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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 September 9.
Published in final edited form as:
Tetrahedron Lett. 2009 September 9; 50(36): 5107–5109.
doi:  10.1016/j.tetlet.2009.06.099
PMCID: PMC2758692

New Approach to 4-Phenyl-β-aminotetralin from 4-(3-Halophenyl)tetralen-2-ol Phenylacetate


Mixed trifluoroacetyl phenylacetyl anhydride and 3-halostyrenes (fluoro, chloro, and bromo) or vinylcycloalkanes (cyclohexyl, cyclooctyl), undergo cascade Friedel-Crafts cycli-acylalkylation, enolization, and O-acylation to give 4-substituted tetralen-2-ol phenylacetates, without additional solvent in good yields. Base alcoholysis of 4-phenyltetralen-2-ol phenylacetate reveals the tetral-2-one for asymmetric transfer hydrogenation. Bromophenyltetralen-2-ol phenylacetate undergoes Suzuki coupling, and provides a short route to trans-4-phenyl-β-aminotetralin.

Keywords: β-aminotetralin, cascade, halostryene, phenylacetate, tetralen-2-ol

The β-aminotetralin moiety is a pharmacophore element recognized by several classes of aminergic neurotransmitter G protein-coupled receptors (GPCRs). For example, asymmetric (–)-trans-4R-phenyl-2S-dimethylaminotetralin (1, Scheme 1) exhibits anorectic and antipsychotic efficacy after peripheral administration to rodents via actions at brain serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 GPCRs.1 The 4-(3-halophenyl) analogs of 12 are active at 5-HT2 receptors, important drug targets for many human psychological and physiological disorders. Halophenyltetralen-2-ol phenylacetate 3 intermediates, from readily available reagents 4 and [5] (Scheme 1), provide these analogs and avoid the requirement to isolate corresponding 4-(3-halophenyl)tetral-2-ones 2. Versatile aryl halide and enol phenylacetate functionalities on 3 make these molecules useful for diversified organic syntheses, pharmaceuticals, and catalyzed asymmetric transformations.3

Scheme 1
Retrosynthesis to trans-4-Phenyl-β-aminotetralins.

Although 4-phenyltetral-2-ones are of great interest to organic synthesis, methods to synthesize them are low yielding, scarce, difficult to diversify, and require fast, efficient use to avoid decomposition.4 Direct ring-closure reports to non-halogenated 4-phenyltetral-2-one 2a include (Scheme 2): (a) dimethylamine addition to symmetrical dibenzoylethylene 6 gives 2-(N,N-dimethylamino)-1,4-diphenyl-1,4-butanedione, to reduce and then cyclize in refluxing acid;5 (b) enolate addition of phenylacetone 7 to benzaldehyde provides 1,4-diphenylbut-1-en-3-one, to cyclize under Friedel-Crafts (FC) conditions with metal Lewis acid or PPA;6 (c) one-step FC-cycli-acylalkylation (FC-CAA)7 with phenylacetyl chloride 8, styrene 4a (or TMS activated 4a), and metal Lewis acid in dichloromethane.8 Free of many aforementioned drawbacks one-step FC-CAA (d) with phenylacetic acid 9, TFAA, phosphoric acid,9 and 4a, readily dimerizes 4a and furnishes only a trace amount of 2a by GC-MS.10 While, mixed trifluoroacetyl phenylacetyl anhydride [5] can esterify alcohols11 or FC-acylate aryls to give 10, one report includes traces of aryl enolates 11.12 Stable tetralen-2-ol phenylacetates avoid difficulties handling and storing expensive 4-phenyltetral-2-ones and are made directly with one procedure, without additional solvent. We now report a facile cascade reaction to 4-(3-halophenyl)tetralen-2-ol phenylacetates and their utility in asymmetric transfer hydrogenation (ATH), palladium cross-coupling, and palladium hydrodebromination applications.

Scheme 2
Literature Examples for 4-Phenyltetral-2-one.

Cascade FC-CAA, enolization, and O-acylation was investigated with TFAA activated phenylacetic acid and 4a, 3-halostyrenes 4b–d (Table), as well as, vinylcycloalkanes 4e,f (Scheme 3). Reactive 4a was heated to 60 °C prior to reaction with [5] in order to accelerate the inherently slow enolization13 of 2a in the reaction media and allow isolation of O-acylated 3a (15%). At rt, or cooling to −78 °C, resulted in loss of reactive 2a in a complex mixture. Additional solvents (ACN, hexanes, dichloromethane) resulted in self-condensed phenylacetyl anhydride with styrene persisting, as did addition of 4a to the activated acid. Surprisingly, moderately reactive 3-halostyrenes 4b–d14 withstood dimerization in the reaction media and resulted in higher conversions to the desirable tetral-2-one. Equimolar 3-fluorostyrene 4b and [5] gave major 2b (42%) and minor 3b (8%). Chlorophenyltetral-2-one 2c (70%) was prepared from 3-chlorostyrene 4c with 3-equiv of [5], and underwent further treatment with equimolar [5] to provide 3c (38%). Warming to rt over 24 h 3-bromostyrene 4d with 3-equiv of [5] gave 3d (50%), over 3-fold increase in yield from non-halogenated 3a. Vinylcyclohexane 4e and vinylcyclooctane 4f provided solids 3e (63%) and 3f (40%), respectively, when reacted separately with [5]. Conformational difference between 4-cycloalkyltetralen-2-ol and 4-phenyltetralen-2-ol cores was indicated by allylic proton coupling in the former. Tetralen-2-ol phenylacetates were isolated with less than 5% of the regioisomer (unlike silyl tetralen-2-ol ethers15), stable to atm, and enantio-resolvable using chiral stationary phase (CSP)-HPLC (e.g., for 3e, tR1 = 15.7 [α]25 D = −79.1, tR2 = 16.8 [α]25 D = +78.8.

Scheme 3
Cascade Reaction with Vinylcycloalkanes.
Cascade Reaction with Styrene or 3-Halostyrenes for 2 and 3, Conditions, Yields, and UV Trace.

Three steps (Scheme 4), (a) ATH,16 (b) tosylation, and (c) SN2 inversion with aq dimethylamine,17 provided enantioenriched cis-(4R-2R)-12a (74%), cis-(4R-2R)-13 (75%), and trans-(4R-2S)-1 (70%) with β-hydride elimination byproducts.18 Pure trans-4R-2S-1 was obtained by CSP-HPLC (74% ee). Carbonyl reduction of 3d with (d) sodium borohydride gave 12d (90%) and (e) hydrodebromination19 provided (±)-12a (99%). Employing brominated 3d in one additional step gave (±)-12a in 45% yield from reagents, an improvement over the 11% yield using the non-halogenated 3a. Suzuki coupling20 of 3d with (f) phenylboronic acid smoothly provided 4-(biphenyl-3-yl)tetralen-2-ol phenylacetate 14 (70%). Thus, simple palladium insertion modifications to bromophenyl functionality with 3d and 12d were established.

Scheme 4
Utility of 4-(3-Bromophenyl)tetralen-2-ol Phenylacetate.

Cascade Friedel-Crafts cycli-acylalkylation, enolization, and O-acylation with activated phenylacetic acid and moderately reactive halostyrene or vinylcycloalkanes, provides 4-(3-halophenyl or cycloalkyl)tetralen-2-ol phenylacetate. An electron withdrawing substituted styrene dimerizes less and provides higher yields in the reaction media than unsubstituted styrene. Base alcoholysis on 4-phenyltetralen-2-ol phenylacetate reveals 4-phenyltetral-2-one for use in situ. Simple palladium insertion cross-coupling with 4-(3-bromophenyl)tetralen-2-ol phenyl-acetate is established and a short 5-step sequence provides a 3-times (6% to 18%) more efficient route to trans-1.

Supplementary Material


This work was supported by USPHS (NIH) grants MH068655, DA023928, and MH081193.


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Supporting Information Available

General experimental methods, procedures, characterization data, copies of 1H and 13C-NMR spectra for synthesized compounds. This material is available free of charge via the Internet at

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