Diels-Alder reaction ketene equivalents

A key transformation in Corey s prostaglandin synthesis is a Diels-Alder reaction between a 5-(alkoxymethyl)-l,3-cyclopenta-diene and a ketene equivalent such as 2-chloroacrylonitrile (16). As we have already witnessed in Scheme 3, it is possible to bring about a smooth [4+2] cycloaddition reaction between 5-substituted cyclopentadiene 15 and 2-chloroacrylonitrile (16) to give racemic 14 as a mixture of epimeric chloronitriles. Under these conditions, the diastereomeric chloronitriles are both produced in racemic form because one enantiotopic face of dienophile 16 will participate in a Diels-Alder reaction with the same facility as the other enantiotopic face. In subsequent work, Corey s group demonstrated that racemic hydroxy acid 11, derived in three steps from racemic 14 (see Scheme 3), could be resolved in a classical fashion with (+)-ephe-... 

Diels-Alder reactions of 1-(phenylseleno)-2-(p-toluensulphonyl)ethyne a novel die-nophile and ketene equivalent [138]... 

The synthetic utility of the Diels-Alder reaction can be significantly expanded by the use of dienophiles that contain masked functionality and are the synthetic equivalents of unreactive or inaccessible species (see Section 13.2 for a more complete discussion of the concept of synthetic equivalents). For example, a-chloroacrylonitrile shows satisfactory reactivity as a dienophile. The a-chloronitrile functionality in the adduct can be hydrolyzed to a carbonyl group. Thus, a-chloroacrylonitrile can function as the equivalent of ketene,... 

Ketene equivalents have found widespread use as partners in Diels-Alder reactions for the construction of cyclic, fused, and bridged unsaturated ketones. However, ketene equivalents based on simple vinyl sulfoxides are poor dienophiles and show low levels of diastereocontrol. Recently, Aggarwal and colleagues reported that (l/ ,3/ )-2-methylene-l,3-dithiolane 1,3-dioxide (187) was a highly reactive and highly selective chiral ketene equivalent.116 Diels-Alder cycloaddition of this... 

For some other recent applications of the Diels-Alder reaction of furans with ketene equivalents see I. Yamamato and K. Narasaka, Chem. Lett.,... 

The final example given in Scheme 2.122 illustrates the utilization of 1,1-disubstituted ethylenes such as 354 as equivalents to ketene. Diels-Alder reaction of 354 followed by hydrolysis of the gew-chlorocyano function in adduct 355 yields the bicylic cycloxenenone derivative 356, which has been elaborated further in the stereocontrolled synthesis of prostaglandins. "... 

Oxidative desulfonylation.1 Aryl sulfones are converted into ketones by oxidation of the a-carbamon (LDA) with Mo03Py-HMPT in THF at —78° in 50-97% yield. This conversion permits use of phenyl vinyl sulfone as an equivalent of ketene in Diels-Alder reactions. 

Rearrangement of Diels-Alder adducts from 2-chloroacrylomtrile. 2-Chloro-acrylonitrile has been used as a ketene equivalent in Diels-Alder reactions (3,... 

Methyl 3-bromopropiolate has been used in Diels-Alder reactions either as a methoxycarbonyl ketene equivalent or for the synthesis of functionali2ed naphthalenes. ... 

Nitroethene and vinyl sulfoxides have also been employed as ketene equivalents. Nitroethene is an excellent dienophile and oxidation of the initial nitro-adduct gives the corresponding ketone. However, the thermal instability of nitroethene limits its appUcation to cycloadditions with reactive dienes. An attractive feature of vinyl sulfoxides as ketene equivalents is that they can be obtained in optically active form because of the chirality of the sulfoxide group, thus allowing enan-tioselective Diels-Alder reactions. Cycloaddition of p-tolyl vinyl sulfoxide with cyclopentadiene requires heat and gives a mixture of all four (two exo and two... 

The arylsulfonylhydrazone 18 is a stable precursor of the cyelohexadienyllithium 7. In order to prepare this starting reagent, 3-acetoxymethyl-2,4-dimethyl-1,3-penta-diene 12 is subjected to a Diels-Alder reaction with the ketene equivalent ehloro-acrylnitrile 11a. The cyeloadduct 16 primarily obtained is hydrolyzed to the hyd-roxyketone 17 in i-butyl alcohol. Subsequent reaction with /-butyldimethylsilyl-chloride (TBSCl) and imidazole in dichloromethane serves to protect the primary aleohol function of the intermediate 10 in which the keto carbonyl group is deriva-tized to the required arylsulfonylhydrazone 18 with 2,4,6-triisopropylphenylsul-fonylhydrazide in tetrahydrofuran (THF) as solvent. 

The scope of the Diels-Alder cycloaddition in synthesis planning is extended by the fact that both terminal and internal alkynes (RC=CH, RC=CR) enter into [4 - - 2] cycloadditions with dienes in the presence of Co(0) catalysts. These cycloadditions result in cyclohexa-1,4-dienes arising from a formal Diels-Alder reaction [33, 34]. Finally, numerous synthetic equivalents for ketene to be used in [4 + 2] cycloadditions have been developed in the context of prostaglandin sjmtheses. Thus, a broad range of possibilities for achieving these cycloadditions is now available [35, 36, 37] (Scheme 6.13). 

Williams has demonstrated the use of 1-phenylsulfinyl-l-trimethylsilylethene (164) and phenyl vinyl sulfoxide as effective ketene equivalents for the Diels-Alder reaction [142,143], important as it is known that ketenes do not undergo satisfactory [4+2] cycloadditions. The initial cycloadduct (165), derived from the Diels-Alder reaction between 1-phenylsulfinyl-l-trimethylsilylethene (164) and cyclopentadiene, undergoes a facile sila-Pummerer rearrangement to give the thioacetal (166), which yields the product (167) upon hydrolysis (Scheme 5.55) [142]. 

As compared with the intermolecular Diels-Alder reaction, the applicability of intramolecular Diels-Alder reactions [25] is more limited. The synthesis of requisite trienes for intramolecular Diels-Alder reactions is itself a significant task, and the incorporation of a ketene equivalent, for example, adds to the burden. Singleton and Lee [26] have reported the first examples of intramolecular Diels-Alder reaction on vinylboranes, which provide a two-step, very highly ste-... 

The use of ketene equivalents in 4- -2-cycloaddition reactions for organic synthesis has been reviewed. " a-Carbonyl ketenes behave as dienes in Diels-Alder reactions with 4-aryl-2-methyl-2,3-dihydro-l,5-benzothiadiazepines to yield regiospecific cycloadducts. The reactions of diphenylketene with cyclic ( -cw)-l,3-dienes such as cyclopentadiene and cyclohexadiene initially yield the Diels-Alder adducts, which are converted into the Staudinger cyclobutanones by [3,3]-sigmatropic rearrangementsl-Benzyl-l,3-diazabuta-l,3-dienes react with ketenes to produce the 4 - - 2-cycloadducts, substituted l-benzyl-4-(benzylidenimino)-4-phenylazetidin-2-ones, which rearrange into the more stable 5,6-dihydro-3//-pyrimidin-4-ones. The formal 4 - - 2-cycloaddition reaction of ketenimines has been used to synthesize benzoimidazo[l,2-Z ]isoquinolines. ... 

A detailed study of the cycloaddition of trifluoromethylethene has appeared as has work on a-siloxy-a -unsaturated ketones as dienophiles under Lewis-acid catalysis. Amongst the new dienophiles that have been reported are the two novel ketene equivalents methyl methoxypropiolate (129) and methyl phenyl-thiopropiolate (130). A series of 3-(acyloxy)but-3-en-2-ones (131) has been prepared and used as dienophiles in a route to anthracylinones, and, as part of a route to highly functionalized cyclohexenones, the vinyl sulphone (132) has been used in a Diels-Alder reaction with various dienes. ... 

Ketene Is not a good dienophlle. Therefore there Is a need for "new chemistry". .. the development of a ketene equivalent for use In DIels-Alder reactions. 

The temperature at which the Diels-Alder could be conducted was lowered by developing a-chloroacryloyl chloride (57) as the ketene equivalent. Acid chlorides are much more reactive than their nitrile or ester counterparts in Diels-Alder reactions, and this is an excellent example of putting this kinetic fact to use. A Curtius rearrangment was used as the key functional group transformation in estabUshing the ketene equivalency. 

Illustrate how the following reagents could serve as ketene equivalents for use in Diels-Alder reactions with 1,3-cyclopentadiene. (Prostaglandins-6)... 

For references see Williams, R. V. Lin, X. New ketene equivalents for the Diels-Alder reaction. Vinyl sulfoxide cycloaddition. /. Chem. Soc., Chem. Commun. 1989, 1872-1873. Ruden, R. Bonjouklian, R. Cycloaddition of vinyl triphenyl-phosphonium bromide. New synthesis of cyclic phosphonium salts. Tetmhedron Lett. 1974, 15, 2095-2098. Ranganathan, S. Ranganathan, D. Mehrotra, A. K. Nitroethylene as a versatile ketene equivalent. Novel one-step preparation of prostaglandin intermediates by reduction and abnormal Nef reaction. J. Am. Chem. Soc. 1974, 96, 5261-5262. Kozikowski, A. P. Floyd, W. S. Kuniak, M. P. 1,3-Diethoxycarbonylallene an active dienophile and ethoxycar-bonylketene equivalent in the synthesis of antibiotic C-nucleosides. J. Chem. Soc., Chem. Commun. 1977, 582-583. 

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