The Reactions of 6-(Hydroxymethyl)-2,2-dimethyl-1-azaspiro[4.4]nonanes with Methanesulfonyl Chloride or PPh3-CBr4

Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh3-CBr4 system is a commonly used pathway to various functional derivatives. The reactions of (5R(S),6R(S))-1-X-6-(hydroxymethyl)-2,2-dimethyl- 1-azaspiro[4.4]nonanes 1a–d (X = O·; H; OBn, OBz) with MsCl/NR3 or PPh3-CBr4 were studied. Depending on substituent X, the reaction afforded hexahydro-1H,6H-cyclopenta[c]pyrrolo[1,2-b]isoxazole (2) (for X = O), a mixture of 2 and octahydrocyclopenta[c]azepines (4–6) (for X = OBn, OBz), or perhydro-cyclopenta[2,3]azeto[1,2-a]pyrrol (3) (for X = H) derivatives. Alkylation of the latter with MeI with subsequent Hofmann elimination afforded 2,3,3-trimethyl-1,2,3,4,5,7,8,8a-octahydrocyclopenta[c]azepine with 56% yield.


Introduction
Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh 3 -CBr 4 system is a commonly used pathway to various functional derivatives [1][2][3]. Recently, we reported on simple synthesis of (5R(S),6R(S))-2, 2-dimethyl-6-(hydroxymethyl)-1-azaspiro [4.4]nonane-1-oxyl 1a from commercially available 5,5-dimethyl-1-pyrroline N-oxide (DMPO) [4]. The above nitroxide and its analogs were prepared as single enantiomeric pair with hydroxymethyl group close to the nitroxide one. Close proximity of hydroxy and nitroxide groups make these compounds potential precursors of rigid spin labels, which might allow precise distance measurements via site-directed spin labeling-PELDOR technique [5,6]. Synthesis of these spin labels would require replacement of the hydroxyl group to methanethiosulfonate or maleimido moiety, and Appel reaction or treatment with methanesulfonyl chloride seems to be a proper step towards this direction.

Results and Discussion
Both mesylation and the Appel reaction were successfully used in nitroxide chemistry, however, the Appel reaction often gives low to moderate yields of brominated nitroxides [17], while the yields of OMs derivatives are high [18][19][20]. The reactions of (5R(S),6R(S))-6-(hydroxymethyl)-2,2-dimethyl-1-azaspiro [4.4]nonan-1-oxyl (1a) with MsCl/NEt3 or with PPh3-CBr4 afforded no expected nitroxides 7. The reaction mixtures turned brown with significant tarring and the earlier described 3,3-dimethyloctahydrocyclopenta[c]pyrrolo [1,2-b]isoxazole 2 [4] was isolated from both reaction mixtures with a moderate yield (Scheme 2). Unusual behavior of 1a can only be explained by close proximity of hydroxymethyl and nitroxide groups in this molecule (ca. 3 Å distance). The possible mechanism of the formation of 2 is shown in Scheme 3. The reaction must anyway include one-electron reduction and cyclization via nucleophilic substitution steps. It is not clear whether activation of nitroxide oxygen to nucleophilic attack with one-electron transfer is required for a cyclization step or cyclic radical-cation can be formed spontaneously first and then Scheme 1. The reactions of 6-(hydroxymethyl)-2,2-dimethyl-1-azaspiro [4.4]nonanes 1a-d with MsCl/NR 3 and PPh 3 -CBr 4 .

Results and Discussion
Both mesylation and the Appel reaction were successfully used in nitroxide chemistry, however, the Appel reaction often gives low to moderate yields of brominated nitroxides [17], while the yields of OMs derivatives are high [18][19][20]. The reactions of (5R(S),6R(S))-6-(hydroxymethyl)-2,2-dimethyl-1-azaspiro [4.4]nonan-1-oxyl (1a) with MsCl/NEt3 or with PPh3-CBr4 afforded no expected nitroxides 7 . The reaction mixtures  turned  brown  with  significant  tarring  and  the  earlier  described  3 [4] was isolated from both reaction mixtures with a moderate yield (Scheme 2). Unusual behavior of 1a can only be explained by close proximity of hydroxymethyl and nitroxide groups in this molecule (ca. 3 Å distance). The possible mechanism of the formation of 2 is shown in Scheme 3. The reaction must anyway include one-electron reduction and cyclization via nucleophilic substitution steps. It is not clear whether activation of nitroxide oxygen to nucleophilic attack with one-electron transfer is required for a cyclization step or cyclic radical-cation can be formed spontaneously first and then Unusual behavior of 1a can only be explained by close proximity of hydroxymethyl and nitroxide groups in this molecule (ca. 3 Å distance). The possible mechanism of the formation of 2 is shown in Scheme 3. The reaction must anyway include one-electron reduction and cyclization via nucleophilic substitution steps. It is not clear whether activation of nitroxide oxygen to nucleophilic attack with one-electron transfer is required for a cyclization step or cyclic radical-cation can be formed spontaneously first and then yield about 13%). The formation of product 2 in this process may occur via intramolecular alkylation onto O-alkoxyamine atom of intermediate 10 to give cation 11 with subsequent nucleophilic substitution (Scheme 5). HRMS spectra of the other two isolated compounds showed the same molecular ions ([M] + ca. 271, see Experimental part) with a formula C18H25NO, correspondent to products of the formal elimination of water from 1c. The NMR spectra confirmed that both isomers retained benzyloxy moieties. The multiplets at 5.2-5.4 ppm in 1 H NMR spectra and signals at 137-138 and 148-150 ppm in 13 C NMR indicated the formation of a trisubstituted ethylene moiety. Assignment of the structure of the isomers was performed on the basis of 1 H-1 H COSY, 1 H-13 C HMBC and 1 H-13 C HSQC NMR spectra (see Fig. SI42-47 and Appendix A). At room temperature, some signals in the spectra of 5c were broadened, presumably due to slow conformational changes, therefore, the spectra acquired at 333 K with more narrow lines were used for assignments. Analysis of interactions in the 2D spectra allowed us to conclude that compounds 4c and 5c have the same octahydrocyclopenta[c]azepine backbone, differing only in the position of the double >C=CH bond, which is located in 5-or 7-membered ring.
The NMR analysis of the fraction containing 4c (major isomer) obtained via column chromatography showed the extra signals. These signals may belong to a third isomer, 6c, in which a fully substituted double bond is located between the rings. Indeed, in the 1 H NMR spectrum of this fraction recorded at 333 K ( Fig. SI20) a singlet at 1.18 (s, 6H), multiplet signals of five methylene groups in the region of 1.64-2.40 ppm partially overlapped with the signals of the major isomer 4c, the singlet signal of the methylene group at the heteroatom (3.51 ppm) and the signal of the benzyl methylene group at 4.63 ppm were observed. In the 13 C NMR spectrum (Fig. SI22), two signals in the low-field region at 138.17 and 138.27 ppm were observed, which correspond to the carbons of tetrasubstituted C=C bond. The ratio of the products was determined using the NMR spectrum of the reaction mixture: 4с/5с/6с/2 = 12.63/3.28/1/9.42.
The possible mechanism of 4c, 5c, and 6c formation is likely to imply intramolecular alkylation to give N-benzyloxyammonium salt 12 with subsequent Hofmann-type elimination, however, one cannot exclude a contribution of Cope-type elimination via 5-membered transition state with coordination of alkoxyamine oxygen in 1c with the most closely located hydrogen atom (methylene hydrogen of cyclopentane ring, ca. 2.5 Å distance) (Scheme 6) [27]. This may account for predominant formation of isomer 4c. Some examples of the conversion of 1-methyl-1-azoniabicyclo[3.2.0]heptanes into azepane derivatives are known [9,28], but in these examples ring opening occurred via nucleophilic substitution, not via elimination. HRMS spectra of the other two isolated compounds showed the same molecular ions ([M] + ca. 271, see Experimental part) with a formula C 18 H 25 NO, correspondent to products of the formal elimination of water from 1c. The NMR spectra confirmed that both isomers retained benzyloxy moieties. The multiplets at 5.2-5.4 ppm in 1 H NMR spectra and signals at 137-138 and 148-150 ppm in 13 C NMR indicated the formation of a trisubstituted ethylene moiety. Assignment of the structure of the isomers was performed on the basis of 1 H-1 H COSY, 1 H-13 C HMBC and 1 H-13 C HSQC NMR spectra (see Figures S42-S47 and Appendix A). At room temperature, some signals in the spectra of 5c were broadened, presumably due to slow conformational changes, therefore, the spectra acquired at 333 K with more narrow lines were used for assignments. Analysis of interactions in the 2D spectra allowed us to conclude that compounds 4c and 5c have the same octahydrocyclopenta[c]azepine backbone, differing only in the position of the double >C=CH bond, which is located in 5-or 7-membered ring.
The NMR analysis of the fraction containing 4c (major isomer) obtained via column chromatography showed the extra signals. These signals may belong to a third isomer, 6c, in which a fully substituted double bond is located between the rings. Indeed, in the 1 H NMR spectrum of this fraction recorded at 333 K ( Figure S20) a singlet at 1.18 (s, 6H), multiplet signals of five methylene groups in the region of 1.64-2.40 ppm partially overlapped with the signals of the major isomer 4c, the singlet signal of the methylene group at the heteroatom (3.51 ppm) and the signal of the benzyl methylene group at 4.63 ppm were observed. In the 13 C NMR spectrum ( Figure S22), two signals in the lowfield region at 138.17 and 138.27 ppm were observed, which correspond to the carbons of tetrasubstituted C=C bond. The ratio of the products was determined using the NMR spectrum of the reaction mixture: 4c/5c/6c/2 = 12.63/3.28/1/9.42.
The possible mechanism of 4c, 5c, and 6c formation is likely to imply intramolecular alkylation to give N-benzyloxyammonium salt 12 with subsequent Hofmann-type elimination, however, one cannot exclude a contribution of Cope-type elimination via 5-membered transition state with coordination of alkoxyamine oxygen in 1c with the most closely located hydrogen atom (methylene hydrogen of cyclopentane ring, ca. 2.5 Å distance) (Scheme 6) [27]. This may account for predominant formation of isomer 4c. Some examples of the conversion of 1-methyl-1-azoniabicyclo[3.2.0]heptanes into azepane derivatives are known [9,28], but in these examples ring opening occurred via nucleophilic substitution, not via elimination. Under the Appel reaction conditions, 1c was converted into the same products 4c, 5c, 6c and 2 in the ratio of 3.89/1.35/1/4.61, respectively, according to NMR. Total preparative yield of the isomers 4c, 5c, and 6c was 34%.
With the replacement of benzyl group in 1c with electron-withdrawing benzoyl, one could make the N-O-R moiety less prone to intramolecular alkylation. To prepare N-benzoyloxy derivative 1d, the nitroxide 1a was treated with benzhydrazide in the presence of excess MnO2 [29]. This method allowed us to avoid the acylation of hydroxymethyl group and afforded 1d with the yield of 81% as colorless oil not susceptible to oxidation to nitroxide (Scheme 7). The presence of free hydroxy group in 1d was confirmed with IR absorption band at 3452 cm −1 and a broad singlet (1H) at 5.29 ppm in the 1 H NMR spectrum. Scheme 7. Synthesis of N-benzoyloxy derivative 1d. Under the Appel reaction conditions, 1c was converted into the same products 4c, 5c, 6c and 2 in the ratio of 3.89/1.35/1/4.61, respectively, according to NMR. Total preparative yield of the isomers 4c, 5c, and 6c was 34%.
With the replacement of benzyl group in 1c with electron-withdrawing benzoyl, one could make the N-O-R moiety less prone to intramolecular alkylation. To prepare N-benzoyloxy derivative 1d, the nitroxide 1a was treated with benzhydrazide in the presence of excess MnO 2 [29]. This method allowed us to avoid the acylation of hydroxymethyl group and afforded 1d with the yield of 81% as colorless oil not susceptible to oxidation to nitroxide (Scheme 7). The presence of free hydroxy group in 1d was confirmed with IR absorption band at 3452 cm −1 and a broad singlet (1H) at 5.29 ppm in the 1 H NMR spectrum.
could make the N-O-R moiety less prone to intramolecular alkylation. To prepare N-benzoyloxy derivative 1d, the nitroxide 1a was treated with benzhydrazide in the presence of excess MnO2 [29]. This method allowed us to avoid the acylation of hydroxymethyl group and afforded 1d with the yield of 81% as colorless oil not susceptible to oxidation to nitroxide (Scheme 7). The presence of free hydroxy group in 1d was confirmed with IR absorption band at 3452 cm −1 and a broad singlet (1H) at 5.29 ppm in the 1 H NMR spectrum. Scheme 7. Synthesis of N-benzoyloxy derivative 1d. Scheme 7. Synthesis of N-benzoyloxy derivative 1d.
Reaction of 1d with PPh 3 -CBr 4 afforded a mixture, from which three compounds were isolated (Scheme 8).
Molecules 2021, 26, x FOR PEER REVIEW 6 of 18 Reaction of 1d with PPh3-CBr4 afforded a mixture, from which three compounds were isolated (Scheme 8).
One of the isolated compounds, a yellow crystalline solid, showed intense triplet in EPR spectrum with aN = 1.49 mT (Fig. SI57). HRMS with a molecular ion, [M + ] = 302.1752, corresponding to the formula C18H24NO3, IR spectrum with strong absorption band at 1716 cm −1 and no absorption above 3100 cm −1 favored the structure 13, which could result from transesterification and oxidation. The structure was confirmed with 1 H NMR spectrum recorded after reduction of the nitroxide 13 to corresponding ammonium salt 14 with Zn in the presence of trifluoroacetic acid (Scheme 9). The remaining two products were colorless diamagnetic oils. The 1 H and 13 C NMR spectra of both compounds revealed broadening of some signals similarly to those of 5c. A detailed analysis of the 1 H-13 C HMBC, 1 H-13 C HSQC, and 1 H-1 H COSY spectra of isolated compounds ( Fig. SI48-53, Appendix A) allowed us to conclude that major and minor products are isomeric octahydrocyclopenta[c]azepines 4d and 5d. The presence of impurity signals (singlet signal at 1.24 ppm, multiplet signals of five methylene groups in the region of 1.70-2.40 ppm partially overlapped with the signals of the major isomer 5d, the singlet signal of the methylene group at the heteroatom at 3.78 ppm in 1 H NMR spectrum and two signals in the low-field region at 130.84 and 138.45 ppm in 13 C NMR spectrum) of some 5d samples may indicate the formation of the third isomer 6d; however, this isomer was not isolated and no other confirmation for this was obtained.
Formation of both 4 and 5 presumably occurs via corresponding benzyl-or benzoyloxyammonium salts 12. However, we did not find references on perhydro-cyclopenta [2,3] [7]. These strained structures may be unstable themselves or in the presence of bases, which are present in the reaction mixtures during mesylation or Appel reaction. So easy cleavage of C-N bond in perhydro-cyclopenta[2,3]azeto[1,2-a]pyrrolium salts inspired us to study the behavior of One of the isolated compounds, a yellow crystalline solid, showed intense triplet in EPR spectrum with a N = 1.49 mT ( Figure S57). HRMS with a molecular ion, [M + ] = 302.1752, corresponding to the formula C 18 H 24 NO 3 , IR spectrum with strong absorption band at 1716 cm −1 and no absorption above 3100 cm −1 favored the structure 13, which could result from transesterification and oxidation. The structure was confirmed with 1 H NMR spectrum recorded after reduction of the nitroxide 13 to corresponding ammonium salt 14 with Zn in the presence of trifluoroacetic acid (Scheme 9). Reaction of 1d with PPh3-CBr4 afforded a mixture, from which three compounds were isolated (Scheme 8).
One of the isolated compounds, a yellow crystalline solid, showed intense triplet in EPR spectrum with aN = 1.49 mT (Fig. SI57). HRMS with a molecular ion, [M + ] = 302.1752, corresponding to the formula C18H24NO3, IR spectrum with strong absorption band at 1716 cm −1 and no absorption above 3100 cm −1 favored the structure 13, which could result from transesterification and oxidation. The structure was confirmed with 1 H NMR spectrum recorded after reduction of the nitroxide 13 to corresponding ammonium salt 14 with Zn in the presence of trifluoroacetic acid (Scheme 9). The remaining two products were colorless diamagnetic oils. The 1 H and 13 C NMR spectra of both compounds revealed broadening of some signals similarly to those of 5c. A detailed analysis of the 1 H-13 C HMBC, 1 H-13 C HSQC, and 1 H-1 H COSY spectra of isolated compounds (Fig. SI48-53, Appendix A) allowed us to conclude that major and minor products are isomeric octahydrocyclopenta[c]azepines 4d and 5d. The presence of impurity signals (singlet signal at 1.24 ppm, multiplet signals of five methylene groups in the region of 1.70-2.40 ppm partially overlapped with the signals of the major isomer 5d, the singlet signal of the methylene group at the heteroatom at 3.78 ppm in 1 H NMR spectrum and two signals in the low-field region at 130.84 and 138.45 ppm in 13 C NMR spectrum) of some 5d samples may indicate the formation of the third isomer 6d; however, this isomer was not isolated and no other confirmation for this was obtained.
Formation of both 4 and 5 presumably occurs via corresponding benzyl-or benzoyloxyammonium salts 12. However, we did not find references on perhydro-cyclopenta [2,3] The remaining two products were colorless diamagnetic oils. The 1 H and 13 C NMR spectra of both compounds revealed broadening of some signals similarly to those of 5c. A detailed analysis of the 1 H-13 C HMBC, 1 H-13 C HSQC, and 1 H-1 H COSY spectra of isolated compounds ( Figures S48-S53, Appendix A) allowed us to conclude that major and minor products are isomeric octahydrocyclopenta[c]azepines 4d and 5d. The presence of impurity signals (singlet signal at 1.24 ppm, multiplet signals of five methylene groups in the region of 1.70-2.40 ppm partially overlapped with the signals of the major isomer 5d, the singlet signal of the methylene group at the heteroatom at 3.78 ppm in 1 H NMR spectrum and two signals in the low-field region at 130.84 and 138.45 ppm in 13 C NMR spectrum) of some 5d samples may indicate the formation of the third isomer 6d; however, this isomer was not isolated and no other confirmation for this was obtained.
These strained structures may be unstable themselves or in the presence of bases, which are present in the reaction mixtures during mesylation or Appel reaction. So easy cleavage of C-N bond in perhydro-cyclopenta [2,3]azeto[1,2-a]pyrrolium salts inspired us to study the behavior of ((5R(S),6R(S))-6-(hydroxymethyl)-2,2-dimethyl-1-azaspiro [4.4]nonane 1b under Appel reaction conditions and mesylation. Both reactions afforded the same amine 3 with the yield of 65-77%. The amine 3 was characterized as a hydrobromide, a colorless crystalline compound (Scheme 10). Analysis of the 1 H NMR spectrum fine structure of the obtained substance, in addition to signals of pair methyl groups, indicates the presence of two isolated spin systems ( Fig. SI60-61, Table SI3). To confirm the structure of isolated substance, 1 H-1 H COSY, 1 H-13 C HMBC, and 1 H-13 C HSQC NMR spectra were recorded ( Fig. SI39-41, Appendix A). In the 1 H-13 C HMBC spectrum, the long-range interactions are observed between two geminal hydrogen atoms in the weakest field (i.e., adjacent to heteroatom) and carbons of geminal methyl groups and node carbon atom, confirming C(5)-N bond formation. The single crystal X-ray analysis of the hydrobromide 3×HBr provided unambiguous confirmation of the structure (Figure 1, see Fig. SI59). The reaction of amine 3 with an excess of methyl iodide gave a crystalline substance, the NMR spectra of which are very similar to the spectra of 3×HBr, however, in 1 H NMR, a singlet with the intensity of 3H at 2.94 ppm is observed, and in 13 C NMR, a signal at 38.72 ppm is observed, which confirms methylation at the nitrogen atom with the formation of 15, while maintaining the strained tricyclic structure (Scheme 11). Analysis of the 1 H NMR spectrum fine structure of the obtained substance, in addition to signals of pair methyl groups, indicates the presence of two isolated spin systems ( Figures S60 and S61, Table S2). To confirm the structure of isolated substance, 1 H-1 H COSY, 1 H-13 C HMBC, and 1 H-13 C HSQC NMR spectra were recorded ( Figures S39-S41, Appendix A). In the 1 H-13 C HMBC spectrum, the long-range interactions are observed between two geminal hydrogen atoms in the weakest field (i.e., adjacent to heteroatom) and carbons of geminal methyl groups and node carbon atom, confirming C(5)-N bond formation. The single crystal X-ray analysis of the hydrobromide 3×HBr provided unambiguous confirmation of the structure (Figure 1, see Figure S59). Analysis of the 1 H NMR spectrum fine structure of the obtained substance, in addition to signals of pair methyl groups, indicates the presence of two isolated spin systems ( Fig. SI60-61, Table SI3). To confirm the structure of isolated substance, 1 H-1 H COSY, 1 H-13 C HMBC, and 1 H-13 C HSQC NMR spectra were recorded ( Fig. SI39-41, Appendix A). In the 1 H-13 C HMBC spectrum, the long-range interactions are observed between two geminal hydrogen atoms in the weakest field (i.e., adjacent to heteroatom) and carbons of geminal methyl groups and node carbon atom, confirming C(5)-N bond formation. The single crystal X-ray analysis of the hydrobromide 3×HBr provided unambiguous confirmation of the structure (Figure 1, see Fig. SI59). The reaction of amine 3 with an excess of methyl iodide gave a crystalline substance, the NMR spectra of which are very similar to the spectra of 3×HBr, however, in 1 H NMR, a singlet with the intensity of 3H at 2.94 ppm is observed, and in 13 C NMR, a signal at 38.72 ppm is observed, which confirms methylation at the nitrogen atom with the formation of 15, while maintaining the strained tricyclic structure (Scheme 11). Salt 15 was then treated with wet silver (I) oxide and heating of the resulting quaternary ammonium hydroxide gave a mixture of several compounds. According to GC-MS data, two compounds with M = 179 g/mol (that corresponds to elimination of HI) were observed in the reaction mixture, 83 and 1%, and a product with M = 197 g/mol (14% according to GC) (Fig. SI58, Table SI1). The latter compound may correspond to the amino alcohol, a typical byproduct in Hofmann elimination conditions, a result of the substitution reaction [27]. The preparative yield of the main product was 70%, the minor The reaction of amine 3 with an excess of methyl iodide gave a crystalline substance, the NMR spectra of which are very similar to the spectra of 3×HBr, however, in 1 H NMR, a singlet with the intensity of 3H at 2.94 ppm is observed, and in 13 C NMR, a signal at 38.72 ppm is observed, which confirms methylation at the nitrogen atom with the formation of 15, while maintaining the strained tricyclic structure (Scheme 11). Analysis of the 1 H NMR spectrum fine structure of the obtained substance, in addition to signals of pair methyl groups, indicates the presence of two isolated spin systems ( Fig. SI60-61, Table SI3). To confirm the structure of isolated substance, 1 H-1 H COSY, 1 H-13 C HMBC, and 1 H-13 C HSQC NMR spectra were recorded ( Fig. SI39-41, Appendix A). In the 1 H-13 C HMBC spectrum, the long-range interactions are observed between two geminal hydrogen atoms in the weakest field (i.e., adjacent to heteroatom) and carbons of geminal methyl groups and node carbon atom, confirming C(5)-N bond formation. The single crystal X-ray analysis of the hydrobromide 3×HBr provided unambiguous confirmation of the structure (Figure 1, see Fig. SI59). The reaction of amine 3 with an excess of methyl iodide gave a crystalline substance, the NMR spectra of which are very similar to the spectra of 3×HBr, however, in 1 H NMR, a singlet with the intensity of 3H at 2.94 ppm is observed, and in 13 C NMR, a signal at 38.72 ppm is observed, which confirms methylation at the nitrogen atom with the formation of 15, while maintaining the strained tricyclic structure (Scheme 11). Salt 15 was then treated with wet silver (I) oxide and heating of the resulting quaternary ammonium hydroxide gave a mixture of several compounds. According to GC-MS data, two compounds with M = 179 g/mol (that corresponds to elimination of HI) were observed in the reaction mixture, 83 and 1%, and a product with M = 197 g/mol (14% according to GC) (Fig. SI58, Table SI1). The latter compound may correspond to the amino alcohol, a typical byproduct in Hofmann elimination conditions, a result of the substitution reaction [27]. The preparative yield of the main product was 70%, the minor Scheme 11. Methylation of 3 with subsequent Hofmann cleavage of quaternary ammonium hydroxide.
Salt 15 was then treated with wet silver (I) oxide and heating of the resulting quaternary ammonium hydroxide gave a mixture of several compounds. According to GC-MS data, two compounds with M = 179 g/mol (that corresponds to elimination of HI) were observed in the reaction mixture, 83 and 1%, and a product with M = 197 g/mol (14% according to GC) ( Figure S58, Table S1). The latter compound may correspond to the amino alcohol, a typical byproduct in Hofmann elimination conditions, a result of the substitution reaction [27]. The preparative yield of the main product was 70%, the minor products were not isolated. Analysis of the 1 H and 13 C NMR data allows us to conclude that the isolated product contains a double bond of the >C=CH type; therefore, the assumption of the possible formation of a spirocyclic structure with an exomethylene fragment should be rejected. 2D-NMR spectra ( Figures S54-S56, Appendix A) confirmed the octahydrocyclopenta[c]azepine structure of compound 16 and showed that the double carbon-carbon bond is located in the 5-membered ring.

General Information
The IR spectra were recorded on a Bruker Vector 22 FT-IR spectrometer (Bruker, Billerica, MA, USA) in KBr pellets (1:150 ratio) or in neat samples (for oily compounds) (see Figures S1-S11). UV spectra were acquired on a HP Agilent 8453 spectrometer (Agilent Technologies, Santa Clara, CA, USA) in ethanol solutions (concentration~10 −4 M) (see Figure S12). 1  . All the NMR spectra were acquired for 5-10% solutions in CDCl 3 , CD 3 OD, or CDCl 3 -CD 3 OD mixtures at 300 K or in DMSO-d 6 at 333 K using the signal of the solvent as a standard. HRMS analyses were performed with High Resolution Mass Spectrometer DFS (Thermo Electron, Waltham, MA, USA). GC-MS analyses were performed with Chromato-mass spectrometer Agilent 6890 MSD Agilent 5973. HPLC analyses were carried out using an HPLC-UV (Agilent 1100, Agilent Technologies Inc., USA) with an Zorbax C8 column (250 mm × 4.6 mm with 5 µm particle size; Agilent Technologies Inc., USA), and the mobile phase were delivered at a flow rate of 1.0 mL/min. Sample was dissolved in acetonitrile (25 mg/mL). The injection volume was 20 µL, and the column temperature was 35 • C. Mobile phase used was a mixture acetonitrile/water (8:2 v/v).
The structure of compound 3×HBr was determined by single-crystal X-ray analysis (see SI). The X-ray diffraction experiment was carried out on a Bruker KAPPA APEX II diffractometer (graphite-monochromated Mo Kα radiation). Reflection intensities were corrected for absorption by SADABS program [30]. The structure of salt 3×HBr was solved by direct methods using the SHELXS-97 program [31] and refined as a 2-component inversion twin by anisotropic (isotropic for all H atoms) full-matrix least-squares method against F2 of all reflections by SHELXL-2014 [32]. The positions of the hydrogen atoms were calculated geometrically and refined in riding model.  [33]) was employed for simulation of spectra. Carbon tetrabromide (0.84 g, 2.66 mmol) and PPh 3 (0.70 g, 2.66 mmol) were added to a solution of nitroxide 1a (0.25 g, 1.26 mmol) in dry CH 2 Cl 2 (6 mL) and the reaction mixture was stirred at room temperature for 12 h to complete the reaction. The progress of reaction was monitored by TLC (SiO 2 , hexane-diethyl ether 1:1 mixture; stained with Dragendorff's reagent). After evaporation of the solvent under reduced pressure, the crude residue was purified by column chromatography (SiO 2 , hexane-diethyl ether 1:1 mixture as an eluent) to give 2, 0.091 g, yield 40%. Physical properties and spectral characteristics coincide to the literature data [4].
The heterocycles with spiro-(2-hydroxymethyl)cyclopentane moieties can be easily prepared from cyclic nitrones via addition of pent-4-enylmagnesium bromide-oxidationintramolecular cycloaddition-isoxazolidine ring opening sequence [4,34,35]. Here, we demonstrated an example of conversion of these spirocyclic structures into azepane derivatives. Similar transformations may provide a promising pathway to valuable scaffolds for the synthesis of biologically active compounds.