Bimetal-Catalyzed Cascade Reaction for Efficient Synthesis of N-Isopropenyl 1,2,3-Triazoles via In-Situ Generated 2-Azidopropenes

DOI: 10.1002/asia.201900402

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Chemistry - An Asian Journal p. 2149 - 2154 (2019)

Update date:2022-08-05

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Authors:

Liu, Zhenhua

Hao, Wenjing

Liu, Zhixian

Gao, Wen

Zhang, Zhihai

Zhang, Yanan

Li, Xiang

Tong, Lili

Tang, Bo

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Article abstract of DOI:10.1002/asia.201900402

A bimetal-catalyzed cascade reaction for the synthesis of N-isopropenyl 1,2,3-triazoles in high yield is reported. This reaction involves the generation of 2-azidopropenes in situ by C(sp³)-OAr bond cleavage for click reaction and features a broad substrate scope, good functional group tolerance and readily available substrates.

Full text of DOI:10.1002/asia.201900402

CHEMISTRY

AN ASIAN JOURNAL

www.chemasianj.org

Accepted Article

Title: Bimetal-Catalyzed Cascade Reaction for Efficient Synthesis

of N-isopropenyl 1,2,3-Triazoles via in situ Generated 2-

Azidopropenes

Authors: Zhenhua Liu, Wenjing Hao, Zhixian Liu, Wen Gao, Zhihai

Zhang, Yanan Zhang, Xiang Li, Lili Tong, and Bo Tang

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content of this Accepted Article.

To be cited as: Chem. Asian J. 10.1002/asia.201900402

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Bimetal-Catalyzed Cascade Reaction for Efficient Synthesis of N-

isopropenyl 1,2,3-Triazoles via in situ Generated 2-Azidopropenes

Zhenhua Liu*^[a], Wenjing Hao^[a], Zhixian Liu^[a], Wen Gao*^[a], Zhihai Zhang^[a], Yanan Zhang^[a],Xiang Li^[a],

Lili Tong^[a]and Bo Tang*^[a]

Abstract: A bimetal-catalyzed cascade reaction for high-yielding

synthesis of unknown N-isopropenyl 1,2,3-triazoles is reported. This

reaction involves, the first example, generation of 2-azidopropenes in

situ by C(sp3)-OAr bond cleavage for click reaction with eraesing

explosion risk of azides under mild reaction conditions, which was

characterized by broad substrate scope, good functional group

tolerance and readily available substrates.

especially in drug discovery because drug properties strongly

associated with their substitution types¹⁶. Meanwhile, the allyl

group has been widely explored as a protecting group for various

alcohols and amines in organic synthesis¹⁷, which delivers the

deprotected products by selective C(sp3)-OAr bond cleavage with

the release of propylene intact. Therefore, we sought to develop

benign method that generated the explosive 2-azidopropenes in

situ by this flexible protection-deprotection strategy and

subsequently reacted with appropriate substrates without further

isolation.

Introduction

Recently, we have developed two cascade reactions with

readily available vinyl azides¹⁸to assemble functionalized N-

heterocycles¹⁹under copper-mediated system. Owing to our

ongoing efforts to explore novel reactions based on vinyl

azides^15a,20. We herein report, the first example, a one-pot

protocol for the synthesis of N-isopropenyl 1,2,3-triazoles under

mild reaction conditions, which involves the generation of 2-

azidopropenes in situ by selective C(sp³)-OAr bond cleavage to

conduct click reaction with high yields (Figure 1d). This portable

and scalable method exhibited a straightforward and safe

pathway to access neotype N-isopropenyl 1,2,3-triazoles under

easy operation conditions, thus enriching the toolbox for

functionalized 1,2,3-triazoles with the potential application in the

drug discovery and materials chemistry. This reaction displayed a

broad substrate scope and good functional-group tolerance with

uniformly good to excellent yields.

1,2,3-Triazoles are important structural motifs found in various

areas, including organic synthesis¹, materials science², chemical

biology³, and medicinal development⁴. As a subset of them, N-

vinyl substituted 1,2,3-triazoles are one of the most important

precursors for industrially functional polymers⁵. Their facile

polymerization under free radical conditions motivated chemists

for large scale production of electron rich polymers⁶.

Conventionally, two approaches for the construction of N-vinyl-

1,2,3-triazoles were developed via the post-modification of

NH/sulfonyl-triazoles with suitable electrophile⁷and

the

cycloaddition between vinyl azides and compounds having an

active methylene^8-11(Figure 1a,1b). However, the application of

these methods is fettered by narrow substrate scope, redundant

preparation steps, the risk of explosion/toxicity of the reagents.

Therefore, a powerful, sustainable, costeffective route to access

diverse vinyl-triazoles are highly desirable.

With the advent of click chemistry popularized by Meldal^12aand

Sharpless,^12bthe click reaction between azides and alkynes under

copper(I) and ruthenium(II)¹³catalyst has been evolved into

alternatively powerful strategies for the regioselective

construction of N-vinyl 1,2,3-triazoles by vinyl azides as reaction

parameter (Figure 1c). However, the substituent (R¹or R²) of vinyl

azides are merely restricted to aryl and polycarboalkyl groups

because of their potentially explosive equation^13b,14. To obtain the

readily explosive azidoethenes from substituted alkanes,

hypothermia and strong base were indispensable^13b,15. The above

requirements detract the significant role of N-vinyl 1,2,3-triazoles

[a]

Zhenhua Liu*, Wenjing Hao, Zhixian Liu, Wen Gao*, Zhihai Zhang,

Xiang Li, Lili Tong, Bo Tang*

College of Chemistry, Chemical Engineering and Materials Science,

Collaborative Innovation Center of Functionalized Probes for

Chemical Imaging in Universities of Shandong, Key Laboratory of

Molecular and Nano Probes, Ministry of Education, Shandong

Provincial Key Laboratory of Clean Production of Fine Chemicals

Shandong Normal University

Jinan, 250014, P. R. China

E-mail: tangb@sdnu.edu.cn

Scheme 1. Transformations for N-vinyl-1,2,3-triazoles.

Supporting information for this article is given via a link at the end of

the document.

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Results and Discussion

air decreased the yield of the desired product by the cascade

transformation (Table 1, entry 16). Product 3a was only detected

in 68% yield when 2.0 eq. Et₃N was employed in the three-

component reaction (Table 1, entry 17).

Our initial investigations started with dissociation kinetics of

vinyl azides bearing different substituents to deliver 2-

azidopropene in the presence of NaBH₄in Et₃N at 60 ^oC (Scheme

2). These results clearly indicated that both position and electronic

characteristics of the substituents strongly affected the efficiency

of C(sp³)-OAr bond cleavage. For instance, when electron-

donating and -withdrawing groups anchored on the para-position

of benzene ring (2a-2c), good reactivity was observed for the

product 3a’-3c’ rather than the desired ones. Fortunately, when

2d was performed in the reaction, the proposed product 3a could

be obtained in a relatively low yield. Encouraged by this initial

results, other substituted vinyl azides (2e-2h) were subjected to

the reaction and the substrate 2g with 2,4,6-tribromophenyl group

gave the preferable reactivity for product 3a via the three-

component cascade reaction. Other vinyl azides with adjacent

hydroxyl 2i and nitrogen atom (2j, 2k) displayed as unproductive

substrates to deliver the targeted N-isopropenyl 1,2,3-triazole

product 3a.

Table 1. Optimization of the reaction conditions. ^a

Entry

Cat1

CuTc

......

Cat2

Sol.

3a/%

......

CH₃CN

Pd(PPh₃)₄

CH₃CN

CuTc

Cu₂O

CuCl₂

Cu(OAc)₂

CuI

Pd(PPh₃)₄

Pd(PPh₃)₂Cl₂

Pd(OAc)₂

Pd(PPh₃)₄

CH₃CN

trace

45^b

68^c

CuI

DMF

CuI

DMSO

Toluene

DCE

^aReaction conditions: 1a (0.24 mmol), 2 (0.2 mmol.), CuI (0.04 eq.), Pd(PPh₃)₄

(0.02 eq.), NaBH₄(0.5 eq.), Et₃N (2 mL), 60 °C, Ar (balloon), 4 h; Isolated

yield.

CuI

1,4-DOE

CH₃CN

Scheme 2. Scope of vinyl azides^a.

CuI

Accordingly, the model reaction was carried out with

phenylacetylene 1a, 2g and NaBH₄as substrates for the initial

reaction optimization by three-component cascade reaction to

preparation of N-isopropenyl-1,2,3-triazoles. The reaction was

shut down with the sole CuTc or Pd(PPh₃)₄as catalyst (Table 1,

entries 1 and 2). Taking into consideration of selective C(sp³)-OAr

bond cleavage and subsequent click reaction process, we

performed the cascade reaction with the Pd/Cu bimetallic

catalysts for the next screening. Notably, the desired

transformation was observed and produced 3a in 83% yield with

CH₃CN/Et₃N as reaction solvents (Table 1, entry 3). Studies of

other copper salts (Table 1, entries 4-7) uncovered that CuI

significantly improved the efficiency of cascade reaction with the

target product 3a in 93% yield (Table 1, entry 7). The reaction

showed inferior reactivity when the alternative Pd sources were

used (Table 1, entries 8-9). Furthermore, solvents such as EG,

DMF, DMSO, toluene, 1,4-dioxane, afforded lower yields of N-

vinyl-1,2,3-triazoles 3a (Table 1, entries 10-15). The use of open

[a] Reaction conditions: 1a (0.24 mmol), 2g (0.2 mmol.), [cat1] (0.04 eq.),

[cat2] (0.02 eq.), NaBH₄(0.5 eq.), Et₃N (0.5 mL), Sol. (1.5 mL), 60 °C, Ar

(balloon), 4 h; Isolated yield. b) Open air. c) 2.0 eq. Et₃N and 1.5 mL CH₃CN

was used. EG = ethylene glycol, DMSO = dimethyl sulfoxide, DMF =

dimethylformamide, DCE = 1,2-dichloroethane, 1,4-DOE=1,4-dioxane.

The optimized reaction conditions in hand, using 1a, 2g and

NaBH₄, were then applied to evaluate the scope of alkynes with

various groups in the bimetallic-accelerated sequential

reaction (Schemes 3). In general, diverse aromatic and

aliphatic alkynes with electron-deficient or -rich substituents

were allowed to the corresponding 1,2,3-triazoles (3b-3zf) in

good to excellent yields. For instance, the varied electron-

donating groups at para-position of the aromatic ring (3b-3g)

were well-tolerated in this cascade reaction and had no

significant influence on the efficiency of the conversion in 88-

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95% yields. The aromatic alkynes with sterically congested

para-substituents (1h-1i) also exhibited satisfactory reactivity

to access the product (3h-3i) in 92% and 90% yield,

respectively. Alkynes with electron-withdrawing groups such

as fluoro (1j), bromo (1k), chloro (1l) yielded the corresponding

products with intact halogen handles for further derivatizations.

The structure of 3l was further corroborated by X-ray diffraction

analysis²¹(See the details in SI). Similarly, alkyne substrate

with ester group at the para position could smoothly be

converted to 1,2,3-triazoles 3m in 95% yield without showing

much of electronic factors. When additional functionality such

as methyl, methyl sulfamic or chloro group was at the meta-

position of benzene ring, excellent reactivity was furnished with

90-93% yields for the homologous products (3n-3p). Notably,

replacing the phenyl group of 1a with other rings, including 2-

naphthyl (1q), 3-thienyl (1r) and cyclohexenyl (1s), were also

compatible for the corresponding triazoles in good yields.

Aliphatic alkynes possessing long alkyl substituents (1t-1v)

and functionalized alkyl groups (1w-1x) worked well to give the

expected products. The reaction system also displayed good

tolerance toward a range of functional groups such as hydroxyl

(1y), ester (1z), alkoxy (1za) and aryloxy (1zb-1zd) in the

three-component click reaction with the satisfactory yields. It is

worth noting that aliphatic alkynes anchored nitrogen-atom as

reaction partner gave the product 3ze and 3zf with the

excellent yields.

structure of product 4a was unambiguously confirmed by X-ray

diffraction²¹(See the details in SI). We then examined other

functionalized alkynes and secondary amines via in situ

generation of 2-azidopropene derivatives for click reaction,

which were observed with the good reactivity for the exclusive

formation of adorned triazoles (4b-4l) in good to excellent

yields. For example, alkynes decorated with electron-donating

and -withdrawing benzene ring were performed with high

reactivity to assemble the targeted products 4b-4e. Several

functionalized terminal alkynes, such as 2-ethynylthiophene

and 1-ethynylcyclohexene could also successfully afford the

corresponding 4f and 4g in 90% and 91% yield, respectively.

Alkynes with long carbon chain and nitrogenous carbon chain

were further applied to the cascade click reaction for the

preparation of 1,2,3-triazole derivatives (4h-4i) in good yields.

When the reaction was conducted with cyclic and acyclic

secondary amines, the pre-set course effectively proceeded to

synthesis of the functionalized triazoles (4j-4l).

[a] Reaction conditions: 1a (0.24 mmol), 2g (0.2 mmol.), CuI (0.04 eq.),

Pd(PPh₃)₄(0.02 eq.), NHR₂(2.0 eq.), Et₃N (0.5 mL), CH₃CN (1.5 mL),

60 °C, Ar (balloon), 4 h; Isolated yield.

Scheme 4. Scope of alkynes and secondary amines ^a.

To further demonstrate the practicability and scalability of

this cascade reaction, we carried out the gram-scope

conversion with 2g (11.8 mmol, 13 $) to produce 3a in 85%

yield with the recovery of 2,4,6-tribromophenol after workup.

Product 3a could be further derivatization to dibrominated

1,2,3-triazole 6 in good yield by treating bromine^8b. N-alkyl-

1,2,3-triazoles was isolated with nearly quantitative conversion

through hydrogenation of 3a under H₂(balloon) in the presence

of Pd/C (0.1 eq.) in methanol^8b. Analogously, other vinyl-

triazoles tethered with meta-methyl aromatic ring and

thiophene were also amenable to hydrogenation reaction with

good yields. These results highlighted the advantages of this

cascade reaction for the isolation of N-isopropenyl-1,2,3-

triazoles, which opened the door to access various N-alkyl-

substituted 1,2,3-triazoles rather than through available

CuAAC reaction with explosive and costly 2-azidopropane (1g,

> $600) as reaction parameter.

[a] Reaction conditions: 1a (0.24 mmol), 2g (0.2 mmol.), CuI (0.04 eq.),

Pd(PPh₃)₄(0.02 eq.), NaBH₄(0.5 eq.), Et₃N (0.5 mL), CH₃CN (1.5 mL),

60 °C, Ar (balloon), 4 h; Isolated yield.

Scheme 3. Scope of alkynes ^a.

Owing to the good generality of this three-component

reaction, we further investigated other nucleophilic reagent to

N-substituted 1,2,3-triazoles in one pot via generation of

functionalized 2-azidopropenes in situ. Amines with good

nucleophilicity were well extended to this cascade reaction by

replacing NaBH₄. It is noteworthy that the morpholine as

reaction parameter well tolerated the defined conditions to

provide the corresponding product 4a in 93% yield. The

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Scheme 5. Gram-scope reaction and further transformations.

Encouraged by these results, we subsequently

implemented control reactions for shedding light to the

mechanism of this cascade process. Apart from the isolation of

the desired product 3a, 2,4,6-tribromophenol could be

recovered after workup in 96% yield under the standard

reactions (Scheme 6, Eq.1). This result verified the cleavage

of the C(sp³)-OAr bond during the cascade reaction. Radical

scavenger studies were conducted in an effort to find evidence

of radical species. When the additive such as 2,6-di-tert-butyl-

4-methylphenol (BHT) or 2,2,6,6-tetramethylpiperidinooxy

(TEMPO) was added as radical scavengers in the reaction, the

tandem course proceeded well and generated product 3a in

83% and 80% yield, respectively (Scheme 6, Eq. 2). This

indicated that ionic pathway was prior over the radical pathway

in the standard reaction process. To illuminate the fracture

sequence of C(sp³)-OAr bond, we performed the cascade

reaction using the reactant 9 as substrate under the optimal

conditions. Yet the desired product 3a was not observed after

4 h and 100% of 9 was recovered. This showed that the C(sp³)-

OAr bond cleavage for 2-azidopropene was in preference to

click reaction under the standard conditions. When 2.0 eq. D₂O

was added to the reaction under the optimalized conditions,

deuterium-incorporated product 3a-D was obtained with a 34%

of D/H ratio at the triazole ring. Not surprisingly, 1a-D as

reaction partner was allowed to the targeted product 3a/3a-D

in 88% total yield with a deuterium content of 23%. The two

results implied that the click reaction underwent through the

previous process^13band both H₂O and the substrate 1a did not

provide hydrogen source for constructing methyl group of

targeted product 3. We suspected that NaBH₄in the reaction

system offered hydrogen atom for the methyl group of 2-

azidopropene. We then introduced NaBD₄into the cascade

reaction and isolated the product 3a-D’ with a deuterium

content of 85% on methyl group. This finding was further

confirmed that NaBH₄was the hydrogen source for assembling

methyl group in the desired product 3.

Scheme 6. Mechanistic investigations.

On the basis of the control results and former

investigations^12,13b,17, a probable mechanism for the cascade

reaction was depicted in Scheme 7. Initially, the Pd⁰(PPh₃)₄

catalyst underwent ligand dissociation and formed the dual-

ligand palladium species A, which proceeded oxidative

addition with 2g to generate the key cationic π-

allylpalladium(II) complex B. Subsequently, NaBH₄(HNR₂)

served as the nucleophile to react with intermediate B by

delivering the intermediate D in situ and deallylated complex

C. TBBOH could be recovered after the workup. In the

meantime, the activation of alkynes 1 was by formation of Cu(I)

acetylides E from substrate 1 and Cu(I). Eventually, 2-

azidopropene intermediate D without any isolation occurred

the subsequent cyclization reaction with the active species E

for preparation of Cu(I) triazolides F, which underwent site-

selective protonation to release the final product 3(4) and

regenerated the copper(I) catalyst.

Scheme 7. Possible mechanism for the reaction.

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Conclusions

ZR2018JL008) and the China Postdoctoral Science Foundation

(2017M610442).

In conclusion, we have disclosed a mild and efficient tandem

reaction for the formation of new-type N-isopropenyl 1,2,3-

triazoles from safe and easy-to-handle reagents. This reaction

process involves in situ generation of explosive 2-azidopropenes

by artful cleavage of C(sp³)-OAr bond, which subsequently

participate in the click reaction for the unique 1,2,3-triazole

skeleton by eliminating tedious isolation. This one-pot protocol is

successfully achieved with broad substrate scope and good

functional-group compatibility and readily costeffective substrates.

This reaction enables an ideal and efficient strategy to convey

volatile 2-azidopropenes under mild reaction conditions for the

first time, which erases the explosive danger of vinyl azides to

furnish 1,2,3-triazole scaffolds. Their synthetic application has

been demonstrated by gram-scope reaction and secondary

modifications for useful molecules. Meanwhile, a possible

reaction pathway is tentatively proposed based on our preliminary

tests and previous literatures. Further applications will facilitate a

broad set of potential building blocks for the development of

pharmaceuticals and new materials.

Keywords: bimetal-catalyzed • vinyl azides • alkynes •1,2,3-

triazoles

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Experimental Section

Typical synthetic procedure for the synthesis 3 (with 3a as an

example): To a schlenk tube was added phenylacetylene (1a, 0.027 mL,

0.24 mmol), (2g, 82.4 mg, 0.2 mmol), NaBH₄(3.8 mg, 0.1mmol),

Pd(PPh₃)₄(4.7 mg, 0.004 mmol) , CuI (1.5 mg, 0.008 mmol) ,CH₃CN (1.5

mL) and Et₃N (0.5 mL). Then the tube was charged with Ar (1 atm), and

was stirred at 60 ^oC (oil bath temperature) for the indicated time (about 4

h) until complete consumption of starting material as monitored by TLC.

The resulting reaction mixture was cooled to room temperature and taken

up by dichloromethane (3 × 15 mL). The organic layer was dried over

MgSO₄, and concentrated under reduced pressure. The crude product was

further purified by flash column chromatography (silica gel) using

petroleum ether/ethyl acetate as an eluent and concentration in vacuo

afforded 3a in 91% yield.

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Typical synthetic procedure for the synthesis 4 (with 4a as an

example): To a schlenk tube was added phenylacetylene (1a, 0.027 mL,

0.24 mmol), (2g, 82.4 mg, 0.2 mmol), morpholine (0.035 mL, 0.4 mmol),