Multicomponent Reaction-Based Heteroannulations: A Direct Access to Fused Tetrazolo Piperazinones and 1,4-Diazepanones

Abstract

By exploiting the chemistry of bifunctional isocyanides, straightforward, rapid, and scalable Ugi-tetrazole-based multicomponent reaction heteroannulations were developed. Our synthetic approach provides a series of diverse fused tetrazolo piperazinones and 1,4-diazepanones in just one step.

Key words

isocyanides - tetrazoles - piperazinones - diazepanones - Ugi reaction - multicomponent reaction

Despite the emergence of various hit-generating technologies through the application of artificial intelligence, high-throughput screening of small molecules is still the cornerstone of drug development, not only in major pharmaceutical companies, but also in public–private partnerships, such as the European Lead Factory consortium.[1] [2] The need to compile a library of compounds for such purposes in a ‘smart’ and efficient way is of outmost importance.[3] There has been considerable discussion and analysis of what makes a good library, but it is generally accepted that it should consist of sufficiently diverse druglike scaffolds with an intermediate level of complexity, as those factors should permit sustainable structure–activity relationship studies.[4] All these factors, when taken into account along with the calculated huge chemical space (10⁶⁰) and the fact that the chemical space of purchasable compounds has been growing by approximately twofold every 2.5 years since 1990, render efficient synthetic approaches toward such libraries a priority.[5] [6]

Nitrogen-containing heterocycles or azaheterocycles have a prominent place in drug design and development because they imitate several endogenous metabolites and natural products. It is not surprising that approximately 75% of drugs approved by the U.S. Food and Drug Administration (FDA) are nitrogen-containing heterocycles.[7] [8] Ketopiperazines[9–19] and 1,4-diazepanones[20–24] (six and seven-membered rings, respectively) are some of the most common azaheterocycles in FDA-approved pharmaceuticals, known for their excellent biological activity.[18] [25] [26] [27] [28] [29] [30] Prominent FDA-approved ketopiperazines include praziquantel (1, Biltricide) for schistosomiasis, dihydroergotamine (2, Migranal) for acute migraines, dolutegravir (3, Tivicay), and bictegravir (4, Biktarvy) for HIV infection. Representative examples of fused diazepinones include diazepam (5, Valium), lorazepam (6, Ativan), clonazepam (7, Klonopin), and temazepam (8, Restoril) for anxiety disorders, insomnia and seizures (Figure [1]).[31] [32]

Figure 1 FDA-approved fused ketopiperazine and 1,4-diazepanone drugs

The 1,5-tetrazole moiety has a prominent place in medicinal chemistry due to the significant improvement in physicochemical properties that offers and its bioisosterism with carboxylic acids and cis-amides.[33] Consequently, Hulme and co-workers,[34] utilized a Ugi tetrazole four-component reaction (UT-4CR), with reactants including an oxo component and methyl isocyanoacetate, for the solution-phase synthesis of fused tetrazole ketopiperazines,[35] [36] expanding on his group’s researches on the synthesis of diketopiperazines through isocyanide-based multicomponent reactions (IMCRs).[37] [38] An automated 1536-well-plate nanoscale synthesis based on this work has also been reported.[39] In 2015, the Dömling group[40] described a two-step synthesis of tetrazole-fused ketopiperazines, as potential bioisosteres to epelsiban, by two sequential Ugi four-component reactions (U-4CRs); later, the same group investigated the use of ammonia in syntheses of N-unsubstituted tetrazolopiperidinones.[41] Additionally, the use of mono-Boc-protected hydrazine has been employed in an UT-4CR approach to isolate a series of aminotetrazolopyrazinones and tetrazolotriazepinones in a one-pot fashion under acidic conditions (Figure [2]).[42]

Figure 2 Representative reported examples of tetrazolo piperazinones and diazepanones

Regarding access to fused tetrazolobenzodiazepines, Hulme and co-workers,[43] disclosed a one-pot two-step approach using an N-Boc-amino aldehyde, a secondary amine, methyl isocyanoacetate, and trimethylsilyl azide to afford the desired bicyclic scaffolds. An IMCR-based synthesis of tetrazolodiazepines has also been demonstrated by Nayak and Batra,[44] starting from Baylis–Hillman adducts of acrylates, and by the Voskressensky group,[45] employing o-aminobenzoate-derived isocyanides. In 2014, the Dömling group used primary amines and cyclic ketones in a UT-4CR to give an intermediate tetrazole core, which subsequently gave the desired tetrazolo[1,5-a][1,4]benzodiazepine derivatives by an ester hydrolysis/amide-bond-formation protocol (Figure [2]).[46]

In continuation to our interest in bifunctional isocyanides,[47] [48] we employed the ethyl isocyanoalkanoates 9a and 9b and the ethyl isocyano(het)arylcarboxylates 9c and 9d as versatile building blocks, exploiting both their -NC and -CO₂Et functionalities (Scheme [1]). Our aim was to apply a UT-4CR to provide easy and direct access to fused tetrazolo-1,4-diazepinones and tetrazolopiperazinones as a screening deck for future high-throughput screening. In addition, it would be beneficial to develop a truly multicomponent reaction (MCR) without isolating the intermediate UT adduct, unlike most examples reported in the literature.

Scheme 1 (A) Suitably bifunctionalized isocyanides employed for heteroannulations; (B) The UT-5C-4CR towards tetrazolo bi- and tricyclic 1,4-diazepinones and piperazinones.

We discovered that by heating an aldehyde, a primary amine, and a bifunctional isocyanide 9a–d with TMSN₃ in the presence of Et₃N under mild conditions (40 °C, 48 h), we readily obtained the required tetrazolo-1,4-diazepinones and tetrazolopiperazinones 10a–k (Scheme [1]). The reaction affords these scaffolds directly, without the need to isolate the intermediate UT adduct, through a Ugi-tetrazole four-component five-center reaction (UT-4C-5CR). A variety of aliphatic (10a, 10f, 10h) and aromatic aldehydes (10c, 10d, 10i) were employed, with good tolerance to a range of functional groups, e.g. cyclopropyl, amino, or ester. Esters of glycine and l-alanine were chosen as the amine component, as they provide additional hydrogen-bond donors or/and acceptors, potentially creating bifurcated hydrogen-bond acceptor patterns with the participation of the carbonyl group of the amide. Furthermore, these groups can serve as handles for subsequent modifications: the resulting scaffolds could be hydrolyzed and used as acids, either in additional MCRs[49] or in classical transformations. Aliphatic amines also reacted nicely (10g), whereas anilines reacted sluggishly. All the isocyanides, which are the key components, reacted smoothly and by tweaking their structure or length, afforded either bi- or tricyclic 1,4-diazepinones or piperazinones, demonstrating the potential of this synthetic strategy. Basic conditions (Et₃N; 2 equiv) are essential for the synthesis, and the reaction proved scalable; for example, the synthesis of 10c was scaled up to 5 mmol.

Figure 3 (A) Calculated properties of the synthesized compounds 10, fulfilling the criteria for the Ro5; (B) Cheminformatics features of druglikeness, shape index, and molecular flexibility, as calculated by using DataWarrior software.

To profile those scaffolds and to obtain some initial insights into what a possible screening deck might look like, we calculated several of their physicochemical properties, such as their molecular weight, lipophilicity, hydrogen-bond acceptor (HBA) or donor (HBD) parameters, number of rotatable bonds, and the polar surface area, by using DataWarrior software [see the Supporting Information (SI)]. All of our compounds obey the rule of five [Ro5, (HBD ≤ 5, HBA ≤ 10, ClogP ≤ 5, MW ≤ 500)], as shown in the radar graph in Figure [3]A.[50] [51] Moreover, we calculated some additional chemoinformatic features such as druglikeness, shape index, and molecular flexibility (Figure [3]B). Our compounds were calculated to have a balance between a spherical and a linear shape (~0.5) with average flexibility (see the SI).

In addition, by using the Cambridge Crystallographic Data Centre (CCDC) software suite, we were able to generate full interaction maps (FIMs) of two compounds, interpreting the basis of their pharmacophore (Figure [4]). FIMs represent regions with a higher probability of finding interactions with certain functional groups, generating a 3D interaction map. Thus, for 10c and 10j, the acceptor and donor probe maps (the red and blue contours, respectively) are depicted. The highest probability acceptor regions are mainly wrapped around the free amino group, whereas the blue regions are localized around the carbonyl groups. For 10j, a bifurcated HBA is expected (Figure [4]).

Figure 4 Full interaction maps of 10c (A) and 10j (B), revealing their donor and acceptor regions as calculated by using the CCDC software suite

To summarize, we have synthesized a representative library of fused tetrazolo-1,4-diazepinones and tetrazolopiperazinones in moderate to good yields from the appropriate bifunctionalized isocyanides.[52] [53] Our approach is based on a Ugi-tetrazole four-component five-center reaction that proceeds under mild conditions and is scalable and straightforward. Certain chemoinformatic and topological features were calculated to give a preliminary evaluation of this library.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

• 1 Dandapani S, Rosse G, Southall N, Salvino JM, Thomas CJ. Curr. Protoc. Chem. Biol. 2012; 4: 177
• 2 van Vlijmen H, Ortholand J.-Y, Li VM.-J, de Vlieger JS. B. Drug Discovery Today 2021; 26: 2406
• 3 Saha A, Varghese T, Liu A, Allen SJ, Mirzadegan T, Hack MD. J. Chem. Inf. Model. 2018; 58: 2057
• 4 Wigglesworth MJ, Murray DC, Blackett CJ, Kossenjans M, Nissink JW. M. Curr. Opin. Chem. Biol. 2015; 26: 104
• 5 Dahlin JL, Walters MA. Future Med. Chem. 2014; 6: 1265
• 6 Glick M, Jacoby E. Curr. Opin. Chem. Biol. 2011; 15: 540
• 7 Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
• 8 Amin A, Qadir T, Sharma PK, Jeelani I, Abe H. Open Med. Chem. J. 2022; 16: e187410452209010
• 9 Procopiou PA, Ancliff RA, Bamford MJ, Browning C, Connor H, Davies S, Fogden YC, Hodgson ST, Holmes DS, Looker BE, Morriss KM. L, Parr CA, Pickup EA, Sehmi SS, White GV, Watts CJ, Wilson DM, Woodrow MD. J. Med. Chem. 2007; 50: 6706
• 10 Powell NA, Ciske FL, Clay EC, Cody WL, Downing DM, Blazecka PG, Holsworth DD, Edmunds JJ. Org. Lett. 2004; 6: 4069
• 11 El Kaim L, Gageat M, Gaultier L, Grimaud L. Synlett 2007; 500
• 12 Hulme C, Peng J, Louridas B, Menard P, Krolikowski P, Kumar NV. Tetrahedron Lett. 1998; 39: 8047
• 13 Hulme C, Cherrier M.-P. Tetrahedron Lett. 1999; 40: 5295
• 14 Hulme C, Ma L, Kumar NV, Krolikowski PH, Allen AC, Labaudiniere R. Tetrahedron Lett. 2000; 41: 1509
• 15 Abelman MM, Fisher KJ, Doerffler EM, Edwards PJ. Tetrahedron Lett. 2003; 44: 1823
• 16 Gellerman G, Hazan E, Kovaliov M, Albeck A, Shatzmiler S. Tetrahedron 2009; 65: 1389
• 17 Vaňková B, Brulíková L, Wu B, Krchňák V. Eur. J. Org. Chem. 2012; 5075
• 18 Ben Haj Salah K, Legrand B, Bibian M, Wenger E, Fehrentz J.-A, Denoyelle S. Org. Lett. 2018; 20: 3250
• 19 Wang W, Ollio S, Herdtweck E, Dömling A. J. Org. Chem. 2011; 76: 637
• 20 Pérez-Martín C, Rebolledo F, Brieva R. Adv. Synth. Catal. 2022; 364: 1326
• 21 Biftu T, Feng D, Qian X, Liang G.-B, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Scapin G, Patel S, Gao Y.-D, Singh S, Wu J, Zhang X, Thornberry NA, Weber AE. Bioorg. Med. Chem. Lett. 2007; 17: 49
• 22 Mravljak J, Monasson O, Al-Dabbagh B, Crouvoisier M, Bouhss A, Gravier-Pelletier C, Le Merrer Y. Eur. J. Med. Chem. 2011; 46: 1582
• 23 Gravier-Pelletier C, Charvet I, Le Merrer Y, Depezay J.-C. J. Carbohydr. Chem. 1997; 16: 129
• 24 Wang S, Wang S, Song S, Gao Q, Wen C, Zhang Z, Zheng L, Xiang J. J. Org. Chem. 2021; 86: 6458
• 25 Medda F, Martinez-Ariza G, Hulme C. Tetrahedron Lett. 2015; 56: 5295
• 26 Staniszewska M, Zdrojewski T, Gizińska M, Rogalska M, Kuryk Ł, Kowalkowska A, Łukowska-Chojnacka E. Eur. J. Med. Chem. 2022; 230: 114060
• 27 Farhid H, Khodkari V, Nazeri MT, Javanbakht S, Shaabani A. Org. Biomol. Chem. 2021; 19: 3318
• 28 Lecointre B, Narozny R, Borrello MT, Senger J, Chakrabarti A, Jung M, Marek M, Romier C, Melesina J, Sippl W, Bischoff L, Ganesan A. Philos. Trans. R. Soc., B 2018; 373: 20170364
• 29 Hulme C, Ma L, Cherrier M.-P, Romano JJ, Morton G, Duquenne C, Salvino J, Labaudiniere R. Tetrahedron Lett. 2000; 41: 1883
• 30 Shi L, Wen M, Li F. Chin. J. Chem. 2021; 39: 317
• 31 Heravi MM, Zadsirjan V. RSC Adv. 2020; 10: 44247
• 32 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 33 Neochoritis CG, Zhao T, Dömling A. Chem. Rev. 2019; 119: 1970
• 34 Nixey T, Kelly M, Hulme C. Tetrahedron Lett. 2000; 41: 8729
• 35 Akritopoulou-Zanze I, Gracias V, Djuric SW. Tetrahedron Lett. 2004; 45: 8439
• 36 Umkehrer M, Kolb J, Burdack C, Ross G, Hiller W. Tetrahedron Lett. 2004; 45: 6421
• 37 Hulme C, Morrissette MM, Volz FA, Burns CJ. Tetrahedron Lett. 1998; 39: 1113
• 38 Dömling A, Huang Y. Synthesis 2010; 2859
• 39 Gao L, Shaabani S, Reyes Romero A, Xu R, Ahmadianmoghaddam M, Dömling A. Green Chem. 2023; 25: 1380
• 40 Zarganes-Tzitzikas T, Patil P, Khoury K, Herdtweck E, Dömling A. Eur. J. Org. Chem. 2015; 2015: 51
• 41 Patil P, Kurpiewska K, Kalinowska-Tłuścik J, Dömling A. ACS Comb. Sci. 2017; 19: 343
• 42 Wang Y, Patil P, Kurpiewska K, Kalinowska-Tłuścik J, Dömling A. ACS Comb. Sci. 2017; 19: 193
• 43 Nixey T, Kelly M, Semin D, Hulme C. Tetrahedron Lett. 2002; 43: 3681
• 44 Nayak M, Batra S. Tetrahedron Lett. 2010; 51: 510
• 45 Borisov RS, Polyakov AI, Medvedeva LA, Khrustalev VN, Guranova NI, Voskressensky LG. Org. Lett. 2010; 12: 3894
• 46 Yerande SG, Newase KM, Singh B, Boltjes A, Dömling A. Tetrahedron Lett. 2014; 55: 3263
• 47 Fragkiadakis M, Anastasiou P.-K, Zingiridis M, Triantafyllou-Rundell ME, Reyes Romero A, Stoumpos CC, Neochoritis CG. J. Org. Chem. 2023; 88: 12709
• 48 Fragkiadakis M, Neochoritis CG. Synlett 2022; 33: 1913
• 49 Zarganes-Tzitzikas T, Chandgude AL, Dömling A. Chem. Rec. 2015; 15: 981
• 50 Lipinski CA. Drug Discovery Today: Technol. 2004; 1: 337
• 51 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Adv. Drug Delivery Rev. 2001; 46: 3
• 52 Ugi-Tetrazole Four-Component Synthesis of 10a–k; General Procedure The aldehyde (1.0 mmol) was added to a stirred solution of the amine (1.0 mmol) and Et₃N (1.0 mmol) in MeOH (1.0 mL), and the mixture was stirred for 10 min. The isocyanide 9 (1.0 mmol) and TMSN₃ (1.0 mmol) were then added, and the mixture was stirred vigorously for 48 h at 40 °C. The solvent was removed under reduced pressure, and the residue was purified by column chromatography [silica gel, PE–EtOAc (5:1 to 1:1)].
• 53 Ethyl 3-(4-Cyclopropyl-9-methyl-6-oxo-4H-tetrazolo[1,5-a]thieno[2,3-f][1,4]diazepin-5(6H)-yl)propanoate (10a) Yellow oil; yield: 157 mg (51%). ¹H NMR (500 MHz, CDCl₃): δ = 7.37–7.33 (d, J = 19.5 Hz, 1 H), 4.10–4.06 (m, 1 H), 3.70–3.68 (d, J = 7.5 Hz, 3 H), 3.64–3.61 (d, J = 12.9 Hz, 2 H), 3.15–3.12 (m, 1 H), 2.45–2.43 (m, 1 H), 2.34–2.30 (m, 1 H), 2.00–1.94 (d, J = 16.1 Hz, 3 H), 1.13–0.95 (m, 1 H), 0.63–0.47 (m, 1 H), 0.33–0.31 (m, 1 H), 0.15–0.13 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 173.0, 160.1, 158.6, 157.8, 136.9, 134.1, 127.2, 60.5, 58.1, 52.7, 51.7, 43.0, 34.6, 15.6, 13.3, 4.3, 3.3, 2.9. HRMS (ESI): m/z [M + CH₃OH]⁺ calcd for C₁₇H₂₃N₅O₄S: 394.1514; found: 394.1547. Ethyl [8-(4-Chlorophenyl)-6-oxo-5,6-dihydrotetrazolo[1,5-a]pyrazin-7(8H)-yl]acetate (10i) Yellow oil; yield: 162 mg (57%). ¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.40 (m, 2 H), 7.26–7.25 (m, 2 H), 6.13 (s, 1 H), 5.31–5.26 (m, 2 H), 4.75–4.71 (d, J = 17.5 Hz, 1 H), 4.19–4.17 (m, 2 H), 3.54–3.50 (d, J = 17.5 Hz, 1 H), 1.26–1.24 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 167.6, 161.6, 149.6, 136.1, 132.9, 129.9, 128.9, 61.9, 57.3, 47.8, 45.9, 13.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₅ClN₅O₃: 336.0842; found: 336.0856.

Publication History

Received: 11 December 2023

Accepted after revision: 05 January 2024

Accepted Manuscript online:
05 January 2024

Article published online:
07 February 2024