Alkynones cyclization

Karpf and Dreiding arrived at modhephene by thermal a-alkynone cyclization (Scheme XCIII) The synthesis of key intermediate 792 was unfortunately plagued by isomer problems. Also, the pyrolysis of 792 did not afford 786 cleanly. With the availability of this last intermediate, arrival at modhephene followed earlier precedent. 

CycUzation. 3-Alkynones cyclize to afford furan derivatives in the presence of gold(III) chloride. Furans bearing an alkynyl chain undergo intramolecular cycloaddition further. Transformation into bicyclic phenols is noteworthy because the hydroxy group is at a pen-position. 

Schlessinger et al. have outlined a new approach to pentalenolactone (71), which has as a key step the conversion of (69) to (70) by intramolecular acylation, and Karpf and Dreiding describe an intriguing design for the synthesis of the propellane natural product, modhephene (74), based on the thermal or-alkynone cyclization (72) - (73). 

Simiraly, alkynones undergo arylative cyclization with arylboronic acids in the presence of a rhodium catalyst (Equation (49)).400 When acetylenic /3-keto esters are employed as shown in Equation (50), arylative cyclization (formation of cyclobutanols) and subsequent, facile acid-catalyzed bond cleavage take place to give <5-keto esters.401 Ring expansions of cyclic [3-keto esters are also possible according to this reaction. 

Alkoxides that arise from simple carbonyl additions have also functioned as excellent in situ nucleophiles for intramolecular hydroalkoxylation reactions. Garbinols derived from the addition of allyltin reagents have proved to be potent nucleophiles in reactions of this type (Equation (99)),349 and this approach has also been used for the combined addition-cyclization of alkynals under Pd(n)350 or Cu(i)351 catalysis, and alkynones under Pd(n) catalysis.352... 

A convenient synthesis of 33 -difurans was presented. Treating alkynones with Pd(PPh3>4 (THF, EtaN) at room temperature gave 2,5-disubstituted furans, but under similar conditions with Pda2(PPh3)z by a tandem dimerization and cyclization 33 -difurans were obtained predominantly <99TL4841>. 

In subsequent work, it was demonstrated that the straight chain conjugated alkynone 1-nonyn-3-one cyclizes smoothly to the corresponding cyclopentenone24. 

On addition of SO4 - to the triple bond in the 10-member cycloalkyne 24 and cyclo-alkynone 27, a nonchain, and anionic, self-terminating radical cyclization cascade is induced. In the former reaction (equation 22) the bicyclic ketones 25 and 26 are formed, and in the latter reaction (equation 23) the a,/i-epoxy ketones 28 and 29 are formed in good yields. Because of the difficulty of oxidizing isolated triple bonds, SCh - does not react as an electron-transfer reagent in these reactions but acts as a donor of atomic oxygen. 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

Electrochemically generated NO3 has been reported to add to medium-ring alkynes and alkynones to furnish bicyclic ketones and epoxy ketones, respectively.50 The postulated mechanism involves the addition of N03 to the alkyne followed by transannular cyclization/elimination of NO3. 

Alkynals and alkynones have been alkylatively cyclized in a palladium(0)-catalysed trans-addition of organoboronic acids.349... 

Palladium-monophosphine complexes catalyse trans-selective arylative, alkenyla-tive, and alkylative cyclization reactions of alkynals [e.g. (68)] and alkynones with organoboronic reagents. These reactions afford six-membered allylic alcohols (69) (g) and/or their five-membered counterparts (70), whose ratios are dramatically affected... 

Finally, Ling and coworkers [161] have presented an intriguing Pd-catalyzed dimerization-cyclization sequence of alkynones 222 to furnish 3,3 -bifurans 223 with good to high selectivity with respect to the furans 224 in good yields (Scheme 93). 

Scheme 94 Mechanistic rationale of sequential dimerization-cyclization of alkynones [161]...

The peculiar circumstance of an essentially base free reaction medium now allows an entry to Lewis or Brpnsted acidic conditions, still in a one-pot fashion. In the presence of hydrogen halide acids y-hydroxy alkynones can be successfully cyclized to give 3-chloro-, 3-bromo-, and 3-iodofurans [194]. Therefore, a sequence... 

Mechanistically, the sequence commences by coupling of the (hetero)aroyl chloride 7 and the aUcyne 4 to give the alkynone 8 (Scheme 43). Upon addition of the tryptamine derivative 73 the enaminone 75 is obtained. Finally, the addition of the a, p-unsaturated acid chloride 71 triggers the aza-annulation reaction to furnish the acyliminium ion 76 which terminates the sequence by a Pictet-Spengler cyclization. 

Drouin, Conia et al. have found that these reactions can be carried out under even milder conditions by cyclization of silyl enol ethers of alkynones. Treatment of (194), as an (E)-(Z) mixture, with HgCb in CH2CI2 in the presence of hexamethyldisilazene for 30 min at 30 C gives vinylmercurial (195 R = HgCl) in quantitative yield. Cleavage of the carbon-mercury bond can be carried out to give (195 R - H, D, CQzMe, Br or COMe). 

Alkynones and indoles. Stitching of the aryl group of an iodonium salt with a 1 -alkyne by CO furnishes alkynones. On the other hand, CO serves as a reducing agent in the cyclization of 2-nitrostyrenes which results in the formation of indoles ... 

Although less common than conversions of a,3-, and of p,Y-acetylenic ketones, Y,5-alkynones can also lead to formation of furans. The Y,8-acetylenic ketone 227 undergoes a Pd-catalyzed cyclization to furnish 2,5-disubstituted furan 228 (no yield provided) [180]. 

Enones are converted into furans with much less frequency than alkynones. One example of this transformation entails conversion of P-iodo-p.y-cnone 229 into 2,5-disubstituted furan 230 via a Pd-catalyzed cyclization using Herrmann s palladacycle catalyst 168 [181]. 

As shown below, cross-coupling of add chlorides with THP-protected propargyl alcohol derivatives gave rise to the corresponding alkynone, which underwent acid-assisted electrophilic addition of hydrogen halide with concomitant deprotection and cyclization, affording 3-halofurans. If RB(OH)2 was added into the reaction system before work-up, the reaction can provide Suzuki-coupled products in moderate yields. 

Cycloisomerization. Conjugated alkynones bearing at the a -position an allenyl substituent (a -carbon usually quaternary) undergo cyclization to afford cyclopentenones. ... 

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