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Synlett 2024; 35(13): 1557-1560
DOI: 10.1055/a-2216-4765
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Base-Promoted [3+2] Annulation of Carbodiimides with Diazoacetonitrile for Synthesis of 5-Amino-4-cyano-1,2,3-triazoles

Lu-Nan Zhou
a   Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, P. R. of China
,
Fa-Guang Zhang 
a   Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, P. R. of China
,
Chi Wai Cheung  ∗
a   Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, P. R. of China
,
Jun-An Ma∗
a   Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, P. R. of China
b   Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, Fuzhou 350207, P. R. of China
› Author Affiliations

This work was supported by the National Natural Science Foundation of China (Nos. 22271212, 22271216), the National Key Research and Development Program of China (No. 2019YFA0905100), and the Tianjin Municipal Science and Technology Commission (20JCYBJ00900) and the Graduate School of Tianjin University (Graduate Outstanding Innovation Award Program for Humanities and Sciences 2023 Year Project, Project Number: B1-2023-002).
› Further Information
 
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Abstract

1,2,3-Triazoles are a privileged class of heterocycles in medicinal and agrochemical science. Here, we describe the base-promoted [3+2] annulation of carbodiimides with diazoacetonitrile. This reaction protocol permits access to a variety of novel 5-amino-4-cyano-1,2,3-triazoles in a regiospecific manner. Further derivatization is exemplified by a skeletal rearrangement and an N-functionalization of triazole products.


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Key words

annulation - triazoles - [3+2] annulation - carbodiimides - diazoacetonitrile

1,2,3-Triazoles are privileged structural motifs in pharmaceuticals, agrochemicals, and materials science.[1] By installing transformable substituents, the resulting functionalized triazoles become open to multiple derivatizations, providing an enhanced chemical space for the development of structurally varied heterocycles, providing a broader synthetic utility.[2] Nitriles and amines are among the most versatile functional groups in organic synthesis. In this context, the [3+2] annulations[3] of azides with nitrile- or amine-based synthons have been widely developed to access a variety of cyano-[4] or amino-substituted[5] 1,2,3-triazoles (Scheme [1a], left). In stark contrast, access to cyano and amino co-substituted 1,2,3-triazoles remains underdeveloped (Scheme [1a], right), hinging on the [3+2] annulation of azides with malononitrile[6] (Scheme [1b]) or a nontrivial multistep synthesis based on the cyclization of 2,3-diaminomaleonitrile[7] (Scheme [1c]). Recently, carbodiimides have emerged as versatile synthons for the synthesis of amino heterocycles.[8] Notably, Zhang and co-workers harnessed carbodiimides and diazoacetate esters as annulation synthons to access a wide range of cyano- and carbo-substituted 1,2,3-triazoles.[9] Based on our interest and endeavors in the annulation chemistry of diazoacetonitriles to access cyano heterocycles,[10] [11] [12] we envisioned that the [3+2] annulation between carbodiimides 1 and diazoacetonitrile (2) might be achievable, affording the target cyano- and amino-substituted triazoles 3 (Scheme [1d]). Herein, we describe our findings on this alternative approach to a general synthesis of 5-amino-4-cyano-1,2,3-triazoles. This unexplored class of heterocycles further undergoes skeletal isomerization and peripheral-group modifications, as exemplified by viable elaborations of the amino- and cyano-based triazole entities.

Zoom Image
Scheme 1 Synthetic strategies toward cyano- and amino-substituted 1,2,3-triazoles

We commenced our study by using diphenylcarbodiimide (1a) and diazoacetonitrile (2) as the reaction substrates (Table [1]). Both inorganic (Table [1], entries 1–9) and organic (entries 10–12) bases promoted the annulation in acetonitrile as the solvent at room temperature, giving the target product 1-phenyl-5-(phenylamino)-1,2,3-triazole-4-carbonitrile (3a). Cs2CO3 and triethylamine were the optimal bases, affording 3a in ~70% yield (entries 4 and 10). When the reaction was performed at 0 °C, the yields were slightly elevated to ~75% (entries 13 and 14). Alternatively, by cooling a MeCN solution of 2 to 0 °C, followed by its addition to the mixture of 1a and base, the resulting mixture reacted at room temperature to afford 3a in 85% yield (entry 15). Presumably, 2 is more stable at 0 °C, and its decomposition is thus minimized, providing an improved conversion and productivity. Notably, the annulation reaction provided 3a as the sole product without other isomeric byproducts. The structure of 3a was confirmed by X-ray crystallographic analysis.[13]

Table 1 Optimization of [3+2] Annulation of Diphenylcarbodiimide (1a) with Diazoacetonitrile (2)a

Entry

Base

Temp (°C)

Yieldb (%)

 1

Li2CO3

rt

11

 2

Na2CO3

rt

35

 3

K2CO3

rt

31

 4

Cs2CO3

rt

69

 5

LiOH

rt

60

 6

NaOH

rt

67

 7

KOH

rt

46

 8

NaOAc

rt

19

 9

KOAc

rt

39

10

Et3N

rt

70

11

DBU

rt

19

12

DABCO

rt

55

13

Cs2CO3

0

75

14

Et3N

0

78

15

Cs2CO3

rtc

85

a Reaction conditions: 1a (0.4 mmol), 2 (0.8 mmol), base (0.6 mmol), MeCN (2 mL), rt, air atmosphere, 8 h.

b Isolated yield.

c The MeCN solution of 2 was precooled to 0 °C for addition to the reaction mixture of 1a and the base, and the resulting mixture was then warmed to rt for reaction.

The reaction proved to be general (Scheme [2]). A variety of symmetrical N,N′-diarylcarbodiimides 1a–j reacted with diazoacetonitrile (2) to afford the corresponding N-aryl-5-(arylamino)-4-cyano-1,2,3-triazoles 3a–j in generally moderate to high yields. Electron-neutral (1a), electron-donating (1b–f), and electron-withdrawing (1g–i) carbodiimides. as well as a sterically bulky carbodiimide (1j) were all suitable reaction substrates. Furthermore, unsymmetrical N-alkyl-N′-aryl carbodiimides (1k–s) underwent regioselective annulation, delivering N-aryl-1,2,3-triazoles 3k–s with butylamino (3k), benzylamino (3l and 3m), cyclopentylamino (3n and 3o), cyclohexylamino (3p and 3q), allylamino (3r), and propargylamino (3s) groups at the 5-position. When N,N′-dialkyl carbodiimide 1t was employed as the reaction partner, no annulation product was formed, probably due to the diminished electrophilicity of the corresponding N,N′-dialkyl carbodiimide (1t) to initiate the nucleophilic addition of diazoacetonitrile.

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Scheme 2 Scope of the [3+2] annulation of carbodiimides with diazoacetonitrile. Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), Cs2CO3 (0.6 mmol), MeCN (2 mL), rt, air atmosphere, 8 h. The MeCN solution of 2 was precooled to 0 °C for addition into the reaction mixture of 1 and Cs2CO3, and the resulting reaction mixture was then warmed to rt for the reaction.

The triazole products underwent transformations to afford new 1,2,3-triazoles and their derivatives (Scheme [3]). For examples, a Dimroth rearrangement of triazole 3m gave the new triazole isomer 4 in 77% yield.[14] Furthermore, the N-alkylation of 3a with ethyl bromoacetate delivered the triazole-containing α-amino acid ester 5 in 73% yield. These reactions showcase the potential elaboration of the cyano- and amino-substituted 1,2,3-triazoles to provide a wide range of structurally distinct triazoles for organic synthesis and drug discovery.

Finally, we proposed the plausible reaction mechanism shown in Scheme [4].[15] The resonance structure 2′ of diazoacetonitrile (2) bears a nucleophilic carbon center, which undergoes nucleophilic addition to the electrophilic carbon center of carbodiimide 1k to give the adduct intermediate Int-1. The proton of the α-C–H bond of Int-1 becomes more acidic and is readily deprotonated by carbonate to form the anionic species Int-2. Subsequently, Int-2′, a resonance hybrid of Int-2, is protonated by hydrogen carbonate to form Int-3, owing to the more-basic alkylamido moiety. Cyclization of Int-3, facilitated by the more electrophilic N-aryl imino moiety, eventually takes place to afford the target 4-cyano-N-phenyl-5-phenylamino-1,2,3-triazole product 3k. We speculated that another viable intermediate Int-3′ would bear a more-electron-rich N-alkyl imino moiety, thus disfavoring its cyclization to form the alternative regioisomeric product 3k′. This reaction mechanism probably dictates the regiospecific formation of the observed product 3k.

In conclusion, we have developed the base-promoted [3+2] annulation reaction of carbodiimides with diazoacetonitrile to give a variety of N-aryl-5-amino-4-cyano-1,2,3-triazoles regiospecifically.[16] This class of functionalized heterocycles, in association with their derivatives, could find potential applications in academic and industrial settings.

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Scheme 3 Chemical transformations of N-aryl-5-amino-4-cyano-1,2,3-triazoles
Zoom Image
Scheme 4 Proposed mechanism of the [2+1] annulation of carbodiimides with diazoacetonitrile

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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2216-4765.
  • Supporting Information

Corresponding Authors

Chi Wai Cheung
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University
Tianjin 300072
P. R. of China   

Jun-An Ma
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University
Tianjin 300072
P. R. of China   

Jun-An Ma
Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University
Binhai New City, Fuzhou 350207
P. R. of China   

Publication History

Received: 30 October 2023

Accepted after revision: 22 November 2023

Accepted Manuscript online:
22 November 2023

Article published online:
03 January 2024

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   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Synthetic strategies toward cyano- and amino-substituted 1,2,3-triazoles
Zoom Image
Scheme 2 Scope of the [3+2] annulation of carbodiimides with diazoacetonitrile. Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), Cs2CO3 (0.6 mmol), MeCN (2 mL), rt, air atmosphere, 8 h. The MeCN solution of 2 was precooled to 0 °C for addition into the reaction mixture of 1 and Cs2CO3, and the resulting reaction mixture was then warmed to rt for the reaction.
Zoom Image
Scheme 3 Chemical transformations of N-aryl-5-amino-4-cyano-1,2,3-triazoles
Zoom Image
Scheme 4 Proposed mechanism of the [2+1] annulation of carbodiimides with diazoacetonitrile