Metal-Free Tandem Approach for Triazole-Fused Diazepinone Scaffolds via [3 + 2]Cycloaddition/C-N Coupling Reaction

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Metal-Free Tandem Approach for Triazole-Fused Diazepinone

Scaﬀolds via [3 + 2]Cycloaddition/C−N Coupling Reaction

Kashif Majeed, Lingna Wang, Bangjie Liu, Zijian Guo, Fengtao Zhou,* and Qiuyu Zhang*

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ABSTRACT: A novel metal-free, eﬃcient cascade reaction has been developed to construct 1,2,3-triazole-fused 1,4-diazepinone

skeletons. Mechanism investigation indicated that sodium azide has not only served as a 1,3-dipoles synthon in [3 + 2] cycloaddition

but also prompted C−N bond formation. Furthermore, the potential utility of this protocol was demonstrated by scale-up synthesis

of 1,2,3-triazole-fused diazepinone derivatives and the derivatization of them.

is still extremely desirable for further structure−activity

relationship (SAR) studies.

INTRODUCTION

■

Diazepines¹are the most important heterocyclic structures

that exist in natural products, biologically active compounds,

and pharmaceuticals (Figure 1). The 1,4-benzodiazepine ring

system is considered as a privileged scaﬀold^1,2and has

occupied a dominant place in the treatment of central

nervous system (CNS) disorders in the last 40 years.³

Modiﬁcation of 1,4-benzodiazepines with other heterocycles

is an expedient strategy to tune their bioactivities and

selectivities, leading to the discovery of many marketed

treatment reagents and therapeutic leads.⁴The most notable

examples of the fusion of the diazepine with the 1,2,4-triazole

moiety resulted in the successful development of alprazolam

and estazolam, which has continued to be used today for the

treatment of insomnia^3a(Figure 1). The 1,2,3-triazoles have

been reported to have a wide range of bioactivity⁵such as

antiviral^5aand anticancer.^5bRecent literature has shown that

the fusion of the 1,4-benzodiazepine scaﬀold with the 1,2,3-

triazole moiety exhibits good bioactivity as protease inhibitors

(A)⁶(Figure 1). Due to the pharmacological signiﬁcance of

these 1,4-benzodiazepine derivatives, several synthetic meth-

odologies were developed for the construction of triazolo-

fused 1,4-benzodiazepine frameworks in the past few decades

(Scheme 1).^6,7However, these traditional approaches have

some limitations, including preactivated substrates, installing

the −N₃group into the substrates, and, most importantly, a

narrow substrate scope, which limit the application of

triazolo-fused 1,4-benzodiazepine derivatives. For example,

studies on the synthesis and bioactivity of naphthotriazolo-

diazepinones (2) (Figure 1), as a subset of benzodiazepines,

are limited due to the diﬃculties in their synthesis.^7aHence,

an atom-economical, tandem reaction that could provide

direct access to naphthotriazolodiazepinone frameworks (2)

Recently, copper-catalyzed tandem reaction of [3 + 2]

cycloaddition/C−C, C−N, C−S, and C−Sn bond formations

has been proved as a powerful approach for the eﬃcient

construction of diverse nitrogen-containing heterocycles.⁸For

example, in 2012, Cai’s^8dgroup developed the copper-

catalyzed azide-alkyne cycloaddition (CuAAC) reaction

followed by an intramolecular Ullmann-type C−N coupling

process for the one-pot synthesis of [1,2,3]triazolo[1,5-

a]quinoxalin-4(5H)-ones. In spite of mild conditions, high

eﬃciency, and good selectivity, copper-catalyzed [3 + 2]

cycloaddition suﬀers from the potential toxicity of copper

when these products are designed to be used for biological

applications.⁹On the other hand, the shortcomings associated

with copper-catalyzed N-arylation reactions, including tox-

icity, need for ligands, and risk of product contamination,

have attracted researchers’ attention to develop metal-free N-

arylation reactions.¹⁰However, these metal-free N-arylation

reactions need high temperature and a strong base and has a

narrow scope of substrates.¹¹Thus, the development of

metal-free tandem reaction of [3 + 2]cycloaddition/N-

arylation under mild reaction conditions is urgently needed.

Herein, we wish to report a novel metal-free tandem reaction

for the synthesis of 1,2,3-triazolo-fused 1,4-diazepinone

scaﬀolds by the reaction of N-(8-iodonaphthalen-1-yl)-N-

methyl-propiolamides with sodium azide. This unique

Received: August 21, 2020

https://dx.doi.org/10.1021/acs.joc.0c02022

J. Org. Chem. XXXX, XXX, XXX−XXX

A

The Journal of Organic Chemistry

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Figure 1. Selected examples of bioactive benzodiazepines, their derivatives, and analogues.

Scheme 1. Diﬀerent Approaches toward Triazolo 1,4-Benzodiazepine Frameworks

protocol involves the intermolecular azide-alkyne [3 +

2]cycloaddition reaction followed by aryl C−N bond

formations.

100 °C in 46% yield and the structure of 2a was conﬁrmed

by X-ray diﬀraction analysis¹⁵(Table 1, entry 1). Encouraged

by the discovery of this metal-free tandem reaction, we

optimized reaction conditions by changing the amount of

sodium azide, solvent, and temperature. To our delight, the

yield was greatly improved to 86% using 2.0 equiv of sodium

azide (Table 1, entry 3). Among the other screened solvents

such as N,N-dimethylformamide (DMF), N-methyl pyrroli-

done (NMP), toluene, and 1,4-dioxane, DMSO was found as

the optimal solvent for this tandem reaction (Table 1, entries

4−8). The high temperature seems to be very crucial for this

transformation, no product 2a was formed at 60 °C, and only

the [3 + 2] cycloaddition product 3a was obtained with a

yield of 48% (Table 1, entry 9).

With the optimized reaction conditions in hand, we then

explored the scope of substrates 1 with variable R¹and R²

substituents for this metal-free transformation, and the results

are displayed in Table 2. A variety of substrates were

synthesized eﬃciently and proceeded smoothly with sodium

azide to give the desired products in good to excellent yields.

When the R²substituent was phenyl or phenyl-substituted

RESULTS AND DISCUSSION

■

We started to visualize peri-substituted naphthalenes as the

ideal starting materials to construct 1,2,3-triazole-fused

diazepinone frameworks because two peri-substituents in

naphthalenes are present at much closer proximity than

ortho-substitution, presumably rustling in unique reactivity,

which is diﬀerent from the ortho-substituted species.¹²

However, studies on reactivities of peri-substituted naph-

thalenes have not yet been fully explored because of

diﬃculties in preparing them.^7aWith this in mind, we put

our eﬀorts to prepare peri-substituted naphthalenes 1a from

8-iodonaphthalen-1-amine¹³and ethynylbenzene in one

step.¹⁴Then, initial studies were carried out by choosing

N-(8-iodonaphthalen-1-yl)-N-methyl-3-phenylpropiolamide 1a

with sodium azide as a model reaction. As shown in Table 1,

to our delight, in the presence of the solvent dimethyl

sulfoxide (DMSO), the desired product 2a was obtained at

B

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base¹⁶in C−N coupling transformation. To our delight, the

cyclization product was also obtained in the presence of

sodium hydride or sodium carbonate in DMSO at 100 °C

(Table 3, entries 5 and 6). Inspired by this exciting discovery,

we assume that this metal-free protocol may also work for

substrates used in a previous work.^8dFortunately, when 3.0

equiv of sodium azide was used, the target products were

obtained in good to excellent yields in DMSO at 130 °C.

The scope of N-(2-iodophenyl)propiolamide substrates was

also investigated, and the results are shown in Table 4. When

the R¹substituent was phenyl-substituted with electron-

donating groups (such as −Me, −Et, −tBu, and −OMe) or

substituted with halogen (F, Br), the corresponding products

were obtained in good yields (5b−5g). The alkyl-substituted

substrate 4h was also tolerated well, delivering the product in

good yield. Finally, the bromide substrate 4i was also a

suitable substrate for this transformation, giving production in

moderate yields (Table 4).

Furthermore, this cascade reaction could easily scale up to

2.0 mmol without the decrease of yield for 2f (74%) and 2s

(47%). The utility of this protocol was further demonstrated

by transformation of the core structure of 1,2,3-triazole-fused

diazepinone derivatives, which aimed at providing rapidly

synthetic routes for the construction of libraries of small

molecules with structure diversity. For example, 1,4-diazepine

6 was obtained in good yield by the treatment of 2s with

BH₃·THF solution. Transformation of 2f into diary ether 7

could be easily achieved by the deprotection of the methoxy

group with BBr₃followed by O-arylation with 4-ﬂuoro-1-

nitrobenzene in good yield (Scheme 2).

a b

,

Table 1. Optimization of Reaction Conditions

entry

substrate

solvent

DMSO

DMF

T (°C)

yield (%)

46

1

2

3

4

5

6

7

8

9

1a

100

60

c

64

d

86

d

31

d

NMP

34

de

,

1,4-dioxane

MeCN

toluene

DMSO

n.d.

de

,

de

,

f

a

Reagents and reaction conditions: 1 (0.1 mmol, 1.0 equiv), NaN₃

b

c

(0.1 mmol, 1.0 equiv), solvent (1 mL), 6 h. Isolated yields. NaN₃

d

e

(0.15 mmol, 1.5 equiv). NaN₃(0.2 mmol, 2.0 equiv). No desired

f

product was detected. 3a was isolated in 48% yield.

with electron-donating groups (such as −Me, −Et, −nPr, and

−OMe), the corresponding products were obtained in good

yields (2a−2f). When the R²substituent was phenyl-

substituted with electron-withdrawing groups (such as −Cl,

−F, −CN, and −CO₂Me), the corresponding products were

obtained in good yields (2g−2l). The above results indicate

that the electronic density of the aromatic substituents on the

alkynl moiety had little eﬀect on the yield of the product.

Further investigation revealed that R²could also be bulk

polycyclic aromatic substituents such as 1-naphthyl, 2-

naphthyl, and phenanthryl, aﬀording the desired products in

yields of 55, 71, and 74%, respectively (2m−2o). To our

delight, aromatic heterocyclic substituents (R²), such as 3-

pyridinyl and 2-thienyl, also were well-tolerated in this

reaction, delivering the products 2p and 2q in 53 and 69%

yields. Other N-substituted substrates such as allyl or benzyl

group (1r and 1s) also proceeded smoothly with sodium

azide, giving the corresponding products in yields of 90 and

61%, respectively (2r and 2s). When R²was replaced with

alkyl groups such as −Et, −nPr, and −nPentyl, the

corresponding products were also obtained in 33−79% yields

(2t−2v). To our delight, other less reactive aryl bromide

substrates (such as 1w, 1x, 1y, and 1z) also were well-

tolerated, delivering 2w, 2a, 2f, and 2h in 57, 56, 82, and

65% yields, respectively. Furthermore, aryl chloride 1aa was

also a suitable substrate in this reaction, giving the product in

moderate yield of 49%.

CONCLUSIONS

■

In summary, a novel metal-free tandem approach for various

1,2,3-triazole-fused diazepinone derivatives has been devel-

oped. A wide range of substrates was tolerated in the

reaction, giving the corresponding products in moderate to

high yields. This metal-free protocol also allows N-(2-

iodophenyl)propiolamide to aﬀord the triazole-fused quinox-

alinones in good yields. Furthermore, the utility of this

protocol was demonstrated by scale-up synthesis of the

metal-free core structure 1,4-benzodiazepine derivatives and

their transformations. Mechanism investigation demonstrated

that a [3 + 2]azide-alkyne cycloaddition followed by

intramolecular C−N bond formation was involved in this

tandem process. Most importantly, sodium azide not only

serves as a starting material but also is very crucial for the

formation of the C−N bond. Further research and

applications of this metal-free strategy for the synthesis of

other bioactive nitrogen-containing heterocycles are currently

underway in our laboratory.

To get insights into the mechanism of this metal-free

tandem reaction, we tried to convert intermediate 3a into

product 2a. Unfortunately, we could not detect the target

product 2a when 3a was carried out in DMSO at 100 °C for

12 h (Table 3, entry 1). We also did not obtain the product

when the intermediate 3a was treated with 1 equiv of

potassium carbonate or cesium carbonate at 100 °C for 12 h

in DMSO (Table 3, entries 2 and 3). To our delight, the C−

N coupling product 2a was obtained in 61% yield when

intermediate 3a was treated with 1 equiv of NaN₃in DMSO

at 100 °C for 12 h (Table 3, entry 4), which implies that

sodium azide plays a very important role in C−N bond

formation. We speculated that sodium azide served as a

EXPERIMENTAL SECTION

■

General Method. Unless otherwise stated, all starting materials

were obtained from commercial suppliers and used without further

puriﬁcation. All of the reactions were performed in an oven-dried

Schlenk ﬂask. All new compounds were fully characterized. Thin-

layer chromatography (TLC) analysis was performed using pre-

coated glass plates. Visualization of spots on TLC plates was

accomplished with UV light (254 nm) and staining over the I₂

chamber. Column chromatography was performed using silica gel

1

(200−300 mesh). H NMR spectra were recorded in CDCl₃on 400

MHz NMR spectrometers, and resonances (δ) are given in parts per

million relative to tetramethyl silane (internal standard). Data are

reported as follows: chemical shift, multiplicity (s, singlet; d,

C

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a b

,

Table 2. Screening of Substrate Scope

a

b

Reagents and reaction conditions: 1 (0.3 mmol), NaN₃(0.6 mmol) in DMSO (3.0 mL) at 100 °C for 6 h. Isolated yields.

doublet; t, triplet; m, multiplet; q, quadruple), coupling constants

(Hz), and integration. ¹³C spectra were recorded in CDCl₃on 100

MHz NMR spectrometers, and resonances (δ) are given in ppm.

High-resolution mass spectra were recorded with an HPLC-QTof

mass spectrometer. The X-ray crystal structure determinations of 2a

were obtained on a single-crystal X-ray diﬀraction system.

D

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in freshly prepared dry tetrahydrofuran (THF) and cooled to −78

°C. At this temperature, a solution of n-BuLi (2.6 mL, 6.5 mmol, 1.3

equiv, 2.5 M in hexane) was slowly added by a syringe. After the

solution was stirred at −78 °C for 30 min, a solution of 1-iodo-8-

isocyanatonaphthalene (prepared from above) in 5 mL of dry THF

was slowly added by a syringe. Then, the reaction mixture was

warmed up to −40 °C within 2 h. At this temperature, methyl

iodide (0.46 mL, 7.5 mmol, 1.5 equiv) was added and the solution

was allowed to warm slowly to room temperature overnight. A

saturated aqueous solution of NH₄Cl was added, the mixture was

extracted with DCM (10 mL×3), and the combined organic phase

was washed with brine, dried over with Na₂SO₄, and concentrated

under reduced pressure. The residue was puriﬁed by silica gel

column chromatography using eluent:petroleum ether/EtOAc = 5/1

to aﬀord the desired 1a as brown solids (1.02 g, 49%). 1a: m.p.:

Table 3. Control Experiments

entry

solvent

t (°C)

base

yield (%)

1

2

3

4

5

6

DMSO

100

0

61

51

63

K₂CO₃

Cs₂CO₃

NaN₃

NaH

Na₂CO₃

1

139−140 °C, H NMR (400 MHz, CDCl₃) for the major isomer: δ

8.32 (dd, J = 7.6, 1.2 Hz, 1H), 8.02−7.92 (m, 2H), 7.60−7.53 (m,

2H), 7.24−7.19 (m, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.12−7.05 (m,

2H), 6.78−6.67 (m, 2H), 3.38 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ 155.7, 142.9, 139.6, 135.8,

132.1, 130.9, 129.9, 129.7, 129.4, 128.0, 127.2, 125.9, 120.1, 91.2,

86.6, 82.9, 38.7 ppm. HRMS (ESI) calcd for C₂₀H₁₅INO (M + H)⁺

412.0193, found, 412.0195.

Synthesis of Amides. The syntheses of 1a−z, 1aa, and 4a−4i

are described below. Substrates 1a−1q, 1w, and 1aa were prepared

from acetylene derivatives by general procedure A.¹⁷Substrates 1s−

v prepared from propiolic acid derivatives and 8-iodonaphthalen-1-

amine were according to general procedure B.^8c,14

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(p-tolyl)propiolamide

(1b). General procedure A was followed for the synthesis of 1b from

8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv), Et₃N (2.1

mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol, 1.0 equiv),

4-ethynyltoluene (0.76 mL, 6.0 mmol, 1.2 equiv), n-BuLi (2.6 mL,

6.5 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide (0.46 mL,

7.5 mmol, 1.5 equiv). The crude reaction mixture was puriﬁed by

silica gel column chromatography (EtOAc/hexane 1:8) to give the

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-phenylpropiolamide

(1a). General procedure A: To a solution of 8-iodonaphthalen-1-

amine (1.34 g, 5.0 mmol, 1.0 equiv) and Et₃N (2.1 mL, 15.0 mol,

3.0 equiv) in dry dichloromethane (DCM) under the condition of

ice-bath, triphosgene was added in three portions (1.48 g, 5.0 mmol,

1.0 equiv). After removing the ice-bath, the reaction mixture was

stirred at room temperature. The reaction was quenched with water

until complete conversion, which was monitored by TLC (2−5 h).

The mixture was extracted with DCM (10 mL × 3), and the

combined organic phase was washed with brine, dried over with

Na₂SO₄, and concentrated under reduced pressure. The crude

product was directly used for the next reaction without further

puriﬁcation. In a heat-gun-dried and nitrogen-ﬁlled 250 mL Schlenk

ﬂask, phenyl acetylene (0.65 mL, 6.0 mmol, 1.2 equiv) was dissolved

1

product as brown solids (1.02 g, 48%). 1b: m.p.: 134−135 °C, H

NMR (400 MHz, CDCl₃) for the major isomer: δ 8.31 (dd, J = 7.2,

1.2 Hz, 1H), 8.00−7.90 (m, 2H), 7.59−7.54 (m, 2H), 7.16 (t, J =

7.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H),

3.38 (s, 3H), 2.23 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃)

for the major isomer: δ 155.9, 142.9, 140.2, 139.7, 135.8, 132.1,

130.8, 129.8, 129.4, 128.8, 127.2, 125.9, 117.0, 91.7, 86.6, 82.6, 38.6,

a b

,

Table 4. New Metal-Free Protocol for the Synthesis of Triazole-Fused Quinoxalinones

a

b

Reagents and reaction conditions: 4 (0.3 mmol), NaN₃(0.6 mmol) in DMSO (3.0 mL) at 130 °C for 6 h. Isolated yields.

E

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Scheme 2. Scale-up Synthesis and Transformation of 1,2,3-Triazole-Fused Diazepinone Derivatives

21.4 ppm. HRMS (ESI) calcd for C₂₁H₁₇INO (M + H)⁺426.0349,

found, 426.0364.

mmol, 1.2 equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in

hexane), and methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 1:7) to give the product as yellow

3-(4-Ethylphenyl)-N-(8-iodonaphthalen-1-yl)-N-methylpropiola-

mide (1c). General procedure A was followed for the synthesis of 1c

from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv), Et₃N

(2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol, 1.0

equiv), 1-ethyl-4-ethynylbenzene (0.84 mL, 6.0 mmol, 1.2 equiv), n-

BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and methyl

iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction mixture

was puriﬁed by silica gel column chromatography (EtOAc/hexane

1:6) to give the product as white solids (1.11g, 51%). 1c: m.p.:

1

solids (880 mg, 40%). 1e: m.p.: 139−140 °C, H NMR (400 MHz,

CDCl₃) for the major isomer: δ 8.32 (dd, J = 7.6, 1.2 Hz, 1H),

7.94−7.92 (m, 2H), 7.60−7.53 (m, 2H), 7.17 (t, J = 8.0, Hz, 1H),

6.84 (s, 1H), 6.30 (s, 2H), 3.38 (s, 3H), 2.10 (s, 6H) ppm. ¹³C{¹H}

NMR (100 MHz, CDCl₃) for the major isomer: δ 155.8, 142.9,

139.8, 137.6, 135.8, 131.6, 130.8, 129.8, 129.4, 127.2, 126.0, 119.7,

91. 9, 86.8, 82.4, 38.6, 20.8 ppm. HRMS (ESI) calcd for C₂₂H₁₉INO

(M + H)⁺440.0506, found, 440.0505.

1

123−124 °C, H NMR (400 MHz, CDCl₃) for the major isomer: δ

8.31 (dd, J = 7.6, 1.2 Hz, 1H), 8.01−7.91 (m, 2H), 7.58−7.55 (m,

2H), 7.16 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.64 (d, J =

8.0 Hz, 2H), 3.38 (s, 3H), 2.52 (q, J = 7.6 Hz, 2H), 1.11 (t, J = 7.6

Hz, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) for the major

isomer: δ 155.8, 146.4, 142.9, 139.7, 135.7, 132.2, 130.8, 129.8,

129.7, 129.4, 127.6, 127.2, 125.9, 117.2, 91.7, 86.6, 82.5, 38.6, 28.7,

15.0 ppm. HRMS (ESI) calcd for C₂₂H₁₉INO (M + H)⁺440.0506,

found, 440.0505.

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(4-propylphenyl)-

propiolamide(1d). General procedure A was followed for the

synthesis of 1d from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol,

1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g,

5.0 mmol, 1.0 equiv), 1-ethynyl-4-propylbenzene (0.95 mL, 6.0

mmol, 1.2 equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in

hexane), and methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 1:6) to give the product as

brown solids (885 mg, 39%). 1d: m.p.: 85−86 °C, ¹H NMR

(400 MHz, CDCl₃) for the major isomer: δ 8.31 (d, J = 7.6 Hz,

1H), 7.98−7.92 (m, 2H), 7.68−7.41 (m, 2H), 7.18−7.13 (m, 1H),

6.90 (dd, J = 8.0, 2.0 Hz, 2H), 6.63 (dd, J = 8.0, 2.0 Hz, 2H), 3.38

(s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 1.53−1.47 (m, 2H), 0.84 (t, J =

7.2 Hz, 2H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) for the major

isomer: δ 155.9, 144.9, 142.9, 139.7, 135.8, 132.2, 130.9, 129.9,

129.8, 129.4, 128.2, 127.2, 125.9, 117.3, 91.8, 86.6, 82.6, 38.7, 37.8,

24.0, 13.6 ppm. HRMS (ESI) calcd for C₂₃H₂₁INO (M + H)⁺

454.0662, found, 454.0666.

N-(8-Iodonaphthalen-1-yl)-3-(4-methoxyphenyl)-N-methylpro-

piolamide (1f). General procedure A was followed for the synthesis

of 1f from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 1-ethynyl-4-methoxybenzene (792 mg, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as brown solids (950 mg, 43%). 1f:

m.p.: 159−160 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.31 (dd, J = 7.6, 1.2 Hz, 1H), 8.02−7.88 (m, 2H), 7.62−

7.49 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 6.72−6.53 (m, 4H), 3.71 (s,

3H), 3.38 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 160.7,

156.0, 142.9, 139.8, 135.8, 134.0, 130.8, 129.8, 129.8, 129.4, 127.2,

125.9, 113.7, 112.0, 92.0, 86.7, 82.3, 55.2, 38.6 ppm. HRMS (ESI)

calcd for C₂₁H₁₇INO₂(M + H)⁺442.0298, found, 442.0310.

3-(2-Chlorophenyl)-N-(8-iodonaphthalen-1-yl)-N-methylpropio-

lamide (1g). General procedure A was followed for the synthesis of

1g from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 1-chloro-2-ethynylbenzene (0.73 mL, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as brown solids (1.0 g, 45%). 1g:

m.p.: 141−142 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.32 (dd, J = 7.2, 1.2 Hz, 1H), 7.96−7.90 (m, 2H), 7.62−

7.52 (m, 2H), 7.16−7.03 (m, 5H), 3.35 (s, 3H) ppm. ¹³C{¹H}

NMR (100 MHz, CDCl₃) for the major isomer: δ 155.3, 155.3,

142.9, 139.1, 136.2, 136.0, 134.2, 131.1, 130.7, 129.9, 129.7, 128.9,

127.2, 126.1, 126.1, 120.5, 87.3, 87.2, 86.4, 39.0 ppm. HRMS (ESI)

calcd for C₂₀H₁₄ClINO (M + H)⁺445.9803, found, 445.9810.

3-(3,5-Dimethylphenyl)-N-(8-iodonaphthalen-1-yl)-N-methyl-

propiolamide (1e). General procedure A was followed for the

synthesis of 1e from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol,

1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g,

5.0 mmol, 1.0 equiv), 1-ethynyl-3,5-dimethylbenzene (780 mg, 6.0

F

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3-(4-Chlorophenyl)-N-(8-iodonaphthalen-1-yl)-N-methylpropio-

lamide (1h). General procedure A was followed for the synthesis of

1h from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 4-chloro-2-ethynylbenzene (816 mg, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as dark-brown solids (1.12 g, 50%).

major isomer: δ 165.9, 155.2, 142.9, 139.3, 135.7, 131.9, 131.0,

130.7, 129.9, 129.6, 129.4, 129.1, 127.3, 125.9, 124.5, 89.8, 86.5,

84.9, 52.2, 38.7 ppm. HRMS (ESI) calcd for C₂₂H₁₇INO₃(M + H)⁺

470.0248, found, 470.0257.

3-(4-Cyanophenyl)-N-(8-iodonaphthalen-1-yl)-N-methylpropio-

lamide (1l). General procedure A was followed for the synthesis of

1l from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 4-ethynylbenzonitrile (762 mg, 6.0 mmol, 1.2 equiv), n-

BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and methyl

iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction mixture

was puriﬁed by silica gel column chromatography (EtOAc/hexane

1:6) to give the product as dark-brown solids (725 mg, 33%). 1l:

m.p.: 158−160 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.33 (dd, J = 7.6, 1.2 Hz, 1H), 8.01−7.94 (m, 2H), 7.58−

7.56 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H),

6.83 (d, J = 8.0 Hz, 2H), 3.39 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ 154.9, 143.0, 139.1, 135.7,

132.4, 131.7, 131.2, 129.9, 129.6, 129.4, 127.3, 125.9, 124.9, 117.8,

112.9, 88.5, 86.4, 85.9, 38.7 ppm. HRMS (ESI) calcd for

C₂₁H₁₄IN₂O (M + H)⁺437.0145, found, 437.0138.

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(naphthalen-1-yl)-

propiolamide (1m). General procedure A was followed for the

synthesis of 1m from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol,

1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g,

5.0 mmol, 1.0 equiv), 1-ethynylnaphthalene (912 mg, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as brown solids (924 mg, 40%) 1m:

m.p.: 154−155 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.34 (dd, J = 7.2, 1.3 Hz, 1H), 8.05 (dd, J = 8.0, 1.7 Hz,

1H), 8.00 (dd, J = 8.2, 1.3 Hz, 1H), 7.73 (d, J = 8.4, Hz, 1H),

7.68−7.58 (m, 4H), 7.42 (dd, J = 7.2, 1.2 Hz, 1H), 7.36−7.31 (m,

1H), 7.29−7.24 (m, 1H), 7.18 (t, J = 8.0, Hz, 1H), 7.04−6.96 (m,

1H), 6.54 (dd, J = 8.4, 1.2 Hz, 1H), 3.41 (s, 3H) ppm. ¹³C{¹H}

NMR (100 MHz, CDCl₃) for the major isomer: δ 155.9, 143.2,

139.6, 136.1, 133.0, 132.6, 132.5, 131.1, 130.4, 1309.0, 130.0, 129.6,

128.0, 127.5, 126.6, 126.3, 125.1, 124.9, 117.8, 89.6, 87.7, 86.5, 39.0

ppm. HRMS (ESI) calcd for C₂₄H₁₇INO (M + H)⁺462.0349,

found, 462.0363.

1

1h: m.p.: 110−111 °C, H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.32 (dd, J = 7.3, 1.2 Hz, 1H), 7.92−7.92 (m, 2H), 7.59−

7.52 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H),

6.65 (d, J = 8.4 Hz, 2H), 3.38 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ 155.4, 142.9, 139.5, 135.9,

135.7, 133.2, 131.0, 129.9, 129.7, 129.4, 128.5, 127.3, 125.9, 118.5,

90.0, 86.6, 83.6, 38.7 ppm. HRMS (ESI) calcd for C₂₀H₁₄ClINO (M

+ H)⁺445.9803, found, 445.9810.

3-(3-Fluorophenyl)-N-(8-iodonaphthalen-1-yl)-N-methylpropio-

lamide (1i). General procedure A was followed for the synthesis of

1i from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 1-ethynyl-3-ﬂuorobenzene (0.69 mL, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as brown solids (989 mg, 46%). 1i:

m.p.: 121−122 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.33 (dd, J = 7.6, 1.2 Hz, 1H), 8.03−7.93 (m, 2H), 7.63−

7.52 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.12−7.02 (m, 1H), 6.96−

6.89 (m, 1H), 6.62−6.55 (m, 1H), 6.39−6.29 (m, 1H), 3.38 (s, 3H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) for the major isomer: δ

161.7 (C-F, 1J_C‑F= 246.0 Hz), 155.3, 142.9, 139.3, 135.7, 131.0,

129.9, 129.7 (C-F, 3J_C‑F= 9.0 Hz), 129.6, 129.3, 127.9 (C-F, 4J_C‑F

=

4.0 Hz), 127.3, 125.9, 121.8 (C-F, 3J_C‑F= 9.0 Hz), 118.7 (C-F, 2J_C‑F

= 23.0 Hz), 117.1 (C-F, 2J_C‑F= 21.0 Hz), 89.5 (C-F, 4J_C‑F= 4.0

Hz), 86.5, 83.3, 38.6 ppm. HRMS (ESI) calcd for C₂₀H₁₄FINO (M

+ H)⁺430.0099, found, 430.0094.

3-(4-Fluorophenyl)-N-(8-iodonaphthalen-1-yl)-N-methylpropio-

lamide (1j). General procedure A was followed for the synthesis of

1j from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 1-ethynyl-4-ﬂuorobenzene (0.69 mL, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as light-brown solids (817 mg,

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(naphthalen-2-yl)-

propiolamide (1n). General procedure A was followed for the

synthesis of 1n from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol,

1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g,

5.0 mmol, 1.0 equiv), 2-ethynylnaphthalene (912 mg, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product (919 mg, 39%). 1n: m.p.: 149−150

1

38%). 1j: m.p.: 158−160 °C, H NMR (400 MHz, CDCl₃) for the

major isomer: δ 8.32 (dd, J = 7.6, 1.2 Hz, 1H), 7.99−7.92 (m, 2H),

7.61−7.49 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 6.82−6.75 (m, 2H),

6.73−6.68 (m, 2H), 3.38 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz,

CDCl₃) for the major isomer: δ 163.2 (C-F, 1J_C‑F= 251.0 Hz),

155.6, 142.9, 139.6, 135.8, 134.3 (C-F, 3J_C‑F= 8.0 Hz), 130.9, 129.9,

129.7, 129.4, 127.2, 125.9, 116.2 (C-F, 4J_C‑F= 4.0 Hz), 115.5 (C-F,

2J_C‑F= 22 Hz), 90.2, 86.6, 82.7 (C-F, 4J_C‑F= 4 Hz), 38.7 ppm.

HRMS (ESI) calcd for C₂₀H₁₄FINO (M + H)⁺430.0099, found,

430.0094.

1

°C, H NMR (400 MHz, CDCl₃) for the major isomer: δ 8.33 (dd,

J = 7.2, 1.2 Hz, 1H), 8.04−7.96 (m, 2H), 7.72−7.64 (m, 1H),

7.63−7.49 (m, 4H), 7.45−7.40 (m, 2H), 7.26−7.16 (m, 2H), 6.71

(dd, J = 8.4, 1.6 Hz, 1H), 3.41 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ 155.7, 142.7, 139.6, 135.8,

133.2, 133.1, 132.2, 130.9, 129.9, 129.8, 129.4, 127.7, 127.7, 127.7,

127.5, 127.3, 127.2, 126.5, 126.0, 117.2, 91.7, 86.7, 83.2, 38.6 ppm.

HRMS (ESI) calcd for C₂₄H₁₇INO (M + H)⁺462.0349, found,

462.0363.

Methyl 4-(3-((8-Iodonaphthalen-1-yl)(methyl)amino)-3-oxo-

prop-1-yn-1-yl)benzoate (1k). General procedure A was followed

for the synthesis of 1k from 8-iodonaphthalen-1-amine (1.34 g, 5.0

mmol, 1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene

(1.48 g, 5.0 mmol, 1.0 equiv), methyl 4-ethynylbenzoate (1.212 g,

6.0 mmol, 1.2 equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M

in hexane), and methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 1:6) to give the product as dark-

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(phenanthren-9-yl)-

propiolamide (1o). General procedure A was followed for the

synthesis 1o from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol, 1.0

equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0

mmol, 1.0 equiv), 9-ethynylphenanthrene (1.01 g, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as reddish-brown solids (1.08 g,

1

brown solids (775 mg, 33%). 1k: m.p.: 106−107 °C, H NMR (400

MHz, CDCl₃) for the major isomer: δ 8.32 (dd, J = 7.2, 1.2 Hz,

1H), 7.99−7.92 (m, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.60−7.55 (m,

2H), 7.17 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 2H), 3.85 (s,

3H), 3.39 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) for the

1

42%). 1o: m.p.: 186−187 °C, H NMR (400 MHz, CDCl₃) for the

major isomer: δ 8.51 (t, J = 8.4 Hz, 2H), 8.36 (dd, J = 7.2, 1.2 Hz,

G

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1H), 8.08−8.01 (m, 2H), 7.80−7.59 (m, 5H), 7.57−7.48 (m, 2H),

7.21 (t, J = 7.6 Hz, 1H), 7.10−7.06 (m, 1H), 6.67 (d, J = 7.6 Hz,

2H), 3.43 (s, 3H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) for the

major isomer: 155.8, 143.3, 139.6, 136.1, 134.8, 131.1, 130.6, 130.4,

130.3, 130.0, 129.9, 129.7, 129.5, 128.8, 128.2, 127.5, 126.9, 126.9,

126.6, 126.3, 125.9, 122.4, 122.4, 116.6, 89.8, 87.2, 86.6, 39.0 ppm.

HRMS (ESI) calcd for C₂₈H₁₉INO (M + H)⁺512.0506, found,

512.0520.

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(pyridin-3-yl)-

propiolamide (1p). General procedure A was followed for the

synthesis of 1p from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol,

1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g,

5.0 mmol, 1.0 equiv), 3-ethynylpyridine (618 mg, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as brown solids (314 mg, 15%). 1p:

m.p.: 135−136 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.42 (dd, J = 4.8, 1.6 Hz, 1H), 8.33 (dd, J = 7.2, 1.2 Hz,

1H), 8.01−7.93 (m, 3H), 7.76 (d, J = 2.2 Hz, 1H), 7.60−7.55 (m,

2H), 7.22−7.18 (m, 2H), 7.09−7.05 (m, 1H), 3.40 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, CDCl₃) for the major isomer: δ 155.1,

N-Benzyl-N-(8-iodonaphthalen-1-yl)-3-phenylpropiolamide (1s).

Under a nitrogen atmosphere, to the solution of 8-iodonaphthalen-

1-amine¹³(673 mg, 2.5 mmol, 1.0 equiv) in dry CH₃CN (15 mL)

were added 3-phenylpropiolic acid (402 mg, 2.75 mmol, 1.1 equiv)

and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium

chloride (DMTMM) (885 mg, 3.0 mmol, 1.2 equiv) at room

temperature. After stirring at room temperature overnight, the

mixture was quenched with water and extracted with ethyl acetate.

The combined organic layer was washed with brine and dried over

Na₂SO₄. After ﬁltration and concentration, the crude residue was

dissolved in dry THF (10 mL) at 0 °C and to the solution was

added NaH (120 mg, 3.0 mmol, 1.2 equiv) in small portions. After

stirring for 20 min at 0 °C, benzyl bromide (0.36 mL, 3.0 mmol, 1.2

equiv) was added dropwise and the reaction mixture was allowed to

warm to room temperature and stirred for another 2 h. After

quenching with water, the residue was extracted with ethyl acetate

twice for three times. The combined organic layer was washed with

brine, dried over Na₂SO₄, ﬁltrated and concentrated, and puriﬁed by

column chromatography using eluent:petroleum ether/EtOAc = 5/1

to aﬀord the desired 1s as yellow solids (672 mg, 56%). 1s: m.p.:

1

162−163 °C, H NMR (400 MHz, CDCl₃) for the major isomer: δ

8.37 (dd, J = 7.6, 1.2 Hz, 1H), 7.96−7.90 (m, 2H), 7.36−7.27 (m,

4H), 7.25−7.13 (m, 3H), 7.13−7.03 (m, 2H), 6.92 (dd, J = 7.2, 1.2

Hz, 1H), 6.83−6.75 (m, 2H), 5.91 (d, J = 14.4 Hz, 1H), 3.88 (d, J

= 14.4 Hz, 1H) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 155.7,

143.1, 136.8, 136.4, 135.9, 132.2, 131.8, 131.0, 130.1, 129.8, 129.7,

129.2, 128.4, 128.1, 127.7, 127.1, 125.3, 120.2, 92.0, 86.4, 83.1, 54.8

ppm. HRMS (ESI) calcd for C₂₆H₁₉INO (M + H)⁺488.0506,

found, 488.0500.

152.6, 149.8, 143.0, 139.3, 139.0, 135.8, 131.2, 130.0, 129.7, 129.4,

127.4, 125.9, 122.8, 117.4, 87.5, 86.5, 85.6, 38.7 ppm. HRMS (ESI)

calcd for C₁₉H₁₄IN₂O (M + H)⁺413.0145, found, 413.0159.

N-(8-Iodonaphthalen-1-yl)-N-methyl-3-(thiophen-2-yl)-

propiolamide (1q). General procedure A was followed for the

synthesis of 1q from 8-iodonaphthalen-1-amine (1.34 g, 5.0 mmol,

1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g,

5.0 mmol, 1.0 equiv), 2-ethynylthiophene (0.60 mL, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as brown solids (643 mg, 49%). 1q:

m.p.: 127−128 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 8.31 (dd, J = 7.6, 2.4 Hz, 1H), 8.01−7.93 (m, 2H), 7.82−

7.46 (m, 2H), 7.17−7.12 (m, 2H), 6.82−6.59 (m, 2H), 3.39 (s, 3H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) for the major isomer: δ

155.5, 142.9, 139.3, 135.8, 134.7, 130.9, 130.0, 129.9, 129.7, 129.3,

127.2, 127.0, 125.9, 119.8, 87.0, 86.5, 85.0, 38.6 ppm. HRMS (ESI)

calcd for C₁₈H₁₃INOS (M + H)⁺417.9757, found, 417.9769.

(E)-N-(8-Iodonaphthalen-1-yl)-3-phenyl-N-(prop-1-en-1-yl)-

propiolamide (1r). General procedure B: Under a nitrogen

atmosphere, to the solution of 8-iodonaphthalen-1-amine¹³(673

mg, 2.5 mmol, 1.0 equiv) in dry CH₃CN (15 mL) were added 3-

phenylpropiolic acid (402 mg, 2.75 mmol, 1.1 equiv) and 4-(4,6-

dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride

(DMTMM) (885 mg, 3.0 mmol, 1.2 equiv) at room temperature.

After stirring at room temperature overnight, the mixture was

quenched with water and extracted with ethyl acetate. The

combined organic layer was washed with brine and dried over

Na₂SO₄. After ﬁltration and concentration, the crude residue was

dissolved in dry THF (10 mL) at 0 °C and to the solution was

added NaH (120 mg, 3.0 mmol, 1.2 equiv) in small portions. After

stirring for 20 min at 0 °C, allyl bromide (0.26 mL, 3.0 mmol, 1.2

equiv) was added dropwise and the reaction mixture was allowed to

warm to room temperature and stirred for another 2 h. After

quenching with water, the residue was extracted with ethyl acetate

twice for three times. The combined organic layer was washed with

brine, dried over Na₂SO₄, ﬁltrated and concentrated, and puriﬁed by

column chromatography using eluent:petroleum ether/EtOAc = 5/1

to aﬀord the desired 1r as yellow solids (594 mg, 55%). 1r: m.p.:

N-(8-Iodonaphthalen-1-yl)-N-methylpent-2-ynamide (1t). Gen-

eral procedure B was followed for the synthesis of 1t: Under a

nitrogen atmosphere, to the solution of 8-iodonaphthalen-1-amine

(673 mg, 2.5 mmol, 1.0 equiv) in dry CH₃CN (15 mL) were added

pent-2-ynoic acid (270 mg, 2.75 mmol, 1.1 equiv) and DMTMM

(885 mg, 3.0 mmol, 1.2 equiv) at room temperature. After stirring at

room temperature overnight, the mixture was quenched with water

and extracted with ethyl acetate. The combined organic layer was

dried over Na₂SO₄and concentrated by vacuum, and then the crude

product was treated with NaH (673 mg, 2.5 mmol, 1.0 equiv) in dry

THF (10 mL) at 0 °C for 30 min, followed by the addition of

methyl iodide (673 mg, 2.5 mmol, 1.0 equiv). The reaction mixture

was stirred at room temperature overnight, quenched with water,

and extracted with ethyl acetate. The combined organic layer was

concentrated and puriﬁed by column chromatography using

eluent:petroleum ether/EtOAc = 5/1 to aﬀord the desired product

1

as white solids (426 mg, 47%). 1t: m.p.: 64−65 °C, H NMR (400

MHz, CDCl₃) for the major isomer: δ 8.31 (d, J = 7.6 Hz, 1H),

7.96−7.86 (m, 2H), 7.57−7.45 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H),

3.30 (s, 3H), 1.83 (q, J = 7.2 Hz, 2H), 0.49 (t, J = 7.2 Hz, 3H)

ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 155.7, 142.6, 139.7,

135.7, 130.6, 129.8, 129.6, 129.1, 127.0, 125.8, 95.6, 86.5, 74.8, 38.5,

12.1. HRMS (ESI) calcd for C₁₆H₁₅INO (M + H)⁺364.0193,

found, 364.0204.

N-(8-Iodonaphthalen-1-yl)-N-methylhex-2-ynamide (1u). Gen-

eral procedure B was followed for the synthesis of 1u: Under a

nitrogen atmosphere, to the solution of 8-iodonaphthalen-1-amine

(673 mg, 2.5 mmol, 1.0 equiv) in dry CH₃CN (15 mL) were added

hex-2-ynoic acid (308 mg, 2.75 mmol, 1.1 equiv) and DMTMM

(885 mg, 3.0 mmol, 1.2 equiv) at room temperature. After stirring at

room temperature overnight, the mixture was quenched with water

and extracted with ethyl acetate. The combined organic layer was

dried over Na₂SO₄and concentrated by vacuum, and then the crude

product was treated with NaH (673 mg, 2.5 mmol, 1.0 equiv) in dry

THF (10 mL) at 0 °C for 30 min, followed by the addition of

methyl iodide (673 mg, 2.5 mmol, 1.0 equiv). The reaction mixture

was stirred at room temperature overnight, quenched with water,

and extracted with ethyl acetate. The combined organic layer was

concentrated and puriﬁed by column chromatography using

eluent:petroleum ether/EtOAc = 5/1 to aﬀord the desired product

1

90−91 °C, H NMR (400 MHz, CDCl₃) for the major isomer: δ

8.33 (dd, J = 7.6, 1.2 Hz, 1H), 7.97−7.93(m, 2H), 7.57−7.47 (m,

2H), 7.25−7.02 (m, 4H), 6.83−6.71 (m, 2H), 6.12−5.91 (m, 1H),

5.26−5.01 (m, 3H), 3.63−3.51 (m, 1H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ155.1, 143.0, 137.1, 135.8,

132.1, 131.6, 131.2, 131.0, 123.0, 129.7, 129.3, 128.0, 127.1, 125.4,

120.0, 119.5, 91.4, 86.5, 83.0, 54.0 ppm. HRMS (ESI) calcd for

C₂₂H₁₇INO (M + H)⁺438.0349, found, 438.0353.

1

as brown solids (396 mg, 42%). 1u: m.p.: 75−76 °C, H NMR (400

H

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MHz, CDCl₃) for the major isomer: δ 8.31 (dd, J = 7.2, 1.2 Hz,

1H), 7.93−7.88 (m, 2H), 7.56−7.45 (m, 2H), 7.14 (t, J = 7.6 Hz,

1H), 3.30 (s, 3H), 1.83 (t, J = 7.2 Hz, 2H), 0.92−0.86 (m, 2H),

0.36 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) for the

major isomer: δ155.8, 142.8, 139.8, 135.8, 130.8, 129.9, 129.6,

129.3, 127.1, 125.9, 94.5, 86.6, 75.5, 38.6, 20.7, 20.4, 12.7. HRMS

(ESI) calcd for C₁₇H₁₇INO (M + H)⁺378.0349, found, 378.0350.

N-(8-Iodonaphthalen-1-yl)-N-methyloct-2-ynamide (1v). Gener-

al procedure B was followed for the synthesis of 1v: Under a

nitrogen atmosphere, to the solution of 8-iodonaphthalen-1-amine

(673 mg, 2.5 mmol, 1.0 equiv) in dry CH₃CN (15 mL) were added

oct-2-ynoic acid (385 mg, 2.75 mmol, 1.1 equiv) and DMTMM

(885 mg, 3.0 mmol, 1.2 equiv) at room temperature. After stirring at

room temperature overnight, the mixture was quenched with water

and extracted with ethyl acetate. The combined organic layer was

dried over Na₂SO₄and concentrated by vacuum, and then the crude

product was treated with NaH (673 mg, 2.5 mmol, 1.0 equiv) in dry

THF (10 mL) at 0 °C for 30 min, followed by the addition of

methyl iodide (673 mg, 2.5 mmol, 1.0 equiv). The reaction mixture

was stirred at room temperature overnight, quenched with water,

and extracted with ethyl acetate. The combined organic layer was

concentrated and puriﬁed by column chromatography using

eluent:petroleum ether/EtOAc = 5/1 to aﬀord the desired product

mmol, 1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene

(1.48 g, 5.0 mmol, 1.0 equiv), 1-ethynyl-4-methoxybenzene (792

mg, 6.0 mmol, 1.2 equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5

M in hexane), and methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv).

The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 1:6) to give the product as yellow

1

solids (965 mg, 49%). 1y: m.p.: 122−123 °C, H NMR (400 MHz,

CDCl₃) for the major isomer: δ 7.98 (dd, J = 7.6, 2.0 Hz, 1H),

7.94−7.89 (m, 2H), 7.63−7.51 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H),

6.77−6.36 (m, 4H), 3.70 (s, 3H), 3.40 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ 160.6, 155.3, 139.0, 136.5,

134.4, 133.9, 130.4, 129.7, 128.9, 128.3, 126.6, 126.2, 116.4, 113.7,

112.0, 91.6, 82.0, 55.1, 37.7. HRMS (ESI) calcd for C₂₁H₁₇BrNO₂

(M + H)⁺394.0437, found, 394.0430.

N-(8-Bromonaphthalen-1-yl)-3-(4-chlorophenyl)-N-methylpro-

piolamide (1z). General procedure A was followed for the synthesis

of 1z from 8-bromonaphthalen-1-amine¹⁹(1.10 g, 5.0 mmol, 1.0

equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0

mmol, 1.0 equiv), 4-chloro-2-ethynylbenzene (816 mg, 6.0 mmol,

1.2 equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane),

and methyl iodide (0.46 mL, 7.5 mmol, 1 equiv). The crude

reaction mixture was puriﬁed by silica gel column chromatography

(EtOAc/hexane 1:6) to give the product as yellow solids (1.01 g,

1

50%) 1z: m.p.: 123−124 °C, H NMR (400 MHz, CDCl₃) for the

as white solids (344 mg, 34%). 1v: m.p.: 55−56 °C, H NMR (400

major isomer: δ 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.95−7.88 (m, 2H),

7.60−7.53 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz,

2H), 6.64 (d, J = 8.4 Hz, 2H), 3.41 (s, 3H) ppm. ¹³C{¹H} NMR

(100 MHz, CDCl₃) for the major isomer: δ 154.8, 138.7, 136.4,

135.8, 134.5, 133.2, 130.6, 129.7, 129.0, 128.4, 126.7, 126.2, 118.5,

116.3, 89.6, 83.4, 37.8 ppm. HRMS (ESI) calcd for C₂₀H₁₄BrClNO

(M + H)⁺397.9942, found, 397.9940.

MHz, CDCl₃) for the major isomer: δ 8.31 (dd, J = 7.6, 1.2 Hz,

1H), 7.96−7.84 (m, 2H), 7.58−7.44 (m, 2H), 7.14 (t, J = 7.6 Hz,

1H), 3.28 (s, 3H), 1.87−1.83 (m, 2H), 0.94−0.83 (m, 4H), 0.71−

0.68 (m, 5H). ¹³C{¹H} NMR (100 MHz, CDCl₃) for the major

isomer: δ 155.8, 142.8, 139.8, 135.8, 130.7, 129.9, 129.6, 129.3,

127.1, 125.8, 94.6, 86.5, 75.4, 38.6, 30.0, 26.8, 21.8, 18.4, 13.6.

HRMS (ESI) calcd for C₁₉H₂₁INO (M + H)⁺406.0662, found,

406.0664.

N-(8-Chloronaphthalen-1-yl)-N-methyl-3-phenylpropiolamide

(1aa). General procedure A was followed for the synthesis of 1aa

from 8-cholronaphthalen-1-amine (1.10 g, 5.0 mmol, 1.0 equiv),

Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol,

1.0 equiv), 4-chloro-2-ethynylbenzene (816 mg, 6.0 mmol, 1.2

equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and

methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 1:6) to give the product as yellow solids (1.01 g, 50%) 1aa:

m.p.: 128−129 °C, ¹H NMR (400 MHz, CDCl₃) for the major

isomer: δ 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (dd, J = 8.0, 1.2 Hz,

1H), 7.63 (dd, J = 7.6, 1.2 Hz, 1H), 7.60−7.50 (m, 2H), 7.42 (t, J =

8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H),

6.72 (dd, J = 8.0, 1.6 Hz, 2H), 3.41 (s, 3H) ppm. ¹³C{¹H} NMR

(100 MHz, CDCl₃) for the major isomer: δ 154.9, 138.5, 136.6,

132.2, 130.5, 130.4, 129.9, 129.7, 128.8, 128.3, 128.1, 127.6, 126.4,

126.4, 120.2, 91.0, 82.7, 37.5 ppm. HRMS (ESI) calcd for

C₂₀H₁₅ClNO (M + H)⁺320.0837, found, 320.0838.

General Procedures for the Synthesis of Triazole-Fused

Products. General procedure C: A mixture of N-(8-iodonaph-

thalen-1-yl)-N-methyl-propionamides (0.3 mmol), NaN₃(39.0 mg,

0.6 mmol), and DMSO (3.0 mL) was added in a closed vessel, and

then the reaction mixture was heated in an oil bath with stirring at

100 °C for 6 h in the oil bath. After disappearance of the reactant

(monitored by TLC), 1 mL of ammonia solution was added to the

mixture, washed with water, and extracted with EtOAc 3 times (3 ×

25 mL). The extract was washed with brine, dried over anhydrous

Na₂SO₄, and concentrated under reduced pressure. The residue was

puriﬁed by silica gel column chromatography using eluent:petroleum

ether/EtOAc = 3/1 to aﬀord the desired 2a−2w.

N-(8-Bromo-7-methylnaphthalen-1-yl)-N-methyl-3-phenylpro-

piolamide (1w). General procedure A was followed for the synthesis

of 1w from 8-bromo-7-methylnaphthalen-1-amine¹⁸(1.180 g, 5.0

mmol, 1.0 equiv), Et₃N (2.1 mL, 15.0 mol, 3.0 equiv), triphosgene

(1.48 g, 5.0 mmol, 1.0 equiv), phenyl acetylene (0.65 mL, 6.0 mmol,

1.2 equiv), n-BuLi (2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane),

and methyl iodide (0.46 mL, 7.5 mmol, 1.5 equiv). The crude

reaction mixture was puriﬁed by silica gel column chromatography

(EtOAc/hexane 1:6) to give the product as brown solids (772 mg,

1

41%). 1w: m.p.: 122−123 °C, H NMR (400 MHz, CDCl₃) for the

major isomer: δ 7.94 (dd, J = 7.2, 2.2 Hz, 1H), 7.81 (d, J = 8.4 Hz,

1H), 7.57−7.49 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.24−7.17 (m,

1H), 7.14−7.05 (m, 2H), 6.75 (d, J = 7.2, Hz, 2H), 3.39 (s, 3H),

2.63 (d, J = 3.1 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) for the

major isomer: δ 155.1, 139.6, 138.5, 135.0, 132.1, 130.3, 130.0,

129.5, 129.3, 128.6, 128.2, 128.0, 125.2, 120.2, 117.8, 90.9, 82.8,

37.7, 25.5. HRMS (ESI) calcd for C₂₁H₁₇BrNO (M + H)⁺

378.0488, found, 378.0498.

N-(8-Bromonaphthalen-1-yl)-N-methyl-3-phenylpropiolamide

(1x). General procedure A was followed for the synthesis of 1x from

8-bromonaphthalen-1-amine¹⁹(1.10 g, 5.0 mmol, 1.0 equiv), Et₃N

(2.1 mL, 15.0 mol, 3.0 equiv), triphosgene (1.48 g, 5.0 mmol, 1.0

equiv), phenyl acetylene (0.65 mL, 6.0 mmol, 1.2 equiv), n-BuLi

(2.6 mL, 6.5 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide

(0.46 mL, 7.5 mmol, 1.5 equiv). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 1:6)

to give the product as brown solids (780 mg, 43%).1x: m.p.: 136−

1

137 °C, H NMR (400 MHz, CDCl₃) for the major isomer: δ 7.98

(dd, J = 7.6, 2.0 Hz, 1H), 7.95−7.87 (m, 2H), 7.63−7.51 (m, 2H),

7.35 (t, J = 8.0 Hz, 1H), 7.25−7.16 (m, 1H), 7.16−7.03 (m, 2H),

7.73 (d, J = 8.4 Hz, 2H), 3.41 (s, 3H) ppm. ¹³C{¹H} NMR (100

MHz, CDCl₃) for the major isomer: δ 155.1, 138.8, 136.5, 134.5,

132.1, 130.5, 129.7, 129.6, 128.9, 128.0, 126.6, 126.1, 120.1, 116.3,

90.9, 82.6, 37.7 ppm. HRMS (ESI) calcd for C₂₀H₁₅BrNO (M +

H)⁺364.0332, found, 364.0325.

7-Methyl-9-phenylnaphtho[1,8-ef][1,2,3]triazolo[1,5a][1,4]-

diazepin-8(7H)-one (2a). General procedure C was followed for the

reaction of amides 1a (123 mg, 0.3 mmol) with NaN₃(39.0 mg, 0.6

mmol). The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 3:1) to give the product as light-

1

yellow solids (84 mg, 86%). 2a: m.p.: 170−171 °C, H NMR (400

MHz, CDCl₃) δ 8.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.93−7.90 (m, 3H),

7.70 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0

Hz, 1H), 7.50−7.42 (m, 4H), 3.57 (s, 3H). ¹³C{¹H} NMR (100

N-(8-Bromonaphthalen-1-yl)-3-(4-methoxyphenyl)-N-methyl-

propiolamide (1y). General procedure A was followed for the

synthesis of 1y from 8-bromonaphthalen-1-amine¹⁹(1.10 g, 5.0

I

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MHz, CDCl₃) δ 157.3, 152.6, 137.0, 134.9, 131.5, 130.0, 129.2,

129.1, 129.0, 128.2, 126.5, 126.4, 125.5, 125.2, 121.7, 121.2, 119.2,

40.9. HRMS (ESI) calcd for C₂₀H₁₄N₄O (M + H)⁺327.1240,

found, 327.1240.

1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0, 1.2 Hz, 1H), 7.01

(d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.57 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 160.3, 157.5, 152.5, 137.0, 134.9, 131.6, 130.5,

129.1, 126.5, 126.4, 125.5, 124.5, 122.4, 121.6, 121.2, 119.1, 113.7,

55.3, 40.9. HRMS (ESI) calcd for C₂₁H₁₆N₄O₂(M + H)⁺357.1346,

found, 357.1343. Preparation procedure for 1 mmol scale: General

procedure C was followed for the reaction of amides 1f (441 mg,

1.0 mmol) with NaN₃(130.0 mg, 2.0 mmol). The crude reaction

mixture was puriﬁed by silica gel column chromatography (EtOAc/

hexane 3:1) to give the product as white solids (260 mg, 73%).

9-(2-Chlorophenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2g). General procedure C was followed

for the reaction of amides 1g (133 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

7-Methyl-9-(p-tolyl)naphtho[1,8-ef][1,2,3]triazolo[1,5a][1,4]-

diazepin-8(7H)-one (2b). General procedure C was followed for the

reaction of amides 1b (127 mg, 0.3 mmol) with NaN₃(39.0 mg, 0.6

mmol). The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 3:1) to give the product as light-

1

yellow solids (64 mg, 63%). 2b: m.p.: 189−190 °C, H NMR (400

MHz, CDCl₃) δ 8.55 (dd, J = 7.6, 1.2 Hz, 1H), 7.90 (dd, J = 8.4,

1.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H),

7.65 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (dd, J = 7.6,

1.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 3.56 (s, 3H), 2.41 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.4, 152.8, 139.0, 137.0,

1

a gray powder (88 mg, 81%). 2g: m.p.: 240−241 °C, H NMR (400

134.9, 131.6, 129.1, 129.0, 127.1, 126.5, 126.4, 125.5, 125.0, 121.6,

121.2, 119.1, 40.8, 21.4. HRMS (ESI) calcd for C₂₁H₁₆N₄O (M +

H)⁺341.1397, found, 341.1369.

MHz, CDCl₃) δ 8.60 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H),

7.73−7.63 (m, 3H), 7.57 (t, J = 8.0 Hz, 1H), 7.53−7.49 (m, 1H),

7.45−7.37 (m, 3H), 3.54 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 156.9, 150.0, 136.9, 135.1, 133.7, 131.5, 131.4, 130.3,

129.8, 129.7, 129.5, 127.5, 126.9, 126.6, 126.4, 125.6, 121.5, 121.2,

119.1, 40.5. HRMS (ESI) calcd for C₂₀H₁₃ClN₄O (M + H)⁺

361.0851, found, 361.0850.

9-(4-Ethylphenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo[1,5-a]-

[1,4]diazepin-8(7H)-one (2c). General procedure C was followed for

the reaction of amides 1c (132 mg, 0.3 mmol) with NaN₃(39.0 mg,

0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

1

light-yellow solids (70 mg, 66%). 2c: m.p.: 130−131 °C, H NMR

9-(4-Chlorophenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2h). General procedure C was followed

for the reaction of amides 1h (133 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

(400 MHz, CDCl₃) δ 8.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.90 (dd, J =

8.0, 1.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 8.0, 1.2 Hz,

1H), 7.65 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (dd, J

= 7.6, 1.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 3.57 (s, 3H), 2.71 (q,

J = 7.6 Hz, 2H), 1.29 (t, J = 7.6, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 157.4, 152.8, 145.3, 137.1, 134.9, 131.6, 129.1, 129.0,

127.8, 126.5, 126.4, 125.5, 124.9, 121.7, 121.2, 119.1, 40.9, 28.8,

15.4. HRMS (ESI) calcd for C₂₂H₁₈N₄O (M + H)⁺355.1553,

found, 355.1553.

1

a gray powder (77 mg, 71%). 2h: m.p.: 178−179 °C, H NMR (400

MHz, CDCl₃) δ 8.55 (d, J = 7.6, 1.2 Hz, 1H), 7.93−7.88 (m, 3H),

7.71 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0

Hz, 1H), 7.46−7.42 (m, 3H), 3.57 (s, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 157.3, 151.5, 136.9, 135.1, 135.0, 131.5, 130.5,

129.4, 128.5, 128.5, 126.6, 126.5, 125.6, 125.4, 121.7, 121.3, 119.3,

40.9. HRMS (ESI) calcd for C₂₀H₁₃ClN₄O (M + H)⁺361.0851,

found, 361.0850.

7-Methyl-9-(4-propylphenyl)naphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2d). General procedure C was followed

for the reaction of amides 1d (136 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

9-(3-Fluorophenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2i). General procedure C was followed

for the reaction of amides 1i (129 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

1

white solids (84 mg, 76%). 2d: m.p.: 136−137 °C, H NMR (400

MHz, CDCl₃) δ 8.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.89 (dd, J = 8.4,

1.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H),

7.64 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 7.6,

1.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 3.56 (s, 3H), 2.65 (t, J = 7.2

Hz, 2H), 1.75−1.65 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 157.5, 152.9, 143.9, 137.1, 135.0, 131.7,

129.2, 129.0, 128.5, 127.4, 126.6, 126.5, 125.6, 125.0, 121.8, 121.3,

119.2, 41.0, 38.0, 24.4, 14.0. HRMS (ESI) calcd for C₂₃H₂₀N₄O (M

+ H)⁺369.1710, found, 369.1709.

1

a gray powder (86 mg, 83%). 2i: m.p.: 159−160 °C, H NMR (400

MHz, CDCl₃) δ 8.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.91 (dd, J = 8.0,

1.2 Hz, 1H), 7.78−7.62 (m, 4H), 7.58 (t, J = 8.0 Hz, 1H), 7.48−

7.40 (m, 2H), 7.18−7.09 (m, 1H), 3.57 (s, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 162.5 (C-F, 1J_C‑F= 243.0 Hz), 157.2, 151.3

(C-F, 4J

= 2.0 Hz), 136.9, 135.0, 132.0 (C-F, 3J_C‑F= 8.0 Hz),

C‑F

131.4, 129.7 (C-F, 3J_C‑F= 8.0 Hz), 129.4, 126.6, 126.5, 125.6, 124.9,

124.9 (C-F, 4J_C‑F= 3.0 Hz), 121.8, 121.4, 119.3, 116.2 (C-F, 2J_C‑F

9-(3,5-Dimethylphenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo-

[1,5a][1,4]diazepin-8(7H)-one (2e). General procedure C was

followed for the reaction of amides 1e (132 mg, 0.3 mmol) with

NaN₃(39.0 mg, 0.6 mmol). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 3:1) to give

the product as white solids (84 mg, 79%). 2e: m.p.: 239−240 °C,

¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J = 7.6 Hz, 1H), 7.87 (d, J

= 8.0 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H),

7.54 (t, J = 8.0 Hz, 1H), 7.50 (s, 2H), 7.41 (d, J = 7.6 Hz, 1H),

7.07 (s, 1H), 3.56 (s, 3H), 2.40 (s, 6H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 157.4, 153.1, 137.7, 137.1, 135.0, 131.7, 130.9, 129.9,

129.2, 126.9, 126.6, 126.5, 125.5, 125.3, 121.8, 121.3, 119.2, 40.9,

21.5. HRMS (ESI) calcd for C₂₂H₁₈N₄O (M + H)⁺355.1553,

found, 355.1553.

9-(4-Methoxyphenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo-

[1,5-a][1,4]diazepin-8(7H)-one (2f). General procedure C was

followed for the reaction of amides 1f (132 mg, 0.3 mmol) with

NaN₃(39.0 mg, 0.6 mmol). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 3:1) to give

the product as white solids (81 mg, 76%). 2f: m.p.: 184−185 °C,

¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J = 7.6, 1.2 Hz, 1H),

=

23.0 Hz), 116.0 (C-F, 2J_C‑F= 21.0 Hz), 40.9. HRMS (ESI) calcd for

C₂₀H₁₃FN₄O (M + H)⁺345.1146, found, 345.1146.

9-(4-Fluorophenyl)-7-methylnaphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2j). General procedure C was followed

for the reaction of amides 1j (129 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

1

white solids (83 mg, 80%). 2j: m.p.: 138−139 °C, H NMR (400

MHz, CDCl₃) δ 8.55 (d, J = 7.6 Hz, 1H), 7.95−7.89 (m, 3H), 7.71

(d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz,

1H), 7.43 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 3.57 (s,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.3 (C-F, 1J_C‑F

=

247.0 Hz), 157.4, 151.7, 137.0, 135.0, 131.6, 131.1 (C-F, 3J_C‑F= 9.0

Hz), 129.3, 126.6, 126.5, 126.1 (C-F, 4J_C‑F= 4.0 Hz), 125.6, 125.2,

121.7, 121.3, 119.3, 115.3 (C-F, 2J_C‑F= 21.0 Hz), 40.91. HRMS

(ESI) calcd for C₂₀H₁₃FN₄O (M + H)⁺345.1146, found, 345.1146.

Methyl 4-(7-Methyl-8-oxo-7,8-dihydronaphtho[1,8-ef][1,2,3]-

triazolo[1,5-a][1,4] diazepin-9-yl)benzoate (2k). General procedure

C was followed for the reaction of amides 1k (140 mg, 0.3 mmol)

with NaN₃(39.0 mg, 0.6 mmol). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 3:1)

7.91−7.88 (m, 3H), 7.69 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz,

J

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1

to give the product as a gray powder (85 mg, 74%). 2k: m.p.: 215−

white solids (52 mg, 53%). 2p: m.p.: 189−190 °C, H NMR (400

MHz, CDCl₃) 9.14 (d, J = 2.0 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz,

1H), 8.56 (dd, J = 7.6, 1.2 Hz, 1H), 8.28 (dt, J = 8.0, 2.0 Hz, 1H),

7.92 (dd, J = 8.4, 1.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.67 (t, J =

8.0 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.45−7.39 (m, 2H), 3.57 (s,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.0, 149.9, 149.8,

149.6, 136.7, 136.4, 135.0, 131.3, 129.5, 126.6, 126.4, 126.3, 126.0,

125.7, 123.0, 121.6, 121.4, 119.3, 40.9. HRMS (ESI) calcd for

C₁₉H₁₃N₅O (M + H)⁺328.1193, found, 328.1192.

1

216 °C, H NMR (400 MHz, CDCl₃) δ 8.56 (dd, J = 7.6, 1.2 Hz,

1H), 8.15 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.92 (d, J

= 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H),

7.58 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 3.95 (s, 3H),

3.58 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.8, 157.2,

151.5, 136.9, 135.0, 134.4, 131.4, 130.6, 129.5, 129.4, 129.1, 126.6,

126.5, 126.0, 125.7, 121.8, 121.5, 119.4, 52.2, 40.9. HRMS (ESI)

calcd for C₂₂H₁₆N₄O₃(M + H)⁺385.1295, found, 385.1295.

4-(7-Methyl-8-oxo-7,8-dihydronaphtho[1,8-ef][1,2,3]triazolo-

[1,5-a][1,4]diazepin-9-yl)benzonitrile (2l). General procedure C was

followed for the reaction of amides 1l (131 mg, 0.3 mmol) with

NaN₃(39.0 mg, 0.6 mmol). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 3:1) to give

the product as a gray powder (64 mg, 61%). 2l: m.p.: 251−252 °C,

¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J = 7.6, 1.2 Hz, 1H), 8.09

(d, J = 8.4 Hz, 2H), 7.93 (dd, J = 8.2, 1.2 Hz, 1H), 7.75 (d, J = 8.4

Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.59 (t,

J = 8.0 Hz, 1H), 7.45 (dd, J = 7.6, 1.2 Hz, 1H), 3.58 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ157.0, 150.5, 136.7, 135.0,

134.5, 131.9, 131.3, 129.7, 129.6, 126.7, 126.5, 126.2, 125.8, 121.8,

121.5, 119.5, 118.8, 112.4, 41.0. HRMS (ESI) calcd for C₂₁H₁₃N₅O

(M + H)⁺352.1193, found, 352.1192.

7-Methyl-9-(thiophen-2-yl)naphtho[1,8-ef][1,2,3]triazolo[1,5-a]-

[1,4]diazepin-8(7H)-one (2q). General procedure C was followed

for the reaction of amides 1q (125 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

1

light-yellow solids (69 mg, 69%). 2q: m.p.: 218−219 °C, H NMR

(400 MHz, CDCl₃) δ 8.50 (dd, J = 7.6, 1.2 Hz, 1H), 8.10 (dd, J =

3.6, 1.2 Hz, 1H), 7.90 (dd, J = 8.4, 1.2 Hz, 1H), 7.69 (d, J = 8.0 Hz,

1H), 7.65 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.46 (dd, J

= 5.2, 1.2 Hz, 1H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H), 7.17−7.14 (m,

1H), 3.61 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.2,

147.3, 136.8, 134.9, 131.4, 131.3, 129.3, 129.2, 127.8, 127.4, 126.5,

126.4, 125.5, 123.5, 121.4, 121.1, 119.2, 40.9. HRMS (ESI) calcd for

C₁₈H₁₂N₄OS (M + H)⁺333.0805, found, 333.0804.

(Z)-9-Phenyl-7-(prop-1-en-1-yl)naphtho[1,8-ef][1,2,3]triazolo-

[1,5-a][1,4]diazepin-8(7H)-one (2r). General procedure C was

followed for the reaction of amides 1r (131 mg, 0.3 mmol) with

NaN₃(39.0 mg, 0.6 mmol). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 3:1) to give

the product as white solids (95 mg, 90%). 2r: m.p.: 176−177 °C,

¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J = 7.6, 1.2 Hz, 1H),

7.96−7.85 (m, 3H), 7.73−7.59 (m, 3H), 7.57−7.38 (m, 4H), 6.15−

6.00 (m, 1H), 5.44−5.27 (m, 2H), 4.66−4.46 (m, 2H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 157.1, 152.2, 136.7, 135.0, 133.4, 131.4,

129.8, 129.3, 129.1, 128.8, 128.3, 126.7, 126.4, 125.9, 125.2, 121.9,

120.8, 119.4, 116.7, 56.6. HRMS (ESI) calcd for C₂₂H₁₆N₄O (M +

H)⁺353.1397, found, 353.1396.

7-Methyl-9-(naphthalen-1-yl)naphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2m). General procedure C was followed

for the reaction of amides 1m (138 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

a gray powder (62 mg, 55%). 2m: m.p.: 141−142 °C, ¹H NMR

(400 MHz, CDCl₃) δ 8.65 (dd, J = 7.6, 1.2 Hz, 1H), 7.98 (d, J =

8.2 Hz, 1H), 7.95−7.89 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.76−

7.65 (m, 3H), 7.63−7.53 (m, 2H), 7.54−7.44 (m, 2H), 7.40 (d, J =

7.6 Hz, 1H), 3.46 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

156.7, 152.0, 137.0, 135.1, 133.6, 131.9, 131.6, 129.6, 129.4, 128.7,

128.4, 127.8, 127.3, 126.6, 126.5, 126.4, 125.9, 125.5, 125.3, 125.1,

121.5, 121.1, 119.2, 40.6. HRMS (ESI) calcd for C₂₄H₁₆N₄O (M +

H)⁺377.1397, found, 377.1396.

7-Benzyl-9-phenylnaphtho[1,8-ef][1,2,3]triazolo[1,5-a][1,4]di-

azepin-8(7H)-one (2s). General procedure C was followed for the

reaction of amides 1s (146 mg, 0.3 mmol) with NaN₃(39.0 mg, 0.6

mmol). The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 3:1) to give the product as a gray

7-Methyl-9-(naphthalen-2-yl)naphtho[1,8-ef][1,2,3]triazolo[1,5-

a][1,4]diazepin-8(7H)-one (2n). General procedure C was followed

for the reaction of amides 1n (138 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

1

powder (74 mg, 61%). 2s: m.p.: 213−214 °C, H NMR (400 MHz,

1

CDCl₃) δ8.50 (dd, J = 7.6, 1.2 Hz, 1H), 7.94−7.91 (m, 2H), 7.87

(dd, J = 8.0, 1.2 Hz, 1H), 7.67−7.60 (m, 2H), 7.49−7.38 (m, 5H),

7.36−7.30 (m, 2H), 7.30−7.26 (m, 3H), 5.21 (s, 2H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 157.7, 152.4, 136.8, 136.5, 135.0, 131.4,

129.8, 129.4, 129.2, 128.9, 128.8, 128.4, 127.4, 126.7, 126.5, 126.3,

126.0, 125.3, 122.2, 121.4, 119.6, 57.4. HRMS (ESI) calcd for

C₂₆H₁₈N₄O (M + H)⁺403.1553, found, 403.1553. Preparation

procedure for 1 mmol scale: General procedure C was followed for

the reaction of amides 1s (487 mg, 1.0 mmol) with NaN₃(130.0

mg, 2.0 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

white solids (226 mg, 56%).

a gray powder (80 mg, 71%). 2n: m.p.: 199−200 °C, H NMR (400

MHz, CDCl₃) δ 8.58 (dd, J = 7.6, 1.2 Hz, 1H), 8.49 (s, 1H), 7.99−

7.85 (m, 5H), 7.74−7.62 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.54−

7.49 (m, 2H), 7.44 (dd, J = 7.7, 1.1 Hz, 1H), 3.58 (s, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 157.3, 152.6, 136.9, 135.4, 134.9, 133.5,

133.1, 131.5, 129.2, 128.6, 127.6, 127.6, 127.4, 126.6, 126.5, 126.5,

126.3, 126.1, 125.5, 125.4, 121.6, 121.2, 119.1, 40.8. HRMS (ESI)

calcd for C₂₄H₁₆N₄O (M + H)⁺377.1397, found, 377.1369.

7-Methyl-9-(phenanthren-9-yl)naphtho[1,8-ef][1,2,3]triazolo-

[1,5-a][1,4]diazepin-8(7H)-one (2o). General procedure C was

followed for the reaction of amides 1o (153 mg, 0.3 mmol) with

NaN₃(39.0 mg, 0.6 mmol). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 3:1) to give

the product as light-yellow solids (95 mg, 74%). 2o: m.p.: 210−211

9-Ethyl-7-methylnaphtho[1,8-ef][1,2,3]triazolo[1,5-a][1,4]-

diazepin-8(7H)-one (2t). General procedure C was followed for the

reaction of amides 1t (109 mg, 0.3 mmol) with NaN₃(39.0 mg, 0.6

mmol). The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 3:1) to give the product as light-

1

°C, H NMR (400 MHz, CDCl₃) δ 8.78 (d, J = 8.4 Hz, 1H), 8.74

(d, J = 8.4 Hz, 1H), 8.68 (dd, J = 7.6, 1.2 Hz, 1H), 8.00 (s, 1H),

7.96−7.91 (m, 2H), 7.83 (dd, J = 8.4, 1.2 Hz, 1H), 7.73−7.65 (m,

4H), 7.64−7.51 (m, 3H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H), 3.44 (s,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 156.7, 152.0, 137.0,

135.2, 131.6, 131.2, 131.0, 130.8, 130.6, 129.9, 129.6, 129.3, 127.7,

127.4, 126.9, 126.8, 126.8, 126.7, 126.6, 126.1, 125.6, 123.1, 122.7,

121.5, 121.2, 119.2, 40.6. HRMS (ESI) calcd for C₂₈H₁₈N₄O (M +

H)⁺427.1553, found, 427.1553.

1

yellow solids (46 mg, 55%). 2t: m.p.: 110−111 °C, H NMR (400

MHz, CDCl₃) δ 8.50 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H),

7.66 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6

Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 3.57 (s, 3H), 3.12 (q, J = 7.6

Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 157.7, 156.6, 137.0, 135.1, 131.6, 129.1, 126.4, 125.3,

125.0, 121.0, 120.6, 118.9, 40.5, 20.1, 13.3. HRMS (ESI) calcd for

C₁₆H₁₄N₄O (M + H)⁺279.1240, found, 279.1240.

7-Methyl-9-(pyridin-3-yl)naphtho[1,8-ef][1,2,3]triazolo[1,5a]-

[1,4]diazepin-8(7H)-one (2p). General procedure C was followed

for the reaction of amides 1p (124 mg, 0.3 mmol) with NaN₃(39.0

mg, 0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

7-Methyl-9-propylnaphtho[1,8-ef][1,2,3]triazolo[1,5-a][1,4]-

diazepin-8(7H)-one (2u). General procedure C was followed for the

reaction of amides 1u (113 mg, 0.3 mmol) with NaN₃(39.0 mg, 0.6

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mmol). The crude reaction mixture was puriﬁed by silica gel column

N-(2-Iodophenyl)-3-(4-methoxyphenyl)-N-methylpropiolamide

(4b). General procedure A was followed for the synthesis of 4b from

2-iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8

mmol, 3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), 1-

ethynyl-4-methoxybenzene (792 mg, 6.0 mmol, 1.3 equiv), n-BuLi

(2.4 mL, 6.0 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide

(0.39 mL, 6.0 mmol, 1.3 equiv). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 1:6)

to give the product 4b as yellow solids (1.2 g, 67%). 4b: m.p.: 91−

chromatography (EtOAc/hexane 3:1) to give the product as a gray

1

powder (69 mg, 79%). 2u: m.p.: 117−118 °C, H NMR (400 MHz,

CDCl₃) δ 8.49 (dd, J = 7.6, 1.2 Hz, 1H), 7.87 (dd, J = 8.0, 1.2 Hz,

1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.53 (t, J =

8.0 Hz, 1H), 7.36 (dd, J = 7.6, 1.1 Hz, 1H), 3.57 (s, 3H), 3.08 (t, J

= 7.6 Hz, 2H), 1.90−1.80 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.7, 155.4, 137.0, 135.0,

131.6, 129.1, 126.4, 126.4, 125.3, 125.3, 121.1, 120.6, 118.8, 40.5,

28.4, 22.3, 14.0. HRMS (ESI) calcd for C₁₇H₁₆N₄O (M + H)⁺

293.1397, found, 293.1396.

1

92 °C, H NMR (400 MHz, CDCl₃) δ 8.56 (dd, J = 8.4, 1.6 Hz,

1H), 8.34 (d, J = 8.8 Hz, 2H), 7.59−7.54 (m, 1H), 7.43−6.39 (m,

2H), 7.04 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.73 (s, 3H) ppm.

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 161.0, 154.7, 145.7, 139.8,

134.3, 130.1, 129.8, 129.5, 114.0, 112.0, 99.8, 91.4, 81.8, 55.4, 35.2.

HRMS (ESI) calcd for C₁₇H₁₅INO₂(M + H)⁺392.0142, found,

392.0149.

7-Methyl-9-pentylnaphtho[1,8-ef][1,2,3]triazolo[1,5-a][1,4]-

diazepin-8(7H)-one (2v). General procedure C was followed for the

reaction of amides 1v (121 mg, 0.3 mmol) with NaN₃(39.0 mg, 0.6

mmol). The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 3:1) to give the product as light-

1

N-(2-Iodophenyl)-N-methyl-3-(p-tolyl)propiolamide (4c). Gener-

al procedure A was followed for the synthesis of 4c from 2-

iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8 mmol,

3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), 1-ethynyl-4-

methylbenzene (696 mg, 6.0 mmol, 1.3 equiv), n-BuLi (2.4 mL, 6.0

mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide (0.39 mL, 6.0

mmol, 1.3 equiv). The crude reaction mixture was puriﬁed by silica

gel column chromatography (EtOAc/hexane 1:6) to give the

product 4c as yellow solids (1.29 g, 75%). 4c: m.p.: 97−98 °C,

¹H NMR (400 MHz, CDCl₃) δ 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.45

(td, J = 7.6, 1.6 Hz, 1H), 7.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.13 (td, J

= 7.6, 1.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz,

1H), 3.28 (s, 3H), 2.28 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 154.5, 145.6, 140.6, 139.8, 132.5, 130.1, 129.8, 129.6, 129.2, 117.1,

99.8, 91.2, 82.1, 35.3, 21.7. HRMS (ESI) calcd for C₁₇H₁₅INO (M

+ H)⁺376.0193, found, 376.0193.

3-(4-Ethylphenyl)-N-(2-iodophenyl)-N-methylpropiolamide (4d).

General procedure A was followed for the synthesis of 4d from 2-

iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8 mmol,

3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), 1-ethynyl-4-

methylbenzene (780 mg, 6.0 mmol, 1.3 equiv), n-BuLi (2.4 mL, 6.0

mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide (0.39 mL, 6.0

mmol, 1.3 equiv). The crude reaction mixture was puriﬁed by silica

gel column chromatography (EtOAc/hexane 1:6) to give the

product 4d as yellow solids (1.08 g, 61%). 4d: m.p.: 66−67 °C,

¹H NMR (400 MHz, CDCl₃) δ 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.44

yellow solids (32 mg, 33%). 2v: m.p.: 70−71 °C, H NMR (400

MHz, CDCl₃) δ 8.49 (dd, J = 7.6, 1.2 Hz, 1H), 7.87 (dd, J = 8.0,

1.2 Hz, 1H), 7.66 (dd, J = 8.0, 1.2 Hz, 1H), 7.62 (t, J = 8.0 Hz,

1H), 7.53 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.37 (dd, J

= 7.6, 1.2 Hz, 1H), 3.57 (s, 3H), 3.08 (t, J = 8.0 Hz, 2H), 1.85−

1.80 (m, 2H), 1.41−1.38 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.7, 155.6, 137.0, 135.0,

131.6, 129.1, 126.4, 126.4, 125.3, 125.2, 121.1, 120.6, 118.8, 40.5,

31.7, 28.6, 26.5, 22.5, 14.0. HRMS (ESI) calcd for C₁₉H₂₀N₄O (M

+ H)⁺321.1710, found, 321.1709.

6,7-Dimethyl-9-phenylnaphtho[1,8-ef][1,2,3]triazolo[1,5-a][1,4]-

diazepin-8(7H)-one (2w). General procedure C was followed for the

reaction of amides 1w (113 mg, 0.3 mmol) with NaN₃(39.0 mg,

0.6 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product as

1

white solids (58 mg, 57%). 2w: m.p.: 139−140 °C, H NMR (400

MHz, CDCl₃) δ 8.08−7.98 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.61

(dd, J = 8.0, 1.2 Hz, 1H), 7.53−7.41 (m, 5H), 7.35 (dd, J = 7.6, 1.2

Hz, 1H), 3.52 (s, 3H), 2.84 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 158.0, 149.5, 136.8, 133.1, 131.6, 130.9, 129.7, 129.0,

128.9, 128.7, 128.3, 127.9, 125.9, 125.6, 125.0, 124.9, 121.7, 40.6,

21.3. HRMS (ESI) calcd for C₂₁H₁₆N₄O (M + H)⁺341.1397,

found, 341.1396.

N-(8-Iodonaphthalen-1-yl)-N-methyl-5-phenyl-1H-1,2,3triazole-

5-carboxamide (3a). 3a was obtained as white solids from 1a (123

mg, 0.3 mmol) reacted with 2 equiv of sodium azide (39.0 mg, 0.6

mmol) in DMSO at 60 °C in an oil bath for 12 h. The crude

reaction mixture was puriﬁed by silica gel column chromatography

(EtOAc/hexane 5:1) to give the product as white solids (65 mg,

(td, J = 7.6, 1.6 Hz, 1H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.12 (td, J

= 7.6, 1.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz,

1H), 3.28 (s, 3H), 2.57 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz,

3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.6, 146.8, 145.6,

139.8, 132.6, 130.1, 129.8, 129.6, 128.0, 117.4, 99.8, 91.2, 82.0, 35.2,

28.9, 15.2. HRMS (ESI) calcd for C₁₈H₁₇INO (M + H)⁺390.0349,

found, 390.0345.

1

48%). 3a: m.p.: 170−171 °C, H NMR (400 MHz, CDCl₃) for the

major isomer: δ 12.51 (s, 1H), 8.20 (dd, J = 7.6, 1.2 Hz, 1H), 7.74

(dd, J = 8.0, 1.2 Hz, 1H), 7.73−7.65 (m, 2H), 7.42−7.33 (m, 3H),

7.14 (t, J = 7.6 Hz, 1H), 7.13−7.04 (m, 2H), 3.40 (s, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃) δ 164.0, 142.9, 139.7, 135.7, 130.6, 130.3,

129.9, 129.2, 129.0, 128.7, 128.6, 128.4, 128.4, 127.2, 126.3, 125.5,

87.3, 40.7. HRMS (ESI) calcd for C₂₀H₁₆IN₄O (M + H)⁺455.0363,

found, 455.0358.

3-(4-(tert-Butyl)phenyl)-N-(2-iodophenyl)-N-methylpropiola-

mide (4e). General procedure A was followed for the synthesis of 4e

from 2-iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8

mmol, 3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), 1-

(tert-butyl)-4-ethynylbenzene (948 mg, 6.0 mmol, 1.3 equiv), n-BuLi

(2.4 mL, 6.0 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide

(0.39 mL, 6.0 mmol, 1.3 equiv). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 1:6)

to give the product 4e as yellow solids (1.801 g, 94%). 4e: m.p.:

N-(2-Iodophenyl)-N-methyl-3-phenylpropiolamide (4a). General

procedure A was followed for the synthesis of 4a from 2-iodoaniline

(1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8 mmol, 3.0 equiv),

triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), ethynylbenzene (612

mg, 6.0 mmol, 1.3 equiv), n-BuLi (2.4 mL, 6.0 mmol, 1.3 equiv, 2.5

M in hexane), and methyl iodide (0.39 mL, 6.0 mmol, 1.3 equiv).

The crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 1:6) to give the product 4a as

1

91−92 °C, H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J = 8.0, 1.6

Hz, 1H), 7.47−7.42 (m, 1H), 7.38 (dd, J = 7.6, 1.6 Hz, 1H), 7.24

(dd, J = 8.0, 1.6 Hz, 2H), 7.13 (td, J = 7.6, 1.6 Hz, 1H), 7.05 (dd, J

= 8.0, 1.6 Hz, 2H), 3.29 (s, 3H), 1.24 (s, 9H). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 154.6, 153.6, 145.7, 139.8, 132.4, 130.1, 129.8,

129.6, 125.4, 117.2, 99.8, 91.1, 82.0, 35.2, 34.9, 31.0. HRMS (ESI)

calcd for C₂₀H₂₁INO (M + H)⁺418.0662, found, 418.0655.

3-(4-Fluorophenyl)-N-(2-iodophenyl)-N-methylpropiolamide

(4f). General procedure A was followed for the synthesis of 4f from

2-iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8

mmol, 3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), 1-

ethynyl-4-ﬂuorobenzene (720 mg, 6.0 mmol, 1.3 equiv), n-BuLi (2.4

1

yellow solids (1.39 g, 84%). 4a: m.p.: 110−111 °C, H NMR (400

MHz, CDCl₃) δ 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 (td, J = 7.6, 1.6

Hz, 1H), 7.42−7.37 (m, 1H), 7.36−7.29 (m, 1H), 7.26−7.20 (m,

2H), 7.18−7.12 (m, 1H), 7.09−7.06 (m, 2H), 3.30 (s, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.4, 145.5, 139.9, 132.5,

130.2, 130.0, 129.8, 129.6, 128.3, 120.2, 99.8, 90.7, 82.4, 35.3.

HRMS (ESI) calcd for C₁₆H₁₃INO (M + H)⁺362.0036, found,

362.0041.

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mL, 6.0 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide (0.39

mL, 6.0 mmol, 1.3 equiv). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 1:6) to give

the product 4f as yellow solids (1.301 g, 75%). 4f: m.p.: 109−110

¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.1, 148.5, 130.0, 129.4,

129.3, 129.3, 129.2, 128.4, 124.2, 122.0, 122.0, 116.7, 115.5, 29.1.

HRMS (ESI) calcd for C₁₆H₁₃N₄O (M + H)⁺277.1084, found,

277.1076.

1

°C, H NMR (400 MHz, CDCl₃) δ 7.95 (dd, J = 8.0, 1.6 Hz, 1H),

3-(4-Methoxyphenyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5b).^8d5b was obtained as white solids from 4b (117

mg, 0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

solids (72 mg, 78%). The ¹H and ¹³C NMR spectra of 5b were

consistent with the literature.⁹5b: m.p.: 196−197 °C, ¹H NMR

(400 MHz, CDCl₃) δ 8.52 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.4 Hz,

2H), 7.54 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.02 (d, J =

8.4 Hz, 2H), 3.87 (s, 3H), 3.70 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 160.5, 154.4, 148.5, 130.7, 130.1, 129.3, 124.1, 122.2,

121.8, 121.0, 116.8, 115.5, 113.8, 55.4, 29.1. HRMS (ESI) calcd for

C₁₇H₁₅N₄O₂(M + H)⁺307.1190, found, 307.1185.

7.44 (td, J = 7.6, 1.6 Hz, 1H), 7.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.13

(td, J = 7.6, 1.6 Hz, 1H), 7.08−6.99 (m, 2H), 6.93−6.85 (m, 2H),

3.27 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.5 (C-F,

1J_C‑F= 251.0 Hz), 154.3, 145.5, 139.9, 134.7 (C-F, 3J_C‑F= 9.0 Hz),

130.2, 129.8, 129.6, 116.3 (C-F, 4J_C‑F= 4.0 Hz), 115.8 (C-F, 2J_C‑F

=

22.0 Hz), 99.7, 89.6, 82.3, 35.3. HRMS (ESI) calcd for C₁₆H₁₂FINO

(M + H)⁺379.9942, found, 379.9946.

3-(4-Bromophenyl)-N-(2-iodophenyl)-N-methylpropiolamide

(4g). General procedure A was followed for the synthesis of 4g from

2-iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8

mmol, 3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), 1-

bromo-4-ethynylbenzene (1.080 mg, 6.0 mmol, 1.3 equiv), n-BuLi

(2.4 mL, 6.0 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide

(0.39 mL, 6.0 mmol, 1.3 equiv). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 1:6)

to give the product 4g as yellow solids (1.890 g, 94%). 4g: m.p.:

3-(4-Methylphenyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5c). 5c was obtained as white solids from 4c (113 mg,

0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

1

106−107 °C, H NMR (400 MHz, CDCl₃) δ 7.87 (dd, J = 8.0, 1.6

Hz, 1H), 7.41−7.35 (m, 2H), 7.32−7.27 (m, 3H), 7.17−7.12 (m,

2H), 7.04−6.98 (m, 1H), 4.06 (d, J =5.2 Hz, 2H), 4.05 (s, 2H),

3.24 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 153.6, 145.2,

134.0, 136.8, 130.4, 129.8, 129.7, 128.4, 128.1, 128.0, 99.6, 87.7,

80.1, 70.9, 56.6, 35.4. HRMS (ESI) calcd for C₁₆H₁₂BrINO (M +

H)⁺439.9141, found, 439.9143.

1

solids (74 mg, 85% yield). 5c: m.p.: 208−209 °C, H NMR (400

MHz, CDCl₃) δ 8.52 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 8.0 Hz, 2H),

7.54 (t, J = 8.0 Hz, 1H), 7.40−7.44 (m, 2H), 7.30 (d, J = 8.0 Hz,

2H), 3.70 (s, 3H), 2.42 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃)

δ 154.3, 148.7, 139.4, 130.1, 129.4, 129.2, 129.1, 126.4, 124.2, 122.2,

121.4, 116.8, 115.5, 29.1, 21.5. HRMS (ESI) calcd for C₁₇H₁₅N₄O

(M + H)⁺291.1240, found, 291.1230.

4-(Benzyloxy)-N-(2-iodophenyl)-N-methylbut-2-ynamide (4h).

General procedure A was followed for the synthesis of 4h from 2-

iodoaniline (1.0 g, 4.6 mmol, 1.0 equiv), Et₃N (2.1 mL, 13.8 mmol,

3.0 equiv), triphosgene (1.776 g, 6.0 mmol, 1.3 equiv), ((prop-2-yn-

1-yloxy)methyl)benzene (876 mg, 6.0 mmol, 1.3 equiv), n-BuLi (2.4

mL, 6.0 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide (0.39

mL, 6.0 mmol, 1.3 equiv). The crude reaction mixture was puriﬁed

by silica gel column chromatography (EtOAc/hexane 1:6) to give

3-(4-Ethylphenyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5d). 5d was obtained as white solids from 4d (117 mg,

0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

1

the product 4h as a yellow oil (0.980 g, 53%). 4h: H NMR (400

1

solids (83 mg, 91% yield). 5d: m.p.: 177−178 °C, H NMR (400

MHz, CDCl₃) δ 7.70 (dd, J = 7.6, 2.8 Hz, 1H), 7.39−7.34 (m, 2H),

7.30−7.27 (m, 2H), 7.17−7.14 (m, 2H), 6.95−6.90 (m, 1H), 3.29

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

CDCl₃) δ 162.72, 160.19, 154.43, 142.06, 142.02, 132.46, 130.52,

130.43, 130.13, 128.94, 128.91, 128.42, 127.54, 127.50, 126.76,

126.52, 120.13, 116.62, 116.40, 115.44, 99.71, 90.93, 82.23, 35.36,

29.71. HRMS (ESI) calcd for C₁₈H₁₆INNaO₂(M + H)⁺428.0118,

found, 428.0109.

MHz, CDCl₃) δ 8.55−8.48 (m, 1H), 8.26 (d, J = 8.0 Hz, 2H), 7.52

(td, J = 7.6, 1.6 Hz, 1H), 7.40−7.32 (m, 4H), 3.69 (s, 3H), 2.72 (q,

J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (100

MHz, CDCl₃) δ 154.2, 148.7, 145.7, 130.1, 129.4, 129.3, 127.9,

126.6, 124.1, 122.1, 121.4, 116.8, 115.5, 29.1, 28.8, 15.5. HRMS

(ESI) calcd for C₁₈H₁₆N₄O (M + Na)⁺327.1222, found, 327.1216.

3-(4-tert-Butylphenyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5e). 5e was obtained as white solids from 4e (125 mg,

0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

N-(2-Bromo-5-methylphenyl)-N-methyl-3-phenylpropiolamide

(4i). General procedure A was followed for the synthesis of 4i from

2-iodoaniline (1.0 g, 5.4 mmol, 1.0 equiv), Et₃N (2.3 mL, 16.2

mmol, 3.0 equiv), triphosgene (2.07 g, 7.0 mmol, 1.3 equiv), 1-

ethynyl-4-methylbenzene (658 mg, 6.5 mmol, 1.2 equiv), n-BuLi

(2.5 mL, 7.0 mmol, 1.3 equiv, 2.5 M in hexane), and methyl iodide

(0.5 mL, 8.3 mmol, 1.5 equiv). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 1:6)

to give the product 4i as yellow solids (1.35 g, 77%). 4i: m.p.: 94−

1

solids (93 mg, 93% yield). 5e: m.p.: 169−170 °C, H NMR (400

MHz, CDCl₃) δ 8.53 (dd, J = 8.4, 1.6 Hz, 1H), 8.27 (d, J = 8.0 Hz,

2H), 7.58−7.50 (m, 3H), 7.39−7.41 (m, 2H), 3.70 (s, 3H), 1.38 (s,

9H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.3, 152.5, 148.6,

130.1, 129.4, 129.0, 126.4, 125.4, 124.1, 122.2, 121.4, 116.8, 115.5,

34.8, 31.3, 29.1. HRMS (ESI) calcd for C₂₀H₂₁N₄O (M + H)⁺333.

1710, found, 333. 1698. Large-scale procedure: 5e was obtained as

white solids from 4e (1.0 g, 2.4 mmol) reacted with 3 equiv of

sodium azide (468.0 mg, 7.2 mmol) in DMSO (20.0 mL) at 130 °C

for 12 h in an oil bath. The crude reaction mixture was puriﬁed by

silica gel column chromatography (EtOAc/hexane 5:1) to give the

product as white solids (726 mg, 91% yield).

1

95 °C, H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 8.0 Hz, 1H),

7.35−7.29 (m, 1H), 7.27−7.20 (m, 3H), 7.13−7.09 (m, 3H), 3.28

(s, 3H), 2.33 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.4,

141.8, 138.9, 133.1, 132.5, 131.0, 130.9, 123.0, 128.3, 120.4, 120.2,

90.2, 82.3, 35.1, 20.8. HRMS (ESI) calcd for C₁₇H₁₅BrNO (M +

H)⁺328.0332, found, 328.0327.

5-Methyl-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-one

(5a).^8d5a was obtained as white solids from 4a¹⁸(108 mg, 0.3

mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9 mmol)

in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The crude

reaction mixture was puriﬁed by silica gel column chromatography

(EtOAc/hexane 5:1) to give the product as white solids (67 mg,

3-(4-Fulrophenyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5f). 5f was obtained as white solids from 4f (113 mg,

0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

1

81%). The H and ¹³C NMR spectra of 5a were consistent with the

9

1

literature. 5a: m.p.: 215−216 °C, H NMR (400 MHz, CDCl₃) δ

8.49 (dd, J = 8.4, 1.2 Hz, 1H), 8.38−8.30 (m, 2H), 7.56−7.46 (m,

3H), 7.46−7.40 (m, 1H), 7.40−7.33 (m, 2H), 3.68 (s, 3H).

1

solids (73 mg, 82% yield). 5f: m.p.: 233−234 °C, H NMR (400

MHz, CDCl₃) δ 8.56 (dd, J = 8.4, 1.6 Hz, 1H), 8.45−8.34 (m, 2H),

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7.59 (td, J = 7.6, 1.6 Hz, 1H), 7.45−7.41 (m, 2H), 7.19 (t, J = 8.8

Hz, 2H), 3.73 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 163.5

(C-F, 1J_C‑F= 247.0 Hz), 154.3, 147.7, 131.3 (C-F, 3J_C‑F= 8.0 Hz),

130.1, 129.6, 125.5 (C-F, 4J_C‑F= 3.0 Hz), 124.3, 122.1, 121.5, 116.9,

115.5 (C-F, 4J_C‑F= 4.0 Hz), 115.3, 29.2. HRMS (ESI) calcd for

C₁₉H₁₂FN₄O (M + H)⁺295.0990, found, 295. 0979. Large-scale

procedure: 5f was obtained as white solids from 4f (1.0 g, 2.6

mmol) reacted with 3 equiv of sodium azide (514.0 mg, 7.9 mmol)

in DMSO (20.0 mL) at 130 °C for 12 h in an oil bath. The crude

reaction mixture was puriﬁed by silica gel column chromatography

(EtOAc/hexane 5:1) to give the product as white solids (680 mg,

87% yield).

7-Methyl-9-(4-(4-nitrophenoxy)phenyl)naphtho[1,8-ef][1,2,3]-

triazolo[1,5-a][1,4]diazepin-8(7H)-one (7). General procedure C

was followed for the reaction of amides 1f (882 mg, 2.0 mmol) with

NaN₃(260.0 mg, 4.0 mmol). The crude reaction mixture was

puriﬁed by silica gel column chromatography (EtOAc/hexane 3:1)

to give the product 2f as white solids (527 mg, 74%). To the

solution of 2f (50 mg, 0.14 mmol, 1.0 equiv) in dry DCM (10 mL)

at 0 °C was added a 1.0 M solution of BBr₃in DCM (0.7 mL, 0.7

mmol, 1.0 equiv), and then, the reaction mixture was stirred at room

temperature overnight. The reaction was quenched with water (10

mL) and extracted with DCM three times (3 × 10 mL). The

combined organic phase was concentrated by vacuum to aﬀord the

crude product. The above crude product was dissolved in 5.0 mL of

dry DMF, and then, K₂CO₃(97 mg, 0.7 mmol, 5.0 equiv) and 1-

ﬂoro-4-nitrobenzene (24 mg, 0.17 mmol, 1.2 equiv) were added

under N₂, following which the reaction mixture was stirred at 80 °C

overnight in an oil bath. The mixture was then quenched with water

and extracted with ethyl acetate three times. The organic layer was

combined, dried over Na₂SO₄, concentrated in vacuum to get the

crude product, and loaded on a silica column to aﬀord 7 as white

3-(4-Bromophenyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5g). 5g was obtained as white solids from 4g (131 mg,

0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

1

solids (96 mg, 90% yield). 5g: m.p.: 198−199 °C, H NMR (400

MHz, CDCl₃) δ 8.56 (d, J = 8.8 Hz, 2H), 8.29 (d, J = 8.0 Hz, 2H),

7.63−7.57 (m, 3H), 7.42−7.46 (m, 2H), 3.73 (s, 3H). ¹³C{¹H}

NMR (100 MHz, DMSO-d₆) δ 154.1, 145.9, 131.8, 131.2, 130.6,

130.1, 129.0, 124.5, 123.1, 122.8, 121.9, 117.1, 116.3, 29.6. HRMS

(ESI) calcd for C₁₆H₁₂BrN₄O (M + H)⁺355.0189, found, 355.

0181.

1

solids (40 mg, 61%).7: m.p.: 217−218 °C, H NMR (400 MHz,

CDCl₃) δ 8.56 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 9.2 Hz, 2H), 8.03

(d, J = 9.2 Hz, 2H), 7.92 (dd, J = 8.0, 1.2 Hz, 1H), 7.71 (dd, J =

8.0, 1.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H),

7.43 (dd, J = 7.6, 1.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.11(d, J =

8.8 Hz, 1H), 3.58 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ

162.9, 157.4, 155.4, 151.6, 142.8, 136.8, 135.0, 131.5, 131.3, 129.4,

127.2, 126.6, 126.5, 126.0, 125.7, 125.2, 121.7, 121.4, 120.1, 119.3,

117.5, 41.0. HRMS (ESI) calcd for C₂₆H₁₈N₅O₄(M + H)⁺

464.1353, found, 464.1354.

3-((Benzyloxy)methyl)-5-methyl-[1,2,3]triazolo[1,5-a]quinoxalin-

4(5H)-one (5h). 5h was obtained as white solids from 4h (122 mg,

0.3 mmol) reacted with 3 equiv of sodium azide (59.0 mg, 0.9

mmol) in DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The

crude reaction mixture was puriﬁed by silica gel column

chromatography (EtOAc/hexane 5:1) to give the product as white

1

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02022.

solids (86 mg, 90% yield). 5h: m.p.: 125−126 °C, H NMR (400

■

MHz, CDCl₃) δ 8.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.63−7.54 (m, 1H),

7.47−7.38 (m, 4H), 7.37−7.29 (m, 2H), 7.30−7.23 (m, 1H), 5.10

(s, 2H), 4.74 (s, 2H), 3.71 (s, 3H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 154.0, 145.8, 138.0, 130.2, 129.6, 128.4, 128.0, 127.7,

124.3, 123.7, 122.1, 116.9, 115.7, 72.9, 62.3, 28.8. HRMS (ESI)

calcd for C₁₈H₁₇N₄O₂(M + H)⁺321.1346, found, 321.1338.

5,7-Dimethyl-3-phenyl-[1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-

one (5i). 5i was obtained as white solids from 4i (98 mg, 0.3 mmol)

reacted with 3 equiv of sodium azide (59.0 mg, 0.9 mmol) in

DMSO (2.0 mL) at 130 °C for 12 h in an oil bath. The crude

reaction mixture was puriﬁed by silica gel column chromatography

(EtOAc/hexane 5:1) to give the product as white solids (46 mg,

sı

Details about experimental conditions, characterization

1

data, copies of H and ¹³C NMR spectra of all new

compounds (PDF)

FAIR data includes the primary NMR FID ﬁles for

compounds 1a, 1aa, 1b−1z, 2a−2w, 3, 4a−4i, 5a−5i,

6, and 7 Crystallographic data for 2a (CIF) (ZIP)

Accession Codes

1

53% yield). 5i: m.p.: 219−220 °C, H NMR (400 MHz, CDCl₃) δ

CCDC 1952770 contains 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.

CCDC1952770 contains the supplementary crystallo-

graphic 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

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

8.39−8.29 (m, 3H), 7.52−7.40 (m, 3H), 7.20−7.09 (m, 2H), 3.66

(s, 3H), 2.46 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 154.3,

148.3, 140.1, 129.9, 129.4, 129.3, 128.3, 125.1, 121.3, 119.9, 116.5,

115.7, 29.0, 21.9. HRMS (ESI) calcd for C₁₇H₁₅N₄O (M + H)⁺

291.1240, found, 291.1232.

7-Benzyl-9-phenyl-7,8-dihydronaphtho[1,8-ef][1,2,3]triazolo-

[1,5-a][1,4]diazepine (6). General procedure C was followed for the

reaction of amides 1s (974 mg, 2.0 mmol) with NaN₃(260.0 mg,

4.0 mmol). The crude reaction mixture was puriﬁed by silica gel

column chromatography (EtOAc/hexane 3:1) to give the product 2s

as white solids (378 mg, 47%). To the solution of 2s (250 mg, 0.62

mmol, 1.0 equiv) in 20.0 mL of dry THF was added slowly a 1.0 M

solution of BH₃in THF (3.1 mL, 3.1 mmol, 5.0 equiv) at 0 °C, and

then, the reaction mixture was reﬂuxed overnight. The mixture was

then quenched with NaHCO₃solution and extracted with ethyl

acetate three times. The organic layer was combined, dried over

Na₂SO₄, concentrated in vacuum to get the crude product, and

loaded on a silica column to aﬀord product 6 as light-yellow solids

AUTHOR INFORMATION

Corresponding Authors

■

Fengtao Zhou − Xi’an Key Laboratory of Functional

Organic Porous Materials, Department of Applied

Chemistry, School of Chemistry and Chemical Engineering,

Northwestern Polytechnical University, Xi’an, Shaanxi

710072, P. R. China; Email: fengtaozhou@126.com

Qiuyu Zhang − Xi’an Key Laboratory of Functional Organic

Porous Materials, Department of Applied Chemistry, School

of Chemistry and Chemical Engineering, Northwestern

1

(97 mg, 40% yield). 6: m.p.: 213−214 °C, H NMR (400 MHz,

CDCl₃) δ 8.21 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.60−

7.46 (m, 4H), 7.43−7.31 (m, 4H), 7.18−7.09 (m, 6H), 4.56 (s,

2H), 4.42 (s, 2H). ¹³C {¹H} NMR (100 MHz, CDCl₃) δ 147.8,

136.9, 136.9, 132.4, 130.4, 129.9, 128.7, 128.6, 127.9, 127.8, 127.5,

127.1, 126.6, 125.7, 122.4, 121.2, 116.3, 58.5, 43.4. HRMS (ESI)

calcd for C₂₆H₂₁N₄(M + H)⁺389.1761, found, 389.1762.

N

https://dx.doi.org/10.1021/acs.joc.0c02022

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

[1,4]benzodiazepine Analogue, the First Bivalent α 5 Subtype

Selective Bzr/GABAA Antagonist. J. Med. Chem. 2003, 46, 5567−

5570. (b) Insuasty, B.; Orozco, F.; Quiroga, J.; Abonia, R.;

Nogueras, M.; Cobo, J. Microwave Induced Synthesis of Novel

8,9-Dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Anti-

tumor Agents. Eur. J. Med. Chem. 2008, 43, 1955−1962.

(c) Antonow, D.; Thurston, D. E. Synthesis of DNA-Interactive

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). Chem. Rev. 2011, 111,

2815−2864. (d) Gerratana, B. Biosynthesis, synthesis, and biological

activities of pyrrolobenzodiazepines. Med. Res. Rev. 2012, 32, 254−

293. (e) Liu, J. J.; Higgins, B.; Ju, G.; Kolinsky, K.; Luk, K. C.;

Packman, K.; Pizzolato, G.; Ren, Y.; Thakkar, K.; Tovar, C.; Zhang,

Z. M.; Woykulich, P. M. Discovery of a Highly Potent, Orally Active

Mitosis/Angiogenesis Inhibitor R1530 for the Treatment of Solid

Tumors. ACS Med. Chem. Lett. 2013, 4, 259−263. (f) Insuasty, B.;

Ramirez, J.; Becerra, D.; Echeverry, C.; Quiroga, J.; Abonia, R.;

Robledo, S. M.; Velez, I. D.; Upegui, Y.; Munoz, J. A.; Ospina, V.;

Nogueras, M.; Cobo, J. An Efficient Synthesis of New Caffeine-

Based Chalcones, Pyrazolines And Pyrazolo [3,4-b][1,4]diazepines

as Potential Antimalarial, Antitrypanosomal and Antileishmanial

Agents. Eur. J. Med. Chem. 2015, 93, 401−413. (g) Baud, M. G. J.;

Lin-Shiao, E.; Zengerle, M.; Tallant, C.; Ciulli, A. New Synthetic

Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope

of the Bump-and-Hole Approach for Selective Bromo and Extra-

Terminal (BET) Bromodomain Inhibition. J. Med. Chem. 2016, 59,

1492−1500. (h) Taylor, A. M.; Vaswani, R. G.; Gehling, V. S.;

Hewitt, M. C.; Leblanc, Y.; Audia, J. E.; Bellon, S.; Cummings, R.

T.; Cote, A.; Harmange, J.-C.; Jayaram, H.; Joshi, S.; Lora, J. M.;

Mertz, J. A.; Neiss, A.; Pardo, E.; Nasveschuk, C. G.; Poy, F.; Sandy,

P.; Setser, J. W.; Sims, R. J., III; Tang, Y.; Albrecht, B. K. Discovery

of Benzotriazolo [4,3-d][1,4]diazepines as Orally Active Inhibitors

of BET Bromodomains. ACS Med. Chem. Lett. 2016, 7, 145−150.

(5) (a) Cheng, H. M.; Wan, J. T.; Lin, M. I.; Liu, Y. X.; Lu, X. Y.;

Liu, J. S.; Xu, Y.; Chen, J. X.; Tu, Z. C.; Cheng, Y. S. E.; Ding, K.

Design, Synthesis, and in Vitro Biological Evaluation of 1H-1,2,3-

Triazole-4-carboxamide Derivatives as New Anti-influenza A Agents

Targeting Virus Nucleoprotein. J. Med. Chem. 2012, 55, 2144−2153.

(b) Macan, A. M.; Harej, A.; Cazin, I.; Klobucar, M.; Stepanic, V.;

Pavelic, K.; Pavelic, S. K.; Schols, D.; Snoeck, R.; Andrei, G.; Raic-

Malic, S. Antitumor and Antiviral Activities of 4-Substituted 1,2,3-

Triazolyl-2,3-Dibenzyl-L-Ascorbic Acid Derivatives. Eur. J. Med.

Chem. 2019, 184, 111739. (c) Xu, Z.; Zhao, S.-J.; Liu, Y. 1,2,3-

Triazole-Containing Hybrids as Potential Anticancer Agents:

Current Developments, Action Mechanisms and Structure-Activity

Relationships. Eur. J. Med. Chem. 2019, 183, No. 111700.

(6) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I. Click

Chemistry Based Rapid One-Pot Synthesis and Evaluation for

Protease Inhibition of New Tetracyclic Triazole Fused Benzodiaze-

pine Derivatives. Bioorg. Med. Chem. Lett. 2009, 19, 5241−5245.

(7) (a) Nagawa, Y.; Honda, K.; Nakanishi, H. Synthesis and

Reactivity of 1-(8-Amino-1-naphthyl)-1H-1,2,3-Triazoles. Synthesis

1987, 1987, 905−906. (b) Akritopoulou-Zanze, I.; Gracias, V.;

Djuric, S. W. A Versatile Synthesis of Fused Triazolo Derivatives by

Sequential Ugi/Alkyne-Azide Cycloaddition Reactions. Tetrahedron

Lett. 2004, 45, 8439−8441. (c) Donald, J. R.; Martin, S. F. Synthesis

and Diversification of 1,2,3-Triazole-Fused 1,4-Benzodiazepine

Scaffolds. Org. Lett. 2011, 13, 852−855. (d) Vachhani, D. D.;

Kumar, A.; Modha, S. G.; Sharma, S. K.; Parmar, V. S.; Van der

Eycken, E. V. Diversely. Substituted Triazolo[1,5-a][1,4]-

benzodiazepinones: A Post-Ugi Copper-Catalyzed Tandem Azide-

Alkyne Cycloaddition/Ullmann C −N Coupling Approach. Eur. J.

Org. Chem. 2013, 2013, 1223−1227. (e) Chambers, C. S.; Patel, N.;

Hemming, K. Intramolecular 1,3-Dipolar Cycloaddition as A Route

to Triazolobenzodiazepines and Pyrrolobenzodiazepines. Tetrahedron

Lett. 2010, 51, 4859−4861. (f) Majumdar, K. C.; Ganai, S. An

Expedient Approach to Substituted Triazolo[1,5-a][1,4]-

Benzodiazepines via Cu-Catalyzed Tandem Ullmann C −N Cou-

pling/Azide-Alkyne Cycloaddition. Tetrahedron Lett. 2013, 54,

6192−6195.

Polytechnical University, Xi’an, Shaanxi 710072, P. R.

China; orcid.org/0000-0002-4823-5031;

Email: qyzhang@nwpu.edu.cn

Authors

Kashif Majeed − Xi’an Key Laboratory of Functional

Organic Porous Materials, Department of Applied

Chemistry, School of Chemistry and Chemical Engineering,

Northwestern Polytechnical University, Xi’an, Shaanxi

710072, P. R. China

Lingna Wang − Xi’an Key Laboratory of Functional Organic

Porous Materials, Department of Applied Chemistry, School

of Chemistry and Chemical Engineering, Northwestern

Polytechnical University, Xi’an, Shaanxi 710072, P. R.

China

Bangjie Liu − Xi’an Key Laboratory of Functional Organic

Porous Materials, Department of Applied Chemistry, School

of Chemistry and Chemical Engineering, Northwestern

Polytechnical University, Xi’an, Shaanxi 710072, P. R.

China

Zijian Guo − Xi’an Key Laboratory of Functional Organic

Porous Materials, Department of Applied Chemistry, School

of Chemistry and Chemical Engineering, Northwestern

Polytechnical University, Xi’an, Shaanxi 710072, P. R.

China

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02022

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors are grateful for the support and funding from the

National Natural Science Foundation of China (Nos.

21702165 and 51673156), the Natural Science Foundation

of Shaanxi Province China (No. 2018JQ2018), the

Fundamental Research Funds for the Central Universities

(No. 3102017jc01001), and the Opening Project of State

Key Laboratory of Polymer Materials Engineering (Sichuan

University) (Grant No. sklpme2018-4-34).

REFERENCES

■

(1) (a) Renfroe, B.; Harrington, C.; Proctor, G. R. Heterocyclic

Compounds: Azepines; Wiley-Interscience: New York, 1984.

(b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The Combinatorial

Synthesis of Bicyclic Privileged Structures or Privileged Substruc-

tures. Chem. Rev. 2003, 103, 893−930. (c) Welsch, M. E.; Snyder, S.

A.; Stockwell, B. R. Privileged Scaffolds for Library Design and Drug

Discovery. Curr. Opin. Chem. Biol. 2010, 14, 347−361.

(2) Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.;

Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;

Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T.

B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. Methods

for Drug Discovery: Development of Potent, Selective, Orally

Effective Cholecystokinin Antagonists. J. Med. Chem. 1988, 31,

2235−2246.

(3) (a) Hester, J. B.; Rudzik, A. D.; Kamdar, B. V. 6-Phenyl-4H-s-

triazolo[4,3-a][1,4]benzodiazepines Which Have Central Nervous

System Depressant Activity. J. Med. Chem. 1971, 14, 1078−1081.

(b) Sternbach, L. H. The Benzodiazepine Story. J. Med. Chem. 1979,

22, 1−7. (c) Ellman, J. A. Design, Synthesis, and Evaluation of

Small-Molecule Libraries. Acc. Chem. Res. 1996, 29, 132−143.

(4) (a) Li, X. Y.; Cao, H.; Zhang, C. C.; Furtmueller, R.; Fuchs,

K.; Huck, S.; Sieghart, W.; Deschamps, J.; Cook, J. M. Synthesis, in

Vitro Affinity, and Efficacy of a Bis 8-Ethynyl-4H-Imidazo[1,5a]-

O

https://dx.doi.org/10.1021/acs.joc.0c02022

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(8) (a) Cai, Q.; Zhou, F.; Xu, T.; Fu, L.; Ding, K. Copper-

Catalyzed Tandem Reactions of 1-(2-Iodoary)-2-yn-1-ones with

Isocyanides for the Synthesis of 4-Oxo-indeno[1,2-b]pyrroles. Org.

Lett. 2011, 13, 340−343. (b) Zhou, F.; Liu, J.; Ding, K.; Liu, J.; Cai,

Q. Copper-Catalyzed Tandem Reaction of Isocyanides with N-(2-

Haloaryl)propiolamides for the Synthesis of Pyrrolo[3,2-c]quinolin-

4-ones. J. Org. Chem. 2011, 76, 5346−5353. (c) Cai, Q.; Yan, J.;

Ding, K. A CuAAC/Ullmann C-C Coupling Tandem Reaction:

Copper-Catalyzed Reactions of Organic Azides with N-(2-Iodoaryl)-

propiolamides or 2-Iodo-N-(prop-2-ynyl)benzenamines. Org. Lett.

2012, 14, 3332−3335. (d) Yan, J.; Zhou, F.; Qin, D.; Cai, T.; Ding,

K.; Cai, Q. Synthesis of [1,2,3]Triazolo[1,5-a]quinoxalin-4(5H)-ones

through Copper-Catalyzed Tandem Reactions of N-(2-Haloaryl)-

propiolamides with Sodium Azide. Org. Lett. 2012, 14, 1262−1265.

(e) Selvaraju, M.; Sun, C.-M. One-Pot Synthesis of Triazoloquina-

zolinones via Copper-Catalyzed Tandem Click and Intramolecular

C-H Amidation. Adv. Synth. Catal. 2014, 356, 1329−1336.

(f) Wang, W. G.; Peng, X. L.; Wei, F.; Tung, C. H.; Xu, Z. H.

Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of

Diverse 5-Hetero-Functionalized Triazoles. Angew. Chem., Int. Ed.

2016, 55, 649−653. (g) Xu, P.; Zhu, Y.-M.; Li, X.-J.; Wang, F.;

Wang, S.-Y.; Ji, S.-J. Copper-Catalyzed Reaction of Aryl Isocyanides

with Active Methylene Isocyanides and Arylsulfonothioates: Syn-

thesis of Sulfur-Containing Trisubstituted Imidazoles. Adv. Synth.

Catal. 2019, 361, 4909−4913.

(18) Tsubaki, K.; Hai, D. T. T.; Reddy, V. K.; Ohnishi, H.; Fuji,

K.; Kawabata, T. Synthesis of chiral 2,2 ′-dimethyl-1,1 ′-binaphthyl-

8,8 ′-diamine and barriers of atropisomerization of the related

binaphthyls. Tetrahedron: Asymmetry 2007, 18, 1017−1021.

(19) Jurok, R.; Cibulka, R.; Dvorakova, H.; Hampl, F.; Hodacova,

J. Planar Chiral Flavinium Salts -Prospective Catalysts for

Enantioselective Sulfoxidation Reactions. Eur. J. Org. Chem. 2010,

2010, 5217−5224.

̌

́

̌

́

(9) (a) Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R.

Second-Generation Difluorinated Cyclooctynes for Copper-Free

Click Chemistry. J. Am. Chem. Soc. 2008, 130, 11486−11493.

(b) Jewett, J. C.; Sletten, E. M.; Bertozzi, C. R. Rapid Cu-Free Click

Chemistry with Readily Synthesized Biarylazacyclooctynones. J. Am.

Chem. Soc. 2010, 132, 3688−3690.

(10) (a) Purkait, N.; Kervefors, G.; Linde, E.; Olofsson, B.

Regiospecific N-Arylation of Aliphatic Amines under Mild and

Metal-Free Reaction Conditions. Angew. Chem., Int. Ed. 2018, 57,

11427−11431. (b) Sun, C.-L.; Shi, Z.-J. Transition-Metal-Free

Coupling Reactions. Chem. Rev. 2014, 114, 9219−9280.

́

(11) (a) Cano, R.; Ramon, D. J.; Yus, M. Transition-Metal-Free

O-, S-, and N-Arylation of Alcohols, Thiols, Amides, Amines, and

Related Heterocycles. J. Org. Chem. 2011, 76, 654−660. (b) Guo,

F.; Wang, L.; Wang, P.; Yu, J.; Han, J. Transition-Metal-Free N-

Arylation of Carbazoles and C-Arylation of Tetrahydrocarbazoles by

using Diaryliodonium Salts. Asian J. Org. Chem. 2012, 1, 218−221.

(12) (a) Kilian, P.; Knight, F. R.; Woollins, J. D. Synthesis of

Ligands Based on Naphthalene peri-Substituted by Group 15 and 16

Elements and Their Coordination Chemistry. Coord. Chem. Rev.

2011, 255, 1387−1413. (b) Kilian, P.; Knight, F. R.; Woollins, J. D.

Naphthalene and Related Systems peri-Substituted by Group 15 and

16 Elements. Chem. − Eur. J. 2011, 17, 2302−2328. (c) Luo, X.;

Yuan, J.; Yue, C. D.; Zhang, Z. Y.; Chen, J.; Yu, G. A.; Che, C. M.

Synthesis of peri-Substituted (Naphthalen-1-yl)phosphine Ligands

by Rhodium(I)-Catalyzed Phosphine-Directed C-H Arylation. Org.

Lett. 2018, 20, 1810−1814.

(13) Noland, W. E.; Narina, V. S.; Britton, D. Synthesis and

Crystallography of 8-Halonaphthalene-1-Carbonitriles and Naphtha-

lene-1,8-dicarbonitrile. J. Chem. Res. 2011, 35, 694−697.

(14) Yanada, R.; Obika, S.; Kobayashi, Y.; Inokuma, T.; Oyama,

M.; Yanada, K.; Takemoto, Y. Stereoselective Synthesis of 3-

Alkylideneoxindoles using Tandem Indium-Mediated Carbometalla-

tion and Palladium-Catalyzed Cross-Coupling Reactions. Adv. Synth.

Catal. 2005, 347, 1632−1642.

(15) For details, see the Supporting Information.

(16) The pH value of 1.0 M solution of sodium azide in distilled

water is determined to be 9.46 by pH meter at 20 °C (PHS-3C,

INESA Scientiﬁc Instrument Co. Ltd.).

(17) D’Souza, D. M.; Kiel, A.; Herten, D.-P.; Rominger, F.; Muller,

̈

T. J. J. Synthesis, Structure and Emission Properties of Spirocyclic

Benzofuranones and Dihydroindolones: A Domino Insertion-

Coupling-Isomerization Diels-Alder Approach to Rigid Fluoro-

phores. Chem. − Eur. J. 2008, 14, 529−547.

P

https://dx.doi.org/10.1021/acs.joc.0c02022

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Metal-Free Tandem Approach for Triazole-Fused Diazepinone Scaffolds via [3 + 2]Cycloaddition/C-N Coupling Reaction

DOI: 10.1021/acs.joc.0c02022

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Article abstract of DOI:10.1021/acs.joc.0c02022

Full text of DOI:10.1021/acs.joc.0c02022

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