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Article

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

by
Naděžda Cankařová
1,* and
Viktor Krchňák
1,2
1
Department of Organic Chemistry, Faculty of Science, Palacký University, 17 listopadu 12, 771 46 Olomouc, Czech Republic
2
Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame, IN 46556, USA
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(7), 3062; https://doi.org/10.3390/molecules28073062
Submission received: 27 February 2023 / Revised: 22 March 2023 / Accepted: 25 March 2023 / Published: 29 March 2023
(This article belongs to the Special Issue Heterocyclic Chemistry with Applications)
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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.

Graphical Abstract

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
Molecules 28 03062 i002
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
Molecules 28 03062 i003
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
Molecules 28 03062 i004
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
Molecules 28 03062 i005
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
Molecules 28 03062 i006
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
Molecules 28 03062 i007
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
Molecules 28 03062 i008
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
Molecules 28 03062 i009
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
Molecules 28 03062 i010
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
Molecules 28 03062 i011
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
Molecules 28 03062 i012
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
Molecules 28 03062 i013
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
Molecules 28 03062 i014
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
Molecules 28 03062 i015
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.

Supplementary Materials

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

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.

Funding

This research received no external funding.

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.

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Molecules 28 03062 g001 550
Figure 1. Bioactive natural products containing piperazinone, 5,6-dihydropyrazin-2(1H)-one, and pyrazin-2(1H)-one scaffolds.
Figure 1. Bioactive natural products containing piperazinone, 5,6-dihydropyrazin-2(1H)-one, and pyrazin-2(1H)-one scaffolds.
Molecules 28 03062 g001
Molecules 28 03062 g002 550
Figure 2. Generic structure of the dipeptide produced by U-4CR with two cyclization directions.
Figure 2. Generic structure of the dipeptide produced by U-4CR with two cyclization directions.
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Molecules 28 03062 sch001 550
Scheme 1. Diversity-oriented synthesis of nitrogen heterocycles from Ugi advanced intermediate.
Scheme 1. Diversity-oriented synthesis of nitrogen heterocycles from Ugi advanced intermediate.
Molecules 28 03062 sch001
Molecules 28 03062 sch002 550
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 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.
Molecules 28 03062 sch002
Molecules 28 03062 sch003 550
Scheme 3. Protecting group-dependent cyclization outcome. Reagents and conditions: (i) 50% TFA/CH2Cl2, rt, 16 h.
Scheme 3. Protecting group-dependent cyclization outcome. Reagents and conditions: (i) 50% TFA/CH2Cl2, rt, 16 h.
Molecules 28 03062 sch003
Molecules 28 03062 sch004 550
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 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.
Molecules 28 03062 sch004
Molecules 28 03062 sch005 550
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 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.
Molecules 28 03062 sch005
Molecules 28 03062 sch006 550
Scheme 6. Preparation of bridged heterocycle 6a (only one enantiomer is shown). 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.
Molecules 28 03062 sch006
Table
Table 1. List of synthesized and fully characterized products.
Table 1. List of synthesized and fully characterized products.
Molecules 28 03062 i001
ProductR1R2R’R3R4Purity (%) aPurity (%) bYield (%) c
2aBn–NO2PhNA dNA d939569
2bBn–CNPhNA dNA d909669
2cBn–NO2p-NO2–C6H4–NA dNA d719961
2dn-Bu–NO2PhNA dNA d959840
2en-Bu–NO2p-NO2–C6H4–NA dNA d489929
2fn-Bu–NO2Fmoc–NH–(CH2)2–NA dNA d509940
2gBn–NO2Pyrrolidine-2-ylNA dNA d839760
3an-Bu–NO2NA d–HFmoc518944
3bn-Bu–NO2NA d–CH3Fmoc659845
3cBn–NO2NA d–CH2OHFmoc329931
4an-Bu–NO2NA d–CH3NA d319911
4bBn–NO2NA dBnNA d409727
5aBn–NO2NA dBn–H879758
6an-Bu–NO2NA dNA dNA d379910
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).
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MDPI and ACS Style

Cankařová, N.; Krchňák, V. Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles. Molecules 2023, 28, 3062. https://doi.org/10.3390/molecules28073062

AMA Style

Cankařová N, Krchňák V. Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles. Molecules. 2023; 28(7):3062. https://doi.org/10.3390/molecules28073062

Chicago/Turabian Style

Cankařová, Naděžda, and Viktor Krchňák. 2023. "Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles" Molecules 28, no. 7: 3062. https://doi.org/10.3390/molecules28073062

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