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

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.

Readily(oftencommercially)available2-bromo(hetero)aryl aldehydes (1,S cheme 1) constitute powerful and popular units for the construction of ortho-fused carbocyclic rings. [1] Tw os trategies commonly employed in the multitudinous syntheses described in the literature involve 1) the derivatization of 1 to intermediates of type A,w ith a p-system attacking an electrophile that is ultimately derived from the aldehyde by functional-group manipulations (e.g., an alcohol, acetal, or even the aldehyde itself);o r2 )formyl group homologation to an anion-stabilizing unit that attacks as uitably activated p-bond (B). Whereas many elegant catalytic systems that use intermediates A or B have already been described, [2,3] thep reparation of the suitable precursors is often step-intensive,r aising questions on the overall process efficiency in the "age of sustainability". [4] We speculated that an ew annulation strategy,b ased on aC annizzaro-type reaction via intermediate C,might be possible.Asthe hydride transfer simultaneously exposes apowerful Michael acceptor (ynone or equivalent) and ac arbanion in close proximity, efficient annulation might be expected to occur (especially if C is directly attained in situ). Herein, we describe the use of such as trategy for the formation of eight-membered rings. Thep aucity of direct single-pot/step procedures to such medium rings attests to the known issues associated with their synthesis; [5] they therefore provide as tringent test for strategy C. Although redox-based Cannizzaro reactions, including asymmetric and triggered C À Cb ond-forming versions,h ave recently been developed, [6] to the best of our knowledge,they have not been employed for carboannulation reactions to medium rings.G enuine single-pot/step procedures to eight-membered rings are very limited-Reppes historical catalytic access to cyclooctatetraene [7] and Murakamis [4+ +2+ +2] approach [8] being notable exceptions.Modern alternatives frequently describe catalytic cyclizationst hat proceed with exquisitely high yields (for the final step). Unfortunately,t heir overall synthetic efficiency is often compromised by the multistep syntheses required to obtain the cyclization precursors. [9] Initial investigation of our own proposal (C) centered on the combination of readily available 2-bromobenzaldehyde (1a), trimethylsilylacetylene (2a), and propargyl chloride 3a.
Encouragingly,e ven an initial run returned significant amounts of benzo [8]annulene derivative 4aaa (Table 1, entry 1, ca. 7%)w hose identity and regiochemistry was confirmed by X-ray crystallography (see the Supporting Information) as initial NMR data was not conclusive. [10] Unfortunately,u nder the conditions of entry 1, multiple side products were also produced. Upon changing from an organocopper to an organocuprate formulation (entry 2), the reaction became much cleaner, but the yield of 4aaa remained low.T he recovered side products of entry 2 included significant amounts of the alcohols 5a and 6a together with unreacted 3a.W ecould confirm that formation of D was almost quantitative in < 20 min under all conditions tried (Et 2 Oo rT HF, À78 to 0 8 8C, based on recovered 5a in independent reactions). We therefore suspected issues associated with both nBuLi-halogen exchange from D and the copper-promoted S N 2' reaction leading to the progenitor for eight-ring formation. Further experiments were designed to probe these hypotheses (Table 1).
With an optimized procedure for the preparation of parent compound 4aaa in hand, we studied the scope of the reaction with respect to the 2-bromo(hetero)aryl aldehyde component 1.U sing the conditions of entry 4( Table 1) and aldehydes 1b-1j,the eight-ring compounds that are shown in Scheme 2w ere attained. Substitution at the 3-position was better tolerated than at the 1-and 4-positions (products 4baa/ 4caa vs. 4daa/4faa). Monosubstitution at the 2-postion was also tolerated. Ac omparison of the yields of 4baa-4gaa indicates that steric factors are more important than electronic ones;for example,intramolecular OMe steric contacts increase the ortho steric profile of 4eaa versus 4jaa.T he yields of compounds 4haa-4jaa also support this trend. Whereas the yields of 4aaa-4jaa are modest, it should be borne in mind that they represent one-pot processes to analytically pure crystalline products on up to multigram scales,u sing only inexpensive commercial starting materials. Thenew process compares very favorably to the consolidated yields and time efficiencies of previously reported eight-ring syntheses. [9] By varying the acetylene component using the readily attained starting materials 2b-2f,f ive further examples of eight-ring compounds 4 were synthesized (Scheme 3). The terminal alkyne substituent could encompass alkyl, vinyl, or aryl units,a nd the corresponding products were all obtained in acceptable yields.F inally,v ariation of the propargyl chloride was investigated using simple 3b-3i (Scheme 3). Thea ryl moiety could accommodate both electron-donating and -withdrawing substituents and some functional groups (4aae and 4aaf).

Angewandte
Chemie is presumably placed in close proximity to the potent ynone Michael acceptor,w hich leads to efficient ring closure.T he use of an aryl moiety as the R 2 substituent is apparently sufficient to stabilize the allyl anion and allow the necessary trans to cis isomerization. Protonation of the non-classical enolate G results in the formation of 4.S everal pieces of evidence support this chain of events.F irst, attempts to use 2-thienylcyanocuprates derived from ar elated aza substrate led to the isolation of 7 (X-ray structure) where the intermediate allene has been carbometalated rather than having accepted ah ydride.F or the formation of 4iaa,w e could isolate appreciable amounts of 8,which is the expected product of aC annizzaro-type hydride transfer without subsequent annulation. Use of the deuterated aldehyde 2-BrC 6 H 4 CDO ([D]-1a)led to the formation of the expected product [D]-4aaa,c onfirming the participation of the aldehyde in the Cannizzaro process. Them echanistic proposal shown in Scheme 4w as also probed by DFT calculations at the M06-2X/6-31G(d) and CBS-QB3 levels of theory [11] on the "metal-free" anions anti-C' ' and syn-C' ' (Scheme 5; see also the Supporting Information). Whereas the relationship of anti-C' ' and syn-C' ' to the reaction coordinate of the true organometallic species involved in the cascade process needs to be treated with caution, it does provide further evidence for the proposed mechanism. Thec alculated barriers for the Cannizzaro-type hydride transfer and the rearrangement of the allyl anion (the equivalent of the transformation of C' ' into F in Scheme 4) were approximately 5a nd 7kcal mol À1 ,r espectively.T he calculations also indicate that non-classical enolates of type G are favored in the reaction over the equivalent allenoate structures.This idea was further reinforced by the observation that trapping of the reaction intermediates with iodine, iodomethane,o rc arbon dioxide,a so pposed to ap roton, leads to the formation of derivatives 9-11 (Scheme 5).
To the best of our knowledge,t his Cannizzaro-triggered cascade process is unique.T he nearest analogues that we could find are cyclizationsr eported by the Oonishi and Sato groups; [9b,d] however, in these cases,t he allene intermediate must be separately synthesized, and no Cannizzaro-type process is involved. Similarly,asingle eight-ring side product (formed in 10 %y ield) was obtained by Alajarin and Vidal through a1 ,5-hydride shift/8p electrocyclization from an eutral 1,2-allenylacetal at 110 8 8C. [12] Again, no Cannizzaro-type trigger was proposed. Whereas Cannizzaro shifts have been used for oxidation-state manipulations in ortho-fused systems, in these processes,noa nnulation steps were involved. [13] The most similar ynone eight-ring closure process that could be identified was developed by Schreiber and Kelly, [14] but this transformation involves an alkoxide nucleophile.
In conclusion, we believe that this very simple formation of ortho-fused cycloocta-2,5-dien-1-one units demonstrates the potential of the developed method for rapid and efficient annulations.I nvestigations into extending the scope of both the present reaction and other variants are ongoing. development and demonstration (308768). J.R. is grateful to European Thermodynamics Ltd and the Engineering Physical Sciences Research Council (EPSRC) for provision of as tudentship.L .B.t hanks the EPSRCs National Service for Computational Chemistry (NSCCS) for providing computational facilities,a nd O.K. acknowledges aK ishore Va igyanik Protsahan Yojana (KVPJ) Fellowship.