Synthesis of New Functionally Substituted 9-Azabicyclo[4.2.1]nona-2,4,7-trienes by Cobalt(I)-Catalyzed [6π + 2π]-Cycloaddition of N-Carbocholesteroxyazepine to Alkynes

Catalytic [6π + 2π]-cycloaddition of N-carbocholesteroxyazepine with functionally substituted terminal alkynes and 1,4-butynediol was performed for the first time under the action of the Co(acac)2(dppe)/Zn/ZnI2 three-component catalytic system. The reaction gave previously undescribed but promising 9-azabicyclo[4.2.1]nona-2,4,7-trienes (in 79–95% yields), covalently bound to a natural metabolite, cholesterol. The structure of the synthesized azabicycles was confirmed by analysis of one- and two-dimensional (1H, 13C, DEPT 13C, COSY, NOESY, HSQC, HMBC) NMR spectra.

We previously reported [39][40][41] the development of an efficient one-pot synthesis of some substituted 9-azabicyclo  According to previously published data, an efficient method for the synthesis of 9azabicyclo[4.2.1]nonane cages is based on the cycloaddition reactions of N-substituted azepines catalyzed by transition metal complexes [30]. However, these reactions have been studied rather superficially, being addressed in a few publications on the photoinduced cyclo-codimerization of tricarbonyl(η 6 -N-carboalkoxyazepine)chromium(0) [31][32][33][34][35][36] and tricarbonyl(η 6 -N-cyanoazepine)chromium(0) [37] with alkenes and alkynes. Meanwhile, data on catalytic versions of these reactions are scarcely reported in the literature, except for two examples of Cr(0)-catalyzed cycloaddition of N-carbomethoxyazepine [34] and N-carbethoxyazepine [38] to ethyl acrylate (Scheme 1). Hence, the catalytic cycloaddition of N-substituted azepines is an alternative approach to the synthesis of 9azabicyclo[4.2.1]nonanes, and therefore, these reactions require further thorough investigation.  We previously reported [39][40][41]  We previously reported [39][40][41]  In order to further develop the above promising trend towards new 9-azabicyclo[4.2.1]nonanes, and in view of the high relevance of the development of biologically active substances for the synthesis of new-generation pharmaceutical agents, we set ourselves the task of preparing 9-azabicyclo[4.2.1]nona-2,4,7-trienes containing a natural compound fragment in their molecules. It is well known that half of the currently existing medicinal drugs have been, and continue to be, developed on the basis of natural compounds' skeletons and their numerous synthetic analogues. As the natural compound for the present work, we chose cholesterol, which performs very important functions in the human body [42][43][44][45][46][47][48][49][50][51]. Cholesterol is a structural component of cell membranes and provides their stability, participates in the biosynthesis of steroid sex hormones and corticosteroids, serves as a basis for the formation of bile acids and vitamin D, and also protects red blood cells from the action of hemolytic poisons. Thus, to our knowledge, the present study is the first to report on the catalytic [6π + 2π]-cycloaddition of N-carbocholesteroxyazepine to alkynes in order to access new 9-azabicyclo[4.2.1]nona-2,4,7-trienes containing, additionally, cholesterol building blocks (Scheme 2). To this end, we emphasize here the novelty of our planned investigation, since we succeeded in preparing, for the first time, an Ncarbocholesteroxyazepine system.  With N-carbocholesteroxyazepine 2 in our hands, we investigated its cycloaddition to the terminal alkynes 3a-t. Thus, we found that the desired [6π + 2π]-cycloaddition process occurred, being catalyzed by the Co(acac)2(dppe)/Zn/ZnI2 (dppe-1,2-bis(diphenylphosphino)ethane) system [52][53][54][55][56][57] under developed conditions (10 mol% With N-carbocholesteroxyazepine 2 in our hands, we investigated its cycloaddition to the terminal alkynes 3a-t. Thus, we found that the desired [6π + 2π]-cycloaddition process occurred, being catalyzed by the Co(acac) 2 (dppe)/Zn/ZnI 2 (dppe-1,2-bis(diphenylphosphino)ethane) system [52][53][54][55][56][57] under developed conditions (10 mol% Co(acac) 2 (dppe), 30 mol% Zn, and 20 mol% ZnI 2 , in DCE (1,2-dichloroethane) as solvent, for 20 h at 60 • C) to afford substituted 9-azabicyclo It is well known that at elevated temperatures, the transition from one rotamer to another is accelerated. Therefore, we studied the exchange process between rotamers upon heating and calculated the energy barrier at an operating temperature of 333 K. The investigation of the temperature dependence of the NMR spectra of compound 4r in C7D8 at 333 K has shown the presence of coalescence of a number of characteristic signals in the It is well known that at elevated temperatures, the transition from one rotamer to another is accelerated. Therefore, we studied the exchange process between rotamers upon heating and calculated the energy barrier at an operating temperature of 333 K. The investigation of the temperature dependence of the NMR spectra of compound 4r in C 7 D 8 at 333 K has shown the presence of coalescence of a number of characteristic signals in the 13 C NMR spectrum-for example, the signal of the carbamide carbon atom C(10) (Figure 2). In this case, at room temperature, double signals of the carbamide carbon atom C(10) are observed with a difference of 0.05 ppm (δ) or 25 Hz in accordance with the frequency scale. The value of the energy barrier at 333 K (T coal. ), calculated using the approximate formula or the Eyring equation (1)   Our experiments clearly demonstrated the Co(acac)2(dppe)/Zn/ZnI2 three-component catalytic system [52][53][54][55][56][57] being not only tolerant but equally efficient for a large variety of the substituents (alkyl, phenyl, p-halophenyl, alcohol, nitrile, ester, sulfide, phthalimide, cycloalkane, naphthalene, and phenanthrene) in the starting alkynes.

General Procedures
Briefly, 1 Н, 13 С spectra were measured in CDCl3 on a Bruker Avance-500 spectrometer (500 MHz for 1 H; 125 MHz for 13 C). High-resolution mass spectra (HRMS) were measured on an instrument (MaXis impact, Bruker Daltonik GmbH, Bremen, Germany) using a time-of-flight mass analyzer (TOF) with electrospray ionization (ESI). In experiments on selective collisional activation, the activation energy was set at the maximum abundance Scheme 6. Cycloaddition of N-carbocholesteroxyazepine to 1,4-butynediol.

General Procedures
Briefly, 1 Н, 13 C spectra were measured in CDCl 3 on a Bruker Avance-500 spectrometer (500 MHz for 1 H; 125 MHz for 13 C). High-resolution mass spectra (HRMS) were measured on an instrument (MaXis impact, Bruker Daltonik GmbH, Bremen, Germany) using a time-of-flight mass analyzer (TOF) with electrospray ionization (ESI). In experiments on selective collisional activation, the activation energy was set at the maximum abundance of fragment peaks. A syringe injection was used for solutions in MeCN (flow rate: 5 µL/min). Nitrogen was applied as a dry gas; the interface temperature was set at 180 • C. All solvents were dried and freshly distilled before use. All reactions were carried out under a dry argon atmosphere. Cholesteryl chloroformate, sodium azide, the terminal alkynes, alkynols, and ZnI 2 were purchased from commercial sources and used without further purification. Co(acac) 2 (dppe), ethyl pent-4-ynoate, 5-bromopent-1-yne, and sulfanylalkynes were synthesized according to procedures described in the literature [59][60][61]. For column chromatography, silica gel from Acros Organics (Thermo Fisher Scientific, Geel, Belgium) (0.060-0.200 mm) was used.

Synthesis of Cholesteryl Azidoformate
A mixture of cholesteryl chloroformate (2.25 g, 5 mmol) and sodium azide (1.14 g, 17.5 mmol) in dry acetone (97 mL) was heated at 40 • C for 6 h with vigorous stirring. After this period, the reaction mixture was left to reach room temperature, when minerals were filtered off. The organic filtrate was concentrated under reduced pressure to dryness to provide crude сholesteryl azidoformate 1 (2.278 g, 100% yield with respect to cholesteryl chloroformate) as a white solid. This material was used as is in the next experiments without further purification.

Synthesis of N-Carbocholesteroxyazepine
A solution of cholesteryl azidoformate 1 (2.28 g, 5 mmol) in dry benzene (106 mL) was heated in an autoclave at 125 • C for 2 h with stirring, under autogenous pressure. After this period, the cooled reaction solution was stripped of benzene under reduced pressure. Chromatographic purification over silica gel (petroleum ether/ethyl acetate 20:1) afforded the target product 2 (1.517 g, 60% yield with respect to cholesteryl azidoformate) as a yellow solid.

Cycloaddition of N-Carbocholesteroxyazepine to Alkynes
Zinc powder (0.020 g, 0.3 mmol) was added to a solution of Co(acac) 2 (dppe) (0.066 g, 0.1 mmol) in DCE (1.5 mL) for 3a-f,h,j-l,n-p,r-t (in 1 mL DCE for 3g,i,m,q,5) in a Schlenk tube under a dry argon atmosphere, and the mixture was stirred at room temperature for 2 min. Next, N-carbocholesteroxyazepine (0.505 g, 1.0 mmol), the alkyne (1.5 mmol) in DCE (1.5 mL) for 3a-f,h,j-l,n-p,r-t (in 2 mL trifluoroethanol for 3g,i,m,q,5), and dry ZnI 2 (0.064 g, 0.2 mmol) were added successively. After heating at 60 • C for 20 h, the reaction was stopped by the addition of petroleum ether and stirring in air for 10 min to deactivate the catalyst. After filtration through a short pad of silica, the volatiles were removed under vacuum. Chromatographic purification over silica gel (petroleum ether/ethyl acetate 5:1 as eluent for 4a-p,s,t,6; petroleum ether/ethyl acetate 2:1 for 4q,r) afforded the target products 4a-t, 6.