Cycloaddition of phenyl azide to unsymmetrical azabicyclic alkenes

Addition of phenyl azide to selected derivatives of the 2-azabicyclo[2.2.1]hept-5-ene, 2-azabicyclo[2.2.1]hept-5-en-3-one and 2-azabicyclo[2.2.2]oct-5-en-3-one ring systems is described. Modest levels of regioselectivity are observed; 100% exo-facial selectivity is found in the [2.2.1] systems but exo-and endo-adducts are formed from the [2.2.2] substrate allowing isolation of all four possible stereoisomers. Photolytic removal of dinitrogen from the triazolines gives aziridines which are potential precursors to stereospecifically functionalised aziridino-cyclopentanes and aziridino-cyclohexanes.


Introduction
The cycloaddition of azides to norbornenes and benzonorbornadienes 1 has been well studied as has the effect of a bridging heteroatom in 7-oxa 2 and 7-aza-3 derivatives of the latter ring systems.Typical benzo-annelated examples demonstrate the characteristic addition from the exoface giving triazolines 1a; subsequent photolysis of the triazolines yields aziridines 2a (Figure 1).Analogous addition of diazomethane gives pyrazolines 1b from which cyclopropanes 2b are accessible via photolytic deazetisation; 4 epoxides are accessible via direct epoxidation of norbornene, 5 as are the corresponding benzo-derivatives 2c from 1,4-iminonaphthalenes (benzonorbornadienes) and 1,4-imino-anthracenes.We are not aware of corresponding studies with bicyclic alkenes containing unsymmetrically-placed amino-nitrogen and we have therefore examined azide addition to the strained bicyclic amine 5. Turning to higher homologues, potential substrates such as the heterobicyclo[2.2.2]octenes 3 unfortunately decompose rapidly by retro-Diels-Alder cycloaddition and we were therefore unable, for example, to achieve [4+2] cycloaddition of cyclic dienes to 3. 7 However, the alternative cycloaddition of dienes to the lactam 4 proceeds readily and subsequent removal of the carbonyl group using hydride reduction is straightforward. 7We have therefore examined the reaction of 4 with phenyl azide in order to probe the potential facial selectivity and regioselectivity offered by this unsymmetrical substrate.We have also included the lactam 6.This readily-available substrate 8 has formed the basis for recent syntheses of epoxy 9 and cyclopropano 10 derivatives of 7 and their conversion into stereospecifically-substituted bicyclo[3.1.0]hexanes8 which are intermediates in the synthesis of novel nucleoside variants (Scheme 1).We are prompted to report our results by the developing activity in this area and also by a recent report of the formation of the aziridines 7c by cycloaddition of azides to 6 (in its N-Boc-protected form) using high pressure, followed by deazetisation. 11

Scheme 1
Whilst we expected attack to occur exclusively from the exo-face of 5 and 6, we were mindful of a report that endo-addition has been observed in epoxidation of 6. 8 We expected both faces of the double bond in 4 to be accessible to cycloaddition on the basis of our earlier work on the addition of cyclic dienes. 7There has been disagreement concerning the influence of the homoallylic nitrogen in analogues of 5 on the regioselectivity of addition to the double bond 12

Results and Discussion
The amine 5 was treated with phenyl azide in dichloromethane solution at room temperature; the reaction was followed by IR spectroscopy and was complete within 5 days (Scheme 2).A quantitative yield of triazolines 9 and 10 was obtained in a 40:60 ratio as measured by NMR integration.The exo-stereochemistry was assigned on the basis of the small coupling constants J 1,6 and J 4,5 (< 1 Hz).Early work with norbornene/phenyl azide adducts established that the proton adjacent to N=N was further downfield than that next to the N-phenyl substituent; 1 this distinction was evident in all of the adducts obtained in the present study and formed a consistent basis for assignment of 1 H NMR signals.Clearly, the bridgehead proton H 1 always appears downfield of H 4 but the amino-nitrogen at the 2-position exerts an additional influence in a variety of 2-alkyl-2-azabicyclo-[2.2.1]heptane and -[2.2.2]octane derivatives, causing H 6-endo to appear downfield of H 5-endo (Scheme 2) by between 0.2 and 0.5 ppm. 13Despite the complexity of the spectrum of the mixture of triazolines 9 and 10, two downfield doublets were resolved at δ 4.91 (major) and 4.65 (minor) and these signals were therefore assigned to H 6endo in 10 and H 5endo in 9 respectively, consistent with the assignment of 10 as the major component.The cycloadducts could not be separated and the mixture of 9 and 10 was photolysed in acetone solution in a quartz vessel using a medium pressure mercury lamp.Conversion into the single aziridine 11 was complete within 4 hours and gave a yield of 90% after chromatography on silica (Scheme 2).The corresponding reaction of phenyl azide with the lactam 6 (Scheme 3) occurred more slowly but was complete on heating overnight in dichloromethane in a sealed tube at 90 o C. Attempts to perform the reaction at higher temperatures in toluene led to substantial decomposition.Similar cycloadditions of azides to the N-Boc-protected lactam 6a were reported to require high pressure; 11 the use of a secondary lactam in our study may be significant in making the reaction easier but we did not investigate this question further.The exo-selectivity in attack on 6 was maintained, as was the 40:60 ratio of cycloadducts 12:13 [the ratio of regioisomers 15:16 from 6a is based on isolated yields 11 and is included in Scheme 3 for comparison].The assignments for 12 and 13 were confirmed by considering the major and minor signals at δ 3.13 and 3.22 due to the bridgehead protons H 4 (adjacent to the amide carbonyl group).
Examination of bridgehead proton signals in the compounds produced in this work shows that the bridgehead proton (H 1 or H 4 ) on the same side as the N=N bond of the triazoline is consistently at lower field than the corresponding bridgehead proton adjacent to the triazoline Nphenyl, allowing assignment of the minor signal at δ 3.22 to H 4 in isomer 12.A NOESY experiment confirmed this, showing an interaction between H 4 and the aryl ring in the case of 13 but not 12.The isomeric triazolines 12 and 13 were not separated and photolysis of the mixture gave 14 as a single stereoisomer.Clearly, 14 can be converted into a 6-azabicyclo[4.1.0]hexanederivative corresponding to 8 using established hydrolysis or reduction procedures.
We wanted to explore the feasibility of addition to the 2-azabicyclo[2.2.2]oct-5-ene-3-one ring system as a potential source of the corresponding 7-azabicyclo[4.1.0]heptanehomologues and we chose the readily available benzo-derivative 4.
Equimolar amounts of phenyl azide and the lactam 4 were heated in toluene solution at 85 o C for 17 hours.The product was shown by NMR and TLC analysis to consist of a mixture of four cycloadducts (Scheme 4) and the triazoline products were investigated in some detail.A small quantity of each of the triazolines 18 -21 was separated by chromatography on silica (60% recovery, together with ca.10% of unchanged 4).Additional mixed fractions were eluted containing [18 & 19] and [20 & 21].Analysis of the 1 H NMR spectra of all of the isolated fractions gave the percentages indicated in Scheme 4. The mixed fractions were photolysed separately; each pair of compounds gave a single aziridine showing that in one pair the aziridine was exo-to the benzo-group and in the other pair, it was endo-. 14The structural assignments shown in Scheme 4 were made on the basis of this information and a detailed analysis of the 1 H NMR data (Table 1).The dramatic upfield shift of the N-Me signal for 18 relative to the other three isomers (ca.0.3 ppm) is consistent with the unique placement of the methyl group within the shielding zone of the triazoline N-phenyl group in this stereoisomer and provides a crucial point of reference.The relative J values measured for the aziridines 22 and 23 (Table 1) reflect similar differences in dihedral angle; homonuclear spin-decoupling experiments confirmed the assignments.These aziridines were produced efficiently (ca.80% yield) as single stereoisomers by photolysis of mixed samples of [18 and 19] and [20 and 21] respectively, in acetone solvent.

Summary
We have shown that cycloaddition of phenyl azide to selected bicyclic amines and secondary and tertiary lactams based on the 2-azabicyclo[2.2.1]hept-5-ene and 2-azabicyclo[2.2.2]hex-5-ene ring systems occurs at modest temperatures without the need for high pressure.Modest regioselectivity is observed in attack on the double bond with a very slight preference for the adducts having the N-phenyl group further from the amino-or amido-nitrogen.12b Only exoproducts are formed in attack on the bicyclo[2.2.1]hept-5-ene examples but there is no significant facial discrimination as far as the bicyclo[2.2.2]oct-6-ene system is concerned, allowing isolation and characterisation of all four possible stereoisomers.The yields of aziridines from photolysis of the triazolines in acetone solvent in the present work were significantly higher than those reported for photolyses carried out in acetonitrile. 11The established hydrolysis and reductive cleavage of the amide bond in bicyclic lactams 9,10,11 opens the way to a wider range of nucleoside and, with this in mind, we are currently looking at simpler 2azabicyclo[2.2.2]oct-6-ene examples which should allow formation of both aziridine stereoisomers in the higher homologues of 8 based on the 7-azabicyclo[4.1.0]heptanering system.

Experimental Section
General Procedures.NMR spectra were recorded on Varian EM 390 (90 MHz), Bruker ARX 250, AM 300, or DPX 300 spectrometers.Spectra were measured in CDCl 3 with tetramethylsilane (TMS) as internal reference unless indicated otherwise.Signal characteristics are described using standard abbreviations: s (singlet), d (doublet), dd (doublet of doublets), m (multiplet), br (broad).Selective spin-decoupling experiments were performed on the series of compounds 18 -23 in order to allow measurement of J values and to confirm the assignment of the methine protons.Selected NOESY experiments were performed as described in the discussion section.In the 13 C spectra, (s), (d), (t), (q), are used to indicate quaternary, methine, methylene and methyl carbons respectively, as shown by DEPT experiments.IR spectra were recorded on a Perkin-Elmer 298 spectrometer as solutions in CH 2 Cl 2 unless indicated otherwise.Mass spectra were measured routinely on VG Micromass 14 (EI) [an asterisk is used to indicate the base peak in EI spectra] or Micromass Quattro LC (ES) spectrometers.Accurate mass measurements were obtained using a Kratos Concept mass spectrometer (FAB); they were measured to 5 decimal places but are quoted to 4. Melting point measurements were made using a Kofler hot stage apparatus and are uncorrected.Petroleum ether refers to the fraction b.p. 40 -60 o C.

Addition of phenyl azide to lactam 6
A solution of lactam 6 8 (0.2 g; 1.83 mmol) and phenyl azide (0.22 g; 1.85 mmol) in dichloromethane (2 mL) was heated at 90 o C in a sealed tube for 16 h with magnetic stirring.After removal of the solvent under vacuum, the crude product was washed with cold diethyl ether to give a mixture of two triazolines 12 and 13 (0.33 g; 79%) which could not be separated.

Photolysis of triazolines 12 and 13 to give exo-aziridine 14
A sample of 12 and 13 (0.15 g; 0.657 mmole) was irradiated in acetone (50 mL) in a quartz tube for 4.5 h using a medium pressure mercury lamp.The solvent was evaporated and the product chromatographed on silica using 2:1 diethyl ether:petroleum ether to give the aziridine 14 as a crystalline solid (0.125 g; 95%) which was recrystallised from ethyl acetate/diethyl ether to give colourless crystals, m.p. 140 -142 o C. 1

Addition of phenyl azide to lactam 4
A solution of lactam 4 18 (0.31 g; 1.68 mmol) and phenyl azide (0.2 g; 1.68 mmol) in toluene (2 mL) was heated at 85 o C for 17 h.After cooling, the toluene was removed with a pipette and the yellow solid which remained was then washed with petroleum ether (yield 0.375 g; 75%).TLC the presence of four compounds.The product was chromatographed on silica using 1:1 diethyl ether:ethyl acetate as eluant to give samples of the four triazolines as pure fractions, together with mixed fractions (total 60%) and a small quantity of unchanged  17 Analysis of the 1 H NMR spectra gave the following overall yields: 18 (19%); 19 (33%); 20 (13%); 21 (32%). 1 H NMR data for all four compounds are shown in Table 1.

Photolysis of triazolines 18 and 19; formation of exo-aziridine 22
A mixture of 18 and 19 (96 mg) in acetone (52 mL) was irradiated in a quartz tube for 2.5 h using a Hanovia medium pressure lamp.The solvent was removed under vacuum and chromatograped on silica using 70:30 diethyl ether:petroleum ether to give 22 as white crystals (71 mg; 81%), m.p. 184 -186 o C. 1

Photolysis of triazolines 20 and 21; formation of endo-aziridine 23
A mixture of 20 and 21 (58 mg) in acetone (30 mL) was irradiated for 2.5 h and was chromatographed as described above to give 23 as a white waxy solid (42 mg; 80%). 1

Table 1 1
H NMR data for compounds