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Article

Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles

by
Jingya Li
,
Zhiguo Zhang
*,
Liming Chen
,
Mengjuan Li
,
Xingjie Zhang
and
Guisheng Zhang
*
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(9), 3691; https://doi.org/10.3390/molecules28093691
Submission received: 5 April 2023 / Revised: 22 April 2023 / Accepted: 22 April 2023 / Published: 25 April 2023
(This article belongs to the Special Issue Novel Organic Synthetic Route to Heterocyclic Compounds)
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Abstract

:
3-Azabicyclo[3.1.0]hexanes are common structural components in natural products and bioactive compounds. Traditionally, the metal-mediated cyclopropanation domino reaction of chain enzymes is the most commonly used strategy for the construction of this type of aza[3.1.0]bicycle derivative. In this study, a base-promoted intramolecular addition of alkenes used to deliver conformationally restricted highly substituted aza[3.1.0]bicycles is reported. This reaction was tailor-made for saturated aza[3.1.0] bicycle-containing fused bicyclic compounds that may be applied in the development of concise and divergent total syntheses of bioactive compounds.

1. Introduction

Saturated N-heterocycles such as 3-azabicyclo[3.1.0]hexanes are common structural components in natural products and bioactive compounds with a broad spectrum of activity against various bacteria, mycobacteria, parasites, tumors, and neurological disorders (Figure 1) [1,2,3,4,5,6,7,8,9]. For example, Duocarmycin SA, Yatakemycin, and CC-1065 are representative members of such well-known biomolecules that derive their antitumor activity from their ability to alkylate DNA [10]. Furthermore, they have been identified as useful synthons in a range of organic transformations [11,12,13,14,15,16,17,18,19]. Consequently, the development of methods enabling the efficient construction of such structures has been a research focus in organic chemistry.
A literature review indicates that the metal-mediated cyclopropanation domino reaction of chain enynes is the most commonly used strategy for the construction of aza[3.1.0]bicycle derivatives in terms of scalability and substrate scope, which highly rely on the in situ-generated metal carbene species in the presence of Pd, Au, Ru, Co, Ni, and Rh salts as catalysts [20,21,22,23,24,25,26,27,28,29,30,31,32,33]. Occasionally, the same conversion starting from enyne analogues has also been achieved by a photocatalytic pathway [34,35,36] as well as metal-free organocatalytic processes [37,38,39,40,41,42], mechanisms that are similar to the metal carbene processes (Scheme 1a). Another two effective approaches for the synthesis of 3-azabicyclo[3.1.0]hexanes involve the derivatization reactions of substituted cyclopropanes, such as C(sp3)–H bond activated alkenylation/amination tandem reactions and intramolecular aminolysis reactions (Scheme 1b) [43,44,45,46,47,48,49,50,51,52,53], and the reaction of functionalized maleimide derivatives with one carbon donor generated in situ derived from substituted diazomethanes, bromo(nitro)methane, substituted α-diazoacetates, and N-tosylhydrazones via an intermolecular [2+1] fused-annulation reaction (Scheme 1c) [54,55,56,57,58,59,60,61,62,63,64]. In particular, the base-induced intramolecular spirocyclization method of the alkylation subunit precursor appeared to be a more efficient proprietary reaction to access 3-azabicyclo[3.1.0]hexane scaffold-containing natural products via aryl metal or radical dearomatization/cyclization reactions (Scheme 1d) [65,66,67,68,69,70,71,72,73,74,75,76,77]. Although remarkable processing has been achieved in the last decades, achieving the synthesis of the structurally versatile aza[3.1.0]bicycles through readily available starting materials and simple and efficient chemical transformation remains a challenge. Here, describe our recent effort on the base-promoted intramolecular addition of vinyl cyclopropanecarboxamides 1 to access conformationally restricted aza[3.1.0]bicycles core 2 (Scheme 1e).

2. Results and Discussion

2.1. Reaction Optimization

Very recently, we developed a palladium(II)-catalyzed intramolecular oxidative aza-Wacker-type reaction to access a series of highly substituted aza[3.1.0]bicycles, starting from readily available compounds 1. Combined with our other works related to the derivatization reactions of amides and previous reports, we envisioned that compound 1 may continue to generate highly substituted aza[3.1.0] bicycles 2 via a molecular olefin aza-addition reaction under appropriate bases (Scheme 1e). With this assumption in mind, the model reagent 1-(4-chlorophenyl)-N-(p-tolyl)-2-vinyl cyclopropane-1-carboxamide (1a) was selected to explore the feasibility of the designed transformation; some key results are listed in Table 1. After many attempts, we found that the desired product 1-(4-chlorophenyl)-4-methyl-3-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one (2a) was isolated in 82% yield in the presence of 4.0 equiv. of tBuOK in DMF after 24 h, along with 11% of recovered 1a, which could not be consumed by prolonging the reaction time (Table 1, entry 1). Notably, when we added 4.2 equiv. of 18-crown-6 ether to the reaction [48,78], starting material 1a was completely consumed within 24 h (Table 1, entry 2). However, considering that it did not significantly affect the reaction time and the yield of product 2a, as well as the economy of the transformation, it was not added in the later experiments. Moreover, reactions performed at a lower or higher loading of tBuOK failed to give a higher yield of fuse-heterocycle 2a (Table 1, entries 3–5). Similarly, lower or higher temperatures did not help improve the reaction efficiency (Table 1, entries 6–9). The yield of the target product 2a was not increased when the reactions were carried out in the presence of four other types of bases, namely, K3PO4, NaH, NaOH, and Cs2CO3 (Table 1, entries 10–13). Other solvents, including MeCN, dioxane, toluene, NMP, and DMSO, all provided diminished or no yields of the product (Table 1, entries 14–18).

2.2. Substrate Scope

With the identified optimal reaction conditions in hand, we evaluated the scope and drawbacks of this base-promoted intramolecular addition (Scheme 2). The variation in R1 was examined first. A variety of aryl groups having electron-releasing, -neutral, or -withdrawing groups at the 3- or 4-position of the benzene ring underwent smooth intramolecular annulation leading to the formation of the aza[3.1.0]bicycles 2a–g in 40–85% yields with the regioselectivity ratio ranging from 1:1 to 2:1. Unfortunately, the analogous α-naphthyl-based substrate 1h was not suitable for this system. N-Alkyl-substituted starting material 1i afforded the desired product 2i with excellent yield (85%) in ca 5:4 of dr value.
Next, the scope of the reaction was evaluated using different R2. Selected examples are presented in Scheme 3. It can be seen that the addition reaction was proved to be well tolerated by various 1-aryl-substituted vinyl cyclopropanecarboxamides bearing a MeO– (2j and 2k), Me– (2l–n), F– (2p), and Br– (2q) group at the para-, meta-, or ortho-position, along with the phenyl group-substituted cyclopropane derivative (2o). Notably, the bromobenzene moiety of product 2q retains a derivatization site for further functionalization reactions, including Suzuki–Miyaura [15,79,80,81,82], Buchwald–Hartwig [83,84,85], and Sonogashi coupling reactions [86,87,88,89,90]. In particular, the starting material 1r with a styrene group on the cyclopropyl moiety provided the product 2r with an 81% yield.
With the aim of devising a practical, gram-scale synthesis of a biovaluable aza[3.1.0]bicycle scaffold, a reaction on 7 mmol (1.841 g) was carried out with this improved synthetic method based on the base-promoted intramolecular addition of alkenes. When we treated 1o under optimal conditions, the reaction smoothly furnished a 73% yield of 2o after 72 h under standard conditions, with 17% 1o recovered (86% yield of 2o based on the conversion of the substrate) (Scheme 4).

3. Materials and Methods

3.1. General Remarks

Unless stated otherwise, reactions were conducted in Schlenk under air. All reagents were purchased from commercial sources and used without further treatment unless otherwise indicated. Starting materials were synthesized following the literatures [91,92,93], and the procedures were described in the Supporting Information. DMF, CH3CN, DMSO, THF, and toluene for reactions were distilled under an atmosphere of dry N2. Petroleum ether (PE), used here, refers to the 60–90 °C boiling point fraction of petroleum. Ethyl acetate is abbreviated as EA. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance/600 (1H: 600 MHz, 13C: 151 MHz) or Bruker Avance/400 (1H: 400 MHz, 13C: 101 MHz at 25 °C). Fluorine nuclear magnetic resonance (19F NMR) spectra were recorded on a Bruker Avance/600 spectrometer or a Bruker Avance/400. 1H NMR spectra were calibrated against residual CHCl3 in the solvent (7.26 ppm). 13C NMR spectra were calibrated against the peak of the residual CHCl3 in the solvent (77.2 ppm). NMR data are represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet), coupling constant in hertz (Hz), and integration. All high-resolution mass spectra (HRMS) were measured on a mass spectrometer by using electrospray ionization orthogonal acceleration time-of-flight (ESI-OA-TOF), and the purity of all samples used for HRMS (>95%) was confirmed by 1H NMR and 13C NMR spectroscopic analysis. All reactions were monitored by thin-layer chromatography (TLC) (PE: EA = 10:1) with GF254 silica gel-coated plates.

3.2. Typical Experimental Procedure for 2 (2a as an Example)

In a Schlenk tube (25 mL), 1a (156 mg, 0.5 mmol) and tBuOK (224 mg, 4.0 equiv.) were added. The mixture was stirred well in DMF (2 mL) and stirred at 110 °C in a sand bath under air (the whole process was closely monitored by TLC). After the completion of the reaction, DCM (5 mL) was added to water (10 mL) and extracted with dichloromethane (3 × 10 mL). Then the organic solvent was washed with H2O (15 mL) and saturated NaCl (15 mL) solutions, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography with PE and EA (PE: EA = 20: 1) as eluent to give 2a as a white solid (128 mg, 82%).

3.3. Characterization of Products

  • 1-(4-Chlorophenyl)-4-methyl-3-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one (2a). White solid. (Yield: 82%). Mp = 74–76 °C. dr ≈ 1:1. 1H NMR (600 MHz, CDCl3) δ 7.44–7.40 (m, 4H, Ar-H), 7.34–7.30 (m, 4H, Ar-H), 7.29 (dt, J = 9.0, 2.4 Hz, 2H, Ar-H), 7.17 (t, J = 7.2 Hz, 4H, Ar-H), 7.12 (d, J = 8.4 Hz, 2H, Ar-H), 4.53 (p, J = 6.0 Hz, 1H, N-CH), 4.20 (q, J = 6.4 Hz, 1H, N-CH), 2.38–2.35 (m, 2H, CH), 2.33 (s, 3H, Ar-CH3), 2.33 (s, 3H, Ar-CH3), 2.04 (dd, J = 7.8, 4.8 Hz, 1H, CH), 1.51 (dd, J = 7.8, 4.8 Hz, 1H, CH2), 1.39 (dd, J = 7.8, 4.8 Hz, 1H, CH2), 1.36 (d, J = 6.0 Hz, 3H, CH3), 1.31 (t, J = 4.5 Hz, 1H, CH2), 1.26 (t, J = 4.5 Hz, 1H, CH2), 1.19 (d, J = 6.0 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 173.5 (C=O), 172.4 (C=O), 135.8, 135.3, 135.1, 135.0, 134.9, 134.1, 133.1, 132.8, 130.1, 129.8, 129.61, 129.58, 128.6, 128.5, 124.6, 123.5, 56.4 (C-N), 53.1 (C-N), 34.4 (C), 33.4 (C), 26.9 (CH), 26.6 (CH), 21.5 (Ar-CH3), 21.0 (Ar-CH3), 20.9 (CH3), 20.1 (CH3), 16.9 (CH2), 16.8 (CH2). HRMS (ESI) (m/z) calculated for C19H18ClNO [M + Na]+: 334.0969, found: 334.0968. IR v/cm−1 (KBr) 1678, 1512, 1496, 1391, 1396, 1292, 1182, 1086, 1012, 839, 756, 718, 521.
  • 3-(4-(Tert-butyl)phenyl)-1-(4-chlorophenyl)-4-methyl-3-azabicyclo[3.1.0]hexan-2-one (2b). White solid. (Yield: 81%). Mp = 119–121 °C. dr ≈ 5:3. 1H NMR (600 MHz, CDCl3) δ 7.42 (dd, J = 8.4, 3.6 Hz, 3.3H, Ar-H), 7.39 (s, 0.6H, Ar-H), 7.37 (s, 4.3H, Ar-H), 7.33 (d, J = 8.4 Hz, 2H, Ar-H), 7.29 (d, J = 8.4 Hz, 1.2H, Ar-H), 7.15 (d, J = 8.4 Hz, 1.2H, Ar-H), 4.55 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.23 (q, J = 6.0 Hz, 1H, major, N-CH), 2.36 (dt, J = 7.8, 4.8 Hz, 0.6H, minor, CH), 2.04 (dd, J = 7.8, 4.2 Hz, 1H, major, CH), 1.51 (dd, J = 7.8, 4.8 Hz, 1H, major, CH2), 1.41 (dd, J = 7.8, 4.8 Hz, 0.8H, minor, CH2), 1.38 (d, J = 6.6 Hz, 3H, major, CH3), 1.32 (d, J = 4.8 Hz, 1H, minor, CH2), 1.31 (s, 14H, (CH3)3), 1.25 (t, J = 4.5 Hz, 1.3H, major, CH2), 1.21 (d, J = 6.0 Hz, 2H, minor, CH3). 13C NMR (151 MHz, CDCl3) δ 173.5 (minor, C=O), 172.4 (major, C=O), 148.8 (minor), 148.3 (major), 135.1 (major), 135.01 (major), 134.98 (minor), 134.0 (minor), 133.1 (major), 132.8 (minor), 130.1 (major), 129.7 (minor), 128.6 (major), 128.5 (minor), 125.9 (major), 125.8 (minor), 124.1 (minor), 122.9 (major), 56.2 (major, C-N), 53.0 (minor, C-N), 34.51 (minor, Ar-(CH3)3), 34.46 (major, Ar-(CH3)3), 34.4 (major, C), 33.4 (minor, C), 31.3 ((CH3)3), 27.1 (minor, CH), 26.5 (major, CH), 21.6 (major, CH3), 20.1 (minor, CH3), 17.0 (major, CH2), 16.8 (minor, CH2). HRMS (ESI) (m/z) calculated for C22H24ClNO [M + Na]+: 376.1439, found: 376.1431. IR v/cm−1 (KBr) 1675, 1515, 1493, 1374, 1291, 1266, 1188, 1103, 1067, 1011, 834, 796, 728, 550.
  • 1-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4-methyl-3-azabicyclo[3.1.0]hexan-2-one (2c). White solid. (Yield: 85%). Mp = 98–100 °C. dr ≈ 1:1. 1H NMR (400 MHz, CDCl3) δ 7.45–7.40 (m, 4H, Ar-H), 7.35–7.27 (m, 6H, Ar-H), 7.15–7.10 (m, 2H, Ar-H), 6.93–6.87 (m, 4H, Ar-H), 4.48 (p, J = 6.0 Hz, 1H, N-CH), 4.12 (q, J = 6.0 Hz, 1H, N-CH), 3.80 (s, 6H, Ar-OCH3), 2.39–2.32 (m, 1H, CH), 2.04 (dd, J = 7.6, 4.4 Hz, 1H, CH), 1.51 (dd, J = 7.6, 4.4 Hz, 1H, CH2), 1.38 (dd, J = 7.8, 5.0 Hz, 1H, CH2), 1.34 (d, J = 6.0 Hz, 3H, CH3), 1.30 (t, J = 4.8 Hz, 1H, CH2), 1.27 (t, J = 4.6 Hz, 1H, CH2), 1.17 (d, J = 6.4 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 173.5 (C=O), 172.4 (C=O), 157.7, 157.5, 135.04, 134.97, 133.1, 132.8, 130.4, 130.1, 129.7, 129.6, 128.6, 128.5, 126.4, 125.6, 114.3, 114.3, 56.8 (Ar-OCH3), 55.5 (C-N), 53.5 (Ar-OCH3), 34.2 (C), 33.4 (C), 26.8 (CH), 26.7 (CH), 21.5 (CH3), 20.2 (CH3), 17.0 (CH2), 16.9 (CH2). HRMS (ESI) (m/z) calculated for C19H18ClNO2 [M + Na]+: 350.0918, found: 350.0912. IR v/cm−1 (KBr) 1674, 1512, 1497, 1375, 1300, 1181, 1110, 1088, 1030, 832, 755, 716, 537.
  • 1-(4-Chlorophenyl)-3-(3-methoxyphenyl)-4-methyl-3-azabicyclo[3.1.0]hexan-2-one (2d). White solid. (Yield: 51%). Mp = 78–80 °C. dr ≈ 5:3. 1H NMR (400 MHz, CDCl3) δ 7.44–7.39 (m, 3H, Ar-H), 7.35–7.27 (m, 3.7H, Ar-H), 7.26–7.22 (m, 1.8H, Ar-H), 6.96 (dd, J = 8.0, 1.2 Hz, 1H, major, Ar-H), 6.85 (t, J = 2.2 Hz, 0.6H, minor, Ar-H), 6.80 (dd, J = 8.0, 1.2 Hz, 0.6H, minor, Ar-H), 6.78–6.70 (m, 1.5H, Ar-H), 4.56 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.27 (q, J = 6.4 Hz, 1H, major, N-CH), 3.80 (s, 4.5H, Ar-OCH3), 2.38 (dt, J = 7.9, 5.0 Hz, 0.6H, minor, CH), 2.06 (dd, J = 8.0, 4.4 Hz, 1H, major, CH), 1.51 (dd, J = 7.6, 4.8 Hz, 1H, major, CH2), 1.44–1.38 (m, 3.7H), 1.32 (t, J = 4.8 Hz, 1H, major, CH2), 1.26 (t, J = 4.4 Hz, 1.8H, CH2), 1.23 (d, J = 6.4 Hz, 2H, minor, CH3). 13C NMR (101 MHz, CDCl3) δ 173.5 (minor, C=O), 172.6 (major, C=O), 160.13 (major), 160.07 (minor), 139.2 (major), 138.0 (minor), 134.82 (minor), 134.81 (major), 133.2 (major), 132.9 (minor), 130.3 (major), 129.9 (minor), 129.60 (major), 129.55 (minor), 128.6 (major), 128.5 (minor), 116.5 (minor), 114.6 (major), 111.7 (minor), 111.1 (major), 110.6 (minor), 108.8 (major), 56.1 (minor, Ar-OCH3), 55.4 (major, C-N), 53.1 (major, Ar-OCH3), 34.8 (minor, C), 33.6 (major, C), 26.9 (minor, CH), 26.3 (major, CH), 21.5 (major, CH3), 20.0 (minor, CH3), 16.9 (major, CH2), 16.7 (minor, CH2). HRMS (ESI) (m/z) calculated for C19H18ClNO2 [M + Na]+: 350.0918, found: 350.0914. IR v/cm−1 (KBr) 1681,1602, 1579, 1490, 1456, 1373, 1293, 1173, 1087, 1068, 1037, 848, 756, 570.
  • 1-(4-Chlorophenyl)-4-methyl-3-phenyl-3-azabicyclo[3.1.0]hexan-2-one (2e). White solid. (Yield: 64%). Mp = 88–90 °C. dr ≈ 5:3. 1H NMR (400 MHz, CDCl3) δ 7.49–7.45 (m, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 3H, Ar-H), 7.40–7.37 (m, 1.3H, Ar-H), 7.35 (d, J = 9.2 Hz, 2.8H, Ar-H), 7.33–7.28 (m, 2H, Ar-H), 7.25–7.21 (m, 1.3H, Ar-H), 7.18 (t, J = 7.4 Hz, 1.3H, Ar-H), 4.59 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.27 (q, J = 6.4 Hz, 1H, major, N-CH), 2.42–2.35 (m, 0.6H, minor, CH), 2.06 (dd, J = 7.6, 4.4 Hz, 1H, major, CH), 1.52 (dd, J = 7.6, 4.8 Hz, 1H, major, CH2), 1.43–1.40 (m, 0.5H, minor, CH2), 1.38 (d, J = 6.0 Hz, 3H, major, CH3), 1.33 (t, J = 4.8 Hz, 0.7H, minor, CH2), 1.27 (t, J = 4.6 Hz, 1.5H, major, CH2), 1.21 (d, J = 6.0 Hz, 2H, minor, CH3). 13C NMR (151 MHz, CDCl3) δ 173.5 (minor, C=O), 172.5 (major, C=O), 137.8 (major), 136.8 (minor), 134.9 (major), 134.8 (minor), 133.2 (major), 132.9 (minor), 130.1 (major), 129.8 (minor), 129.0 (major), 128.9 (minor), 128.6 (major), 128.5 (minor), 125.9 (minor), 125.4 (minor), 124.5 (major), 123.2 (major), 56.1 (major, C-N), 53.0 (minor, C-N), 34.6 (major, C), 33.5 (minor, C), 26.9 (minor, CH), 26.5 (major, CH), 21.5 (major, CH3), 20.1 (minor, CH3), 16.9 (major, CH2), 16.8 (minor, CH2). HRMS (ESI) (m/z) calculated for C18H16ClNO [M + Na]+: 320.0813, found: 320.0807. IR v/cm−1 (KBr) 1680, 1595, 1491, 1374, 1294, 1178, 1102, 1065, 1039, 838, 753, 719, 528.
  • 1-(4-Chlorophenyl)-3-(4-fluorophenyl)-4-methyl-3-azabicyclo[3.1.0]hexan-2-one (2f). White solid. (Yield: 61%). Mp = 82–84 °C. dr ≈ 3:2. 1H NMR (400 MHz, CDCl3) δ 7.44–7.36 (m, 5.3H, Ar-H), 7.35–7.31 (m, 2H, Ar-H), 7.31–7.28 (m, 2H, Ar-H), 7.22–7.16 (m, 1.3H, Ar-H), 7.11–7.02 (m, 3.2H, Ar-H), 4.52 (p, J = 6.0 Hz, 0.7H, minor, N-CH), 4.19 (q, J = 6.4 Hz, 1H, major, N-CH), 2.39 (dt, J = 8.0, 4.8 Hz, 0.7H, minor, CH), 2.07 (dd, J = 7.6, 4.4 Hz, 1H, major, CH), 1.53 (dd, J = 7.6, 4.8 Hz, 1H, major, CH2), 1.41 (dd, J = 7.6, 4.8 Hz, 1H, major, CH2), 1.36 (d, J = 6.0 Hz, 3H, major, CH3), 1.31 (t, J = 4.8 Hz, 0.8H, minor, CH2), 1.27 (t, J = 4.8 Hz, 2H, CH2), 1.20 (d, J = 6.4 Hz, 2H, minor, CH3). 13C NMR (151 MHz, CDCl3) δ 173.6 (minor, C=O), 172.5 (major, C=O), 160.5 (d, J = 246.1 Hz, minor, C-F), 160.2 (d, J = 244.6 Hz, major, C-F), 134.7 (major), 134.6 (minor), 133.6 (d, J = 3.0 Hz, major), 133.3 (major), 133.0 (minor), 132.7 (d, J = 2.7 Hz, minor), 130.1 (major), 129.8 (minor), 128.6 (major), 128.5 (minor), 126.4 (d, J = 4.5 Hz, minor), 125.4 (d, J = 7.6Hz, major), 115.9 (d, J = 4.5 Hz, minor), 115.8 (d, J = 6.0 Hz, major), 56.5 (major, N-CH), 53.3 (minor, N-CH), 34.3 (major, C), 33.4 (minor, C), 26.8 (minor, CH), 26.5 (major, CH), 21.4 (major, CH3), 20.1 (minor, CH3), 16.9 (major, CH2), 16.8 (minor, CH2). 19F NMR (565 MHz, CDCl3) δ −115.8 (minor), −116.4 (major). HRMS (ESI) (m/z) calculated for C18H15ClFNO [M + Na]+: 338.0718, found: 338.0716. IR v/cm−1 (KBr) 1682, 1505, 1378, 1180, 1101, 1064, 1014, 833, 718, 533.
  • 1-(4-Chlorophenyl)-3-(3-fluorophenyl)-4-methyl-3-azabicyclo[3.1.0]hexan-2-one (2g). White solid. (Yield: 40%). Mp = 82–84 °C. dr ≈ 2:1. 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 3.8H, Ar-H), 7.36–7.34 (m, 1.5H, Ar-H), 7.33–7.31 (m, 1.7H, Ar-H), 7.30 (d, J = 1.6 Hz, 0.5H, Ar-H), 7.29 (d, J = 3.6 Hz, 0.5H, Ar-H), 7.27–7.26 (m, 0.6H, Ar-H), 7.25–7.23 (m, 0.4H, Ar-H), 7.03 (dd, J = 8.8, 1.2 Hz, 1H, Ar-H), 6.93–6.83 (m, 1.4H, Ar-H), 4.57 (p, J = 6.0 Hz, 0.5H, minor, N-CH), 4.28 (q, J = 6.4 Hz, 1H, major, N-CH), 2.45–2.38 (m, 0.4H, minor, CH), 2.07 (dd, J = 8.0, 4.4 Hz, 1H, major, CH), 1.53 (dd, J = 7.6, 4.8 Hz, 1H, major, CH2), 1.45–1.39 (m, 3.5H), 1.32 (t, J = 4.6 Hz, 0.6H, minor, CH2), 1.28–1.22 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 173.5 (minor, C=O), 172.6 (major, C=O), 163.0 (d, J = 246.1 Hz, major, C-F), 162.9 (d, J = 246.1 Hz, minor, C-F), 139.6 (d, J = 10.6 Hz, major), 138.4 (d, J = 10.6 Hz, minor), 134.5 (d, J = 3.0 Hz, major), 133.4 (major), 133.1 (minor), 130.2 (minor), 130.1 (d, J = 9.1 Hz, major), 130.0 (d, J = 9.1 Hz, minor), 129.9 (major), 128.7 (major), 128.5 (minor), 119.6 (d, J = 3.0 Hz, minor), 117.4 (d, J = 3.0 Hz, major), 112.6 (d, J = 6.0 Hz, minor), 111.8 (d, J = 21.1 Hz, major), 111.5, 109.8 (d, J = 25.7 Hz, major), 55.9 (major, N-CH), 52.9 (minor, N-CH), 34.8 (major, C), 33.6 (minor, C), 26.9 (minor, CH), 26.3 (major, CH), 21.3 (major, CH3), 20.0 (minor, CH3), 16.9 (major, CH2), 16.7 (minor, CH2). 19F NMR (565 MHz, CDCl3) δ -111.3 (major), -111.8 (minor). HRMS (ESI) (m/z) calculated for C18H15ClFNO [M + Na]+: 338.0718, found: 338.0712. IR v/cm−1 (KBr) 1682, 1588, 1491, 1452, 1368, 1296, 1185, 1087, 1064, 1014, 856, 754, 719, 591, 482.
  • 3-Butyl-1-(4-chlorophenyl)-4-methyl-3-azabicyclo[3.1.0]hexan-2-one (2i). yellow oil. (Yield: 85%) °C. dr ≈ 5:4. 1H NMR (600 MHz, CDCl3) δ 7.35 (dd, J = 10.8, 8.4 Hz, 3H, Ar-H), 7.28 (d, J = 7.8 Hz, 3H, Ar-H), 3.98 (p, J = 6.0 Hz, 1H, minor, N-CH), 3.61–3.55 (m, 1.5H, minor), 3.54–3.48 (m, 1H, major, N-CH), 2.90–2.83 (m, 1.6H, major), 2.21–2.16 (m, 1H, major, CH), 1.86 (dd, J = 7.8, 4.2 Hz, 1H, minor, CH), 1.52–1.45 (m, 1.5H, major), 1.45–1.42 (m, 1H, minor), 1.41 (dd, J = 7.8, 4.8 Hz, 1.6H, major), 1.32 (d, J = 6.0 Hz, 2.7H, minor, CH3), 1.31–1.29 (m, 2H), 1.28–1.26 (m, 1.3H), 1.25 (d, J = 6.6 Hz, 3H, major, CH3), 1.08 (t, J = 4.8 Hz, 1H, major, CH2), 0.99 (t, J = 4.2 Hz, 0.8H, minor, CH2), 0.95–0.90 (m, 5H). 13C NMR (151 MHz, CDCl3) δ 173.9 (major, C=O), 173.2 (minor, C=O), 135.4 (minor), 135.3 (major), 132.8 (minor), 132.7 (major), 129.9 (minor), 129.7 (major), 128.5 (major), 128.4 (minor), 53.8 (minor, N-CH), 51.3 (major, N-CH), 39.8 (minor, N-CH2), 39.5 (major, N-CH2), 33.5 (minor, CH2-C-CH2), 33.2 (major, CH2-C-CH2), 29.9 (minor, CH), 29.5 (major, CH), 27.0 (minor, C), 26.9 (major, C), 21.0 (major, CH2-C-CH3), 20.2 (major, CH2-C-CH3), 20.1 (minor, CH3), 19.9 (minor, CH3), 17.1 (major, CH2), 16.6 (minor, CH2), 13.83 (minor, CH2-CH3), 13.79 (major, CH2-CH3). HRMS (ESI) (m/z) calculated for C16H20ClNO [M + Na]+: 300.1126, found: 300.1127. IR v/cm−1 (KBr) 1676, 1497, 1455, 1417, 1376, 1091, 1013, 819, 723, 527.
  • 1-(4-Methoxyphenyl)-4-methyl-3-phenyl-3-azabicyclo[3.1.0]hexan-2-one (2j). White solid. (Yield: 72%). Mp = 48–50 ºC. dr ≈ 2:1. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 2H, Ar-H), 7.42–7.32 (m, 6H, Ar-H), 7.25–7.13 (m, 2H, Ar-H), 6.93–6.84 (m, 3H, Ar-H), 4.59 (p, J = 6.0 Hz, 0.5H, minor, N-CH), 4.27 (q, J = 6.4 Hz, 1H, major, N-CH), 3.81 (s, 3H, major, Ar-OCH3), 3.80 (s, 1.4H, minor, Ar-OCH3), 2.34 (dt, J = 7.6, 4.8 Hz, 0.5H, minor, CH), 2.01 (dd, J = 7.6, 4.0 Hz, 1H, major, CH), 1.50 (dd, J = 7.6, 4.4 Hz, 1H, major, CH2), 1.41–1.36 (m, 4H), 1.29–1.24 (m, 1.5H, CH2), 1.23–1.19 (m, 2.8H). 13C NMR (151 MHz, CDCl3) δ 174.2 (minor, C=O), 173.3 (major, C=O), 158.9 (major), 158.7 (minor), 138.1 (major), 137.0 (minor), 130.2 (major), 129.9 (minor), 129.0 (major), 128.9 (minor), 128.4 (major), 128.3 (minor), 125.6 (minor), 125.1 (major), 124.5 (minor), 123.0 (minor), 114.0 (major), 113.8 (minor), 56.1 (major, Ar-OCH3), 55.4 (major, C-N), 55.3 (minor, Ar-OCH3), 53.0 (minor, C-N), 34.8 (major, C), 33.7 (minor, C), 26.6 (minor, CH), 26.2 (major, CH), 21.5 (major, CH3), 19.6 (major, CH3), 17.0 (minor, CH2), 16.2 (minor, CH2). HRMS (ESI) (m/z) calculated for C19H19NO2 [M + Na]+: 316.1308, found: 316.1308. IR v/cm−1 (KBr) 1682, 1516, 1492, 1392, 1369, 1296, 1177, 1107, 1031, 838, 761, 747, 538.
  • 1-(3-Methoxyphenyl)-4-methyl-3-phenyl-3-azabicyclo[3.1.0]hexan-2-one (2k). White solid. (Yield: 80%). Mp = 78–80 °C. dr ≈ 5:3. 1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 2H, Ar-H), 7.37 (dd, J = 16.6, 8.9 Hz, 3H, Ar-H), 7.28 (t, J = 7.8 Hz, 1H, Ar-H), 7.26–7.15 (m, 4H, Ar-H), 7.11 (s, 1H, Ar-H), 7.04 (d, J = 7.8 Hz, 1H, major, Ar-H), 6.99 (d, J = 7.8 Hz, 0.5H, minor, Ar-H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H, major, Ar-H), 6.81 (dd, J = 7.8, 2.1 Hz, 0.5H, minor, Ar-H), 4.59 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.26 (q, J = 6.0 Hz, 1H, major, N-CH), 3.83 (s, 3H, major, Ar-OCH3), 3.81 (s, 1.7H, minor, Ar-OCH3), 2.40 (dt, J = 7.8, 5.0 Hz, 0.6H, minor, CH), 2.06 (dd, J = 7.8, 4.2 Hz, 1H, major, CH), 1.55 (dd, J = 7.8, 4.8 Hz, 1H, major, CH2), 1.44 (dd, J = 7.8, 4.8 Hz, 0.6H, minor, CH2), 1.39 (d, J = 6.6 Hz, 3H, major, CH3), 1.32 (t, J = 4.8 Hz, 0.6H, minor, CH2), 1.25 (t, J = 4.5 Hz, 1H, major, CH2), 1.21 (d, J = 6.0 Hz, 1.7H, minor, CH3). 13C NMR (101 MHz, CDCl3) δ 173.7 (minor, C=O), 172.8 (major, C=O), 159.64 (major), 159.59 (minor), 138.0 (major), 137.9 (major), 136.9 (minor), 129.4 (major), 129.3 (minor), 129.0 (major), 128.9 (minor), 125.8 (minor), 125.3 (major), 124.6 (minor), 123.2 (major), 120.9 (major), 120.3 (minor), 114.7 (major), 114.0 (minor), 113.0 (minor), 112.8 (major), 56.1 (minor, Ar-OCH3), 55.3 (major, C-N), 53.0 (minor, Ar-OCH3), 35.1 (major, C), 33.9 (minor, C), 27.1 (minor, CH), 26.5 (major, CH), 21.4 (major, CH3), 20.0 (major, CH3), 17.0 (minor, CH2), 16.9 (major, CH2). HRMS (ESI) (m/z) calculated for C19H19NO2 [M + Na]+: 316.1308, found: 316.1308. IR v/cm−1 (KBr) 1682, 1594, 1493, 1456, 1372, 1293, 1186, 1040, 1028, 939, 759, 623.
  • 4-Methyl-3-phenyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one (2l). White solid. (Yield: 67%). Mp = 89–91 °C. dr ≈ 5:4. 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 2H, Ar-H), 7.39–7.34 (m, 7H, Ar-H), 7.25 (s, 0.7H, Ar-H), 7.20–7.13 (m, 5H, Ar-H), 4.59 (p, J = 6.0 Hz, 0.7H, minor, N-CH), 4.27 (q, J = 6.0 Hz, 1H, major, N-CH), 2.37–2.34 (m, 3.8H), 2.33 (s, 2H), 2.02 (dd, J = 7.8, 4.2 Hz, 1H, major, CH), 1.54 (dd, J = 7.8, 4.8 Hz, 1H, major, CH2), 1.42 (dd, J = 7.8, 4.8 Hz, 0.8H, minor, CH2), 1.39 (d, J = 6.0 Hz, 3H, major, CH3), 1.28 (t, J = 4.2 Hz, 1H, major, CH2), 1.23 (d, J = 4.2 Hz, 1H, major, CH2), 1.21 (d, J = 6.6 Hz, 2.4H, minor, CH3). 13C NMR (151 MHz, CDCl3) δ 174.1 (minor, C=O), 173.1 (major, C=O), 138.1 (major), 137.03 (major), 137.00 (minor), 136.7 (minor), 133.3 (major), 133.2 (minor), 129.2 (major), 129.1 (major), 128.95 (major), 128.85 (minor), 128.8 (minor), 128.5 (minor), 125.6 (minor), 125.1 (minor), 124.5 (major), 123.0 (major), 56.1 (major, C-N), 53.0 (minor), 35.0 (major, C), 33.9 (minor, C), 26.8 (minor, CH), 26.4 (major, CH), 21.5 (major, Ar-CH3), 21.15 (minor, Ar-CH3), 21.11 (minor, CH3), 19.6 (major, CH3), 17.0 (major, CH2), 16.2 (minor, CH2). HRMS (ESI) (m/z) calculated for C19H19NO [M + Na]+: 300.1359, found: 300.1358. IR v/cm−1 (KBr) 1678, 1595, 1493, 1456, 1371, 1296, 1179, 1110, 1066, 1031, 922, 762, 640, 529.
  • 4-Methyl-3-phenyl-1-(m-tolyl)-3-azabicyclo[3.1.0]hexan-2-one (2m). White solid. (Yield: 76%). Mp = 103–105 °C. dr ≈ 2:1. 1H NMR (400 MHz, CDCl3) δ 7.52–7.48 (m, 2H, Ar-H), 7.40–7.30 (m, 5H, Ar-H), 7.26–7.14 (m, 5H, Ar-H), 7.13–7.05 (m, 1.6H, Ar-H), 4.59 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.27 (q, J = 6.4 Hz, 1H, major, N-CH), 2.39–2.35 (m, 3.8H), 2.34 (s, 1.7H, minor), 2.04 (dd, J = 8.0, 4.4 Hz, 1H, major, CH), 1.57–1.54 (m, 1H, CH2), 1.45 (dd, J = 7.6, 4.8 Hz, 0.6H, CH2), 1.40 (d, J = 9.6 Hz, 3H, major, CH3), 1.29 (t, J = 4.8 Hz, 0.6H, minor, CH2), 1.24 (d, J = 4.4 Hz, 1H, CH2), 1.22 (d, J = 6.0 Hz, 2H, minor, CH3). 13C NMR (101 MHz, CDCl3) δ 174.0 (C=O), 173.1 (C=O), 138.1, 137.9, 137.0, 136.2, 136.1, 129.7, 129.5, 129.0, 128.9, 128.4, 128.3, 128.1, 127.8, 125.9, 125.7, 125.4, 125.2, 124.5, 123.1, 56.1 (C-N), 53.0 (C-N), 35.2 (C), 34.1 (C), 26.9 (CH), 26.4 (CH), 21.5 (Ar-CH3), 21.4 (CH3), 19.6 (CH3), 17.0, (CH2), 16.2 (CH2). HRMS (ESI) (m/z) calculated for C19H19NO2 [M + Na]+: 300.1359, found: 300.1359. IR v/cm−1 (KBr) 1683, 1494, 1455, 1376, 1296, 1181, 1108, 1067, 758, 606, 511.
  • 4-Methyl-3-phenyl-1-(o-tolyl)-3-azabicyclo[3.1.0]hexan-2-one (2n). White solid. (Yield: 62%). Mp = 100–102 °C. dr ≈ 5:3. 1H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 2H, Ar-H), 7.40–7.31 (m, 4H, Ar-H), 7.27 (s, 0.5H, Ar-H), 7.25–7.14 (m, 7H, Ar-H), 4.66 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.33 (q, J = 6.0 Hz, 1H, major, N-CH), 2.54 (s, 3H, major, Ar-CH3), 2.40 (s, 1.7H, minor, Ar-CH3), 2.22 (dt, J = 7.8, 4.8 Hz, 0.6H, minor, CH), 2.06 (dd, J = 7.2, 3.6 Hz, 1H, major, CH), 1.52 (dd, J = 7.8, 4.8 Hz, 1H, major, CH2), 1.47 (d, J = 4.8 Hz, 0.5H, minor, CH2), 1.45 (d, J = 6.0 Hz, 3H, major, CH3), 1.33–1.29 (m, 2H, CH2), 1.25 (d, J = 6.6 Hz, 2.4H, minor, CH3). 13C NMR (151 MHz, CDCl3) δ 173.9 (minor, C=O), 172.8 (major, C=O), 139.8 (major), 139.2 (minor), 138.0 (major), 137.1 (minor), 134.6 (minor), 134.3 (major), 130.7 (minor), 130.6 (major), 130.5 (major), 130.2 (minor), 128.95 (major), 128.89 (minor), 128.0 (major), 127.9 (minor), 125.9 (minor), 125.74 (major), 125.70 (minor), 125.2 (major), 124.5 (minor), 123.1 (major), 56.3 (major, C-N), 53.2 (minor, C-N), 35.5 (major, C), 34.7 (minor, C), 26.2 (minor, CH), 26.0 (major, CH), 20.9 (major, Ar-CH3), 20.1 (minor, Ar-CH3), 19.6 (minor, CH3), 19.5 (major, CH3), 17.1 (major, CH2), 14.6 (minor, CH2). HRMS (ESI) (m/z) calculated for C19H19NO2 [M + Na]+: 300.1359, found: 300.1358. IR v/cm−1 (KBr) 1682, 1596, 1495, 1456, 1373, 1293, 1179, 1099, 1067, 1027, 923, 751, 728, 659, 533.
  • 4-Methyl-1,3-diphenyl-3-azabicyclo[3.1.0]hexan-2-one (2o). Yellow solid. (Yield: 83%). Mp = 87–89 °C. dr ≈ 3:2. 1H NMR (400 MHz, CDCl3) δ 7.52–7.46 (m, 5H, Ar-H), 7.41–7.33 (m, 6H, Ar-H), 7.32–7.28 (m, 1.2H, Ar-H), 7.28–7.26 (m, 1H, Ar-H),7.25–7.23 (m, 0.7H, Ar-H), 7.22–7.15 (m, 1.6H, Ar-H, 4.60 (p, J = 6.0 Hz, 0.7H, minor, N-CH), 4.28 (q, J = 6.3 Hz, 1H, major, N-CH), 2.43–2.37 (m, 0.7H, minor, CH), 2.07 (dd, J = 7.6, 4.4 Hz, 1H, major, CH), 1.58–1.55 (m, 1H, major, CH2), 1.46 (dd, J = 7.6, 4.8 Hz, 0.7H, minor, CH2), 1.39 (d, J = 6.0 Hz, 3H, major, CH3), 1.32 (t, J = 4.8 Hz, 0.7H, minor, CH2), 1.26 (t, J = 4.8 Hz, 1H, major, CH2), 1.22 (d, J = 6.0 Hz, 2H, minor, CH3). 13C NMR (151 MHz, CDCl3) δ 173.9 (minor, C=O), 173.0 (major, C=O), 138.0 (major), 136.9 (major), 136.3 (minor), 136.2 (minor), 129.0 (minor), 128.9 (major), 128.50, 128.47, 128.4, 127.3, 127.0, 125.7, 125.2, 124.6, 123.1, 56.1 (major, C-N), 53.0 (minor, C-N), 35.2 (major, C), 34.1 (minor, C), 26.9 (minor, C-H), 26.4 (major, C-H), 21.5 (major, CH2), 19.7 (minor, CH2), 17.0 (major, CH3), 16.4 (minor, CH3). HRMS (ESI) (m/z) calculated for C18H17NO [M + Na]+: 286.1202, found: 286.1202. IR v/cm−1 (KBr) 1682, 1598, 1495, 1447, 1372, 1299, 1178, 1101, 1063, 1021, 757, 664, 530.
  • 1-(4-Fluorophenyl)-4-methyl-3-phenyl-3-azabicyclo[3.1.0]hexan-2-one (2p). White solid. (Yield: 79%). Mp = 98–100 °C. dr ≈ 2:1. 1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 1.6H, Ar-H), 7.47–7.43 (m, 2.4H, Ar-H), 7.37 (q, J = 7.8 Hz, 2.5H, Ar-H), 7.24 (d, J = 7.8 Hz, 1H, Ar-H), 7.22–7.16 (m, 1.2H, Ar-H), 7.05 (t, J = 8.7 Hz, 1.6H, major, Ar-H), 7.02 (t, J = 8.7 Hz, 1H, minor, Ar-H), 4.59 (p, J = 6.0 Hz, 0.4H, minor, N-CH), 4.27 (q, J = 6.0 Hz, 1H, major, N-CH), 2.38 (dt, J = 7.8, 5.1 Hz, 0.4H, minor, CH), 2.05 (dd, J = 7.8, 4.2 Hz, 1H, major, N-CH), 1.51 (dd, J = 7.8, 4.2 Hz, 1H, major, CH2), 1.39 (d, J = 6.0 Hz, 3H, major, CH3), 1.31 (t, J = 4.5 Hz, 0.5H, minor, CH2), 1.26 (t, J = 4.5 Hz, 1H, major, CH2), 1.22 (d, J = 6.0 Hz, 1.3H, minor, CH3). 13C NMR (101 MHz, CDCl3) δ 173.8 (minor, C=O), 172.8 (major, C=O), 162.1 (d, J = 246.4 Hz, major, C-F), 162.0 (d, J = 246.4 Hz, minor, C-F), 137.9 (major), 136.8 (minor), 132.1 (d, J = 3.0 Hz, major), 132.0 (d, J = 4.0 Hz, minor), 130.6 (d, J = 8.1 Hz, major), 130.3 (d, J = 8.1 Hz, minor), 129.0 (major), 128.9 (minor), 125.8 (minor), 125.3 (major), 124.5 (minor), 123.2 (major), 115.3 (d, J = 22.2 Hz, major), 115.2 (d, J = 21.2 Hz, minor), 56.1 (major, C-N), 53.0 (minor, C-N), 34.7 (major, C), 33.6 (minor, C), 26.7 (minor, C-H), 26.3 (major, C-H), 21.5 (major, CH2), 19.9 (minor, CH2), 16.9 (major, CH3), 16.5 (minor, CH3). 19F NMR (376 MHz, CDCl3) δ -115.1 (major), -115.5 (minor). HRMS (ESI) (m/z) calculated for C18H16FNO [M + Na]+: 304.1108, found: 304.1107. IR v/cm−1 (KBr) 1685, 1493, 1455, 1406, 1394, 1381, 1250, 1230, 1076, 1066, 1028, 757, 600.
  • 1-(4-Bromophenyl)-4-methyl-3-phenyl-3-azabicyclo[3.1.0]hexan-2-one (2q). White solid. (Yield: 80%). Mp = 119–121 °C. dr ≈ 5:3. 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H, Ar-H), 7.46 (t, J = 8.1 Hz, 3H, Ar-H), 7.40–7.34 (m, 6.5H, Ar-H), 7.24 (d, J = 7.8 Hz, 1H, Ar-H), 7.19 (dt, J = 11.4, 7.5 Hz, 1.6H, Ar-H), 4.58 (p, J = 6.0 Hz, 0.6H, minor, N-CH), 4.27 (q, J = 6.0 Hz, 1H, major, N-CH), 2.39 (dt, J = 7.8, 5.1 Hz, 0.6H, minor, CH), 2.06 (dd, J = 7.2, 4.8 Hz, 1H, major, CH), 1.52 (dd, J = 7.2, 4.8 Hz, 1H, major, CH2), 1.41 (dd, J = 7.8, 4.8 Hz, 1H, major, CH2), 1.38 (d, J = 6.6 Hz, 3H, major, CH3), 1.33 (t, J = 4.8 Hz, 0.7H, minor, CH2), 1.28 (t, J = 4.8 Hz, 1H, major, CH2), 1.21 (d, J = 6.6 Hz, 1.8H, minor, CH3). 13C NMR (101 MHz, CDCl3) δ 173.4 (minor, C=O), 172.4 (major, C=O), 137.8 (major), 136.7 (minor), 135.42 (major), 135.36 (minor), 131.6 (major), 131.4 (minor), 130.5 (major), 130.1 (minor), 129.0 (major), 128.9 (minor), 125.9 (minor), 125.4 (major), 124.6 (minor), 123.2 (major), 121.3 (major), 121.0 (minor), 56.1 (major, C-N), 53.0 (minor, C-N), 34.6 (major, C), 33.5 (minor, C), 26.9 (minor, CH), 26.5 (major, CH), 21.5 (major, CH3), 20.1 (minor, CH3), 16.9 (major, CH2), 16.8 (minor, CH2). HRMS (ESI) (m/z) calculated for C18H16BrNO [M + Na]+: 364.0307, found: 364.0307. IR v/cm−1 (KBr) 1682, 1489, 1389, 1382, 1100, 1066, 1057, 765, 699.
  • 4-Benzyl-1-(4-chlorophenyl)-3-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one: (2r). White solid. (Yield: 81%). Mp = 92–93 °C. dr ≈ 10:1. 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 2H, Ar-H), 7.43 (d, J = 7.8 Hz, 0.2H, Ar-H), 7.37 (d, J = 7.8 Hz, 0.5H, Ar-H), 7.36–7.27 (m, 3.5H, Ar-H), 7.24 (d, J = 7.8 Hz, 2.4H, Ar-H), 7.23–7.16 (m, 2.4H, Ar-H), 7.16–7.10 (m, 1.8H, Ar-H), 4.60–4.55 (m, 0.2H, N-CH), 4.49 (dd, J = 6.0, 3.4 Hz, 1H, N-CH), 3.01 (d, J = 13.8, 3.6 Hz, 1H, CH2), 2.94 (dd, J = 13.8, 6.6 Hz, 1H, CH2), 2.48–2.41 (m, 0.3H, CH2), 2.37 (s, 3H, major, CH3), 2.34 (s, 0.3H, minor, CH3), 2.31–2.45 (m, 0.2H, CH2), 2.17–2.12 (m, 0.2H, CH2), 2.06 (dd, J = 7.8, 4.8 Hz, 1H, CH2), 1.62–1.56 (m, 0.3H, CH2),1.52 (dd, J = 7.8, 5.4 Hz, 0.1H, CH2), 1.46 (dd, J = 7.7, 4.9 Hz, 1H), 1.27 (t, J = 4.4 Hz, 1H), 1.22–1.15 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 173.5 (minor, C=O), 172.8 (major, C=O), 137.2, 136.1, 135.9, 135.2, 135.1, 134., 134.50, 134.1, 133.0, 132.9, 130.2, 129.9, 129.81, 129.78, 129.7, 129.1, 128.9, 128.7, 128.4, 128.3, 126.95, 126.88, 124.8, 122.9, 60.6 (major, N-CH), 59.2 (minor, N-CH), 39.2 (major, Ar-CH2), 37.5 (minor, Ar-CH2), 34.9 (major, CH), 33.8 (minor, CH), 24.9 (minor, C), 24.0 (major, C), 21.1 (minor, CH3), 21.0 (major, CH3), 19.0 (major, CH2), 17.3 (minor, CH2). HRMS (ESI) (m/z) calculated for C25H22ClNO [M + Na]+: 410.1282, found: 410.1275. IR v/cm−1 (KBr) 1681, 1514, 1494, 1384, 1293, 1082, 1066, 836, 749, 726, 531.

4. Conclusions

In summary, we developed a base-promoted intramolecular alkene addition reaction starting from readily available vinyl cyclopropanes to access a series of conformationally restricted biologically valuable highly substituted aza[3.1.0]bicycles in moderate to good yields. The transformation was performed in the presence of tBuOK in DMF at 110 °C under an air atmosphere. Experiments showed that large concentrations of the base are beneficial to the nucleophilic addition process. Although the protocol is limited to substituted cyclopropionamides with a range of functional aryl groups, the cyclopropane moiety in the fused ring is a valuable derivatization unit for the further construction of structurally diverse biologically organic molecules. This reaction was tailor-made for saturated aza[3.1.0]bicycle-containing fused bicyclic compounds. Further derivatization and chemical biology application evaluation of aza[3.1.0]bicyclic compounds are concurrently underway in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28093691/s1. Characterization data for product 2, including 1H-NMR and 13C-NMR spectroscopies, are available online. References [91,92,93] are cited in the Supplementary Materials.

Author Contributions

Conceptualization and writing—review and editing, G.Z.; methodology, J.L., L.C. and M.L.; investigation, data curation, and writing—original draft preparation and writing—review and editing, Z.Z.; project administration, X.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the NSFC (22101074, 21877206, and 21772032), the 111 Project (D17007), the Excellent Youth Foundation of Henan Scientific Committee (222300420012), and the Natural Science Foundation of Henan Province (202300410233).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors thank the Henan Key Laboratory of Organic Functional Molecules and Drug Innovation for financial support. We thank Ian McNaught, for editing the English text of a draft of this manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of compounds are available from the authors.

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Molecules 28 03691 g001 550
Figure 1. Bioactive molecules containing aza[3.1.0]bicycles.
Figure 1. Bioactive molecules containing aza[3.1.0]bicycles.
Molecules 28 03691 g001
Molecules 28 03691 sch001 550
Scheme 1. Strategies for constructing a bicyclic system [21,52,58,68].
Scheme 1. Strategies for constructing a bicyclic system [21,52,58,68].
Molecules 28 03691 sch001
Molecules 28 03691 sch002 550
Scheme 2. Extension of the reaction scope with various R1 a,b. a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), tBuOK (4.0 equiv), and DMF (2 mL) at 110 °C under air in a sealed tube. b Isolated yields are reported, and unless otherwise indicated, the yields in parentheses are based on the conversion of substrate 1. The dr values were determined from the 1H NMR analysis of the crude reaction mixture. c Recovery of 1h.
Scheme 2. Extension of the reaction scope with various R1 a,b. a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), tBuOK (4.0 equiv), and DMF (2 mL) at 110 °C under air in a sealed tube. b Isolated yields are reported, and unless otherwise indicated, the yields in parentheses are based on the conversion of substrate 1. The dr values were determined from the 1H NMR analysis of the crude reaction mixture. c Recovery of 1h.
Molecules 28 03691 sch002
Molecules 28 03691 sch003 550
Scheme 3. Extension of the reaction scope with various R2 a,b. a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), tBuOK (4.0 equiv), and DMF (2 mL) at 110 °C under air in a sealed tube. b Isolated yields are reported, and the yields in parentheses are based on the conversion of substrate 1. The dr values were determined from the 1H NMR analysis of the crude reaction mixture.
Scheme 3. Extension of the reaction scope with various R2 a,b. a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), tBuOK (4.0 equiv), and DMF (2 mL) at 110 °C under air in a sealed tube. b Isolated yields are reported, and the yields in parentheses are based on the conversion of substrate 1. The dr values were determined from the 1H NMR analysis of the crude reaction mixture.
Molecules 28 03691 sch003
Molecules 28 03691 sch004 550
Scheme 4. Gram-scale preparation.
Scheme 4. Gram-scale preparation.
Molecules 28 03691 sch004
Table
Table 1. Survey of the reaction conditions a.
Table 1. Survey of the reaction conditions a.
Molecules 28 03691 i001
EntryBase/equivSolventt/°CTime/hYield/% b
1tBuOK (4.0)DMF1102482 (11)
2tBuOK (4.0)DMF1102486 c
3tBuOK (2.0)DMF1102464 (35)
4tBuOK (3.0)DMF1102472 (6)
5tBuOK (5.0)DMF1102457 (26)
6tBuOK (4.0)DMF1002447 (48)
7tBuOK (4.0)DMF1202477 (16)
8tBuOK (4.0)DMF1302473 (8)
9tBuOK (4.0)DMF1402443
10K3PO4 (4.0)DMF1102439 (58)
11NaH (4.0)DMF1102415 (81)
12NaOH (4.0)DMF1102422 (68)
13Cs2CO3 (4.0)DMF1102420 (72)
14tBuOK (4.0)MeCN1102418 (76)
15tBuOK (4.0)Dioxane110240 (93)
16tBuOK (4.0)Toluene110240 (91)
17tBuOK (4.0)NMP1102468 (6)
18tBuOK (4.0)DMSO110240 (85)
a Unless otherwise indicated, the reaction was conducted with 1a (0.5 mmol, 1.0 equiv), base (4.0 equiv), and solvent (2 mL) at 110 °C under air in a sealed tube, and isolated yields are reported. b The recovery of 1a is shown in parentheses. c In the presence of tBuOK (4.0 equiv) and 18-crown-6 ether (4.2 equiv).
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Li, J.; Zhang, Z.; Chen, L.; Li, M.; Zhang, X.; Zhang, G. Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles. Molecules 2023, 28, 3691. https://doi.org/10.3390/molecules28093691

AMA Style

Li J, Zhang Z, Chen L, Li M, Zhang X, Zhang G. Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles. Molecules. 2023; 28(9):3691. https://doi.org/10.3390/molecules28093691

Chicago/Turabian Style

Li, Jingya, Zhiguo Zhang, Liming Chen, Mengjuan Li, Xingjie Zhang, and Guisheng Zhang. 2023. "Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles" Molecules 28, no. 9: 3691. https://doi.org/10.3390/molecules28093691

APA Style

Li, J., Zhang, Z., Chen, L., Li, M., Zhang, X., & Zhang, G. (2023). Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles. Molecules, 28(9), 3691. https://doi.org/10.3390/molecules28093691

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