Synthesis and X-ray Structural Studies of a Substituted 2,3,4,5-Tetrahydro-1H-3-benzazonine and a 1,2,3,5-Tetrahydro-4,3-benzoxazonine

Using a common 1-(1-phenylethenyl)-1,2,3,4-tetrahydroisoquinoline precursor to the required ylide or N-oxide intermediate, the Stevens [2,3] and analogous Meisenheimer [2,3] sigmatropic rearrangements have been applied to afford concise syntheses of phenyl -substituted representatives of each of the reduced 1H-3-benzazonine and 4,3-benzoxazonine systems, respectively. Single crystal X-ray structure determinations were employed to define the conformational characteristics for each ring type.


Introduction
Annulated medium-ring heterocycles have attracted significant research attention owing to the vast array of systems possible with potential for different chemical and biological properties [1][2][3][4]. For example, some 3-benzazonines with a nine-membered ring show 5-HT2A antagonist activity [5], while the eight-membered ring-containing benzoxazocines display a range of biological properties including analgesic [6] and NK1 (neurokinin receptor) inhibitory activity [7]. Synthetic approaches to these systems often involve rearrangement strategies incorporating a ring expansion [8][9][10][11], although ring formation [12][13][14] and ring cleavage approaches [5,15,16] can also be used. The Meisenheimer [1,2] and [2,3] sigmatropic rearrangements of amine N-oxides [17][18][19] and the analogous Stevens [2,3] sigmatropic rearrangements of ylides [20,21] afford good opportunities for medium ring synthesis. To further explore these synthetic prospects and to assess substituent effects (e.g., a phenyl group vs. a methyl group or hydrogen [17]) on configurational and conformational issues in the products, we have investigated the synthetic utility of the [2,3] versions of these rearrangements from the same starting amine precursor, the 1-(1-phenylethenyl) substituted tetrahydroisoquinoline derivative 3. These rearrangements involve three-atom ring expansions with incorporation of an O-C-C (Meisenheimer) or C-C-C (Stevens) unit into the six-membered N-containing ring. Soldatenkov et al. have also reported that a tetrahydroisoquinoline N-ylide can undergo a somewhat related [1,4] sigmatropic rearrangement on reaction with dimethyl acetylenedicarboxylate affording a 3-benzazonine derivative in good yield [22]. The results of our work and the single crystal X-ray structural analyses of the benzo-fused nine-membered ring heterocycles produced are discussed in this paper.

Scheme 1. Synthesis of the benzazonine 1 and benzoxazonine 2.
Reaction of the tetrahydroisoquinoline 3 with ethyl bromoacetate gave a diastereomeric mixture of the quaternary salts which, on treatment with DBU in acetonitrile at 25 °C, gave mainly the nine-membered 3-benzazonine 1 as a mixture of the E and Z diastereomers from the ylide 4 and a Stevens [2,3] rearrangement. A very minor amount of the Stevens [1,2] rearrangement product 6 ( Figure 1, 8% yield based on 1 H-NMR analysis) was also formed as an inseparable mixture (HPLC) with a trace of another compound tentatively assigned as the isomeric ring-opened product 8 ( Figure 1); a little more of both 6 and 8 were formed on repeating the reaction in acetonitrile heated at reflux but they could not be separated. The structure of the benzazepine 6 followed from the 1 H-NMR spectral data on the mixture, particularly the characteristic coupled doublet signals ascribed to H1 (3.66 ppm) and H2 (4.50 ppm), while for the ring-opened product 8, diagnostic signals consistent with an isolated mono-substituted vinyl group, a separate olefinic proton, and two isolated N-methylene protons (singlets at 3.61 and 3.15 ppm in the 1 H-NMR and at 58.3 and 55.2 ppm in the 13 C-NMR) were apparent. Potentially this latter product could arise via a thermal 1,3-rearrangement [24,25] of the tetrahydroisoquinoline 3 to an eight-membered 5-phenyl-3-benzazocine intermediate and subsequent N-quaternization followed by a DBU-mediated Hofmann elimination to give 8 with the E geometry about the stilbenic double bond. The diastereomers of the benzazonine 1 were separated by preparative HPLC and their structures were elucidated initially on the basis of NMR, mass spectrometric and elemental analytical data. Consistent with the nine-membered ring structure was the presence of a singlet signal downfield at 6.91 ppm in the 1 H-NMR (C6D6 room temperature; 13 C-NMR, C7 at 130.5 ppm) or 6.74 ppm (C6D6, 75 °C; 13 C-NMR, C7 at 131.5 ppm) ascribed to the vinylic proton H7 in the E and Z diastereomers, respectively. The E vs. Z stereochemistry was assigned on the basis of a nOe interaction between H7 and the ortho-6-phenyl protons in the E-1 diastereomer but not the Z-1 diastereomer. The benzazonine Z-1 exhibited conformational flexibility on the basis of the 1 H-NMR spectral analysis at 25 °C in either C6D6 or CDCl3. Broad peaks lacking definition were observed. At 75 °C in C6D6 a single set of signals was obtained for Z-1 which supported the proposed structure. At this temperature only the signals ascribed to H5 and the ethyl ester protons displayed poor peak shape. At −50 °C in CDCl3, two conformations in a ratio of about 1.94:1 appeared, with substantially different diagnostic singlet signals at 2.36 and 2.69 ppm (N-Me group) and multiplet signals at 1.41-1.35 and 0.87-0.81 ppm (ester methyl group) for the major and minor conformations, respectively.
Conversion of the tetrahydroisoquinoline 3 to the N-oxide derivative was achieved by oxidation with m-CPBA in dichloromethane at room temperature to afford the trans-N-oxide 5 (53%), together with a substantial yield of a mixture (up to 25%; 44:56 ratio) of the isomeric rearranged products 2 and 7.
Only the Z-diastereomer of the nine-membered ring benzoxazonine 2 was observed. Similar results were obtained on oxidation with cooling of the solution during the reaction and on work up. The Meisenheimer [2,3] rearrangement product 2 and the Meisenheimer [1,2] rearrangement product 7 were isolated by preparative HPLC. In the 1 H-NMR of the benzoxazonine 2 at 25 °C in CDCl3, the H7 olefinic proton appeared as a downfield singlet at 7.00 ppm, while the H1 and H2 methylene proton signals were broad and integrating as only 2-3 protons. At low temperature (−30 °C), two conformers of the benzoxazonine 2 (ca. 3.5:1 ratio) were apparent in the 1 H and 13 C-NMR spectra, which were probably related by the inversion or "flipping" of the N3-O4-C5 segment of the medium ring. With the seven-membered ring product 7, downfield singlet signals at 5.98 and 5.53 ppm in the 1 H-NMR were consistent with the presence of the methylidene group, while H1 was ascribed to the singlet signal further upfield at 5.15 ppm.
Furthermore, a solution of the benzoxazonine 2 in acetonitrile heated at reflux led to slow isomerisation via a [1,3] shift to yield the benzoxazepine 7; an equilibrium between 2 and 7 (ca. 24:76 ratio, 2:7) was obtained on heating either 2 or 7 at a higher temperature in refluxing xylene for 1 h.
In both the Stevens and Meisenheimer [2,3] rearrangements, the cis isomer of the respective intermediate N-ylide 4 or N-oxide 5 is involved, as a favourable concerted transition state geometry [19,21] can be accessed to give the nine-membered ring products. On the other hand, with the corresponding trans-isomeric ylide or N-oxide, this is not the case, and the diradical mediated [1,2] rearrangements to give seven-membered ring products can then proceed. Interestingly, with a 1-ethenyl or 1-isopropenyl substituent in the tetrahydroisoquinoline precursor of the corresponding ylide, only the Stevens [2,3] rearrangement products were observed, while the analogous N-oxides gave only the Meisenheimer [1,2] rearrangement product (from the 1-ethenyl precursor) or a mixture of the [1,2] and [2,3] rearrangement products (from the 1-isopropenyl precursor) on heating at reflux in acetonitrile for 50 min [17].

X-ray Structural Studies
To support the structural elucidations, single crystals of the 3-benzazonine E-1 and of the 4,3-benzoxazonine 2 were obtained for X-ray crystallographic analysis. Suitable crystals for an X-ray study of Z-1 could not be obtained.
The results of the single crystal X-ray studies on E-1 and 2 were consistent with the above formulations in terms of stoichiometry and connectivity (Figure 2a,b, Tables 1-3), establishing solid-state conformations, and with bond distances and angles generally conforming to expected norms. Counterpart values and figures for two closely related systems (CCDC: AYEKOF [26], SELXUC [27]; see Figure 4 for structures) are also included for comparison.
The crystal packings are of some interest, with that of E-1 comprising sheets normal to c (Figure 3a), similar to that normal to b observed with AYEKOF [26] (Figure 3c), while 2 is a simple translational stacking up b (Figure 3b). The fused aromatic rings with their ortho-methoxy substituents are unremarkable, the methyl groups lying quasi-coplanar with the aromatic ring with the usual exocyclic angle asymmetries at the pendant bonds, and their phenyl pendants quasi-normal to the supporting phenyl ring plane (Figure 4a,b).

Atoms
Notes: In AYEKOF, the protonating hydrogen atom at the nitrogen atom, although shown in Figure 1 of reference [26], is not included in the CCDC cif file, and was restored as an estimate by us for the purpose of the present Figure; the macrocycle double bond is located on the other side of the ring nitrogen atom, between it and the parent phenyl ring in this species.
The conformations of the strings from C(5) to C(1), inclusive of the aromatic bond, are similar in both E-1 and 2 (Figure 4a,b), but there are substantial differences between C(1)…C(5), with inversion at N(3) and a substantial difference in the angle sums about it: 343.3 in E-1, 323.6° in 2, reflecting the difference in the N(3)-X(4) substituent and associated distances [1.450(2) in E-1 (X = C), 1.4544(10) Å in 2 (X = O)]. It is not clear however, which of the two conformations seen in solution at low temperature for E-1 and 2 correlate with the ring conformation for each seen in the solid state. Further studies are required to elucidate this. In each of these two compounds, as well as AYEKOF and SELXUC, with quaternary nitrogen atoms and with the double bond differently located or absent (Figure 4c,d), all of the macrocycle string lies to one side of the supporting aromatic ring plane. However, the conformations are different in each compound; a consequence of the diversity of string components and associated substituents. With related N,O-containing, nine-membered, reduced 2,6-benzoxazonine derivatives [28], the conformations adopted in the crystalline state (MOSXIB and MOSXOH [28]) were shown to be the same as those in solution.
High level calculations are required on the benzo-fused aza and oxaza ring systems in the present work in order to further probe the solution and solid state conformational landscape of these interesting heterocyclic systems.

General
Microanalyses were carried out by the Central Science Laboratory, University of Tasmania, Hobart. Melting points were determined on a Yanagimoto Seisakusho micromelting point apparatus, and are uncorrected. Infrared spectra were recorded on a Digilab FTS-20E Fourier transform spectrometer. The 1 H and 13 C-NMR spectra were recorded on a Bruker AM-300 spectrometer at 300 and 75 MHz, respectively. Chemical shifts in ppm (δ) were measured relative to tetramethylsilane. Unless otherwise stated, the NMR spectra were measured in deuterated chloroform. Peaks are reported as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q) or multiplet (m). Where samples in the 13 C-NMR exhibited several conformers, or isomers, the chemical shift for the major form is given first for each signal type; different forms are denoted with superscripts a,b or x,y in the l H-NMR spectra. The mass spectra were recorded on either a VG MM 7070F or a Kratos Concept ISQ mass spectrometer operating at 70 eV. Peak intensities in parentheses are expressed as a percentage of the base peak. Analytical thin layer chromatography (t.l.c.) and preparative thin layer chromatography (p.t.l.c.) were performed on either Merck silica gel 60 F254 or Camag DSF-5 aluminium oxide. All column chromatography was performed under medium-pressure ("flash chromatography") on either Merck silica gel 60, 230-400 mesh, or on type H aluminium oxide, 100-200 mesh. Preparative HPLC utilised a Dynamax-604 C18 reverse-phase column with a Waters 600 multisolvent delivery system and Waters 486 tunable UV detector. Samples were eluted at 10 mL/min and monitored at 254 nm. Mixtures of the chromatography solvents were made up by volume. Organic solvent extracts were dried with anhydrous sodium sulfate. Where reaction mixture solutions or solvent extracts were concentrated this refers to evaporation under reduced pressure on a rotary evaporator. When anhydrous conditions were necessary the glassware and solvents were dried and the additions or transfers were made via gas-tight syringes or stainless steel tubing, under a positive pressure of nitrogen. Light petroleum refers to a fraction boiling between 60-80 °C.

Synthesis of 6,7-Dimethoxy-2-methyl-1-(1-phenylethenyl)-1,2,3,4-tetrahydroisoquinoline (3)
A solution of 1-phenylethenylmagnesium bromide was prepared by the dropwise addition of 1-bromostyrene (15.0 g, 81.9 mmol) to magnesium turnings (2.22 g, 91.3 mmol) in dry THF (200 mL) under nitrogen over 45 min. The mixture was heated briefly to initiate the reaction at the start of the addition with an iodine crystal present. The reaction temperature was then kept below 35 °C. The solution was stirred for 30 min. after the addition had ceased.
The solution of 1-phenylethenylmagnesium bromide in THF was cooled to <−50 °C in an acetone/liquid nitrogen bath and then the salt 6,7-dimethoxy-2-methyl-3,4-dihydroisoquinolinium iodide (13.52 g, 40.6 mmol; prepared from 6,7-dimethoxy-3,4-dihydroisoquinoline [23] on reaction with excess iodomethane in toluene at room temperature) was added. The mixture was stirred at <−50 °C for 90 min and then allowed to warm slowly to room temperature with stirring for 16 h before the careful addition of ice to decompose excess Grignard reagent. The mixture was basified by the addition of 40% aqueous potassium hydroxide and Et2O (150 mL) was added. The organic layer was decanted from the precipitated inorganic salts then centrifuged to remove any residual solids, washed with water (150 mL), and then concentrated. The residue was dissolved in Et2O (240 mL) which had been used, in three portions, to extract the inorganic solids and then the aqueous wash. The ether solution was washed with water (30 mL) then saturated brine (2 × 20 mL), and then dried and passed through a silica plug. Concentration of the solution afforded a solid which recrystallised to give the title compound 3 (11.11 g, 88%)