (1H, d, J = 8.5 Hz), 7.94 (1H, s), 7.80−7.74 (1H,

m), 7.71 (1H, s), 7.69−7.62 (2H, m), 7.59 (1H, dt, J = 9.5, 4.3 Hz),

7.47 (1H, t, J = 7.5 Hz), 2.49 (3H, s), 2.43 (3H, s); ¹³C{¹H} NMR

(101 MHz, CDCl₃) δ 167.4, 155.8, 142.9, 141.7, 136.2, 133.0, 132.9,

131.7, 131.3, 130.1, 128.8, 128.5, 127.1, 125.5, 124.6, 120.8, 115.9,

114.2, 113.5, 103.5, 21.0, 20.2; HRMS (ESI-ORBITRAP) m/z [M +

H]⁺calcd for C₂₄H₁₈N₃O 364.1444, found 364.1451.

3-(2-(1H-Benzo[d]imidazol-1-yl-2-d)phenyl)-5-phenylisoxazole-

4-d (2a-C₂D-C₄D). A 50 mL Schlenk ﬂask equipped with a stir bar

was charged with 2a (0.337 g, 1 mmol) in dry THF (5 mL) under

nitrogen. The solution was cooled to −78 °C, and n-butyllithium (1.2

mmol) was added dropwise. After the addition of n-butyllithium, the

reaction mixture was allowed to rotate at room temperature for 20

min. After that, again the temperature of the reaction bath was

lowered to −78 °C, and D₂O (1 mL) was added dropwise. The

solution was then slowly warmed to room temperature and allowed to

rotate for 12 h. The solvent was removed under reduced pressure.

The residue was puriﬁed by ﬂash column using ethyl acetate and pet

ether as an eluent: R_f= 0.5 (40% EtOAc + pet ether). The weight of

11(12)-Methyl-1-phenylbenzo[4,5]imidazo[1,2-a]isoxazolo[4,3-

c]quinoline (3v,w). The compound 3v,w were synthesized by the

general procedure described above and obtained as an inseparable

mixture: white solid, 82% yield (286 mg); R_f= 0.6 (10% EtOAc + pet

1

ether); R_f= 0.6 (10% EtOAc + pet ether); H NMR (400 MHz,

1

CDCl₃) δ 9.01−8.94 (2H, m), 8.37 (1H, dt, J = 7.8, 1.9 Hz), 8.30−

8.21 (1H, m), 7.91−7.79 (1H, m), 7.75−7.53 (5H, m), 7.38 (1H, t, J

= 7.6 Hz), 7.21−7.10 (1H, m), 2.51 (3H, s, major + minor); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 167.4, 167.3, 155.6, 144.5, 142.2, 141.8,

136.0, 135.9, 133.8, 133.6, 131.6, 131.6, 131.3, 129.4, 128.8, 128.8,

128.5, 128.4, 127.0, 125.3, 125.3, 125.1, 124.6, 124.6, 120.5, 120.1,

115.8, 115.7, 114.2, 114.1, 113.2, 112.5, 103.2, 22.2, 21.3; HRMS

(ESI-ORBITRAPE) m/z [M + H]⁺calcd for C₂₃H₁₆N₃O 350.1288,

found 350.1289.

11(12)-Methoxy-1-phenylbenzo[4,5]imidazo[1,2-a]isoxazolo-

[4,3-c]quinoline (3xy). The compound 3x,y were synthesized by the

general procedure described above and obtained as an inseparable

mixture: yellowish white solid, 73% yield (266 mg); R_f= 0.5 (10%

EtOAc + pet ether); ¹H NMR (400 MHz, CDCl₃) δ 8.95 (2H, dd, J =

8.2, 1.4 Hz), 8.46 (1H, dd, J = 7.8, 1.5 Hz), 8.22 (1H, d, J = 8.5 Hz),

8.1 (1H, s), 7.80−7.72 (1H, m), 7.69−7.54 (5H, m), 7.49 (1H, t, J =

7.3 Hz,), 4.06 (3H, s, major isomer); ¹³C{¹H} NMR (101 MHz,

CDCl₃) δ 167.5, 155.4, 152.9, 142.3, 139.2, 135.6, 131.8, 131.5, 131.1,

128.8, 128.4, 126.8, 125.7, 125.2, 124.6, 115.4, 114.5, 108.8, 103.0,

96.9, 57.1; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₃H₁₆N₃O₂366.1237; Found:366.1242.

Methyl 1-Phenylbenzo[4,5]imidazo[1,2-a]isoxazolo[4,3-c]-

quinoline-11(12)-carboxylate (3z,za). The compound 3z,za was

synthesized by the general procedure described above and obtained as

an inseparable mixture: yellowish white solid, 71% yield (279 mg); R_f

= 0.5 (10% EtOAc + pet ether); R_f= 0.6 (10% EtOAc + pet ether);

¹H NMR (400 MHz, CDCl₃) δ 9.08−8.96 (2H, m), 8.60−8.50 (2H,

m), 8.48−8.22 (1H, m), 8.21−8.12 (1H, m), 7.99 (1H, d, J = 8.5 Hz),

7.88−7.78 (1H, m), 7.64 (3H, m), 7.59−7.51 (1H, m), 4.02 (3H, s,

major + minor); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.7, 167.3,

167.0, 155.7, 147.7, 145.1, 144.1, 135.7, 132.2, 132.0, 131.8, 131.7,

131.3, 128.9, 128.7, 128.6, 126.7, 125.8, 125.7, 125.5, 125.3, 125.1,

122.7, 120.2, 116.3, 116.1, 115.4, 114.4, 112.9, 102.9, 52.4, 52.2;

HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₄H₁₆N₃O₃

394.1186, found 394.1190.

the product is 240 mg (71% yield): H NMR (400 MHz, CDCl₃) δ

8.16−8.09 (1H, m), 7.91 (1H, d, J = 7.7 Hz,), 7.75−7.66 (2H, m),

7.61−7.55 (1H, m), 7.52−7.46 (2H, m), 7.40−7.28 (5H, m), 7.25

(1H, d, J = 7.6 Hz).

(c) Deuteration at the C4 position of the isoxazole ring

To an oven-dried round-bottom ﬂask were added aldoxime of type

2a (1 mmol), N-bromosuccinimide (1.2 mmol), and 5 mL of DMF,

and the mixture was allowed to rotate 1 h at rt. Then, triethyl ammine

(1.2 mmol) was added dropwise, followed by the dropwise addition of

deutereated phenyl acetylene¹⁸(1.1 mmol). The reaction mixture was

allowed to rotate at 50 °C until the completion of the reaction

(conﬁrmed by TLC). After completion of the reaction, DMF was

evaporated under a high vacuum and extracted with ethyl acetate (10

mL) and water (10 mL). The organic layer was separated, and the

aqueous layer was extracted with ethyl acetate (3 × 10 mL). The

combined organic layer was washed with 10 mL of brine solution,

dried over anhydrous Na₂SO₄, and concentrated in vacuo. The

residue was puriﬁed by column chromatography using 100−200 silica

gel to get the desired products 2a-C₄D: R_f= 0.5 (40% EtOAc + pet

ether). The weight of the product was 230 mg (68% yield).

3-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-phenylisoxazole-4-d

1

(2a-C₄D): H NMR (400 MHz, CDCl₃) δ 8.15−8.08 (1H, m), 7.97

(1H, s), 7.90 (1H, d, J = 7.8 Hz), 7.74−7.65 (2H, m), 7.61−7.54

(1H, m), 7.51−7.45 2H, m), 7.40−7.30 (4H, m), 7.30−7.27 (1H, m),

7.24 (1H, d, J = 7.5 Hz); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.5,

160.0, 143.2, 143.0, 134.7, 133.9, 131.1, 130.7, 130.3, 129.7, 128.8,

128.2, 127.3, 126.8, 125.7, 124.0, 122.9, 120.5, 110.3, 98.1.

General Procedure for the Synthesis of β-Amino α,β-

Unsaturated Ketone 4. To an oven-dried 25 mL round-bottom

ﬂask were added compound 3a (1 mmol), Fe-power (10 mmol), and

3 mL of glacial AcOH, and the mixture was allowed to rotate 1 h

under reﬂux conditions. After completion of the reaction (conﬁrmed

by TLC), the reaction mixture was diluted with ethyl acetate (10 mL)

and neutralized with dilute NaOH solution. The reaction mixture was

extracted with ethyl acetate (10 mL) and water (10 mL). The organic

layer was separated, and the aqueous layer was extracted with ethyl

acetate (3 × 10 mL). The combined organic layer was washed with 10

mL of brine solution, dried over anhydrous Na₂SO₄, and concentrated

in vacuo. The residue was puriﬁed by column chromatography using

silica gel 100−200 to give the desired product.

Deuteration of Compound 2a.

(a) Deuteration at the C2 position of benzimidazole ring¹⁷

A 50 mL Schlenk ﬂask equipped with a stir bar was charged with 2a

(0.337 g, 1 mmol) in dry THF (5 mL) under nitrogen. The solution

was cooled to −78 °C, and n-butyllithium (1.2 mmol) was added

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(5-Aminobenzo[4,5]imidazo[1,2-a]quinolin-6-yl)(phenyl)-

methanone (4). The compound 4 was synthesized by the procedure

as described above and obtained as a yellow liquid: 92% yield (347

mg); R_f= 0.6 (40% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.53 (1H, d, J = 8.4), 8.18 (1H, dd, J = 7.0, 1.9), 7.97 (1H,

d, J = 8.1), 7.87−7.74 (3H, m), 7.63 (1H, dd, J = 6.8, 2.1), 7.48 (2H,

dt, J = 12.6, 7.5), 7.3−7.30 (4H, m), 7.24 (2H, s); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 195.9, 149.1, 149.1, 144.6, 140.3, 136.5, 132.0,

131.9, 130.4, 129.5, 127.8, 123.9, 123.8, 123.6, 121.3, 119.4, 117.0,

116.1, 112.8, 100.6; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd

for C₂₂H₁₆N₃O 338.1288, found 338.1282.

3-Methyl-1-phenylbenzo[h]benzo[4,5]imidazo[2,1-f ][1,6]-

naphthyridine (5a).¹⁹To an oven-dried 25 mL round-bottom ﬂask

were added compound 4 (1 mmol), acetone (0.5 mL), and 5 mL of

20% KOH ethanol solution, and the mixture was allowed to rotate

overnight under reﬂux conditions. After completion of the reaction

(conﬁrmed by TLC), the reaction mixture was quench with 1 N

hydrochloric acid solution and extracted with ethyl acetate (10 mL)

and water (10 mL). The organic layer was separated, and the aqueous

layer was extracted with ethyl acetate (3 × 10 mL). The combined

organic layer was washed with 10 mL of brine solution, dried over

anhydrous Na₂SO₄, and concentrated in vacuo. The residue was

puriﬁed by column chromatography using silica gel 100−200 to give

the desired product 5a as an oﬀ-white solid: 82% yield (294 mg); R_f=

0.7 (20% EtOAc + pet ether); mp 169−171 °C; ¹H NMR (400 MHz,

CDCl₃) δ (400 MHz, CDCl₃) 9.30 (1H, d, J = 8.0), 8.57 (1H, d, J =

8.4), 8.35 (1H, d, J = 8.1), 7.82 (1H, t, J = 7.8), 7.70 (1H, d, J = 8.0),

7.61 (1H, t, J = 7.6), 7.57−7.49 (5H, m), 7.42 (2H, dt, J = 14.9, 7.2),

7.34 (1H, s), 2.84 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

159.6, 150.0, 147.3, 146.1, 144.3, 140.5, 135.8, 130.9, 130.6, 129.0,

127.9, 127.8, 127.1, 126.2, 124.4, 123.6, 123.1, 123.0, 121.0, 115.1,

114.7, 113.4, 25.0; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₅H₁₈N₃360.1495, found 360.1493.

1-Phenylbenzo[4,5]imidazo[1,2-a]pyrimido[5,4-c]quinilone (5b).

To an oven-dried 25 mL sealed tube were added compound 4 (0.25

mmol), thiourea (0.25 mmol), and 2 mL of DMSO, and the mixture

was allowed to rotate at 150 °C in an oil bath. After completion of the

reaction (conﬁrmed by TLC), the reaction mixture was extracted with

ethyl acetate (10 mL) and water (10 mL). The organic layer was

separated, and the aqueous layer was extracted with ethyl acetate (3 ×

10 mL). The combined organic layer was washed with 10 mL of brine

solution, dried over anhydrous Na₂SO₄, concentrated in vacuo. The

residue was puriﬁed by column chromatography using silica gel 100−

200 to give the desired product 5b as a white solid: 93% yield (80

mg); R_f= 0.7 (20% EtOAc + pet ether); mp 222−225 °C; ¹H NMR δ

(400 MHz, CDCl₃) 9.47 (1H, s), 9.20 (1H, dd, J = 8.0, 1.2), 8.56

(1H, d, J = 8.4), 8.34 (1H, d, J = 8.1), 7.96−7.85 (3H, m), 7.80 (1H,

d, J = 7.6), 7.62 (2H, dd, J = 15.1, 7.3), 7.58−7.44 (4H, m); ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 166.7, 157.0, 153.8, 144.0, 139.0, 137.2,

133.1, 131.0, 130.0, 129.8, 127.8, 127.3, 124.9, 124.2, 123.9, 121.4,

121.2, 115.4, 114.3, 113.4; HRMS (ESI-ORBITRAP) m/z [M + H]⁺

calcd for C₂₃H₁₅N₄347.1291, found 347.1297.

128.7, 128.4, 127.8, 127.7, 127.6, 124.6, 123.8, 123.7, 122.4, 121.4,

117.4, 115.1, 113.5, 61.5, 13.6; HRMS (ESI-ORBITRAP) m/z [M +

H]⁺calcd for C₂₇H₂₀N₃O₂418.1550, found 418.1542.

Procedure for the Synthesis of 5d.²⁰To an oven-dried 25 mL

round-bottom ﬂask were added compound 4 (1 mmol), hydrazine

hydrate (1.2 mmol), triethy ammine (1.2 mmol), and 5 mL of

acetonitrile, and the mixture was allowed to rotate overnight under

reﬂux conditions using an oil bath. After completion of the reaction

(conﬁrmed by TLC), the reaction mixture was extracted with ethyl

acetate (10 mL) and water (10 mL). The organic layer was separated,

and the aqueous layer was extracted with ethyl acetate (3 × 10 mL).

The combined organic layer was washed with 10 mL of brine solution,

dried over anhydrous Na₂SO₄, and concentrated in vacuo. The

residue was puriﬁed by column chromatography using silica gel 100−

200 to give the desired product.

1-Phenyl-3H-benzo[4,5]imidazo[1,2-a]pyrazolo[4,3-c]quinoline

(5d). The compound 5d was synthesized by the general procedure

described above and obtained as a yellow liquid: 78% yield (268 mg);

1

R_f= 0.4 (40% EtOAc + pet ether); H NMR δ (400 MHz, DMSO)

14.52 (1H, d, J = 58.0), 8.96−8.53 (4H, m), 8.50 (1H, d, J = 7.6),

7.89 (2H, s), 7.54 (6 H, d, J = 41.8); ¹³C{¹H} NMR (100 MHz,

DMSO) δ 145.2, 144.2, 134.3, 131.3, 130.5, 128.9, 128.8, 125.1,

124.1, 123.8, 123.1, 119.9, 116.9, 114.4, 105.3; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₅N₄335.1291, found

335.1291.

(5-Chlorobenzo[4,5]imidazo[1,2-a]quinolin-6-yl)(phenyl)-

methanone (5e). To a mixture of 4 (1 mmol) in concentrated

hydrochloric acid (1 mL) and water (1 mL) was added NaNO₂(2

mmol) in one portion at 0 °C. After that, the reaction mixture was

allowed to rotate at room temperature for 30 min. After completion of

the reaction (conﬁrmed by TLC), the reaction mixture was extracted

with ethyl acetate (10 mL) and water (10 mL). The organic layer was

separated, and the aqueous layer was extracted with ethyl acetate (3 ×

10 mL). The combined organic layer was washed with 10 mL of brine

solution, dried over anhydrous Na₂SO₄, and concentrated in vacuo.

The residue was puriﬁed by column chromatography using silica gel

100−200 to give the desired product 5e as a reddish yellow solid: 85%

yield (302 mg); R_f= 0.5 (20% EtOAc + pet ether); mp 250−252 °C;

¹H NMR δ (400 MHz, CDCl₃) 8.72 (1H, d, J = 8.5), 8.43 (2H, dd, J

= 14.2, 6.1), 8.08−8.00 (3H, m), 7.95 (1H, t, J = 7.9), 7.66 (2H, dd, J

= 14.2, 7.1), 7.59−7.54 (2H, m), 7.50 (2H, t, J = 7.7); ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 191.0, 145.3, 145.0, 135.5, 135.4, 134.4, 131.5,

131.4, 130.5, 130.0, 128.9, 127.5, 127.1, 124.9, 124.9, 123.6, 121.3,

120.7, 115.3, 113.8; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd

for C₂₂H₁₄ClN₂O 357.0789, found 357.0785.

Benzo[4,5]imidazo[1,2-a]quinolin-6-yl(phenyl)methanone (5f).

To an oven-dried 50 mL Schlenk tube ﬁtted with a nitrogen balloon

were added compound 5e (178 mg 0.5 mmol), 10 mol % Pd(PPh₃)₂,

K₂CO₃(69 mg, 2 mmol), and 2 mL of dry DMF, and the mixture was

allowed to rotate at 120 °C in an oil bath for 12 h. After completion

(conﬁrmed by TLC), the reaction mixture was extracted with ethyl

acetate (10 mL) and water (10 mL). The organic layer was separated,

and the aqueous layer was extracted with ethyl acetate (3 × 10 mL).

The combined organic layer was washed with 10 mL of brine solution,

dried over anhydrous Na₂SO₄, and concentrated in vacuo. The

residue was puriﬁed by column chromatography using silica gel 100−

200 to give the desired product 5f as a yellow solid: 73% yield (235

mg); R_f= 0.5 (20% EtOAc + pet ether); mp 226−228 °C; ¹H NMR δ

(400 MHz, CDCl₃) 8.70 (1H, d, J = 8.5), 8.51−8.44 (1H, m), 8.10−

8.01 (3H, m), 7.97−7.85 (3H, m), 7.65 (1H, t, J = 7.4), 7.61−7.54

(3H, m), 7.50 (2H, t, J = 7.7); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

192.9, 145.8, 144.8, 136.7, 136.2, 133.7, 132.0, 131.2, 130.6, 130.4,

128.5, 128.4, 124.7, 124.6, 123.2, 122.1, 121.4, 115.3, 113.8; HRMS

(ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₅N₂O 323.1179,

found 323.1178.

Ethyl-1-phenylbenzo[h]benzo[4,5]imidazo[2,1-f ][1,6]-

naphthyridine-2-carboxylate (5c). To an oven-dried 25 mL sealed

tube were added compound 4 (1 mmol), ethyl propiolet (1 mmol),

and 2 mL of DMSO, and the mixture was allowed to rotate at 150 °C

using an oil bath. After completion of the reaction (conﬁrmed by

TLC), the reaction mixture was extracted with ethyl acetate (10 mL)

and water (10 mL). The organic layer was separated, and the aqueous

layer was extracted with ethyl acetate (3 × 10 mL). The combined

organic layer was washed with 10 mL of brine solution, dried over

anhydrous Na₂SO₄, and concentrated in vacuo. The residue was

puriﬁed by column chromatography using silica gel 100−200 to give

the desired product 5c as a white solid: 91% yield (379 mg); R_f= 0.7

1

(10% EtOAc + pet ether); mp 181−183 °C; H NMR δ (400 MHz,

CDCl₃) 9.28 (1H, s), 9.25 (1H, d, J = 8.1), 8.55 (1H, d, J = 8.4), 8.33

(1H, d, J = 8.3), 7.91−7.80 (1H, m), 7.66−7.57 (2H, m), 7.58−7.49

(3H, m), 7.46 (1H, t, J = 7.7), 7.43−7.35 (3H, m), 4.12 (2H, q, J =

7.1), 1.03 (3H, t, J = 7.1); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

166.8, 150.3, 149.3, 148.9, 145.3, 144.2, 138.3, 136.2, 131.7, 130.7,

(5-Chlorobenzo[4,5]imidazo[1,2-a]quinolin-6-yl)(phenyl)-

methanol (5g). To a mixture of 5e (100 mg, 0.28 mmol) in ethanol

(1 mL) and chloroform (1 mL) was added NaBH₄(21 mg, 2 mmol)

in one portion at 0 °C. After that, the reaction mixture was allowed to

rotate at room temperature for 1 h. After completion of the reaction

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(conﬁrmed by TLC), the solvent was evaporated under a vacuum and

extracted with ethyl acetate (10 mL) and water (10 mL). The organic

layer was separated, and the aqueous layer was extracted with ethyl

acetate (3 × 10 mL). The combined organic layer was washed with 10

mL of brine solution, dried over anhydrous Na₂SO₄, and concentrated

in vacuo. The residue was puriﬁed by column chromatography using

silica gel 100−200 to give the desired product 5g as a white solid:

95% yield (95 mg); R_f= 0.5 (10% EtOAc + pet ether); mp 227−230

m), 7.89 (1H, dd, J = 10.5, 4.8 Hz), 7.86−7.79 (1H, m), 7.71 (1H, d,

J = 7.1 Hz,), 7.50 (1H, ddd, J = 7.8, 3.3, 0.7 Hz), 3.89 (3H, s, major +

minor); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 188.0, 167.1, 166.9,

146.6, 145.8, 144.9, 143.0, 138.6, 136.9, 136.7, 135.5, 135.4, 131.7,

131.5, 130.5, 130.3, 130.1, 130.0, 128.2, 128.0, 126.3, 125.8, 125.5,

124.5, 123.1, 120.4, 112.3, 109.8, 52.3, 52.2; HRMS (ESI-ORBI-

TRAP) m/z [M + H]⁺calcd for C₁₆H₁₃N₂O₃281.0921, found

281.0923.

1

°C; H NMR δ (400 MHz, CDCl₃) 8.58 (1H, d, J = 8.4), 8.38 (2H,

2-(5(6)-Nitro-1H-benzo[d]imidazol-1-yl)benzaldehyde (1H,I).

The compound 1H,I was synthesized by the procedure as described

above and obtained as an inseparable mixture: yellow solid, 63% yield

dd, J = 21.1, 8.2), 7.99 (1H, d, J = 8.1), 7.82 (1H, t, J = 7.8), 7.74

(2H, d, J = 7.6), 7.67−7.47 (4H, m), 7.33 (2H, t, J = 7.4), 7.25 (1H,

d, J = 7.3), 6.64 (1H, d, J = 11.0); ¹³C{¹H} NMR δ (10 MHz, CDCl₃)

146.3, 143.5, 142.5, 134.6, 131.9, 130.5, 129.9, 128.3, 128.2, 127.6,

127.3, 126.3, 125.0, 124.9, 123.4, 121.4, 120.6, 115.1, 114.0, 73.6;

HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₆ClN₂O [M

+ H]⁺359.0946, found 359.0938.

Experimental Procedure for Compounds 1A−E, 1c−k, 2u−

2zc: General Procedure for the Synthesis of Aldehydes 1A−E.

To a 25 mL round-bottom ﬂask, were added 2-ﬂuorobenzaldehydes

(2.0 equiv, 13.6 mmol), benzo[d]imidazoles (1.0 equiv, 6.8 mmol),

and K₂CO₃(2.0 equiv, 13.6 mmol) in DMF (5.0 mL), and the

reaction was stirred at 90 °C for 10 h. Upon the completion of the

reaction (conﬁrm by TLC), the solvent was removed under reduced

pressure, and the residue was dissolved in AcOEt (150 mL). The

organic layer was washed with H₂O (3 × 40 mL), dried over

anhydrous Na₂SO₄, and removed under the reduced pressure. The

crude was puriﬁed with silica gel column chromatography to aﬀord

the target compound 1.

1

(1.14 g); R_f= 0.4 (60% EtOAc + pet ether); H NMR (400 MHz,

CDCl₃) δ 9.77 (1H, s, major + minor), 8.77 (1H, d, J = 2.1 Hz),

8.29−8.19 (2H, m), 8.18−8.09 (1H, m), 7.93−7.85 (1H, m), 7.80

(1H, td, J = 8.4, 0.6 Hz,), 7.57−7.52 (1H, m, J = 7.8, 4.8, 0.9 Hz),

7.29−7.22 (1H, m); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 188.0,

188.0, 147.7, 147.6, 146.5, 144.7, 144.3, 142.8, 139.3, 135.6, 135.3,

134.8, 132.0, 131.6, 131.5, 130.7, 130.6, 128.4, 128.3, 121.0, 119.9,

118.8, 117.4, 110.2, 107.1; HRMS (ESI-ORBITRAP) m/z [M + H]⁺

calcd for C₁₄H₁₀N₃O₃268.0717, found 268.0719.

General Procedure for the Synthesis of Aldehyde 1c−k.

Et₃N (1.2 equiv) was added to the stirring solution of 1 (1.0 equiv, 10

mmol) and NH₂OH·HCl (1.2 equiv) in 20 mL of methanol. The

resulting solution was allowed to stir at room temperature, and the

progress of the reaction was monitored by TLC until completion.

Upon completion of the reaction, the reaction mixture was

concentrated under reduced pressure by removing the solvent. The

residue was extracted with DCM (25 mL) and water (25 mL). The

organic layer was separated, and the aqueous layer was extracted with

DCM (3 × 25 mL). The organic extract was washed with brine (25

mL), dried over anhydrous Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The crude product was puriﬁed by column

chromatography using silica gel 100−200 to get the desired product.

2-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)benzaldehyde Oxime

(1c). The compound 1c was synthesized by the procedure as

described above and obtained as a yellow solid: 82% yield (2.17 g); R_f

2-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)benzaldehyde (1A).

The compound 1A was synthesized by the procedure as described

above and obtained as a white solid: 44% yield (748 mg); R_f= 0.4

(60% EtOAc + pet ether); ¹H NMR (400 MHz, CDCl₃) δ 9.69 (1H,

s), 8.11 (1H, dd, J = 7.8, 1.5 Hz), 7.94 (1H, s), 7.79 (1H, td, J = 7.7,

1.6 Hz), 7.70−7.58 (2H, m), 7.47 (1H, dd, J = 7.9, 0.8 Hz), 6.98 (1H,

s), 2.37 (3H, s), 2.30 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

188.5, 142.5, 141.9, 138.3, 135.4, 134.4, 133.8, 132.3, 131.6, 129.4,

129.3, 127.8, 120.6, 110.0, 20.5, 20.2; HRMS (ESI-ORBITRAP) m/z

[M + H]⁺calcd for C₁₆H₁₅N₂O 251.1179, found 251.1181.

2-(5(6)-Methyl-1H-benzo[d]imidazol-1-yl)benzaldehyde (1B,C).

The compound 1B,C was synthesized by the procedure as described

above and obtained as an inseparable mixture: yellow liquid, 67%

1

= 0.4 (60% EtOAc + pet ether); H NMR (400 MHz, DMSO-d₆) δ

11.66 (1H, s), 8.36 (1H, s), 8.15−8.05 (1H, m), 7.75−7.69 (2H, m),

7.66 (1H, s), 7.62−7.57 (1H, m), 7.56 (1H, s), 7.00 (1H, s), 2.42

(3H, s), 2.36 (3H, s); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 143.9,

143.8, 141.8, 134.3, 134.1, 132.9, 131.4, 131.1, 130.1, 129.9, 128.7,

126.9, 120.2, 110.6, 40.5, 40.3, 40.1, 39.9, 39.7, 39.5, 39.3, 20.4, 20.2;

HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₁₆H₁₆N₃O

266.1288, found 266.1292.

2-(5(6)-Methyl-1H-benzo[d]imidazol-1-yl)benzaldehyde Oxime

(1d,e). The compound 1d,e was synthesized by the procedure as

described above and obtained as an inseparable mixture: yellow solid,

83% yield (1.50 g); R_f= 0.4 (60% EtOAc + pet ether); ¹H NMR (400

MHz, DMSO) δ 11.58 (1H, s, major + minor), 8.33 (1H, d, J = 10.3

Hz), 8.03−7.96 (1H, m), 7.69−7.53 (3H, m), 7.53−7.44 (2H, m),

7.13−7.06 (1H, m), 7.02−6.87 (1H, m), 2.38 (3H, s, major + minor);

¹³C{¹H} NMR (101 MHz, DMSO) δ 144.7, 144.3, 143.8, 143.8,

1

yield (1.076 g); R_f= 0.5 (60% EtOAc + pet ether); H NMR (400

MHz, CDCl₃) δ 9.71 (1H, s), 8.16−8.11 (1H, m), 8.01 (1H, d, J =

8.3 Hz), 7.84−7.78 (1H, m), 7.78−7.63 (2H, m), 7.49 (1H, d, J = 7.8

Hz), 7.21−6.99 (2H, m), 2.46 (3H, s, major + minor); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 188.4, 188.4, 143.7, 143.2, 142.8, 141.4,

138.1, 136.0, 135.4, 135.4, 134.6, 133.9, 133.1, 131.7, 131.6, 129.5,

129.4, 129.4, 129.4, 127.9, 127.8, 125.9, 124.9, 120.4, 120.2, 109.7,

109.4, 77.4, 77.0, 76.7, 21.7, 21.5; HRMS (ESI-ORBITRAP) m/z [M

+ H]⁺calcd for C₁₅H₁₃N₂O 237.1022, found 237.1028.

2-(5(6)-Methoxy-1H-benzo[d]imidazol-1-yl)benzaldehyde

(1D,E). The compound 1D,E was synthesized by the procedure as

described above and obtained as an inseparable mixture: yellow liquid,

68% yield (1.16 g); R_f= 0.4 (60% EtOAc + pet ether); ¹H NMR (400

MHz, CDCl₃) δ 9.78−9.69 (1H, s), 8.13 (1H, ddd, J = 7.9, 6.6, 1.5

Hz), 7.99 (1H, d, J = 21.6 Hz), 7.81 (1H, qd, J = 7.6, 1.6 Hz), 7.76,

7.11 (1H, d, major + minor), 7.67 (1H, q, J = 7.4 Hz), 7.50 (1H, d, J

= 7.9 Hz), 7.35, 6.64 (1H, d, major + minor), 6.96 (1H, td, J = 9.1,

2.4 Hz), 3.82 (3H, s, major + minor); ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 188.4, 188.8, 157.8, 156.8, 144.3, 143.5, 142.4, 138.0, 137.7,

136.4, 135.5, 135.4, 131.6, 131.5, 130.4, 129.6, 129.5, 127.8, 127.7,

121.2, 114.5, 112.7, 110.4, 102.6, 93.1, 55.8; HRMS (ESI-ORBI-

TRAP) m/z [M + H]⁺calcd for C₁₅H₁₃N₂O₂253.0972, found

253.0976.

143.7, 141.4, 135.7, 134.2, 134.2, 133.6, 132.0, 131.1, 130.2, 130.0,

129.9, 129.9, 128.8, 128.6, 127.0, 125.4, 124.4, 120.0, 119.8, 110.3,

110.3, 21.7, 21.5; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₁₅H₁₄N₃O 252.1131, found 252.1133.

2-(5(6)-Methoxy-1H-benzo[d]imidazol-1-yl)benzaldehyde

Oxime (1f,g). The compound 1f,g was synthesized by the procedure

as described above and obtained as an inseparable mixture: yellow

1

solid, 78% yield (2.08 g); R_f= 0.4 (60% EtOAc + pet ether); H

NMR (400 MHz, DMSO) δ 11.60 (1H, s), 8.45 (1H, d, J = 46.3 Hz),

8.10−7.86 (1H, m), 7.75−7.45 (4H, m), 7.36−7.00 (1H, m), 6.99−

6.88 (1H, m), 6.59 (1H, d, J = 2.3 Hz), 3.70 (3H, s, major + minor);

¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 157.4, 156.7, 144.7, 144.1,

Methyl 1-(2-Formylphenyl)-1H-benzo[d]imidazole-5(6)-carboxy-

late (1F,G). The compound 1F,G was synthesized by the procedure as

described above and obtained as an inseparable mixture: yellow liquid,

72% yield (1.15 g); R_f= 0.4 (60% EtOAc + pet ether); ¹H NMR (400

MHz, CDCl₃) δ 9.69 (1H, s, major + minor), 8.57, 7.21 (1H, d, major

minor), 8.15 (1H, d, J = 13.7 Hz), 8.13−8.08 (1H, m), 8.2−7.77 (1H,

143.9, 143.7, 142.9, 136.6, 135.9, 133.8, 133.8, 131.1, 131.0, 130.0,

130.0, 129.8, 128.7, 127.3, 127.2, 120.5, 114.1, 112.8, 111.4, 102.1,

93.9, 56.0, 56.0; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₁₅H₁₄N₃O₂268.1081, found 268.1084.

Methyl-1-(2-((hydroxyimino)methyl)phenyl)-1H-benzo[d]-

imidazole-5(6)-carboxylate (1h,i). The compound 1h,i was synthe-

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sized by the procedure as described above and obtained as an

MHz, CDCl₃) δ 170.79, 160.07, 160.00, 152.84, 144.19, 142.66,

133.59, 131.38, 131.25, 130.97, 130.92, 130.48, 130.44, 129.98,

129.94, 129.02, 128.95, 128.93, 128.17, 128.08, 127.25, 126.72,

125.85, 125.83, 125.58, 124.57, 110.69, 109.44, 98.17, 98.10, 93.11,

56.71; HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for

C₂₃H₁₈N₃O₂368.1394, found 368.1400.

Methyl 1-(2-(5-Phenylisoxazol-3-yl)phenyl)-1H-benzo[d]-

imidazole-5(6)-carboxylate (2z,za). The compound 2z,za was

synthesized by the procedure as described above and obtained as

an inseparable mixture: reddish yellow liquid, 71% yield (280 mg); R_f

= 0.5 (60% EtOAc + pet ether); ¹H NMR (400 MHz, CDCl₃) δ 8.59

(1H, s), 8.12−7.87 (3H, m), 7.77−7.66 (2H, m), 7.62−7.53 (1H, m),

7.53−7.45 (2H, m), 7.41−7.32 (3H, m), 7.30−7.21 (1H, m), 5.59

(1H, d, J = 9.1 Hz), 3.92 (3H, s, major + minor); ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 170.8, 167.3, 167.1, 159.9, 145.8, 144.7, 142.9, 137.7,

133.4, 133.2, 131.2, 130.9, 130.4, 130.0, 128.9, 128.3, 128.2, 127.5,

127.3, 126.6, 125.9, 125.7, 125.5, 125.2, 124.3, 122.9, 120.2, 112.6,

110.1, 98.0, 98.0, 52.2, 52.1; HRMS (ESI-ORBITRAP) m/z [M +

H]⁺calcd for C₂₄H₁₈N₃O₃396.1343, found 396.1345.

3-(2-(5(6)-Nitro-1H-benzo[d]imidazol-1-yl)phenyl)-5-phenylisox-

azole (2zb,zc). The compound 2zb,zc was synthesized by the

procedure as described above and obtained as an inseparable mixture:

yellow liquid, 67% yield (256 mg); R_f= 0.5 (60% EtOAc + pet ether);

¹H NMR (400 MHz, CDCl₃) δ 8.79 (1H, d, J = 2.1 Hz), 8.19 (1H,

dd, J = 9.0, 2.1 Hz), 8.15 (1H, s), 8.07−8.01 (1H, m), 7.77−7.71

(2H, m), 7.59−7.50 (3H, m), 7.42−7.36 (3H, m), 7.29−7.24 (1H,

m), 5.82 (1H, s, major); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 170.9,

159.7, 146.5, 144.2, 142.7, 138.7, 132.8, 131.4, 131.1, 130.6, 130.5,

129.0, 128.2, 127.4, 126.5, 125.7, 119.7, 117.3, 110.48, 97.9; HRMS

(ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₂H₁₅N₄O₃383.1139,

found 383.1143.

inseparable mixture: yellow solid, 85% yield (2.51 g); R_f= 0.4 (60%

1

EtOAc + pet ether); H NMR (400 MHz, DMSO) δ 11.74−11.59

(1H, m), 8.79−8.65 (1H, m), 8.05−8.13 (1H, m), 8.05−7.92 (2H,

m), 7.79−7.71 (3H, m), 7.65−7.70 (1H, dd, J = 5.9, 3.2 Hz), 7.62

(1H, s), 3.90 (3H, s, major + minor); ¹³C{¹H} NMR (100 MHz,

DMSO-d₆) δ 166.7, 147.8, 146.8, 143.9, 135.2, 133.3, 131.2, 130.4,

130.2, 129.0, 127.6, 125.2, 123.8, 120.4, 112.2, 52.6; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₁₅H₁₄N₃O₃296.1030, found

296.1031.

2-(5-Nitro-1H-benzo[d]imidazol-1-yl)benzaldehyde Oxime (1j,k).

The compound 1j,k was synthesized as an inseparable mixture by the

procedure as described above and obtained as a yellow solid: 78%

1

yield (2.20 g); R_f= 0.4 (60% EtOAc + pet ether); H NMR (400

MHz, DMSO) δ 11.55 (1H, s, major + minor), 8.73 (2H, dd, J = 50.0,

16.2 Hz), 8.14−8.22 (1H, m), 8.08−7.91 (2H, m), 7.75−7.57 (4H,

m), 7.34 (1H, s, major + minor); ¹³C{¹H} NMR (100 MHz, DMSO-

d₆) δ 150.0, 148.8, 147.9, 144.2, 144.1, 144.0, 143.7, 142.8, 139.5,

134.8, 132.8, 132.6, 131.1, 130.6, 130.6, 130.2, 130.1, 129.7, 128.9,

128.1, 128.0, 120.8, 119.6, 118.4, 116.5, 111.5, 107.4; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₁₄H₁₁N₄O₃283.0826, found

283.0832.

General Procedure for the Synthesis of Isoxazoles (2u−zc).

To an oven-dried round-bottom ﬂask were added aldoxime of type 1c

(1 mmol), N-bromosuccinimide (1.2 mmol), and 5 mL of DMF, and

the mixture was allowed to rotate 1 h at rt. Then triethyl ammine (1.2

mmol) was added dropwise, followed by the dropwise addition of

substituted acetylene (1.1 mmol). The reaction mixture was allowed

to rotate at 50 °C (using an oil bath) until the completion of the

reaction (conﬁrmed by TLC). After completion of the reaction, DMF

was evaporated under a high vacuum and extracted with ethyl acetate

(10 mL) and water (10 mL). The organic layer was separated, and the

aqueous layer was extracted with ethyl acetate (3 × 10 mL). The

combined organic layer was washed with 10 mL of brine solution,

dried over anhydrous Na₂SO₄, and concentrated in vacuo. The

residue was puriﬁed by column chromatography using 100−200 silica

gel to get the desired product 2.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02926.

3-(2-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)phenyl)-5-phenyli-

soxazole (2u). The compound 2u was synthesized by the procedure

as described above and obtained as a reddish yellow liquid: 67% yield

Mechanistic studies, NMR spectra, UV, ﬂuorescence

spectra, and X-ray data (PDF)

1

(244 mg); R_f= 0.5 (60% EtOAc + pet ether); H NMR (400 MHz,

CDCl₃) δ 8.16−8.09 (1H, m), 7.82 (1H, s), 7.73−7.66 (2H, m), 7.65

(1H, s), 7.57−7.48 (3H, m), 7.41−7.34 (3H, m), 7.02 (1H, s), 2.40

(3H, s), 2.32 (3H, s); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 170.5,

160.1, 142.2, 141.7, 134.2, 133.3, 133.2, 131.9, 131.1, 130.6, 130.2,

129.5, 128.8, 128.2, 127.2, 126.9, 125.8, 120.3, 110.3, 98.2, 20.5, 20.2;

HRMS (ESI-ORBITRAP) m/z [M + H]⁺calcd for C₂₄H₂₀N₃O

366.1601, found 366.1610.

3-(2-(5(6)-Methyl-1H-benzo[d]imidazol-1-yl)phenyl)-5-phenyli-

soxazole (2v,w). The compound xx was synthesized by the procedure

as described above and obtained as a yellow liquid: 77% yield (270

mg); R_f= 0.5 (60% EtOAc + pet ether); ¹H NMR (400 MHz,

CDCl₃) δ 8.14−8.06 (1H, m), 7.87 (1H, d, J = 14.3 Hz), 7.78−7.61

(3H, m), 7.56−7.51 (1H, m, J = 5.2, 4.3, 2.0 Hz,), 7.51−7.45 (2H,

m), 7.39−7.31 (3H, m), 7.18−7.00 (2H, m), 5.49 (1H, d, J = 13.3

Hz), 2.45 (3H, s, major minor); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ

170.6, 170.5, 160.1, 160.1, 143.5, 142.9, 142.5, 141.2, 134.9, 134.1,

134.0, 134.0, 132.7, 132.7, 131.1, 130.7, 130.7, 130.3, 129.6, 129.5,

128.8, 128.2, 128.1, 127.3, 127.2, 126.8, 125.8, 125.8, 125.5, 124.6,

120.1, 119.9, 110.1, 109.8, 98.2, 98.2, 21.7, 21.5; HRMS (ESI-

ORBITRAP) m/z [M + H]⁺calcd for C₂₃H₁₈N₃O 352.1444, found

352.1445.

Accession Codes

CCDC 2036437 contain the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing

data_request@ccdc.cam.ac.uk, or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

AUTHOR INFORMATION

■

Corresponding Author

Shantanu Pal − Organic Chemistry Laboratory, School of

Basic Sciences, Indian Institute of Technology Bhubaneswar,

Argul, Odisha 752050, India; orcid.org/0000-0001-

5120-1679; Email: spal@iitbbs.ac.in

Author

Subrata Sahoo − Organic Chemistry Laboratory, School of

Basic Sciences, Indian Institute of Technology Bhubaneswar,

Argul, Odisha 752050, India

3-(2-(5(6)-Methoxy-1H-benzo[d]imidazol-1-yl)phenyl)-5-phenyli-

soxazole (2xy). The compound 2xy was synthesized by the procedure

as described above and obtained as an inseparable mixture: yellow

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02926

1

liquid, 71% yield (260 mg); R_f= 0.5 (60% EtOAc + pet ether); H

NMR (400 MHz, CDCl₃) δ 8.11−7.99 (2H, m), 7.92−7.84 (1H, m),

7.72−7.65 (2H, m), 7.55−7.46 (3H, m), 7.40−7.30 (3H, m), 7.00

(1H, dd, J = 55.9, 8.8 Hz), 6.57 (1H, d, J = 41.3 Hz), 5.60 (1H, s,

major + minor), 3.85 (3H, m, major + minor); ¹³C{¹H} NMR (101

Notes

The authors declare no competing ﬁnancial interest.

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carboxamide derivatives of benzimidazo[2,1-a]isoquinoline and

pyrido[3′,2′:4,5]imidazo[2,1-a]isoquinoline. Anti-Cancer Drug Des.

2001, 15, 339.

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Rapid Access to Benzimidazo[1,2- a]quinoline-Fused Isoxazoles via Pd(II)-Catalyzed Intramolecular Cross Dehydrogenative Coupling: Synthetic Versatility and Photophysical Studies

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