Synthesis and Reactions of Benzannulated Spiroaminals: Tetrahydrospirobiquinolines

An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o′-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation–spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core.


■ INTRODUCTION
Access to a broad range of structurally diverse nitrogen heterocycles is important in probing and understanding biological functions and may lead to the discovery of new medicines and agricultural chemicals. Fused-ring nitrogen heterocycles are considered privileged scaffolds in both medicinal chemistry and agrochemistry. 1 There is a need to expand the structural classes of amines, especially to those that are C-(sp 3 )-rich, to enhance the structural complexity and for better interaction with biological targets. 2 Whereas spiroketals, including benzannulated systems, 3−7 are common scaffolds in biologically active heterocyclic compounds and spirocyclic compounds with a single oxygen and single aminonitrogen attached to the spirane center are known, 8,9 spirodiamines, which contain two amino-groups at that center, are far less well studied. 10−13 The spirodiamine core is known in several natural products, including (−)-isochizogamine (1), 14−16 isoschizogaline (2), 17 (+)-melodinine-E (3), 18−20 and the immunosuppressant (±)-spiroreticulatine (4) (Figure 1). 21 Following earlier work, 13 we reported a concise synthesis method of spirodiamine 6 from the crossed Claisen condensation of lactam 5 and decarboxylative spirocyclization. 10 In these studies, we demonstrated that spirodiamine 6 underwent metal complexation or a reaction with electrophiles, with either preservation of the spirocyclic core or ring opening and derivatization of 4-aminobutyl-1-tetrahydropyridine core 7 ( Figure 2). 10 In contrast, the synthesis and reactions of benzannulated spirodiamines have not been reported. Inspired by the ubiquitous biological activity of tetrahydroisoquinoline derivatives, we considered that the tetrahydrospirobiquinoline scaffold may provide access to novel pharmacophores and ligands for metal complexation. Indeed, benzannulated spiroketals, 13, (Figure 3) have been well studied and synthesized most notably by Ding, Wang, and Zhou. 22−25 ■ RESULTS AND DISCUSSION By analogy with benzannulated spiroketals, we envisaged that increasing the rigidity of the diaza scaffold of spirodiamine 6 would displace the spirodiamine 6 to aminoimine 7 equilibrium toward the spirane tautomer. We therefore sought to synthesize a range of tetrahydrospirobiquinolines, 14, from the doublealdol condensation of o-azidobenzaldehydes with ketones to provide the corresponding diazido-dibenzylidene-ketones, followed by reductive cyclization (Figure 3). Initial studies were directed toward the synthesis of tetrahydrospirobiquinoline 14a. o-Azidobenzaldehyde 15a was allowed to react with acetone in the presence of aqueous sodium hydroxide to afford dienone 17a (94% yield). Subsequent hydrogenation over palladium on carbon gave tetrahydrospirobiquinoline 14a (Scheme 1), the structure of which was confirmed by twodimensional NMR spectroscopy and X-ray crystal structure determination.
A two-step reaction was used for the synthesis of a range of tetrahydrospirobiquinolines from the corresponding aromatic aldehydes and acetones, 26,27 including extended aromatic systems; electron-rich and electron-poor systems; as well as ortho-, meta-, and para-substituted examples, 14b−g ( Table 1). The yields show little deviation, with the exceptions of p-Cl (14g, entry 6), for which some dechlorination was observed, and o-Me (14d, entry 4), for which steric congestion is greater.
Furthermore, cyclopentanone and cyclohexanone can readily replace acetone to produce pentacyclic tetrahydrospirobiquinolines 18 and 19, both as single diastereoisomers, as determined by both 1 H and 13 C NMR spectroscopy (Scheme 2). These are consistent with the symmetrical trans product for cyclopentanone derivative 18 and desymmetrized cis product 19. These relative stereochemistries were confirmed in both cases by X-ray crystallography after tetrabromination (see Supporting Information).
The origins of these diastereoselectivities were probed using dispersion-corrected density functional theory calculations (B3LYP+D3BJ/Def2-TZVPP/SCRF = ethanol) 28 of relative free energies (ΔΔG 298 ), with the assumption of fast equilibria between amine−imine and spirodiamine. The dipole moments computed for the former class were uniformly higher (3.8−4.9 D) than those for the latter (1.1−1.7 D). The equilibrium free energies did not provide sufficient support for the observed diastereoselectivity. We speculate that the stabilities of the two intermediate ketones are predominant factors in the overall stereochemical control. On the basis of the known preferential formation of cis-2,5-dibenzyl-cyclopentanone and cis-2,6dibenzyl-cyclohexanone on the palladium-catalyzed hydrogenation of the corresponding 2,5-or 2,6-benzylidene ketones and the facile cis to trans isomerization of the former, equivalent cis to trans isomerization took place prior to spirocyclization with spirane 18 but not with spirane 19. 29, 30 Alternatively, the opposite diastereoisomers do not spirocyclize and exist as amine−imine isomers, which were not isolated chromatographically due to their higher polarities. Attempts were made to isolate these compounds as well as to cyclize

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Article them upon treatment with a variety of Lewis and Brønsted acids; 24 however, this was unsuccessful. Further investigations into these systems are ongoing in our laboratory.
To expand on the potential number of derivatives accessible by the method, unsymmetrical systems were also studied. Application of the known sequential condensation reaction of acetone with two different o-azido-benzaldehyde derivatives, 20 and 22, 31 hydrogenation, and spirocyclization gave tetrahydrospirobiquinolines 24a and 24b (Scheme 3).

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Article Dibromination first occurs para to the nitrogen to yield the dibromo analogue 25; then, it occurs ortho to the nitrogen to yield the tetrabromo analogue 26 (Scheme 4), with both structures being confirmed by X-ray crystal structure determinations.
Bromide 26 was converted to tetraphenyl-derivative 27 (67%) by Suzuki−Miyaura coupling with phenylboronic acid (Scheme 5). Most importantly, this demonstrates the robustness of the benzannulated spirodiamine core, which tolerates palladium-mediated cross-coupling. The structure of spirane-diamine 27 was confirmed by X-ray crystal structure determination.
We also investigated derivatization by substitution at the nitrogen of the spirane center. Unsurprisingly, a combination of electronics and steric congestion of the aniline nitrogens mandated forcing conditions for alkylation reactions. Thus, alkylation of tetrahydrospirobiquinoline 14a with n-butyllithium in tetrahydrofuran (THF) and hexamethylphosphoramide (HMPA) and iodomethane gave dimethyl derivative 28a (90%), and allyl bromide afforded the diallyl derivative 28b (81%), again with preservation of the spirocyclic framework

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Article (Scheme 6). This is in contrast to allylation of spirodiamine 6, which results in reaction of the amino group of aminoimine tautomer 7 (Figure 2). 10 Diallyl tetrahydrospirobiquinoline 28b smoothly underwent ring-closing metathesis, giving pentacyclic tetrahydrospirobiquinoline 29. The structure of spiranediamine 29 was confirmed by X-ray crystal structure determination.

■ CONCLUSIONS
We have developed a chemically robust and straightforward procedure for the synthesis of tetrahydrospirobiquinoline derivatives, a class of understudied heterocyclic compounds. Further syntheses and applications of spirodiamines, including tetrahydrospirobiquinolines, will be reported in due course.
■ EXPERIMENTAL SECTION General Remarks. All reactions were carried out in ovendried glassware under atmospheric conditions using commercially supplied solvents and reagents, unless otherwise stated. Large-scale hydrogenations were carried out in a Parr hydrogenator. Column chromatography was carried out on silica gel using flash chromatography techniques, unless otherwise stated (eluents are given in parentheses). Analytical thin-layer chromatography (TLC) was performed on precoated silica gel F254 aluminum plates, with visualization under UV light or by staining with an acidic vanillin dip. Melting points were measured with a hot-stage apparatus and are uncorrected. IR spectra were recorded on neat films. 1 H NMR and 13 C NMR spectra were recorded at 400 and 101 MHz, respectively, with chemical shifts (δ) quoted in ppm, relative to CHCl 3 ( 1 H: 7.26 ppm, 13 C: 77.16 ppm).

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