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Synthesis of Diverse Nitrogen Heterocycles Explored in Denitrogenative Transformations

Monalisa Akter and Pazhamalai Anbarasan

Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India

1.1 Introduction

Nitrogen heterocycles are extensively present in numerous drug molecules which manifest potent therapeutic activities such as antibacterial, anticancer, antiallergic, potassium-channel activator, antiplatelet, glucosidase, and HIV-1 reverse transcriptase inhibitory activities (Figure 1.1) [1].

Beside living in the core of biologically active molecules, N-heterocycles can act as ligands as well as directing groups in various transition metal catalysis. Importantly, polynitrogen heterocycles can participate in various fruitful transformations that pave the way to access structurally complex molecules of biological importance (Figure 1.2). In this context, N-sulfonyl-1,2,3-triazole and its analogs have been exclusively exploited as safe-to-handle diazo surrogates in various denitrogenative transformations. These methods yield a diverse range of structural motifs to facilitate structural modification and total synthesis of natural products and drug molecules [2–4]. Over a period of time, denitrogenative transformations of some related heterocycles such as 5-iodotriazoles [5], F-containing triazoles [6–8], tetrazoles [9, 10], pyridotetrazoles [11], and aminoindazoles [12] have also been explored and established as efficient synthetic tools.

Consequently, easily accessible, atom-economical, and widely compatible synthetic methodologies to access these diverse N-heterocycles are highly desirable. This chapter briefly showcases the development of such primitive to advanced synthetic methodologies to serve the aforementioned purposes.

1.2 Synthesis of 1,2,3-Triazoles

1.2.1 Synthesis of NH-Triazoles

NH-triazole is one of the polynitrogen heterocycles that undergoes denitrogenative transformation and their recent development emphasized its importance as a building block and their elegant synthesis. Initially, NH-triazoles were prepared via the deprotection of various N-protected triazoles. In this context, various organic azides with removable protecting groups such as benzyl [13], tropylium [14], trimethylsilyl [15, 16], tosyl [17, 18], (trimethylsilyl)ethoxymethyl (SEM) [19], and p-methoxybenzyl [20] azides have been explored along with sodium azide [21, 22]. Later, Sharpless and co-workers [23] introduced three more organic azides, azidomethyl pivalate, azidomethyl morpholine-4-carboxylate, and azidomethyl N,N-diethylcarbamate, which deliver a base-labile N-protected triazole (Scheme 1.1).

Figure 1.1 Representative drug molecules containing N-heterocycles.

Figure 1.2 Representative drug molecules and natural products synthesized through denitrogenative transformations.

Scheme 1.1 Synthesis of NH-triazoles via N-protected triazoles.

Source: Adapted from Sharpless [23].

In 1989, Banert [24] demonstrated an efficient strategy to synthesize NH-triazoles from propargyl azides under mild conditions (Scheme 1.2). Mechanistically, propargyl azide 1.2b is obtained by treatment of propargyl halide 1.2a with sodium azide, which undergoes a [3, 3]-sigmatropic rearrangement to generate the reactive allenyl azides 1.2c that readily cyclizes to triazafulvene intermediate 1.2d. Finally, the intermediate 1.2d is trapped by various nucleophiles to afford corresponding triazole 1.2e.

Scheme 1.2 Synthesis of NH-triazoles by using Banert cascade.

Source: Adapted from Banert [24].

Despite its high reliability and wide substrate scope, its synthetic utility was hardly explored. In 2005, Sharpless and co-workers [25] exclusively studied this pathway to access diverse NH-triazoles and expanded the scope of nucleophiles involved in the process (Scheme 1.3). Recently, Topczewski and co-workers [26] exploited silver(I) fluoride as nucleophile, which facilitated access to α-fluorinated NH-1,2,3-triazoles 1.3e in excellent yields.

Scheme 1.3 Synthesis of diverse NH-triazoles.

In 2016, Dehaen and co-workers [27] disclosed the synthesis of various mono-, di-, and tri-substituted triazoles 1.4c from the reaction of enolizable ketones 1.4a, NH4OAc, and nitrophenyl azide 1.4b under mild acidic condition (Scheme 1.4). Simultaneously, a β-cyclodextrin-mediated multicomponent synthesis of NH-triazoles 1.4e from propynals 1.4d, trimethylsilyl azide, and malononitrile in water was reported by Medvedeva and co-workers [28]. Besides, the use of amine in place of malononitrile under microwave irradiation furnished the imine-substituted triazole with a shorter reaction time [29]. Subsequently, Guan and co-workers [30–33] accomplished the synthesis of various 4-aryl-NH-1,2,3-triazoles 1.4g through three-component reaction of aldehydes 1.4f, nitromethane, and NaN3. Later, Negrón-Silva and co-workers [34] developed a heterogeneous catalytic system consisting of Al-MCM-41 and sulfated zirconia to accomplish the same synthesis.

Scheme 1.4 Synthesis of NH-triazoles through three-component reactions.

In 2019, Shu and Wu reported a molecular iodine-mediated cascade [4 + 1] cyclization of N-tosylhydrazones 1.5a and sodium azide in presence of MsOH to access 4-aryl-NH-1,2,3-triazoles 1.5b (Scheme 1.5) [35]. Subsequently, the group of Gao and Shu achieved the synthesis of 4-aryl-NH-1,2,3-triazoles 1.5d via an iodine-mediated condensation-cyclization of α-azido ketones 1.5c with p-toluenesulfonyl hydrazide [36]. Recently, Wu and co-workers demonstrated the synthesis of NH-triazole under azide-free conditions via an iodine-mediated [2 + 2 + 1] cyclization of methyl ketones 1.5e, p-toluenesulfonyl hydrazide, and 1-aminopyridinium iodide 1.5f [37]. Solvent-free synthesis of 4-aryl-NH-1,2,3-triazoles 1.5i has been demonstrated by Matsugi and co-workers [38] from benzyl ketones 1.5h exploiting diphenyl phosphorazidate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Scheme 1.5 Synthesis of 4-aryl-NH-1,2,3-triazoles.

Catalyst-free synthesis of 4-acyl-NH-1,2,3-triazoles 1.6b was reported by Wen and Wan, which involves water-mediated cycloaddition reactions of enaminones 1.6a and tosyl azide (Scheme 1.6) [39, 40]. Instead of enaminones, Gribanov et al. [41] employed alkylnitriles 1.6c and azide 1.6d in the presence of KOtBu for the synthesis of 5-amino-1,2,3-triazoles 1.6e, which on subsequent Dimroth rearrangement affords 1.6f at elevated temperature under solvent-free conditions in one pot.

Scheme 1.6 Synthesis of various NH-triazoles.

1.2.2 Synthesis of N-Sulfonyl-1,2,3-triazoles

For years, a large number of N-sulfonyl-1,2,3-triazoles have been extensively exploited as diazo surrogate in numerous denitrogenative transformations. In general, sulfonylation of NH-1,2,3-triazoles 1.7a with sulfonyl chlorides could furnish the corresponding N-sulfonyl-1,2,3-triazoles 1.7b (Scheme 1.7). But the major drawback of this strategy is the formation of a mixture of regioisomeric products 7.2 and 1.7c, which significantly reduces its efficiency and applicability [42].

Scheme 1.7 Synthesis of N-sulfonyl-1,2,3-triazoles from NH-triazoles.

Source: Adapted from Beryozkina and Fan [42].

On the other hand, 1,2,3-triazoles 1.8d were readily achieved through the copper-catalyzed azide-alkyne cycloaddition (CuAAC) as reported by Sharpless and co-workers in 2002 (Scheme 1.8) [43–45]. This reaction appeared to be the most effective click reaction over the traditional Huisgen cycloaddition due to its remarkably high regioselectivity and yields. Various 1,4-disubstituted triazoles 1.8d could be synthesized from terminal alkynes 1.8a and azides 1.8b (Scheme 1.8). However, the use of sulfonyl azides led to the formation of various secondary products 1.8g instead of the desired triazoles 1.8d via the generation of ketenimine intermediate 1.8f [46, 47]. The formation of ketenimine was due to the poor stability of the copper-triazole species 1.8c.

Scheme 1.8 Synthesis of N-sulfonyl-1,2,3-triazoles through CuAAC.

Source: Adapted from Sharpless [43].

To increase the stability of sulfonyl substituted 1.8c and for the synthesis of sulfonyltriazoles, in 2007, for the first time, Chang, Fokin...