Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles

Abstract

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

1. Introduction

Multicomponent reactions are a powerful tool for synthesizing various pharmacologically relevant compounds [1,2,3] including peptidomimetics that play an essential role in the improvement of pharmacokinetic profiles [4]. Herein, we describe a one-pot synthesis of 3,4-dihydropyrazin-2(1H)-ones and other diverse heterocycles from Ugi advanced intermediates. An “advanced intermediate” is a substrate with two or three diversity positions that can be used to synthesize molecular scaffolds that are structurally unrelated [5]. Dihydropyrazinone scaffolds are attractive for both organic and medicinal chemists due to their wide range of biological activities. For example, praziquantel (I) (Figure 1), which contains a piperazinone ring, is used to treat schistosomiasis [6]. More complex derivatives, including marine alkaloids, (−)-dibromophakellstatin (II), and (−)-agelastatin A (III), exhibit antineoplastic [7] and antitumor effects [8]. Hamacanthin A (IV), another representative from a class of marine alkaloids, shows antifungal properties; it acts as a growth inhibitor of Candida albicans [9]. A related aromatic nitrogen heterocycle, pyrazin-2(1H)-one, is present in aspergillic acid (V), possessing antibacterial properties [10,11]; in addition, pyrazine-2(1H)-one is present in dragmacidin D (VI), in which the pyrazin-2(1H)-one ring is between two indole rings. Dragmacidin D, a bioactive marine natural product, selectively inhibits neural nitric oxide synthase in the presence of inducible nitric oxide synthase; thus, dragmacidin D is promising in the treatment of neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease [12,13,14,15].

Many protocols devoted to the traditional step-by-step synthesis of dihydropyrazinones have been published using both solid-phase synthesis [16,17,18] and solution-phase synthesis [19,20]. However, traditional step-by-step synthesis is often time-consuming and requires additional reagents for activation, expensive catalysts, etc. Multicomponent reactions (MCRs) are attractive due to their efficiency, atom and step economy, and simplicity [21,22]. MCRs are also very efficient for the synthesis of structurally complex compounds [23], which are important in the search for novel pharmacophores. Synthetic approaches utilizing MCRs that generate dihydropyrazinones and their derivatives are based on two-step procedures involving U-4CR and post-Ugi modifications. Cheng et al. prepared dihydropyrazinones using both solution- and solid-phase synthesis [24]. Different chemotypes derived from the pyrazin-2(1H)-one scaffold were achieved by the Ugi/deprotection/cyclization strategy [25]. Regarding saturated piperazinones, a new multicomponent approach via transition metal-catalyzed imine-directed amide N–H functionalization was described recently [26]. Concerning the fused heterocycles, regioselective formation of β- and γ-lactam-fused dihydropyrazinones was performed from the alkynoic acid-derived Ugi adducts [27]. Recently, pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones were synthesized via tandem post-Ugi cyclization and gold (I)-catalyzed regioselective annulation [28]. Another approach to generate fused heterocycles involved a two-step U-4CR/allenamide cycloisomerization, leading to 6-methyl-3,4-dihydropyrazinones that were further cyclized to pyrazino[2,1-a]isoindoles or pyrazino[2,1-a]isoquinolines [29]. Fused dihydropyrazin-2(1H)-ones were also obtained through a U-4CR/deprotection/intramolecular Heck coupling sequence [30].

Herein, the presented synthetic strategy is based on the U-4CR of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids (including N-protected amino acids), which is followed by a trifluoroacetic acid (TFA)-triggered tandem reaction. As a result, the aldehyde is unmasked and then cyclized to the target 3,4-dihydropyrazin-2(1H)-ones without isolating the Ugi advanced intermediate. Previously, analogous model compounds were synthesized on solid supports by elongating the peptide in a stepwise manner using traditional solid-phase peptide synthesis (Figure 2) [16]. Westbound cyclization was preferable, and eastbound cyclization occurred only when westbound cyclization was not possible or disfavored.

When N-protected amino acid was used as the carboxylic acid component, the carbon of the unmasked carbonyl group could be subsequently attacked by two different nitrogen atoms (of different functional groups, such as amide, carbamate, and amino group) of the peptide chain (Figure 2). Thus, the following routes are possible for cyclization: so-called westbound cyclization (toward the peptide amino terminus) and eastbound cyclization (toward the carboxy terminus) [16].

In addition to 3,4-dihydropyrazin-2(1H)-ones 2 and 3 (Scheme 1), we prepared other nitrogen-containing heterocyclic compounds from Ugi adducts. Deliberate selection of starting compounds, namely, carboxylic acids, provided access to diverse heterocycles, such as pyrazin-2(1H)-one 4, piperazin-2-one 5, and 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione 6. Transformation of common intermediates to products that evince skeletal, stereochemical, or appendage diversity, so-called diversity-oriented synthesis, plays an important role in the drug discovery process [31,32,33].

2. Results

The target 3,4-dihydropyrazin-2(1H)-ones and their derivatives were prepared by one-pot three-step cyclization of Ugi adduct 1 (Scheme 2). All four components of the Ugi reaction (isocyanide, aldehyde, masked amino aldehyde, and a carboxylic acid) were used in equimolar amounts and shaken in MeOH for 16 h. The resulting Ugi adduct 1 was further reacted without isolation. Ugi intermediate 1 was subsequently treated with 50% TFA in CH₂Cl₂, which resulted in a cascade reaction. The masked amino aldehyde was deprotected and intermediate 11 was cyclized to iminium salts 12 and 13, which were spontaneously transformed into 3,4-dihydropyrazin-2(1H)-ones 2 and 3, respectively.

Using simple commercially available building blocks, we designed and synthesized two different types of model compounds, 2 and 3 (Scheme 2). The first model compounds were prepared with carboxylic acids and did not have suitable nucleophiles for westbound cyclization (benzoic acid and p-nitrobenzoic acid). Therefore, the product of eastbound cyclization was formed (compound 2, Route I). Using N-Fmoc-protected α-amino acids (Fmoc-Gly-OH, Fmoc-Ala-OH, and Fmoc-Ser(t-Bu)-OH) as the carboxylic acid component, we introduced an amide into the substrate, and the westbound cyclization product was expectedly formed (compound 3, Route II). Following our previous results [16], the reaction was regioselective, and no eastbound product was detected. In contrast, the model compound prepared using Fmoc-β-Ala-OH provided the eastbound cyclization product because the formation of a six-membered eastbound ring was preferred rather than a potential seven-membered ring (compound 2, R’ = Fmoc–NH–(CH₂)₂–, Route I). When the N-Fmoc-protected α-amino acids were replaced by N-Boc derivatives (Boc-Pro-OH, Boc-Ser-OH, and Boc-Phe-OH), the TFA treatment also cleaved the Boc group and cyclization occurred between the liberated amino group and deprotected aldehyde. In those cases, cyclization of Ugi intermediate containing Boc-proline moiety resulted in the eastbound cyclization product (Route I), while cyclization of Ugi products with Boc-serine or Boc-phenylalanine moieties yielded westbound cyclization products (Route II).

Importantly, the reaction outcome was determined by the character of the amino acid protecting group (Scheme 3). The Ugi reaction of isocyanide, p-nitrobenzaldehyde, aminoacetaldehyde dimethyl acetal, and Fmoc-Ser(t-Bu)-OH yielded adduct 1c, which upon treatment with 50% TFA/CH₂Cl₂ resulted in N-Fmoc-protected 3,4-dihydropyrazin-2(1H)-one 3c. In contrast, U-4CR involving Boc-Ser-OH afforded adduct 1a. Reaction with 50% TFA/CH₂Cl₂ caused not only deprotection of the acetal, but also cleavage of the acid-labile Boc-protecting group (intermediate 11a). Subsequent cyclization led to iminium salt 13a, which underwent TFA-mediated dehydration to 14a. Finally, spontaneous aromatization via a 1,5-hydrogen shift afforded the appropriate pyrazin-2(1H)-one 4a.

In addition, we tested two other Boc-protected amino acids, Boc-Phe-OH and Boc-Pro-OH. Boc-Phe-OH was utilized for the preparation of two different heterocycles. Ugi reaction of Boc-Phe-OH with benzyl isocyanide, p-nitrobenzaldehyde, and aminoacetaldehyde dimethyl acetal afforded the anticipated intermediate 1b (Scheme 4), which was split into two portions. After the volatile substances were evaporated by a stream of nitrogen, the Ugi adduct was treated with two different solutions for subsequent transformations. TFA/CH₂Cl₂ (1:1) solution was added to the first portion. LC/MS revealed the formation of olefin intermediate 3b. The solution was then evaporated by a stream of nitrogen, and DMSO was added for 16 h, which resulted in the formation of an oxidized product, pyrazin-1(2H)-one 4b. The second part of Ugi adduct 1b was reduced to the appropriate saturated derivative, piperazin-2-one 5a, by treatment with TFA/triethylsilane (TES)/CH₂Cl₂ (5:1:4) [17]. This reagent-based approach represents westbound cyclization.

Another example of the application of Boc-protected amino acids is the reaction with Boc-Pro-OH (Scheme 5). Considering the reaction outcome with Boc-Ser-OH and Boc-Phe-OH (Scheme 3 and Scheme 4), we expected a fused ring system to form via westbound cyclization (structure 16g, Scheme 5). However, cyclization did not follow this route and 6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-1(2H)-one 16g was not formed, probably because the conformationally demanding fused ring system was avoided. Instead, cyclization occurred toward the amidic nitrogen, and 4-prolyl-3,4-dihydropyrazin-2(1H)-one 2g was formed as a result of eastbound cyclization.

Unexpected but very interesting results were obtained with anthranilic acid as the carboxylic acid component. Unlike the reaction with Fmoc-β-Ala-OH, which yielded dihydropyrazinone 2f (Table 1), anthranilic acid provided a bridged heterocycle via tandem N-acyliminium ion cyclization–nucleophilic addition [34,35,36]. We reported analogous reactions on unrelated substrates on several occasions for fused [16,37,38,39,40,41] and bridged heterocycles [42].

Herein, we showed the formation of a bridged scaffold using a combination of n-butyl isocyanide, p-nitrobenzaldehyde, aminoacetaldehyde dimethyl acetal, and anthranilic acid, which afforded Ugi adduct 1d. This adduct underwent subsequent cyclization to bridged 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione 6a (Scheme 6). This product was a mixture of two enantiomers due to diastereoselective formation of the bridgehead chiral carbon. We expect that eastbound cyclization occurred first [43], as indicated in the scheme. However, we cannot discount an alternative reaction mechanism that first involves formation of the seven-membered ring and which is then followed by bridge ring formation.

Note that, in addition to various carboxylic acids, we tested different isocyanides and aldehydes for their compatibility with the designed synthetic routes. We chose benzyl isocyanide, n-butyl isocyanides, and p-toluenesulfonylmethyl isocyanide. However, the latter isocyanide reacted sluggishly in combination with benzoic acid, p-nitrobenzaldehyde, and aminoacetaldehyde dimethyl acetal. Even after three days, the reaction mixture contained a majority of a Schiff base (62%; based on LC/MS analysis). We further did not optimize the reaction. Concerning aldehydes, we tested unsubstituted benzaldehyde, p-nitrobenzaldehyde, p-cyanobenzaldehyde, and p-(dimethylamino)benzaldehyde. The first two mentioned aldehydes were compatible with all tested reactions, while p-cyanobenzaldehyde and p-(dimethylamino)benzaldehyde evinced some limitations. Target product 2b (Table 1) was afforded in 90% crude HPLC purity when p-cyanobenzaldehyde was reacted with benzyl isocyanide, benzoic acid, and aminoacetaldehyde dimethyl acetal and underwent TFA-mediated cyclization. However, when benzoic acid was replaced with Fmoc-β-Ala-OH, the Ugi reaction with p-cyanobenzaldehyde failed. p-(Dimethylamino)benzaldehyde in reaction with benzyl isocyanide, aminoacetaldehyde dimethyl acetal, and benzoic acid yielded the expected Ugi product; nevertheless, subsequent cyclization failed. All the prepared compounds are listed in Table 1. The products were confirmed by NMR analysis, LC/MS, and HRMS. The structures of 4-prolyl-3,4-dihydropyrazin-2(1H)-one 2g and bridged heterocycle 6a were confirmed by 2D NMR experiments (COSY and HMBC); for more details, see Supplementary Informations.

3. Materials and Methods

3.1. General Information

All used chemical reagents were purchased from commercial sources. Solvents were reagent grade and used without further purification unless stated otherwise. The LC/MS analyses were carried out using a UPLC Waters Acquity system equipped with PDA and QDa detectors. The system contained an XSelect HSS T3 (Waters) 3 mm × 50 mm C18 reverse phase column XP (2.5 μm particles). Mobile phases: 10 mM ammonium acetate in HPLC grade water (A) and gradient grade MeCN for HPLC (B). A gradient was mainly formed from 20% to 80% of B in 4.5 min and kept for 1 min, with a flow rate of 0.6 mL/min. The MS ESI operated at a 25 V cone voltage, 600 °C probe temperature, and 120 °C source temperature. Purification was carried out using semipreparative HPLC Agilent on a YMC-Actus Pro 20 mm × 100 mm C18 reversed-phase column (5 μm particles). Mobile phases: 10 mM aqueous ammonium acetate and gradient grade MeCN for HPLC at a flow rate of 15 mL/min. All ¹H and ¹³C NMR experiments were performed at magnetic field strengths of 9.39 T (with operating frequencies of 399.78 MHz for 1H and 100.53 MHz for 13C) at ambient temperature (20 °C). In the case of compounds 3b and 3c, the proton measurements were performed at 80 °C. ¹H spectra and ¹³C spectra were referenced relative to the signal of DMSO-d₆ (¹H δ = 2.50 ppm, ¹³C δ = 39.51 ppm). HRMS analyses were performed using a UPLC Dionex Ultimate 3000 equipped with an Orbitrap Elite high-resolution mass spectrometer, Thermo Exactive plus. The settings for electrospray ionization were as follows: oven temperature of 150 °C and a source voltage of 3.6 kV. The acquired data were internally calibrated with diisooctyl phthalate as a contaminant in MeOH (m/z 391.2843). UPLC separation was performed using the Phenomenex Gemini C18 column (2 mm × 50 mm, 3 μm particles). Isocratic elution was performed using the mobile phase formed of 80% MeCN and 20% buffer (10 mM ammonium acetate), and the flow rate was 0.3 mL/min.

General procedure for the synthesis of Ugi intermediate 1. Aldehyde (0.4 mmol) and carboxylic acid (0.4 mmol) were dissolved in 1 mL MeOH. Subsequently, aminoacetaldehyde dimethyl acetal (0.4 mmol) and isocyanide (0.4 mmol) were added to the solution, and the reaction mixture was stirred at room temperature for 16 h. The volatile species were then evaporated by a stream of nitrogen, and the Ugi intermediates were further used without isolation.

General procedure for the synthesis of dihydropyrazin-2(1H)-ones 2a–g and 3a–c and derivatives 4a and 6a. The residues containing Ugi intermediate 1 were treated with 50% TFA/CH₂Cl₂ (1 mL), and the solutions were shaken at room temperature for 16 h. The crude products were purified by semipreparative reversed-phase HPLC using 10 mM aq. ammonium acetate/MeCN mobile phase. MeCN was evaporated by a stream of nitrogen, and the products were freeze-dried.

Procedure for the synthesis of pyrazin-2(1H)-one 4b. Ugi intermediate 1b was treated with 50% TFA/CH₂Cl₂ (1 mL) at room temperature for 16 h. The volatile species were then evaporated by a stream of nitrogen, and 1 mL of DMSO was added. The reaction was shaken at room temperature for 16 h. The crude product was purified by semipreparative reversed-phase HPLC using 10 mM aq. ammonium acetate/MeCN mobile phase. MeCN was evaporated by a stream of nitrogen, and the product was freeze-dried.

Procedure for the synthesis of piperazin-2-one 5a. Ugi intermediate 1b was treated with 50% TFA/10% TES/CH₂Cl₂ (1 mL) at room temperature for 16 h. The crude product was purified by semipreparative reversed-phase HPLC using 10 mM aq. ammonium acetate/MeCN mobile phase. MeCN was evaporated by a stream of nitrogen, and the product was freeze-dried.

3.2. Analytical Data of Individual Compounds

4-Benzoyl-1-benzyl-3-(4-nitrophenyl)-3,4-dihydropyrazin-2(1H)-one 2a

Yield: 0.114 g (69%) of amorphous solid. ESI-MS m/z = 414, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.24 (app d, J = 8.9 Hz, 2 H), 7.71–7.46 (m, 7 H), 7.36–7.18 (m, 5 H), 6.25 (br. s., 1 H), 6.17 (br. s., 1 H), 5.98 (br. s., 1 H), 4.82–4.69 (m, 2 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 167.9, 162.2, 147.4, 143.0, 136.6, 133.2, 131.2, 128.5, 128.5, 127.6, 127.5, 127.5, 127.4, 123.8, 113.3, 110.8, 58.7, 48.4. HRMS (HESI-Orbitrap): m/z calcd. for C₂₄H₂₀N₃O₄ [M + H]⁺ 414.1448, found 414.1449.

4-(1-Benzoyl-4-benzyl-3-oxo-1,2,3,4-tetrahydropyrazin-2-yl)benzonitrile 2b

Yield: 0.108 g (69%) of amorphous solid. ESI-MS m/z = 394, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 7.85 (app d, J = 8.5 Hz, 2 H), 7.67–7.43 (m, 7 H), 7.37–7.18 (m, 5 H), 6.25 (br. s., 1 H), 6.16 (br. s., 1 H), 5.98 (br. s., 1 H), 4.84–4.67 (m, 2 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 167.9, 162.3, 141.0, 136.6, 133.3, 132.7, 131.2, 131.2, 128.5, 128.5, 127.5, 127.3, 127.2, 118.4, 113.3, 116.2, 110.8, 58.8, 48.4. HRMS (HESI-Orbitrap): m/z calcd. for C₂₅H₂₀N₃O₂ [M + H]⁺ 394.1550, found 394.1546; m/z calcd. for C₂₅H₁₈N₃O₂ [M − H]⁻ 392.1394, found 392.1406.

1-Benzyl-4-(4-nitrobenzoyl)-3-(4-nitrophenyl)-3,4-dihydropyrazin-2(1H)-one 2c

Yield: 0.112 g (61%) of amorphous solid. ESI-MS m/z = 457, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.34 (app d, J = 8.2 Hz, 2 H), 8.24 (app d, J = 8.5 Hz, 2 H), 7.87 (app d, J = 8.2 Hz, 2 H), 7.67 (app d, J = 8.5 Hz, 2 H), 7.37–7.19 (m, 5 H), 6.23 (d, J = 5.8 Hz, 1 H), 6.19 (s, 1 H), 6.02 (d, J = 5.8 Hz, 1 H), 4.76 (s, 2 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 166.3, 162.1, 148.7, 147.4, 142.8, 139.4, 136.5, 130.0, 128.6, 127.7, 127.5, 127.4, 123.9, 123.7, 114.1, 109.9, 58.7, 48.5. HRMS (HESI-Orbitrap): m/z calcd. for C₂₄H₁₇N₄O₆ [M + H]⁺ 457.1143, found 457.1154.

4-Benzoyl-1-butyl-3-(4-nitrophenyl)-3,4-dihydropyrazin-2(1H)-one 2d

Yield: 0.060 g (40%) of amorphous solid. ESI-MS m/z = 380, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.23 (app d, J = 8.9 Hz, 2 H), 7.71–7.44 (m, 7 H), 6.22 (d, J = 4.6 Hz, 1 H), 6.11 (br. s., 1 H), 5.98 (d, J = 4.6 Hz, 1 H), 3.60–3.45 (m, 2 H), 1.56–1.43 (m, 2 H), 1.27–1.14 (m, 2 H), 0.84 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 167.8, 161.8, 147.3, 143.1, 133.3, 131.2, 128.5, 127.5, 123.8, 113.6, 110.3, 93.1, 58.6, 45.1, 29.7, 19.1, 13.4. HRMS (HESI-Orbitrap): m/z calcd. for C₂₁H₂₂N₃O₄ [M + H]⁺ 380.1605, found 380.1602; m/z calcd. for C₂₁H₂₀N₃O₄ [M − H]⁻ 378.1448, found 378.1457.

1-Butyl-4-(4-nitrobenzoyl)-3-(4-nitrophenyl)-3,4-dihydropyrazin-2(1H)-one 2e

Yield: 0.049 g (29%) of amorphous solid. ESI-MS m/z = 423, [M − H]⁻. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.36 (app d, J = 8.5 Hz, 2 H), 8.25 (app d, J = 8.5 Hz, 2 H), 7.87 (app d, J = 8.5 Hz, 2 H), 7.66 (app d, J = 8.5 Hz, 2 H), 6.17 (d, J = 5.8 Hz, 1 H), 6.09 (s, 1 H), 6.02 (d, J = 5.8 Hz, 1 H), 3.52 (t, J = 7.0 Hz, 2 H), 1.54–1.44 (m, 2 H), 1.22 (qd, J = 7.1, 14.6 Hz, 2 H), 0.85 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 166.2, 161.8, 148.7, 147.4, 142.9, 139.4, 129.9, 127.6, 123.9, 123.7, 114.4, 109.4, 58.6, 45.2, 29.7, 19.1, 13.5. HRMS (HESI-Orbitrap): m/z calcd. for C₂₁H₂₁N₄O₆ [M + H]⁺ 425.1456, found 425.1457; m/z calcd. for C₂₁H₁₉N₄O₆ [M − H]⁻ 423.1299, found 423.1313.

(9H-Fluoren-9-yl)methyl (3-(4-butyl-2-(4-nitrophenyl)-3-oxo-3,4-dihydropyrazin-1(2H)-yl)-3-oxopropyl)carbamate 2f

Yield: 0.089 g (40%) of amorphous solid. ESI-MS m/z = 569, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.25–8.14 (m, 2 H), 7.87 (d, J = 7.6 Hz, 2 H), 7.72–7.62 (m, 2 H), 7.54 (d, J = 8.9 Hz, 2 H), 7.44–7.24 (m, 5 H), 6.61 (d, J = 5.8 Hz, 1 H), 6.09–5.98 (m, 2 H), 4.32 (d, J = 6.7 Hz, 2 H), 4.27–4.14 (m, 1 H), 3.55–3.41 (m, 2 H), 3.31 (td, J = 6.9, 13.6 Hz, 2 H), 2.89–2.78 (m, 1 H), 2.77–2.65 (m, 1 H), 1.53–1.37 (m, 2 H), 1.18 (qd, J = 7.3, 14.6 Hz, 2 H), 0.89–0.75 (m, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 169.6, 162.0, 156.1, 147.2, 143.9, 143.4, 140.7, 127.5, 127.5, 127.0, 125.1, 123.7, 120.0, 114.2, 108.5, 65.3, 57.3, 46.7, 45.1, 36.2, 32.8, 29.7, 19.1, 13.4. HRMS (HESI-Orbitrap): m/z calcd. for C₃₂H₃₃N₄O₆ [M + H]⁺ 569.2395, found 569.2396; m/z calcd. for C₃₂H₃₁N₄O₆ [M − H]⁻ 567.2238, found 567.2248.

4-(L-Prolyl)-1-benzyl-3-(4-nitrophenyl)-3,4-dihydropyrazin-2(1H)-one 2g

Yield: 0.098 g (60%) of amorphous solid of a mixture of two diastereomers. ESI-MS m/z = 407, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.30–8.15 (m, 4 H), 7.62–7.47 (m, 4 H), 7.35–7.25 (m, 6 H), 7.25–7.18 (m, 4 H), 6.89–6.82 (m, 1 H), 6.76–6.72 (m, 1 H), 6.12–6.01 (m, 4 H), 4.86–4.75 (m, 2 H), 4.69–4.59 (m, 2 H), 4.19–4.11 (m, 1 H), 4.09–4.02 (m, 1 H), 4.00–3.70 (m, 2 H), 2.95–2.80 (m, 2 H), 2.79–2.66 (m, 2 H), 2.16–2.03 (m, 1 H), 1.98–1.86 (m, 1 H), 1.83–1.73 (m, 1 H), 1.73–1.56 (m, 5 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 172.6, 162.3, 162.2, 147.3, 143.5, 143.1, 136.6, 136.6, 128.5, 127.5, 127.4, 127.3, 123.9, 123.8, 113.9, 113.5, 109.2, 108.8, 57.6, 57.5, 48.5, 48.5, 47.0, 46.8, 29.1, 28.9, 26.0, 26.0. HRMS (HESI-Orbitrap): m/z calcd. for C₂₂H₂₃N₄O₄ [M + H]⁺ 407.1714, found 407.1711; m/z calcd. for C₂₂H₂₁N₄O₄ [M − H]⁻ 405.1557, found 405.1569.

(9H-Fluoren-9-yl)methyl 4-(2-(butylamino)-1-(4-nitrophenyl)-2-oxoethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate 3a

Yield: 0.075 g (44%) of amorphous solid. ESI-MS m/z = 555, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.53 (t, J = 5.0 Hz, 1 H), 8.25 (app d, J = 8.5 Hz, 2 H), 7.89 (d, J = 5.5 Hz, 2 H), 7.63 (d, J = 6.1 Hz, 2 H), 7.53 (app d, J = 8.2 Hz, 2 H), 7.46–7.38 (m, 2 H), 7.33 (d, J = 6.1 Hz, 2 H), 6.33–6.22 (m, 1 H), 6.11 (br. s., 1 H), 5.69 (br. s., 1 H), 4.47 (br. s., 2 H), 4.32 (d, J = 4.9 Hz, 1 H), 4.28–4.18 (m, 2 H), 3.22–3.07 (m, 2 H), 1.48–1.36 (m, 2 H), 1.28 (qd, J = 7.3, 14.8 Hz, 2 H), 0.87 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 166.6, 147.2, 143.5, 143.1, 140.7, 129.7, 127.7, 127.2, 125.0, 123.7, 120.2, 110.4, 108.5, 67.5, 57.3, 46.4, 43.3, 38.5, 30.8, 19.5, 13.5. HRMS (HESI-Orbitrap): m/z calcd. for C₃₁H₃₁N₄O₆ [M + H]⁺ 555.2238, found 555.2244; m/z calcd. for C₃₁H₂₉N₄O₆ [M − H]⁻ 553.2082, found 553.2097.

(9H-Fluoren-9-yl)methyl (2S)-4-(2-(butylamino)-1-(4-nitrophenyl)-2-oxoethyl)-2-methyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate 3b

Yield: 0.102 g (45%) of amorphous solid of a mixture of two diastereomers. ESI-MS m/z = 569, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.29–8.19 (m, 6 H), 7.90–7.83 (m, 4 H), 7.66–7.58 (m, 4 H), 7.51 (d, J = 8.2 Hz, 4 H), 7.45–7.38 (m, 4 H), 7.37–7.28 (m, 4 H), 6.25 (s, 1 H), 6.22 (s, 1 H), 6.07–5.98 (m, 2 H), 5.87 (d, J = 6.1 Hz, 1 H), 5.68 (d, J = 6.1 Hz, 1 H), 4.65–4.55 (m, 4 H), 4.55–4.44 (m, 2 H), 4.34 (q, J = 6.1 Hz, 2 H), 3.21–3.11 (m, 4 H), 1.49–1.39 (m, 4 H), 1.35–1.23 (m, 4 H), 1.11–1.00 (m, 6 H), 0.92–0.83 (m, 6 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 166.7, 166.4, 165.3, 165.1, 151.8, 151.6, 147.3, 147.2, 143.6, 143.2, 143.0, 140.8, 129.7, 129.4, 127.7, 127.1, 125.0, 124.7, 123.9, 123.8, 120.1, 111.1, 110.5, 67.3, 67.1, 57.8, 57.1, 53.0, 52.6, 46.6, 38.6, 38.5, 30.8, 30.8, 19.5, 19.4, 15.1, 15.0, 13.5. HRMS (HESI-Orbitrap): m/z calcd. for C₃₂H₃₃N₄O₆ [M + H]⁺ 569.2395, found 569.2400; m/z calcd. for C₃₂H₃₁N₄O₆ [M − H]⁻ 567.2238, found 567.2249.

(9H-Fluoren-9-yl)methyl (2S)-4-(2-(benzylamino)-1-(4-nitrophenyl)-2-oxoethyl)-2-(hydroxymethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate 3c

Yield: 0.078 g (31%) of amorphous solid of a mixture of two diastereomers. ESI-MS m/z = 619, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.82 (br. s., 1 H), 8.73 (br. s., 1 H), 8.25–8.15 (m, 4 H), 7.91–7.84 (m, 4 H), 7.69–7.61 (m, 4 H), 7.58 (dd, J = 5.2, 8.5 Hz, 4 H), 7.45–7.38 (m, 4 H), 7.37–7.22 (m, 14 H), 6.42–6.34 (m, 2 H), 6.26–6.20 (m, 2 H), 5.85 (d, J = 6.1 Hz, 1 H), 5.58 (d, J = 6.1 Hz, 1 H), 4.97–4.88 (m, 2 H), 4.70–4.56 (m, 2 H), 4.55–4.47 (m, 4 H), 4.43–4.38 (m, 4 H), 4.37–4.30 (m, 2 H), 3.73–3.46 (m, 4 H). HRMS (HESI-Orbitrap): m/z calcd. for C₃₅H₃₁N₄O₇ [M + H]⁺ 619.2187, found 619.2185; m/z calcd. for C₃₅H₂₉N₄O₇ [M − H]⁻ 617.2031, found 617.2042.

N-Butyl-2-(3-methyl-2-oxopyrazin-1(2H)-yl)-2-(4-nitrophenyl)acetamide 4a

Yield: 0.015 g (11%) of amorphous solid. ESI-MS m/z = 345, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.71 (t, J = 5.5 Hz, 1 H), 8.29 (app d, J = 8.9 Hz, 2 H), 7.59 (app d, J = 8.5 Hz, 2 H), 7.12–7.09 (m, 1 H), 7.08–7.05 (m, 1 H), 6.65 (s, 1 H), 3.23–3.07 (m, 2 H), 2.33 (s, 3 H), 1.46–1.37 (m, 2 H), 1.26 (qd, J = 7.3, 14.8 Hz, 2 H), 0.86 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 165.7, 156.1, 155.0, 147.6, 142.0, 130.4, 126.0, 124.1, 121.5, 59.7, 38.7, 30.7, 20.7, 19.4, 13.5. HRMS (HESI-Orbitrap): m/z calcd. for C₁₇H₂₁N₄O₄ [M + H]⁺ 345.1557, found 345.1554; m/z calcd. for C₁₇H₁₉N₄O₄ [M − H]⁻ 343.1401, found 343.1411.

N-Benzyl-2-(3-benzyl-2-oxopyrazin-1(2H)-yl)-2-(4-nitrophenyl)acetamide 4b

Yield: 0.025 g (27%) of amorphous solid. ESI-MS m/z = 455, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.22 (t, J = 5.6 Hz, 1 H), 8.27 (app d, J = 8.5 Hz, 2 H), 7.61 (app d, J = 8.9 Hz, 2 H), 7.34–7.22 (m, 10 H), 7.17 (d, J = 4.6 Hz, 1 H), 7.11 (d, J = 4.6 Hz, 1 H), 6.71 (s, 1 H), 4.37 (d, J = 5.8 Hz, 2 H), 4.05 (d, J = 4.9 Hz, 2 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 166.0, 157.5, 154.7, 147.7, 141.4, 138.3, 137.6, 130.6, 129.2, 128.3, 128.2, 127.4, 127.0, 126.4, 126.2, 124.1, 121.7, 60.3, 42.7. HRMS (HESI-Orbitrap): m/z calcd. for C₂₆H₂₃N₄O₄ [M + H]⁺ 455.1714, found 455.1716.

N-Benzyl-2-((S)-3-benzyl-2-oxopiperazin-1-yl)-2-(4-nitrophenyl)acetamide 5a

Yield: 0.053 g (58%) of amorphous solid of a mixture of two diastereomers. ESI-MS m/z = 459, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.87 (t, J = 6.1 Hz, 1 H), 8.84 (t, J = 5.8 Hz, 1 H), 8.23 (app d, J = 8.5 Hz, 2 H), 8.19 (app d, J = 8.9 Hz, 2 H), 7.51 (d, J = 8.9 Hz, 2 H), 7.37–7.15 (m, 22 H), 6.36 (s, 1 H), 6.34 (s, 1 H), 4.43–4.30 (m, 4 H), 3.68 (dd, J = 3.7, 7.9 Hz, 1 H), 3.62 (dd, J = 3.7, 9.2 Hz, 1 H), 3.50–3.42 (m, 1 H), 3.37–3.30 (m, 2 H), 3.22 (dd, J = 3.5, 13.9 Hz, 1 H), 3.13 (dd, J = 3.5, 13.6 Hz, 1 H), 2.98–2.60 (m, 9 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 170.0, 170.0, 168.1, 167.9, 147.0, 147.0, 143.6, 143.2, 139.1, 139.0, 138.9, 138.8, 130.2, 129.9, 129.6, 128.4, 129.3, 128.3, 128.1, 128.0, 127.3, 127.3, 126.9, 126.0, 126.0, 123.5, 123.4, 60.3, 60.2, 59.3, 58.6, 45.9, 45.8, 42.3, 42.3, 41.2, 41.1, 38.0, 37.9. HRMS (HESI-Orbitrap): m/z calcd. for C₂₆H₂₇N₄O₄ [M + H]⁺ 459.2027, found 459.2024; m/z calcd. for C₂₆H₂₅N₄O₄ [M − H]⁻ 457.1870, found 457.1883.

(2R,5R,6S)-3-Butyl-5-(4-nitrophenyl)-2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione and (2S,5S,6R)-3-butyl-5-(4-nitrophenyl)-2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione 6a

Yield: 0.016 g (10%) of amorphous solid. ESI-MS m/z = 395, [M + H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 8.30 (app d, J = 8.5 Hz, 2 H), 7.75 (app d, J = 8.5 Hz, 2 H), 7.55 (d, J = 6.7 Hz, 1 H), 7.40 (d, J = 6.4 Hz, 1 H), 7.36–7.28 (m, 1 H), 6.85–6.74 (m, 2 H), 6.03 (s, 1 H), 5.07 (dd, J = 3.1, 6.1 Hz, 1 H), 3.72 (d, J = 15.3 Hz, 1 H), 3.59 (td, J = 7.7, 13.7 Hz, 1 H), 3.44 (dd, J = 3.4, 15.3 Hz, 1 H), 3.29–3.19 (m, 1 H), 1.59 (br. s., 2 H), 1.31 (qd, J = 7.1, 13.9 Hz, 2 H), 0.93 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) 172.7, 164.0, 147.2, 144.1, 143.0, 132.8, 131.3, 128.9, 123.8, 119.2, 118.1, 118.0, 67.9, 62.2, 44.0, 41.4, 29.0, 19.8, 13.8. HRMS (HESI-Orbitrap): m/z calcd. for C₂₁H₂₃N₄O₄ [M + H]⁺ 395.1714, found 395.1712; m/z calcd. for C₂₁H₂₁N₄O₄ [M − H]⁻ 393.1557, found 393.1570.

4. Conclusions

To conclude, we synthesized Ugi advanced intermediates and achieved straightforward transformations into a diversity of nitrogen-containing heterocycles. The direction of cyclization was dependent on the character (structure, carbon chain length, presence of other nucleophile and protecting groups) of the starting carboxylic acid. Different reaction outcomes were obtained when carboxylic acids without a nucleophilic functional group (benzoic acid and p-nitrobenzoic acid) or amino acids with different lengths of carbon chains and the character of the protecting groups (Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-β-Ala-OH, Fmoc-Ser(t-Bu)-OH, Boc-Ser-OH, Boc-Phe-OH, Boc-Pro-OH, and anthranilic acid) were incorporated into the Ugi intermediate. First, the length of the carbon chain was crucial. Six-membered rings were favorable (with Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ser(t-Bu)-OH) and westbound cyclization of Ugi intermediates occurred, while reaction with Fmoc-β-Ala-OH resulted in eastbound cyclization. Second, the character of the amino acid protecting group determined the formation of the target product. While Fmoc-protected Ser(t-Bu)-OH was included in the Ugi adduct, TFA-mediated cyclization resulted in the formation of 3,4-dihydropyrazin-2(1H)-ones. In contrast, Ugi reaction with Boc-protected Ser-OH resulted in cyclization and spontaneous dehydration followed by aromatization to pyrazin-2(1H)-one. We also reduced the dihydropyrazinone cycle to piperazinone through TFA/TES/CH₂Cl₂ treatment. The Ugi intermediate containing an anthranilic acid moiety resulted in tandem diastereoselective cyclization to a bridged heterocycle with a 3D architecture.

Author Contributions

N.C. performed all synthetic experiments, characterized the compounds, and wrote the manuscript. V.K. verified the product structures and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

This work was supported by the Department of Organic Chemistry, Palacký University in Olomouc, Czech Republic.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures, Schemes and Table

Figure 1. Bioactive natural products containing piperazinone, 5,6-dihydropyrazin-2(1H)-one, and pyrazin-2(1H)-one scaffolds.

Figure 2. Generic structure of the dipeptide produced by U-4CR with two cyclization directions.

Scheme 1. Diversity-oriented synthesis of nitrogen heterocycles from Ugi advanced intermediate.

Scheme 2. Formation of 3,4-dihydropyrazin-2(1H)-ones 2 and 3 from Ugi adduct 1. Reagents and conditions: (i) MeOH, rt, 16 h; (ii) TFA/CH2Cl2 (1:1), rt, 16 h.

Scheme 3. Protecting group-dependent cyclization outcome. Reagents and conditions: (i) 50% TFA/CH2Cl2, rt, 16 h.

Scheme 4. Synthesis of pyrazin-1(2H)-one 4b and piperazin-2-one 5a from Boc-Phe-OH-derived Ugi intermediate 1b. Reagents and conditions: (i) 50% TFA/CH2Cl2, rt, 16 h; (ii) DMSO, rt, 16 h; (iii) TFA/TES/CH2Cl2 (5:1:4), rt, 16 h.

Scheme 5. Preparation of 4-prolyl-3,4-dihydropyrazin-2(1H)-one 2g using Boc-Pro-OH. Reagents and conditions: (i) 50% TFA/CH2Cl2, rt, 16 h.

Scheme 6. Preparation of bridged heterocycle 6a (only one enantiomer is shown). Reagents and conditions: (i) 50% TFA/CH2Cl2, rt, 16 h.

Table 1

List of synthesized and fully characterized products.

[Image omitted. Please see PDF.]
Product	R1	R2	R’	R3	R4	Purity (%) a	Purity (%) b	Yield (%) c
2a	Bn	–NO2	Ph	NA d	NA d	93	95	69
2b	Bn	–CN	Ph	NA d	NA d	90	96	69
2c	Bn	–NO2	p-NO2–C6H4–	NA d	NA d	71	99	61
2d	n-Bu	–NO2	Ph	NA d	NA d	95	98	40
2e	n-Bu	–NO2	p-NO2–C6H4–	NA d	NA d	48	99	29
2f	n-Bu	–NO2	Fmoc–NH–(CH2)2–	NA d	NA d	50	99	40
2g	Bn	–NO2	Pyrrolidine-2-yl	NA d	NA d	83	97	60
3a	n-Bu	–NO2	NA d	–H	Fmoc	51	89	44
3b	n-Bu	–NO2	NA d	–CH3	Fmoc	65	98	45
3c	Bn	–NO2	NA d	–CH2OH	Fmoc	32	99	31
4a	n-Bu	–NO2	NA d	–CH3	NA d	31	99	11
4b	Bn	–NO2	NA d	Bn	NA d	40	97	27
5a	Bn	–NO2	NA d	Bn	–H	87	97	58
6a	n-Bu	–NO2	NA d	NA d	NA d	37	99	10

^a Crude purity of the final product calculated from HPLC-UV (220–500 nm). ^b Purity of the product after reversed-phase high-performance liquid chromatography (HPLC) purification calculated from HPLC-UV (220–500 nm). ^c Isolated yield after HPLC purification. ^d Not applicable. ^e Boc-Ser-OH was used, and the CH₃ group was formed as a consequence of spontaneous dehydration and aromatization (see Scheme 3).

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28073062/s1, ¹H and ¹³C NMR Spectra.

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