One‐Pot Cannizzaro Cascade Synthesis of ortho‐Fused Cycloocta‐2,5‐dien‐1‐ones from 2‐Bromo(hetero)aryl Aldehydes

Abstract

An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.

Diversification of ortho‐Fused Cycloocta‐2,5‐dien‐1‐one Cores and Eight‐ to Six‐Ring Conversion by σ Bond C−C Cleavage

“…Model reactions by using 2‐bromobenzaldehyde, TMS‐acetylene and various propargylic electrophiles were used to gain understanding of the effect of group R 2 on the reaction (Table ). Under our standard conditions, highly chemoselective eight‐ring formation was observed for 1 a , and this was isolated in good yield (70 %). This chemoselectivity was not affected by the leaving group (Cl, O 2 CCF 3 , OAc), although the last of these gave lower yields of 1 a due to incomplete conversion.…”

“…The R 2 substituent and condition‐dependant formation of mixtures of 1 and 2 is most in accord with interconversion of a common intermediate ( 4 ) with both a non‐classical C‐enolate ( 5 ) and alkoxide ( 6 ) prior to final protonation (Scheme ). A carbanion formulation for 5 was supported by our previous computational studies (formation of an eight‐ring allenoate engenders too much ring strain) . The antiperiplanar arrangement in 5 favours C−C σ‐bond cleavage regenerating 4 (Scheme ).…”

“…In many cases, the C‐enolates ( 5 ) are stable at −10 °C and thus offer an excellent point for rapid core diversification. We sought to extend the preliminary observations we had made in this area . It was found that a range of electrophiles can be added directly into the one‐pot cascade sequence to give a wider variety of eight‐ring derivatives or to install reactive handles (Scheme ).…”

“…Addition of elemental iodine led to the formation of 10 , in good yield, which lends itself well to further diversification by Suzuki–Miyaura cross‐coupling reactions giving 11 a – c (79–87 %) as representative examples. Amides 13 a – c and pyrazolone 14 can conveniently be synthesised from our previously described carboxylic acid 12 in 71–95 % yield. The rapid synthesis of pyrazolone 14 (47 % overall yield, 2 steps from 2‐bromobenzaldehyde), amides 13 a – c (35‐40 % overall yield, 2 steps from 2‐bromobenzaldehyde) and furyl 11 c (46 % overall yield, 2 steps from 2‐bromobenzaldehyde) showed how this methodology can swiftly incorporate heteroatoms and drug‐like motifs into the core scaffold.…”

An efficient synthesis of substituted chrysenes

“…Recent work carried out within our group [12] highlighted how cascade reactions based around an unusual Cannizzaro like 1,5-hydride transfer [13] can be used to rapidly develop complex molecules, such as 1 (Scheme 1b), from commercially available 2-bromoaldehydes. We envisaged using a platinum(II) chloride catalysed, 6-endo-dig cyclisation [8, 11a] to attain a substituted chrysene from ethynylnaphthalene 1.…”