Mendeleev Communications Electronic Version, Issue 2, 1998 (pp. 43–82) Stereospecific synthesis of bicyclic diaziridines: 4a-chloro-; 4e,6a- and 4a,6e-dichloro-5-methoxycarbonyl-1,6-diazabicyclo[3.1.0]hexanes Sergey N. Denisenko,a Paul Rademacherb and Remir G. Kostyanovsky*c a Ukrainian State University of Chemistry and Technology, 320005 Dnepropetrovsk, Ukraine. E-mail: denisenk@chem.ufl.edu b Institute of Organic Chemistry, University of Essen, D-45117 Essen, Germany. Fax: +49 201 183 3082; e-mail: radem@ocl.orgchem.uni-essen.de c N.N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation. Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru Amination of 2-methoxycarbonyl-3-chloro-1-pyrroline 1 with H2NOSO3H occurs predominantly from the anti side with respect to chlorine to afford the bicyclic diaziridine 2 with axial orientation of the 4-chloro substituent.Chlorination of 2 takes place exclusively in the 6-endo position to give 3a. 4,6-Dichlorodiaziridine is transformed from chair 3a into boat 3b as a result of endo–exo isomerization. Similarly to a-chloroalkylamines, N-chlorohydrazines have an ionic state and exist in the form of diazenium salts A.1–5 This can be explained by kinetic destabilizing n(N) ® s*(NCl) and n(N)–n(N) interactions.3–5 These interactions can be eliminated by: i, quaternization of the donor N atom to give a stable N-chlorohydrazinium salt B;4 ii, transformation of the nitrogen atom into a bridgehead position of bicyclic N-chlorohydrazine C4,6 or N-chlorodiaziridines D and E,7–16 or iii, attaching a strong electron-withdrawing group to the N atom to form a stable monocyclic N-chlorodiaziridine F.17 In the strained bicyclic compounds the nitrogen atom in the bridgehead position is forced to re-hybridize to accommodate bond angle variations.For example, the donor capacity of the bridgehead nitrogen in bicyclic compounds D,E is greatly reduced due to the decrease of p-character of the lone-pair.Therefore, the contribution of destabilizing n(N) ® s*(NCl) interactions is less pronounced.5 In contrast, the geometry of the donor nitrogen atom in bicyclic diaziridine G is ‘flattened’. Therefore, n(N) ® s*(NCl) interaction is still significant, and N-chloro derivatives of this type cannot be obtained.11 Additional stabilization of structures D,E by electron-withdrawing substituents R16 in position 5 allows the isolation of endo-6-Cl isomers D in quantitative yield.The properties, including molecular and electronic structures, of bicyclic 6-chlorodiaziridines D,E7–16 and their 6-H-precursors7 –16,18–25 have been studied in detail. The boat conformation of 6-exo isomers of type E, e.g. 6-bromodiaziridine (R = CONHMe)9 and the ephedrinium salt of 6-H-derivative (R = CO2 –), was confirmed using X-ray diffraction.23 Reliable 1H, 13C and 15N NMR criteria for the conformational analysis of D,E have been developed, e.g., the downfield chemical shift of the C(3) atom with a conformational change from boat E to chair D (i.e. 21 to 28 ppm).11 A quadrant rule for the N–Hal chromophore of optically active 6-chlorodiaziridines D,E and 6-bromo derivatives of type E has been proposed.14 Although the vicinal interaction n(N) ® s*(N-Hal) is diminished it is still sufficient to ensure N–Hal bond ionization.Therefore, the isomerization of D to E occurs via an intermediate ion pair H (Scheme 1). In our opinion, this intermediate H is also involved in other chemical transformations of D such as nucleophilic substitution of the chlorine atom and thermal decomposition at T � 40 °C, etc.(Scheme 1). We believe that introducing an additional electronegative substituent into position 4 of bicyclic diaziridines 2 will further inhibit the formation of ion pair H. For example, 1-fluoro- 2-tert-butyl-3,3-pentamethylenediaziridine rearranges spontaneously into the corresponding a-fluoroalkyldiazene26 whereas perfluorinated N-fluoro diaziridines are quite stable.27,28 Thus, we have prepared a new bicyclic diaziridine 2 from 2-methoxycarbonyl- 3-chloro-1-pyrroline (Scheme 2).The intermediate 1 was obtained by a known chlorination procedure.29 Surprisingly, the amination of pyrroline 1 by treatment with H2NOSO3H in the presence of a phase-transfer catalyst according to a previously developed methodology15 gave almost exclusively only one isomer of diaziridine 2 (Scheme 2).The stereospecificity of amination of pyrroline 1 can be explained as follows (Scheme 3). Two conformers with an R N N R R R TsO– Me3N N H Cl Cl– N N Cl N N Hal R N N Hal F N N F3C Cl F R N N H A B C D E F G R = CONHMe, CO2Me, CF3 R = CONHMe, CO2Me, CF3, Me, H 1 2 3 4 5 6 R N N Cl R N N Cl R N N Cl R N N OMe N N Cl R R Cl + N2 + C2H4 D H E Scheme 1 MeO– D Table 1 Spin coupling constants 3JHH/Hz of diaziridine 2 and calculated values for 2b,2c. Coupled protons Experiment 2 Calculated by PCMODEL 2b (axial 4-Cl) 2c (equatorial 4-Cl) 2a3a 10.9 11.8 11.9 2a3e 6.3 6.1 6.2 2e3a 7.8 7.0 6.9 2e3e 1.0 0.5 0.5 3a4 5.4 6.0 10.1 3e4 0.0 1.3 7.3 CO2Me N NH N CO2Me N CO2Me ButOCl Cl Cl 1 2 Scheme 2 H2NOSO3 – – HOSO3 –Mendeleev Communications Electronic Version, Issue 2, 1998 (pp. 43-82) axial (1a) or equatorial (1b) 3-Cl atom are possible. Molecular mechanics calculations by the MMX method predict a slight preference of axial conformer 1a compared to 1b. The calculated dihedral angle of the p-bond fragment N=C–C=O is 180° for 1a.At the same time, steric 1,2-repulsion between the equatorial Cl atom and the CO2Me group in conformer 1b changes the N=C–C=O dihedral angle to 155°. Comparison of experimental and calculated coupling constants 3JHH for both conformers confirms the predomination of the envelope conformation 1a with an axial chlorine atom.† However, the energy difference of the conformers is rather small, and therefore both of them might undergo amination (Scheme 3).Nevertheless, the approach of the aminating agent to the C=N bond of 1 from the opposite side of the chlorine atom seems to be preferable owing to steric and dipole–dipole interactions. This leads to the formation of a single isomer 2, which assumes the boat conformation 2b.Comparison of 13C, 1H chemical shifts and spin coupling constants 3JHH with those described earlier19 unambiguously confirmed the axial orientation of the 4-Cl substituent in boat 2b.‡ The axial orientation of the 4-Cl atom in 2b is also convincingly confirmed by comparison of experimental and calculated values of 3JHH for isomers with axial or equatorial 4-Cl substituents (PCMODEL molecular mechanics program, QCPE 395) (Table 1).Hence, equatorial orientation of the hydrogen and accordingly axial orientation of the Cl-atom follow. The 4-Cl substituent in diaziridine 2b leads to a reduction of the energies of the two highest occupied MOs, but is not however, as efficient as a CF3 group in the 5-position.16 Therefore, the configurational and thermal stabilities of 4,6-dichlorodiaziridines 3a,b, derived from 2b, are similar to those of 6-chlorodiaziridines D,E (R = CO2Me).Like in cases reported earlier,11,15 chlorination of 2 with ButOCl occurs stereospecifically to form the 6-endo isomer 3a in quantitative yield. † 1, yield 77%, yellowish oil, bp 40–48 °C (0.1 torr) (chromatographic purity 98%); 1H NMR (300 MHz, CDCl3) d: 2.32 (m, 4-He, 2J = –14.8 Hz, 3J = 5.7, 3.6, 2.2 Hz), 2.47 (m, 4-Ha, 2J = –14.8 Hz, 3J = 7.6, 7.2 Hz), 3.94 (s, MeO), 4.0–4.45 (m, 5-CH2), 5.12 (m, 3-H, 3J = 7.6, 2.2 Hz, 4J = 1.4 Hz); 13C NMR (75 MHz, CDCl3) d: 34.6 (t, 4-C), 53.0 (q, MeO), 58.7 (d, 3-C), 60.8 (t, 5-C), 161.3 (s, 2-C), 165.7 (s, CO); MS, m/z (%): 163, 164 (4) [M+], 133, 131 (48), 126 (30), 105, 103 (100), 99 (36), 94 (26), 78, 76 (90), 67 (31), 66 (38), 59 (37), 54 (37), 45 (29), 41 (95).‡ 2, yield 56%, bp 74.8 °C (0.5 torr); 1H NMR (300 MHz, CDCl3) d: 1.9 (ddd, 3-He, 2J = –14.0 Hz, 3J3e2a = 6.3 Hz, 3J3e2e = 1.0 Hz), 2.3 [m, 3-Ha, 2J = –14.0 Hz, 3J3a2a = 10.9 Hz, 3J3a2e = 7.8 Hz, 3J3a4e = 5.4 Hz,J3a6H = 0.8 Hz, spin–spin coupling constants 5J were observed earlier only in similar systems with a boat conformation, such as 1,5-diazabicyclo[ 3.1.0]hexanes (5J3a6e = 0.7 Hz, 5J3e6e = 0.5Hz)19], 2.51 (br.m, NH), 3.2 (m, 2-He, 2J = –12.8 Hz, 3J2e3a = 7.8 Hz, 3J2e3e = 1.0 Hz), 3.3 (m, 2-Ha, 2J = –12.8 Hz, 3J2a3a = 10.9 Hz, 3J2a3e = 6.3 Hz), 3.86 (s, MeO), 4.82 (d, 4-He, 3J4e3a = 5.4 Hz); 13C NMR (75 MHz, CDCl3) d: 31.1 (t, 3-C), 51.9 (t, 2-C), 53.1 (q, MeO), 57.4 (d, 4-C), 67.9 (s, 5-C), 167.2 (s, CO); MS, m/z (%): 147, 145 (4) [M–MeO], 141 (100), 114 (13), 109 (17), 85 (43), 81 (38), 59 (26), 54 (24), 53 (80).The chair conformation of 3a is sterically inconvenient,19 therefore, 3a transforms quantitatively to the boat conformer 3b within a few hours at room temperature in CDCl3 solution. Conformational change from boat 2b to chair 3a and to boat 3b (Scheme 4) was confirmed by the characteristic chemical shifts of C(3).§ It is noteworthy that the new diaziridines 2 and 3 are of interest as potential inhibitors of monoaminooxidase.30 This work was accomplished with financial support from INTAS (grant no. 94-2839). References 1 (a) V. Ya. Bespalov and M. A. Kuznetzov, Zh. Strukt. Khim., 1974, 15, 740 (in Russian); (b) V. Ya. Bespalov and M.A. Kuznetzov, Teor. Eksp. Khim., 1979, 15, 557 (in Russian). 2 (a) M. A. Kuznetzov, Usp. Khim., 1979, 48, 1054 (Russ. Chem. Rev., 1979, 48, 563); (b) M. A. Kuznetzov, Zh. Org. Khim., 1979, 15, 1793 [J. Org. Chem. USSR (Engl. Transl.), 1979, 1612]. 3 G. V. Shustov, N. B. Tavakalyan, L. L. Shustova, I. I. Chervin and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1058 (Bull.Acad. Sci. USSR, Div. Chem. Sci., 1980, 29, 765). 4 (a) G. V. Shustov, N. B. Tavakalyan and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1677 (in Russian); (b) G. V. Shustov, N. B. Tavakalyan and R. G. Kostyanovsky, Tetrahedron, 1985, 41, 575. 5 G. V. Shustov, M. A. Shochen, S. V. Barmina, A. V. Yeremeev and R. G. Kostyanovsky, Dokl. Akad. Nauk SSSR, 1986, 287, 689 (in Russian). 6 J. W. Davies, J. R. Malpass and R. E. Moss, Tetrahedron Lett., 1985, 26, 4533. 7 G. V. Shustov, S. N. Denisenko and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1983, 1930 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1983, 32, 1754). 8 S. N. Denisenko, G. V. Shustov and R. G. Kostyanovsky, J. Chem. Soc., Chem. Commun., 1983, 1275; corrigendum: J. Chem.Soc., Chem. Commun., 1985, 680. 9 G. V. Shustov, S. N. Denisenko, I. I. Chervin, A. B. Zolotoi, O. A. D’yachenko, S. V. Konovalikhin, G. V. Shilov, L. O. Atovmyan and R. G. Kostyanovsky, Khim. Geterotsikl. Soedin., 1986, 1330 [Chem. Heterocycl. Compd. (Engl. Transl.), 1986, 1076]. 10 G. V. Shustov, V. V. Starovoytov and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1986, 1205 (Bull.Acad. Sci. USSR, Div. Chem. Sci., 1986, 35, 1096). 11 G. V. Shustov, S. N. Denisenko, V. V. Starovoytov, I. I. Chervin and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1988, 1599 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1988, 37, 1415). 12 G. V. Shustov, S. N. Denisenko, M. A. Shochen and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser. Khim., 1988, 1862 (Bull. Acad. Sci.USSR, Div. Chem. Sci., 1988, 37, 1665). 13 G. V. Shustov, S. N. Denisenko, A. Yu. Shibaev, Yu. V. Puzanov, I. K. A. Romero Maldonado and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, § 3a, obtained from 2 under the action of ButOCl in Et2O followed by evaporation in vacuo (0.5 torr, 0 °C), in quantitative yield; 1H NMR (300MHz, CDCl3) d: 2.46 (m, 3-He, 2J = –14.7 Hz, 3J = 10.7, 3.0, 2.1 Hz), 2.76 (m, 3-Ha, 2J = –14.7 Hz, 3J = 9.2, 7.9, 7.6 Hz), 3.38 (m, 2-He, 2J = = –15.3 Hz, 3J = 9.2, 3.7 Hz), 4.1 (m, 2-Ha, 2J = –15.3 Hz, 3J = 10.7, 7.6 Hz), 3.89 (s, MeO), 4.9 (dd, 4-He, 3J = 7.9, 2.1 Hz); 13C NMR (75 MHz, CDCl3) d: 40.1 (t, 3-C), 53.7 (q, MeO), 53.8 (t, 2-C), 56.9 (d, 4-C), 76.3 (s, 5-C), 162.6 (s, CO). 3b, obtained from 3a by keeping its solution in CDCl3 (6 hrs, 20 °C), in quantitative yield; 1H NMR (300 MHz, CDCl3) d: 1.97 (m, 3-He, 2J = = –14.1 Hz, 3J = 7.3, 1.0 Hz), 2.21 (m, 3-Ha, 2J = –14.1 Hz, 3J = 11.3, 8.0, 5.9 Hz), 3.43 (ddd, 2-Ha, 2J = –13.3 Hz, 3J = 11.3, 7.3 Hz), 3.66 (ddd, 2-He, 2J = –13.3 Hz, 3J = 8.0, 1.0 Hz), 3.99 (s, MeO), 4.96 (d, 4-He, 3J = 5.9 Hz); 13C NMR (75 MHz, CDCl3) d: 31.6 (t, 3-C), 53.5 (q, MeO), 54.0 (t, 2-C), 57.4 (t, 4-C), 78.8 (s, 5-C), 164.3 (s, CO).MeO 2C N N H Cl H N CO2Me Cleq H MeO 2C N N H Cl H i i NCO2Me H Clax MeO 2C N N H H Cl MeO 2C N N H H Cl i i 2c (chair, Cl equatorial) 1b 2a (boat, Cl equatorial) 2d (chair, Cl axial) minor product 1a 2b (boat, Cl axial) major product Scheme 3 Reagents and conditions: i, H2NOSO3H/K2CO3 as described.22 N N H H Cl MeO2C N N Cl Cl H MeO2C N N Cl H Cl MeO O i ii 2b 3a 3b Scheme 4 Reagents and conditions: i, ButO Cl in Et2O at 20 °C; ii, 6 h at 20 °C in CDCl3 or 15–20 min in pure form.Mendeleev Communications Electronic Version, Issue 2, 1998 (pp. 43–82) Ser. 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Chem., 1981, 1073. 30 R. G. Kostyanovsky, G. V. Shustov, O. G. Nabiev, S. N. Denisenko, S. A. Sukhanova and E. F. Lavretskaya, Khim.-Farm. Zh., 1986, 20, 671 (in Russian). Received: Moscow, 8th December 1997 Cambridge, 8th January 1998; Com. 7/08974K