Synthesis 2005(15): 2562-2570  
DOI: 10.1055/s-2005-872110
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Wagner-Meerwein Rearrangement of 9-(α-Hydroxyalkyl)xanthenes to 10-Substituted Dibenz[b,f]oxepins: Scope, Limitations and ab initio Calculations

Thomas Storz*a, Eric Vangrevelingheb, Peter Dittmara
a Process R&D, Chemical & Analytical Development, Novartis Pharma AG, 4002 Basel, Switzerland
b Computer-Aided Molecular Design Unit, Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
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Further Information

Publication History

Received 27 February 2005
Publication Date:
04 August 2005 (online)


A series of 9-(hydroxy)alkyl xanthenes 5 was prepared in good yields via: (a) addition of 9-lithioxanthene to functionalized acetaldehydes, or, via a new method, (b) addition of carbanions to xanthene-9-carbaldehyde. A practical and efficient synthesis was found for the latter. Under acidic catalysis, the majority of the addition products underwent Wagner-Meerwein rearrangement to give either the corresponding, 10-substituted dibenz[b,f]oxepin 6 or the xanthenylid-9-ene β-elimination product 7. The first Wagner-Meerwein rearrangement of a homobenzylic cyanohydrin is reported. The dibenz[b,f]oxepins are potential precursors of neuroactive substances. To rationalize product distribution, and probe the scope of the new rearrangement, ab initio quantum mechanical calculations have been carried out on products and transition states in selected cases.


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Typical procedure (5k): To a solution of xanthene 3 (3.64 g, 20 mmol) in anhyd THF (60 mL) under Ar at -65 °C was added n-BuLi (1.1 equiv, 8.1 mL, 2.7 M solution in n-heptane). After stirring at -65 °C for 30 min, a fine red suspension formed. Ethyl formate (1.77 g, 24 mmol) in THF (12 mL) was added dropwise at -65 °C. Stirring at -60 °C to -70 °C for 3 h resulted in a clear, orange solution. After HPLC had indicated complete conversion of 3, glacial AcOH (1.32 g, 22 mmol) was added slowly, such that the temperature did not exceed -60 °C. To the resulting yellowish solution of 4 Huenig’s base (3.1 g, 24 mmol), followed by nitromethane (1.46 g, 24 mmol) were added. The turbid mixture was warmed to r.t. overnight. After quenching with aq AcOH and adjusting the pH to neutral, extraction with CH2Cl2 and purification of the crude product by silica gel chromatography afforded 5k (4.63 g, 85%) as a slightly yellowish solid. Similarly were prepared: 5i [KCN (1.0 equiv), -40 °C to r.t., no base, 91% yield), and 5j [ HPO(OEt)2 (1.1 equiv), -40 °C to r.t., Huenig’s base (1.2 equiv), 91% yield].


For substrates obtained using method B, it is best to avoid workup and isolation (see ref. 12), and instead use the in situ-prepared aldehyde(4) solution (see ref. 13) directly in the next step.