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Article

Catalyst-Free Spontaneous Aza-Mannich/Lactamization Cascade Reaction: Easy Access to Polycyclic δ-Lactams

by
Antonia Di Mola
*,
Caterina Vietri
,
Consiglia Tedesco
and
Antonio Massa
*
Dipartimento di Chimica e Biologia “A. Zambelli”, Università degli Studi di Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(13), 2702; https://doi.org/10.3390/molecules30132702
Submission received: 22 May 2025 / Revised: 12 June 2025 / Accepted: 19 June 2025 / Published: 23 June 2025
(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)
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Versions Notes

Abstract

Ring-fused azacyclic compounds are important building blocks in the synthesis of natural products and pharmaceutical agents. Herein, we report an effective and valuable one-pot approach to obtaining polycyclic fused δ-lactams from readily available 2-formylphenyl acetate and diamines under catalyst-free and green conditions.

Graphical Abstract

1. Introduction

Polycyclic compounds, which contain multiple fused rings in their structure, are important scaffolds in the development of several drugs [1,2]. In particular, polycyclic aza-lactams are of large interest in organic and medicinal chemistry due to their wide range of biological activities. For example, γ-lactam 1 has activity against Candida albicans [3]; γ-lactam 2 shows non-nucleoside HIV reverse transcriptase inhibition [4,5]; and γ-lactam 3 possesses anti-inflammatory, analgesic, tranquilizing, and antitussive properties [6]. Also, polycyclic δ-lactams are fascinating compounds: strychnine 4 is a toxic alkaloid historically used to strengthen muscle contractions [7], while LMP776 has undergone clinical trials for the treatment of solid cancer [8]. In addition, polycyclic δ-lactams offer the possibility to be easily transformed into related heterocycles, as reported by Amat in 2010 [9]. In fact, the polycyclic lactam 5 is a key intermediate in the synthesis of 1-substituted tetrahydroisoquinoline alkaloids (THIQ; see Figure 1), a moiety found in many bioactive natural products such as 6–8 [10,11,12].
Cascade reactions are a powerful approach for the construction of carbon and heterocyclic ring structures. They respect many paradigms of green chemistry like step, pot, and atom economy [13,14]. However, most of the reported methods for the construction of polycyclic lactams are based on transition-metal catalysis [15,16] and/or use halogenated or aromatic solvents [17,18]. Consequently, developing novel and efficient transformations to synthesize some important heterocyclic compounds under transition-metal-free reaction conditions is still highly desirable.
In the present investigation, continuing our program aimed at preparing valuable heterocyclic compounds by diverse cascade and multicomponent reactions [19,20,21,22], we envisaged the possibility of developing a convenient route to obtain polycyclic δ-lactams, focusing on the bifunctional aromatic compound 2-formylphenylacetate 9a.
Successful cascade reactions rely on the careful design of suitable starting materials capable of undergoing sequential, hierarchical transformations. In recent years, our attention has focused on bis-electrophilic compounds, such as 2-cyanobenzaldehydes [19,20] or α-amido sulfones derived from 2-formylbenzoate [21,22]. These systems feature one electrophilic group that is more reactive, enabling the formation of a high-energy intermediate. This intermediate can then undergo intramolecular cyclization with the second, less reactive electrophilic group, facilitating efficient and selective ring closure. In this context, 2-formylphenyl acetate 9a has proven particularly effective for the synthesis of 3-isoquinolones, a class of δ-lactams, via a Mannich-initiated cascade reaction. This transformation involves imines derived from 9a, nitromethane, and dimethyl malonate under catalyst- and solvent-free conditions (Scheme 1) [23].
Furthermore, 2-formylphenyl acetates have been utilized in the synthesis of 3-isoquinolones by Lewis acid-catalyzed domino Strecker-lactamization [24], in Ni(II)-catalyzed reactions [25], in the presence of Grignard reagents [26], and in cyclo-condensation with (R)-phenylglycinol [8]. However, to the best of our knowledge, there are no examples in the literature of the reaction between 9 and diamine 13. According to the proposed mechanistic hypothesis (Scheme 1), a primary amine group of suitable diamines should react with the aldehyde group of 9 to give the imine intermediate A. Then, the second amino group should intramolecularly attack the very reactive imine group to form a cyclic aminal intermediate, which can undergo lactamization to afford new polycyclic products such as 14.

2. Results

Based on the mechanistic hypothesis depicted in Scheme 1, the reaction between 9a and 1,3-diaminopropane 13a, chosen as the diamine model, was investigated in the green solvent ethanol, without the use of any catalyst or additive (Table 1). To find the best conditions for obtaining these valuable heterocycles, we examined not only the reaction parameters, such as the 9a concentration and reaction time, but also the purification procedure. The evidence that purification can also affect the isolated yield was highlighted by an 1H NMR analysis of the crude, which revealed good conversions, but the isolated yields were relatively low (compare Entries 1 and 2 with Entries 3 and 4). The reaction was spontaneous in ethanol, which was used as solvent, but the amount of isolated product increased as the stationary phase used for purification was changed from silica gel to alumina. When using silica or silica deactivated with 1% Et3N, only moderate yields were obtained. This outcome was probably due to the stronger interaction between the silica OH groups and the amino/amide groups (Entries 1 and 2). Indeed, when we moved to alumina, better results were achieved (Entries 3 and 4). Then, with more reliable purification in hand, the reaction conditions were optimized to achieve quantitative conversions by performing the reaction for a longer time and with a higher molar concentration of 0.56 mol/L (Entry 5). Other conditions were also investigated, such as more diluted concentrations (Entries 6 and 7) and an increased reaction temperature of 60 °C (Entry 8); however, these resulted in lower efficiency.
With the optimized conditions in hand, the scope of the reaction was then analyzed using substituted 2-formylphenyl acetates 9 and different diamines 13. In most cases, we obtained the expected new products in high yields, irrespective of the presence of fluorine atoms or nitro electron-withdrawing groups on the aromatic ring of 2-formylphenylacetate (Figure 2). When 1,4-diaminobutane was used, the tricycle compound 14f containing a 1,3-diazepino seven-membered ring was obtained in 76% yield after 72 h under more diluted conditions. Other conditions, such as variations in the concentration reaction temperature and reaction time, were also tested, but lower efficiency was observed (Figure 2). On the other hand, no product was observed when using 1,5-diaminopentane, even when heating up to 80 °C. This outcome was not surprising since the construction of eight-membered rings is a common challenge in chemistry, often due to the strain and unfavorable kinetics of forming such rings [27]. Also, the presence of secondary amines, such as N-methylethylenadiamine, N-benzylethylendiamine, or N-benzyl-1,3-diaminopropane (14b, d, e, i), or a hindered diamine, like 1,2-diphenylethylamine, enabled the isolation of tricyclic products in good yields. In the latter case, only one diastereomer was obtained, and the structure of 14j was confirmed by an X-ray diffraction analysis (Figure 3), showing a 1,3-trans stereochemistry [28]. Interestingly, when using triethylenetetramine, the dimeric structure 14k was obtained in 62% yield as a mixture of two diastereomers. The reaction also performed well in the presence of other 2-formylphenyl acetates further substituted on the aromatic ring (14h and 14i).
To further enlarge the scope of the reaction with the aim of preparing tetracyclic δ-lactams, other readily available or easily preparable aromatic diamines were used in the reaction with aldehyde 9, such as o-xylilendiamine 15, o-phenylendiamine 16, and 2-aminobenzylamine 17 (Figure 4 and Figure 5).
As reported in Figure 5, the 1,3-diazepino polycyclic lactam 18 was obtained in high yield using diamine 15. When o-phenylendiamine 16 was used, the corresponding oxidized product 19, already known in the literature [29], was obtained, though in a rather low yield due to the formation of decomposition products. The analysis of the scope focused on the use of the asymmetric diamine 17 and was extended to other 2-formylphenyl acetates further substituted on the aromatic ring in different positions, leading to the desired products 20a–20e in high yields and regioselectivity.
The preparation of tetracyclic δ-lactams derived from 2-aminobenzylamine 17 could pose concerns about the regioselectivity, according to the mechanism reported in Scheme 2. In the reaction, only one regioisomer was obtained, as detected by an 1H NMR of the crudes. Analyzing the reaction mechanism in more detail, the spontaneous cascade process should consist of imine formation, intramolecular aza-Mannich attack, and final lactamization. We suppose that the observed regioselectivity depends on the higher nucleophilicity of the aliphatic NH group with respect to the NH anilino group of intermediate C (pathway a), leading to only the regioisomer 20a.
Under the optimized conditions reported (Table 1, Entry 5), the tetracyclic δ-lactam 20a was recovered in a short reaction time and in very high yields. Since attempts to obtain suitable crystals for X-rays failed, to assess the structure of the obtained compound 20a, we investigated its second reactivity, such as the amide reduction (Scheme 3), and compared our spectra with those reported in the literature [30,31]. In fact, quinazoline 22 is an already known compound prepared by the reaction of 2-aminobenzaldeyde 23 and 1,2,3,4-tetrahydroisoquinoline 24 in refluxing ethanol for 48 h [30]. The treatment of 20a with BH3(CH3)2S allowed us to recover compound 22 only in traces because the main product was the tetrahydroisoquinoline 21 (94% yield) in which the amide group was reduced and the aminal bond was cleaved. Notably, compound 21, previously obtained by a different methodology, belongs to a class of bioactive α2-adrenergic receptor antagonists [32]. Indeed, when 20a was treated with LiAlH4 1 M solution in THF, 22 was obtained in a very good yield (89%), confirming that pathway (a) is more plausible, as reported in Scheme 2.

3. Materials and Methods

Unless otherwise noted, all chemicals, reagents, and solvents for the performed reactions were commercially available. Aldehydes were prepared according to the literature procedures [15]. All the reactions were monitored by thin-layer chromatography (TLC) on precoated silica gel plates (0.25 mm) and visualized by fluorescence quenching at 254 nm. Flash chromatography was carried out using neutral activated alumina (Merck, Darmstadt, Germany). Yields are given for isolated products showing one spot on a TLC plate. The NMR spectra were recorded on Bruker DRX 600, 400, 300, and 250 MHz spectrometers (600 MHz, 1H, 150 MHz, 13C; 400 MHz, 1H, 100.6 MHz; 13C, 300 MHz, 1H, 75.5 MHz, 13C, 250 MHz, 1H, 62.5 MHz, 13C). The internal reference was set to the residual solvent signals (δH 7.26 ppm, δC 77.16 ppm for CDCl3, δH 2.50 ppm, δC 39.10 ppm for DMSO-d6). The 13C NMR spectra were recorded under broad-band proton decoupling. 1HNMR data and HRMS are reported for all compounds. IR and 13CNMR data are given only for unknown compounds. The following abbreviations are used to indicate the multiplicity in the NMR spectra: s—singlet, d—doublet, t—triplet, q—quartet, dd—doublet of doublets, m—multiplet, and br s—broad signal. High-resolution mass spectra (HRMS) were acquired using a Bruker SolariX XR Fourier transform ion cyclotron resonance mass spectrometer (Bruker Daltonik GmbH, Bremen, Germany) equipped with a 7T refrigerated actively shielded superconducting magnet. For ionization of the samples, electrospray ionization (ESI) or MALDI was applied. IR spectra were recorded on a IR Bruker Vertex 70v spectrometer.

3.1. General Procedure for the Synthesis of Tricyclic Lactams 14a–14k

To a solution of aldehyde 9 (50 mg, 0.28 mmol) in EtOH (500 µL), diamine 13 (0.28 mmol, 1 eq.) was added, and the mixture was stirred at room temperature for 24 h. The solvent was evaporated, and the crude was purified on a short column of neutral alumina (from Pentane 20% in CH2Cl2 to CH2Cl2).
  • 1,2,3,4,7,11b-hexahydro-6H-pyrimido [2,1-a]isoquinolin-6-one 14a
Yellow solid. Yield: 54 mg, 95%. M.p. 147 °C (dec.). Rf. 0.30 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.6 Hz, 1H), 7.27–7.25 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 5.29 (s, 1H), 4.97 (dd, J1 = 12.8 Hz, J2 = 2.0 Hz, 1H), 3.73 (d, J = 21.6 Hz, 1H), 3.65 (d, J = 21.6 Hz, 1H), 3.30 (dd, J1 = 13.6 Hz, J2 = 2.0 Hz, 1H), 3.16–3.08 (m, 1H), 2.90–2.83 (m, 1H), 1.94 (br s, 1H, NH), 1.68–1.63 (m, 2H). 13CNMR (100 MHz, CDCl3): δ 166.4, 131.7, 130.8, 128.5, 127.3, 127.2, 126.8, 73.2, 45.8, 42.3, 34.8, 26.9. HRMS (MALDI-FT ICR): m/z calcd for [C12H14N2O + H]+: 203.1179; found: 203.1179. IR (KBr): 3230, 1717, 689, 650 cm−1.
  • 1-benzyl-1,2,3,4,7,11b-hexahydro-6H-pyrimido [2,1-a]isoquinolin-6-one 14b
Slightly brown solid. Yield: 76 mg, 94%. M.p. 178 °C (dec.). Rf. 0.50 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.0 Hz, 1H), 7.30–7.09 (m, 8H), 5.62 (s, 1H), 4.99 (dd, J1 = 13.2 Hz, J2 = 4.8 Hz, 1H), 3.78 (d, J = 21.2 Hz, 1H), 3.68 (d, J = 21.2 Hz, 1H), 3.47 (d, J = 13.2 Hz, 1H), 3.32 (d, J = 13.2 Hz, 1H), 3.10–2.99 (m, 1H), 2.90 (dt, J1 = 13.2 Hz, J2 = 3.2 Hz, 1H), 2.21–2.08 (m, 1H), 1.32–1.25 (m, 2H). 13CNMR (100 MHz, CDCl3): δ 167.4, 138.8, 132.3, 130.7, 128.6 (2C), 128.5, 128.3 (2C), 127.4, 127.3, 127.1, 127.0, 78.1, 48.3, 47.8, 42.7, 35.0, 18.9. HRMS (MALDI-FT ICR): m/z calcd for [C19H20N2O + H]+: 293.1648; found: 293.1645. IR (KBr): 1717, 687, 647 cm−1.
  • 2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14c
Yellow solid. Yield: 49 mg, 93%. M.p. 91 °C (dec.). Rf. 0.20 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.51–7.49 (m, 1H), 7.31–7.29 (m, 2H), 7.18 (d, J = 6.5 Hz, 1H), 5.33(s, 1H), 3.72–3.45 (m, 5H), 3.30–3.23 (m, 1H), 2.72 (br s, 1H). 13CNMR (75 MHz, CDCl3): δ 165.9, 133.2, 132.0, 128.9, 127.6, 127.3, 124.4, 74.4, 45.2, 44.3, 34.8. HRMS (MALDI-FT ICR): m/z calcd for [C11H12N2O + H]+: 189.1022; found: 189.1024. IR (KBr): 3280, 1711, 690, 652 cm−1.
  • 1-methyl-2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14d
Yellow solid. Yield: 55 mg, 94%. M.p. 77 °C (dec.). Rf. 0.30 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.47–7.44 (m, 1H), 7.31–7.28 (m, 2H), 7.21–7.18 (m, 1H), 5.00 (s, 1H), 3.70–3.54 (m, 4H), 3.28 (dt, J1 = 7.2 Hz, J2 = 2.4 Hz, 1H), 3.06–2.99 (m, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 167.1, 133.3, 132.5, 128.3, 127.6, 126.9, 124.4, 79.0, 54.2, 41.6, 39.9, 38.3. HRMS (MALDI-FT ICR): m/z calcd for [C12H14N2O + H]+: 203.1179; found: 203.1181. IR (KBr): 1716, 689, 653 cm−1.
  • 1-benzyl-2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14e
Yellow oil. Yield: 73 mg, 94%. Rf. 0.45 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.60–7.58 (m, 1H), 7.45–7.43 (m, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.30–7.28 (m, 3H), 7.23–7.21 (m, 1H), 5.22 (s, 1H), 3.82 (m, J = 13.6 Hz, 1H), 3.72–3.55 (m, 5H), 3.19–3.13 (m, 1H), 2.96–2.91 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 167.5, 138.3, 134.2, 128.7 (4C), 128.4, 127.7, 127.6, 127.1 (2C), 124.2, 78.3, 56.7, 50.6, 41.7, 38.8. HRMS (MALDI-FT ICR): m/z calcd for [C18H18N2O + H]+: 279.1492, found: 279.1496. IR (KBr): 1747, 681, 621 cm−1.
  • 2,3,4,5,8,12b-hexahydroazepino [2,1-a]isoquinolin-7(1H)-one 14f
Reaction carried out for 72 h (EtOH, 1 mL for 0.28 mmol). Yellow solid. Yield: 78%, 48 mg. M.p. 68 °C (dec.). Rf. 0.35 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.43–7.40 (m, 1H), 7.26–7.24 (m, 2H), 7.14–7.12 (m, 1H), 5.25 (s, 1H), 4.47–4.41 (m, 1H), 3.72 (d, J = 19.2 Hz, 1H), 3.56 (d, J = 19.2 Hz, 1H), 3.08–2.99 (m, 2H), 2.89–2.83 (m, 1H), 1.92 (br s, 1H), 1.88–1.79 (m, 2H), 1.73–1.64 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 169.3, 134.9, 132.1, 128.3, 127.3, 126.8, 126.3, 74.5, 46.3, 44.2, 37.2, 30.0, 27.3. HRMS (MALDI-FT ICR): m/z calcd for [C13H16N2O + H]+: 217.1335; found: 217.1337. IR (KBr): 3150, 1710, 688, 650 cm−1.
  • 9-nitro-2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14h
Red solid. Yield: 94%, 61 mg. M.p. 180 °C (dec.). Rf. 0.25 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 5.39 (s, 1H), 3.75 (d, J = 18.4 Hz, 1H), 3.69–3.61 (m, 2H), 3.54–3.50 (m, 1H), 3.42–3.36 (m, 1H), 3.33–3.28 (m, 1H), 2.10 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 164.9, 147.6, 139.7, 136.2, 128.5, 123.8, 119.8, 73.6, 45.2, 44.7, 38.8. HRMS (MALDI-FT ICR): m/z calcd for [C11H11N3O3 + H]+: 234.0873; found: 234.0876. IR (KBr): 3260, 1712, 1578, 680, 650 cm−1.
  • 10-fluoro-1-methyl-2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14i
Yellow solid. Yield: 52 mg, 92%. M.p. 177 °C (dec.). Rf. 0.35 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.33–7.28 (m, 1H), 7.02–6.97 (m, 2H), 5.37 (s, 1H), 3.98–3.90 (m, 1H), 3.71 (d, J = 20.0 Hz, 1H), 3.69 (d, J = 20.0 Hz, 1H), 3.37–3.27 (m, 2H), 3.21–3.15 (m, 1H), 2.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.3, 159.5 (d, JC-F = 249 Hz), 134.8 (d, JC-F = 3.5 Hz), 130.4 (d, JC-F = 8.9 Hz), 123.5 (d, JC-F = 3.2 Hz), 117.3 (d, JC-F = 14.3 Hz), 114.2 (d, JC-F = 21.5 Hz), 77.0, 53.1, 40.4, 36.7, 36.2. 19F NMR (377 MHz, CDCl3): δ −121.2. HRMS (MALDI-FT ICR): m/z calcd for [C12H13N2FO + H]+: 221.1085; found: 221.1091. IR (KBr): 1720, 688, 651 cm−1.
  • 2,3-diphenyl-2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14j
Reaction carried out for 72 h at 80 °C. White crystals (CHCl3/Hexane). Yield: 78%, 74 mg. M.p. 112–113 °C. Rf. 0.67 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.74 (app t, J = 7.4 Hz 1H), 7.37–7.29 (m, 4H), 7.18–7.14 (m, 6H), 6.88–6.82 (m, 3H), 6.02 (s, 1H), 4.43 (d, J = 6.0 Hz 1H), 4.49 (m, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.65 (d, J = 16.8 Hz, 1H), 3.20 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 168.2, 136.8, 136.7, 135.4, 135.3, 132.9, 128.5, 128.2 (2C), 127.9 (2C), 127.7, 127.5, 127.4, 127.2 (2C), 127.1 (2C), 123.4, 74.2, 64.4, 63.8, 39.8. HRMS (MALDI-FT ICR): m/z calcd for [C23H20N2O + H]+: 341.1648; found: 341.1647. IR (KBr): 1720, 790, 686, 650 cm−1.
  • 1,1′-(ethane-1,2-diyl)bis(2,3,6,10b-tetrahydroimidazo [2,1-a]isoquinolin-5(1H)-one 14k
To a solution of aldehyde 9 (50 mg, 0.28 mmol, 2 eq.) in EtOH (500 µL), triethylenetetramine (0.14 mmol, 1 eq.) was added, and the mixture was stirred at 50 °C for 24 h. The solvent was evaporated, and the crude was purified on neutral alumina (from Pentane 20% in CH2Cl2 to CH2Cl2). Mixture of diasteroisomers (dr 60/40). Yellow solid. Yield: 35 mg, 62%. Rf. 0.35 (DCM 100/MeOH 1, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.59 (s, 2H), 7.36–7.30 (m, 6H), 5.23 (s, 1H), 5.17 (s, 1H), 3.82–3.49 (m, 8H), 3.48–3.42 (m, 2H), 3.08–3.04 (m, 3H), 2.95–2.84 (m, 3H). 13CNMR (100 MHz, CDCl3): δ 167.2, 167.1, 134.4, 133.9, 132.8, 132.7, 128.4, 128.3, 127.7 (2C), 126.9 (2C), 124.2, 123.9, 78.9, 78.7, 52.9, 52.3, 52.1, 51.7, 41.8, 41.7, 38.8, 38.6. HRMS (MALDI-FT ICR): m/z calcd for [C24H26N4O2 + H]+: 403.2128; found: 403.2141. IR (KBr): 1730, 1714, 690, 652 cm−1.

3.2. General Procedure for the Synthesis of Tetracyclic Lactams 18, 19, 20a–20e

To a solution of aldehyde 9 (50 mg, 0.28 mmol) in EtOH (500 µL), diamine 15, 16, or 17 (0.28 mmol, 1 eq.) was added, and the mixture was stirred at room temperature for 45–120 min. The solvent was evaporated, and the crude was purified on a short column of silica (Ethyl Acetate 10% in Pentane).
  • 8,13,14,14a-tetrahydrobenzo [5,6][1,3]diazepino [2,1-a]isoquinolin-6(5H)-one 18
Reaction carried out for 2 h. Tan solid. Yield: 67 mg, 95%. M.p. 180 °C (dec.). Rf. 0.20 (Pentane 90/Ethyl Acetate 10, SiO2).1H NMR (400 MHz, CDCl3): δ 7.46 (app t, J = 7.4 Hz, 2H), 7.28–7.16 (m, 4H), 7.12–7.06 (m, 2H), 5.64 (s, 1H), 5.40 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 3.31 (d, J = 14.8 Hz, 1H), 4.08 (d, J = 16.0 Hz, 1H), 3.60 (d, J = 21.6 Hz, 1H), 3.55 (d, J = 22.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 167.9, 140. 9, 137.7, 133.2, 131.4, 130.0, 128.4, 128.3, 127.6, 127.5, 127.4, 127.3, 126.9, 78.9, 52.9, 50.5, 35.7. HRMS (MALDI-FT ICR): m/z calcd for [C17H16N2O + H]+: 265.1335; found: 265.1331. IR (KBr): 3319, 1710, 688, 650 cm−1
  • benzo [4,5]imidazo [2,1-a]isoquinolin-6(5H)-one 19
Reaction carried out for 24 h. Yellow solid. Yield: (23 mg, 35%). M.p. 147–150 °C. Rf. 0.50 (Pentane 90/Ethyl Acetate 10, SiO2). Spectra are in agreement with literature data [18]. 1H NMR (400 MHz, CDCl3) δ 8.44–8.37 (m, 1H), 8.29 (d, J = 6.7 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.52–7.36 (m, 4H), 7.35–7.27 (m, 1H), 4.19 (s, 2H). HRMS (MALDI-FT ICR: m/z calcd for [C15H11N2O + H]+: 235.0866; found: 235.0864.
  • 5,8,13,13a- tetrahydro -6H-isoquinolino [1,2-b]quinazolin-6-one 20a
Reaction carried out for 45 min. White solid. Yield: 67 mg, 95%. M.p. 218°C (dec.). Rf. 0.40 (Pentane 90/Ethyl Acetate 10, SiO2) 1H NMR (400 MHz, CDCl3): δ 7.42–7.33 (m, 3H), 7.20 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 2H), 6.87 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.79 (s, 1H), 5.65 (d, J = 20.8 Hz, 1H), 4.36 (d, J = 16.8 Hz, 1H), 4.07 (br s, 1H, NH), 3.80 (d, J = 20.8 Hz, 1H), (3.70 (d, J = 20.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 167.5, 142.7, 131.8, 130.2, 129.1, 127.8, 127.4, 127.1, 127.0, 126.3, 120.5, 120.4, 116.9, 68.7, 43.9, 35.2. HRMS (MALDI-FT ICR): m/z calcd for [C16H15N2O + H]+: 251.1178; found: 251.1188. IR (KBr): 3310, 1715, 689, 676 cm−1. The reaction was scaled up to 1.5 mmols, achieving 92% yield.
  • 2-nitro-5,8,13,13a-tetrahydro-6H-isoquinolino [1,2-b]quinazolin-6-one 20b
Reaction carried out for 1 h. Red solid. Yield: 76 mg, 92%. M.p. 178 °C (dec.). Rf. 0.2 (Pentane 90/Ethyl Acetate 10, SiO2) 1H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.62 (J = 8.0 Hz, 1H), 6.36 (s, 1H), 5.97 (s, 1H), 5.31 (d, J = 16.4 Hz, 1H), 4.28 (J = 16.4 Hz, 1H), 3.84 (d, J = 23.2 Hz, 1H), 3.77 (J = 23.62 Hz, 1H). 13C NMR (150 MHz, DMSO-d6): δ 168.7, 147.9, 145.6, 142.4, 134.3, 131.0, 128.9, 128.5, 125.3, 124.3, 121.5. 120.7, 120.0, 118.2, 69.0, 45.3, 37.1. HRMS (MALDI-FT ICR): m/z calcd for [C16H13N3O3 + H]+: 296.1030; found: 296.1037. IR (KBr): 3240, 1710, 1580, 680, 670 cm−1.
  • 2-bromo-5,8,13,13a-tetrahydro-6H-isoquinolino [1,2-b]quinazolin-6-one 20c
Reaction carried out for 1 h. White solid. Yield: 81 mg, 89%. M.p. 230 °C (dec.). Rf. 0.55 (Pentane 90/Ethyl Acetate 10, SiO2)1H NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 3H), 6.89 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 5.63 (d, J = 16.8 Hz, 1H), 4.35 (J = 16.8 Hz, 1H), 4.01 (br s, 1H), 3.74 (d, J = 20.8 Hz, 1H), 3.66 (J = 20.8 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 168.4, 143.5, 133.8, 133.7, 132.4, 131.0, 131.8, 128.9, 129.6, 122.3, 122.1, 122.0, 118.8, 69.7, 45.4, 36.3. HRMS (MALDI-FT ICR): m/z calcd for [C16H13BrN2O + H]+: 329.0284; found: 329.0282. IR (KBr): 3230, 1700, 687 cm−1.
  • 1-fluoro-5,8,13,13a-tetrahydro-6H-isoquinolino [1,2-b]quinazolin-6-one 20d
Reaction carried out for 1 h. White solid. Yield: 68 mg, 91%. M.p. 218 °C (dec.). Rf. 0.45 (Pentane 90/Ethyl Acetate 10, SiO2) 1H NMR (600 MHz, CDCl3): δ 7.32–7.29 (m, 1H), 7.04–6.95 (m, 4H), 6.81 (dt, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 6.60 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 6.00 (s, 1H), 5.62 (d, J = 16.2 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 4.16 (br s, 1H), 3.76 (d, J = 21.1 Hz, 1H), 3.76 (d, J = 20.4 Hz, 1H), 13C NMR (150 MHz, CDCl3): δ 168.7, 160.9 (d, JC-F = 246 Hz), 144.3, 136.3 (d, JC-F = 2.7 Hz), 132.2, (d, JC-F = 8.55 Hz), 128.9 (JC-F = 54.0 Hz), 124.9 (JC-F = 3.0 Hz), 121.8, 121.3, 117.8 (2C), 119.7 (d, JC-F = 15.3 Hz), 115.0 (d, JC-F = 93 Hz), 65.4 (d, JC-F = 3.75 Hz), 45.4, 36.5. 19F NMR (377 MHz, CDCl3): δ −116.1. HRMS (MALDI-FT ICR): m/z calcd for [C16H13FN2O + H]+: 269.1085; found: 269.1055. IR (KBr): 3210, 1710, 678 cm−1.
  • 3-chloro-5,8,13,13a-tetrahydro-6H-isoquinolino [1,2-b]quinazolin-6-one 20e
Reaction carried out for 1.5 h. White solid. Yield: 71 mg, 90%. M.p. 198 °C (dec.). Rf. 0.50 (Pentane 90/Ethyl Acetate 10, SiO2) 1H NMR (600 MHz, CDCl3): δ 7.40 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.11 (t, J = 6.0 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.79 (s, 1H), 5.65 (d, J = 16.8 Hz, 1H), 4.38 (J = 16.8 Hz, 1H), 3.82 (d, J = 20.4 Hz, 1H), 3.66 (J = 21.0 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 168.3, 136.6, 135.4, 130.1, 129.3, 129.2, 128.95, 128.9 (2C), 128.6, 122.5, 122.5, 118.8, 69.8, 45.4, 36.3. HRMS (MALDI-FT ICR): m/z calcd for [C16H13ClN2O + H]+: 285.0789; found: 285.0756. IR (KBr): 3236, 1708, 684 cm−1.

3.3. Follow-Up Chemistry

3.3.1. Reduction Using BH3(CH3)2S

  • 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)aniline 21
Under a nitrogen atmosphere, to a suspension of 20a (60 mg, 0.24 mmol, 1 equiv.) in THF (3.0 mL), BH3(CH3)2S (10 M, 240 µL, 10 equiv.) was added dropwise. The reaction mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature, and then the solvent and dimethyl sulfide were evaporated. After the addition of 6 N HCl (1.5 mL) to the residue, the solution was heated at 80 °C for 1 h and then cooled to room temperature. The mixture was neutralized with 4 N NaOH and extracted with CH2Cl2. The organic layer was washed with brine and dried over MgSO4. After concentration, the product 19 was isolated by chromatography on silica (from Ethyl Acetate 30% in Pentane to 50%). Pale oil. Yield: 54 mg, 94%. Rf. 0.45 (Pentane 70/Ethyl Acetate 30, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.12–7.10 (m, 4H), 7.05 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 3.68 (s, 2H), 3.60 (s, 2H), 2.88 (t, J = 5.70 Hz, 2H), 2.73 (t, J = 5.70 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 147.2, 134.9, 134.3, 130.5, 128.7, 128.5, 126.7, 126.2, 125.7, 122.3, 117.6, 115.6, 62.0, 55.8, 50.3, 29.4. HRMS (MALDI-FT ICR): m/z calcd for [C16H18N2 + H]+: 239.1543; found: 239.1504. IR (neat): 3236, 789, 684, 678 cm−1.

3.3.2. Reduction Using LiAlH4

  • 5,8,13,13a-tetrahydro-6H-isoquinolino [1,2-b]quinazoline 22 [30]
To a suspension of 20a (60 mg, 0.24 mmol, 1 equiv.) in THF (4 mL) in an ice bath at 0 °C, a solution of LiAlH4 1 M (480 µL, 2 equiv.) in THF was added, and the reaction was stirred at the same temperature for 1 h. Then, the solvent was evaporated, and the mixture was neutralized with 4 N NaOH and extracted with CH2Cl2. The crude material was purified by chromatography on silica gel (diethyl ether 50% in petroleum ether) to give 22 as a viscous colorless oil. Yield: 89%, 50 mg. Spectra are in agreement with the literature data [30,31]. Rf. 0.35 (Et2O 50/petroleum ether 50, SiO2). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 7.2 Hz, 1H), 7.30–7.23 (m, 2H), 7.18 (dd, J = 6.8 Hz, 1H 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.15 (s, 1H), 4.34 (d, J = 16.0 Hz, 1H), 3.86 (d, J = 16.0 Hz, 1H), 3.86 (br s, 1H), 3.22–3.17 (m, 1H), 3.04–2.94 (m, 1H), 2.74–2.68 (m, 1H). HRMS (MALDI-FT ICR): m/z calcd for [C16H18N2 + H]+: 237.1386; found: 237.1383.

4. Conclusions

In summary, we developed an effective one-pot approach for the synthesis of novel polycyclic fused δ-lactams from readily available aldehydes and diamines under catalyst-free and green conditions. This procedure, which combines a sequential aza-Mannich/lactamization cascade, was easily scalable, affording a variety of compounds analogous to natural products and pharmaceuticals, further emphasizing the versatility of the developed methodology. Follow-up chemistry will also be explored to enable access to other bioactive molecules. Further studies are in course to expand the scope of this method using amino alcohols and aminothiols, which may lead to new classes of polyheterocyclic compounds.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30132702/s1. Refs. [23,33,34,35,36,37,38,39,40] are cited in the Supplementary Materials.

Author Contributions

A.D.M.: investigation, writing and supervision. C.V.: investigation. C.T.: X-ray analysis. A.M.: writing and supervision. All authors have read and agreed to the published version of the manuscript.

Funding

We thank MUR and University of Salerno (FARB) for financial support.

Data Availability Statement

CCDC 2452206 Contains the Supplementary Crystallographic Data for Compound 14j of This Paper. These Data Can Be Obtained Free of Charge from The Cambridge Crystallographic Data Centre. See Supporting Information for Further Details. Available online: http://www.ccdc.cam.ac.uk/structures (accessed on 18 June 2025).

Acknowledgments

We thank Patrizia Oliva for help processing the NMR spectra and Patrizia Iannece for performing HRMS.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 02702 g001
Figure 1. Examples of polycyclic aza-lactams.
Figure 1. Examples of polycyclic aza-lactams.
Molecules 30 02702 g001
Molecules 30 02702 sch001
Scheme 1. Previous work and present investigation.
Scheme 1. Previous work and present investigation.
Molecules 30 02702 sch001
Molecules 30 02702 g002
Figure 2. Analysis of the scope of the aza-Mannich/lactamization process.
Figure 2. Analysis of the scope of the aza-Mannich/lactamization process.
Molecules 30 02702 g002
Molecules 30 02702 g003
Figure 3. ORTEP drawing of compound 14j. Ellipsoids are shown at 50% probability level.
Figure 3. ORTEP drawing of compound 14j. Ellipsoids are shown at 50% probability level.
Molecules 30 02702 g003
Molecules 30 02702 g004
Figure 4. Structures of other amines investigated.
Figure 4. Structures of other amines investigated.
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Molecules 30 02702 g005
Figure 5. Tetracyclic δ-lactam scope.
Figure 5. Tetracyclic δ-lactam scope.
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Molecules 30 02702 sch002
Scheme 2. Reactivity of 2-formylphenylacetate 9a in the presence of 2-aminobenzylamine 17.
Scheme 2. Reactivity of 2-formylphenylacetate 9a in the presence of 2-aminobenzylamine 17.
Molecules 30 02702 sch002
Molecules 30 02702 sch003
Scheme 3. Second reactivity of compound 20a [30].
Scheme 3. Second reactivity of compound 20a [30].
Molecules 30 02702 sch003
Table 1. Reaction conditions investigation of the aza-Mannich/lactamization process.
Table 1. Reaction conditions investigation of the aza-Mannich/lactamization process.
Molecules 30 02702 i001
Entry[M] 9aTimeYield % a
1 0.56 2 h 50% b
2 0.56 2 h 52% c
3 0.56 2 h 73% d
4 0.28 2 h 74% d
5 0.56 24 h 95 % d
6 0.28 24 h 88% d
7 0.14 24 h 57% d
8 0.56 2 h 71% d,e
a Isolated yield by chromatography. b Purification by silica. c Purification by silica/Et3N 1%. d Purification by neutral alumina. e Reaction performed at 60 °C. The best result is highlighted in bold.
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Di Mola, A.; Vietri, C.; Tedesco, C.; Massa, A. Catalyst-Free Spontaneous Aza-Mannich/Lactamization Cascade Reaction: Easy Access to Polycyclic δ-Lactams. Molecules 2025, 30, 2702. https://doi.org/10.3390/molecules30132702

AMA Style

Di Mola A, Vietri C, Tedesco C, Massa A. Catalyst-Free Spontaneous Aza-Mannich/Lactamization Cascade Reaction: Easy Access to Polycyclic δ-Lactams. Molecules. 2025; 30(13):2702. https://doi.org/10.3390/molecules30132702

Chicago/Turabian Style

Di Mola, Antonia, Caterina Vietri, Consiglia Tedesco, and Antonio Massa. 2025. "Catalyst-Free Spontaneous Aza-Mannich/Lactamization Cascade Reaction: Easy Access to Polycyclic δ-Lactams" Molecules 30, no. 13: 2702. https://doi.org/10.3390/molecules30132702

APA Style

Di Mola, A., Vietri, C., Tedesco, C., & Massa, A. (2025). Catalyst-Free Spontaneous Aza-Mannich/Lactamization Cascade Reaction: Easy Access to Polycyclic δ-Lactams. Molecules, 30(13), 2702. https://doi.org/10.3390/molecules30132702

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