Furan-annulation

A modification of the Garst-Spencer furan annulation using dimethylsulfonium methylide gives improved yields of 3,4-disubstituted furans in which R and need not be part of a ring annulation (Scheme 9) <1998TL8929>. 

A palladium-catalyzed approach to substituted [3]-annulated furans is based on the use of a cyclic allylic dielectrophile of type 40 and a /3-ketoester which acts as a l,3-C,0-dinucleophile (Equation 64) <2007S39>. The reaction appears to be generally applicable for furan-annulation reactions. 

Vinyloxiranes 206 undergo palladium-catalyzed furan annulation with soft nucleophiles via two cyclization paths to give either 210 or 211 as a primary product, which undergoes further transformations, depending on the substituents (Scheme 11-55) [44,47]. At first, the allenylpalladium 207 is generated this is converted to two kinds of n-... 

Limited options for purification of the diketone. As an oil, recrystallization was not available as a purification option. Chromatography and distillation were considered less attractive options. We spent considerable time trying to identify derivatives which would be crystalline, and could then be reverted back to the diketone, or incorporated directly into the furan annulation sequence (e.g. tosylhydrazones, bisulfite adducts, ketalization). These efforts were not fruitful. 

The rearrangement is also useful for furan annulations, through enlargement of the starting carbocycle. Thus addition of SnCU to either diastereomer of the allylic acetal (4) produces the cis-fused cycloheptatetrahydrofuran (5) in 48-76% yield (eq 12). Acetals derived from frans-diols rearrange to the same cU-fused bi-cyclics in higher yield. The stereochemistry of a terminal alkene is transmitted to the C-3 carbon of the bicyclic products (eq 13). 

Angular annulation of benzo[h]furan with a benzene ring leads to naph-tho[2,l-h]furan and naphtho[l,2-h]furan. 

An illustrative example of the potency of the second-generation Ru catalyst C is found in Paquette s highly efficient total synthesis of the natural products teubrevin G (122) and teubrevin H (123), which feature a cyclooctane core fused and spiroannulated to smaller oxygen-containing rings [76]. In the retrosyn-thetic analysis, the viability of an RCM step for annulation of a cyclooctenone ring to the furan played a central role. 

Scheme 1.2. Synthesis of annulated furans for an access to the terpenes kumausyne and kumausallene.

The usefulness of allene derivatives has also been revealed in other examples. Thus, the annulated tetrasubstituted furan illustrated in the following scheme was delivered in a moderate yield using the diazoallene as precursor by a two-step reaction in the presence of Rh-catalyst <06S3605>. 

A palladium-catalyzed one-step synthesis of dihydrobenzo[fc]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L3601>. 2-Alkyl- or 2-aryl-substituted benzo[ >]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>. 

Gold(I)-catalyzed synthesis of dihydrobenzo[ >]furans from aryl allyl ethers was reported as depicted below <06SL1278>. Highly efficient AuCl3/AgOTf-catalyzed atom-economical annulation of phenols with dienes was developed. This annulation generated various dihydrobenzo[ >]furans under mild conditions <06OL2397>. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

The most unique feature of furan synthesis using palladium chemistry is heteroannulation. Enones, ynones and ynols all have been annulated into furans and benzofurans. More importantly, trapping the reactive Pd(II) intermediates at different stages with electrophiles offers unique opportunities to synthesize substituted furans and benzofurans. 

The total synthesis of the furo[3,2-a]carbazole alkaloid furostifoline is achieved in a highly convergent manner by successive formation of the car-bazole nucleus and annulation of the furan ring (Scheme 15). Electrophilic substitution of the arylamine 30 using the complex salt 6a provides complex 31. In this case, iodine in pyridine was the superior reagent for the oxidative cyclization to the carbazole 32. Finally, annulation of the furan ring by an Amberlyst 15-catalyzed cyclization affords furostifoline 33 [97]. 

An example of the direct annulation of the furan ring onto the benzazepine core has been reported by Cann and co-workers (1990JHC1839). Reaction of N-acetyl-lO-bromodibenzazepine 51 with potassium ferf-butoxide yields the reactive intermediate 52. It further reacts as a dienophile with furan 53 (X = O) to produce 8H-furo[3,4-d]dibenz[fc,/]azepine 54 as a sole product (X = O, Scheme 10, Section 2.1.1.4). 

The synthesis of these rings involves annulation of the furan ring onto the preformed benzoxepine core or intramolecular oxepine C-C bond formation of the furan precursors. Thus, 2-methyldibenzo[ 7,/]furo[2,3-d]oxepines 148 (R = H, Cl)... 

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

Aminopyrans, annulated directly with a seven-membered carbo-cycle, are very rare. One, 139, is formed from substituted cyclohepta[c] furan-4-one 140 with UNs 30 (08CFIE136) (Scheme 50). 

The required 4-amino-7-methylbenzofuran (1103) was prepared starting from the commercial 2-methyl-3-nitrophenol (1104) over five steps in 52% overall yield. In this sequence, the key step is the annulation of the furan ring using bromoacetaldehyde... 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

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