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Novel construction of the benzazocine framework through photoinduced electron transfer (PET) generated arene radical cation

Ganesh Pandey* and M. Karthikeyan

Division of Organic Chemistry (Synthesis) National Chemical Laboratory Pune - 411 008, India
Fax: +91-212-335153


Members of the plant family Berberidaceae are known to contain a new class of isoindolobenzazocine alkaloid magallanesine, isolated from Berberis darwinii. The unique framework of isoindolobenzazocine (I) contains the medium ring nitrogen heterocycle which is generally most difficult to prepare by conventional cyclization methods. As an extension of our research program in the synthetic utilization of photinduced electron transfer (PET) generated arene radical cation (II), to assess the feasibility of preparing carbocyclic and spiro-cyclic compounds, we report herein a straightforward method for the construction of benzazocine skeleton.

Considering the importance of carbocyclization reaction in the synthesis of biologically active natural products, our attention was drawn towards the possible utilization of intramolecular nucleophilic substitution of aromatic rings with efficient nucleophiles.

Many nucleophilic photosubstitution reactions involve the intermediacy of a radical cation particularly with easily oxidized substrates such as alkoxy aromatic or aryl ethers, the solvent or some additive acting as electron acceptor. The aromatic radical ions are relatively stable under favourable conditions but they are short lived when created by photochemical electron transfer since back electron transfer to the closely lying radical ion of opposite sign is highly effective. Hence a low quantum yield is usually measured for these reactions.The stabilization of aromatic radical or ion is assured by resonance with the aromatic ring and is sufficiently stabilized, this process is competitive with back electron transfer and other chemical processes.

Investigations from our group have provided novel applications of the sensitised PET generated arene radical cations from methoxy substituted aromatic compounds for preparing variety of oxygen, nitrogen and carbocyclic aromatic compounds by intramolecular nucleophilic cyclisation reactions. For illustration, coumarins are synthesised (70-90%) directly from the PET cyclisations of corresponding cinnamic acids. The ground state of DCN is used as an electron acceptor in these transformations. The occurence of this photoreaction is complete in a sensitised manner. Several observations, such as diffusion controlled fluorescence quenching of cinnamic acids with DCN and exergonic values for the free energy change (dGet) suggests the ET pathways for this reaction. The regiospecificity of the cyclisation mode is in accord with the calculated electron densities (Huckel or MNDO) at different carbons of the HOMO of the arene radical cation. Precocenes-I, a potent antijuvenile hormone compound and their various analogues, 2-alkylated dihydrobenzofurans, believed to possess antifungal and phytoalexin properties, are also prepared using this methodology.

The success of the strategy is further exemplified by the synthesis of carbo- and spiro-annulated aromatic compounds by the intramolecular cyclisation of silyl enol ethers to PET generated arene radical cations. Two different types of carbocyclic compounds, varying in ring sizes, may be synthesised starting from the same ketone, as two different types of silyl enol ethers can be produced using either thermodynamic or kinetic enolisation procedures.

The spirocyclic compound structurally related to antitumour antibiotic fredericamycin - A, islated from Streptomyces griseus, bearing a unique spiro[4.4]nonane centre, is also prepared using this strategy as key step.

The synthetic utility of these cyclisations is further utilized in the construction of benzazocine skeleton. A variety of benzazocines exhibit analgesic and anti-inflammatory activities. These benzazocine ring system are generally very difficult to prepare by the use of conventional cyclization methods. Our work demonstrate a short route to this framework using PET induced photocyclization reaction as the key step.

Experimental section

A typical photochemical reaction procedure consists of the irradiation of a mixture of silyl enol ehters (2 mmol) and DCN 0.06 g (0.34 mmol) in 500 ml of CH3CN:H2O (4:1) for 4-5 h through Pyrex filtered light (> 280 nm, all light absorbed by enol ether only) using 450 W Hanovia lamp without removing the dissolved oxygen. Excess irradiation time should be avoided to control side reactions leading to secondary products. The progress of the reaction is monitored by TLC and GC. The irradiation is discontinued immediately after the complete consumption of starting silyl enol ether. Removal of solvent and chromatographic purification of the photolysis mixture gave desired cyclized product in 52% yield, characterized by IR, 1H, 13C NMR and mass spectral data. DCN was recovered quantitatively (98%) at the end of the reaction. During the irradiation of silyl enol ethers, small amount (~ 10%) of precursor starting aldehyde also formed which has been shown to be formed by the thermal reversion of the silyl enol ethers by adequate control experiments. The starting silyl enol ether was prepared as depicted in the following scheme, using known procedures under standard conditions.


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M.K. thanks the CSIR, New Delhi for the award of a Senior Research Fellowship, and Director NCL, Dr Krishnan SMIS (NCL) for constant help and encouragement.