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

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.


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 azaaddition 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 t BuOK 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 t BuOK failed to give a higher yield of fuseheterocycle 2a (Table 1, entries [3][4][5]. Similarly, lower or higher temperatures did not help improve the reaction efficiency (Table 1, entries [6][7][8][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, K 3 PO 4 , NaH, NaOH, and Cs 2 CO 3 ( 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 t BuOK (4.0 equiv) and 18-crown-6 ether (4.2 equiv).

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 R 1 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.
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 R 1 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 αnaphthyl-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. Scheme 2. Extension of the reaction scope with various R 1 a,b . a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), t BuOK (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 1 H NMR analysis of the crude reaction mixture. c Recovery of 1h.
Next, the scope of the reaction was evaluated using different R 2 . 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. Scheme 3. Extension of the reaction scope with various R 2 a,b . a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), t BuOK (4.0 equiv), and DMF (2 mL) at 110 Scheme 2. Extension of the reaction scope with various R 1 a,b . a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), t BuOK (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 1 H NMR analysis of the crude reaction mixture. c Recovery of 1h.

Scheme 2.
Extension of the reaction scope with various R 1 a,b . a Unless otherwise indicated, all these reactions were conducted with 1 (0.5 mmol, 1.0 equiv), t BuOK (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 1 H NMR analysis of the crude reaction mixture. c Recovery of 1h.
Next, the scope of the reaction was evaluated using different R 2 . 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).
on the conversion of substrate 1. The dr values were determined from the 1 crude reaction mixture.
With the aim of devising a practical, gram-scale synthe aza[3.1.0]bicycle scaffold, a reaction on 7 mmol (1.841 g) was carr proved synthetic method based on the base-promoted intramolecula When we treated 1o under optimal conditions, the reaction smoo yield of 2o after 72 h under standard conditions, with 17% 1o recov based on the conversion of the substrate) (Scheme 4).

General Remarks
Unless stated otherwise, reactions were conducted in Schlenk u were purchased from commercial sources and used without further erwise indicated. Starting materials were synthesized following th and the procedures were described in the Supporting Information. D THF, and toluene for reactions were distilled under an atmosphere ether (PE), used here, refers to the 60-90 °C boiling point fraction o etate is abbreviated as EA. 1 H NMR and 13 C NMR spectra were r Avance/600 ( 1 H: 600 MHz, 13 C: 151 MHz) or Bruker Avance/400 ( 1 MHz at 25 °C). Fluorine nuclear magnetic resonance ( 19 F NMR) spe a Bruker Avance/600 spectrometer or a Bruker Avance/400. 1 H NM brated against residual CHCl3 in the solvent (7.26 ppm). 13 C NMR sp against the peak of the residual CHCl3 in the solvent (77.2 ppm). sented as follows: chemical shift (ppm), multiplicity (s = singlet, d = = quartet, and m = multiplet), coupling constant in hertz (Hz), and resolution mass spectra (HRMS) were measured on a mass spectr trospray ionization orthogonal acceleration time-of-flight (ESI-OA of all samples used for HRMS (>95%) was confirmed by 1 H NMR a scopic analysis. All reactions were monitored by thin-layer chrom EA = 10:1) with GF254 silica gel-coated plates.

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, CH 3 CN, DMSO, THF, and toluene for reactions were distilled under an atmosphere of dry N 2 . Petroleum ether (PE), used here, refers to the 60-90 • C boiling point fraction of petroleum. Ethyl acetate is abbreviated as EA. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance/600 ( 1 H: 600 MHz, 13 C: 151 MHz) or Bruker Avance/400 ( 1 H: 400 MHz, 13 C: 101 MHz at 25 • C). Fluorine nuclear magnetic resonance ( 19 F NMR) spectra were recorded on a Bruker Avance/600 spectrometer or a Bruker Avance/400. 1 H NMR spectra were calibrated against residual CHCl 3 in the solvent (7.26 ppm). 13 C NMR spectra were calibrated against the peak of the residual CHCl 3 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 1 H NMR and 13 C NMR spectroscopic analysis. All reactions were monitored by thin-layer chromatography (TLC) (PE: EA = 10:1) with GF254 silica gel-coated plates.

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 t BuOK 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.