Dieckmann reaction 3-substitution

Many of the standard methods of C-C bond formation in aliphatic systems can be extended to heterocyclic systems, e.g., the Dieckmann reaction (cf. 66 67) and alkylation of active methylene compounds (e.g., 68 69). An example of the application of the Dieckmann reaction to the preparation of 3-thiepanone 70 is shown in Scheme 42 <1952JA917>. Several more recent examples of applications of the Dieckmann condensation in the synthesis of substituted 4- and 3-piperidones are discussed in CHEC-III . 

In Kozikowski s synthesis of showdomycin, treatment of the oxabicyclic 130 with bicarbonate induced a retro-Dieckmann reaction to reveal the highly substituted tetrahydrofuran intermediate 131, Eq. 93 [142]. 

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Even fully substituted aromatic compounds can be prepared utilizing the Mi-chael/Dieckmann strategy. As reported by Covarrubias-Zuniga and coworkers (Scheme 2.32) [67], reaction of the anion of l-allyl-l,3-acetonedicarboxylate (2-138) and the ynal 2-139 afforded the intermediate 2-140 which led to the resorcinol 2-142 with spontaneous aromatization under acidic conditions via 2-141 in an overall yield of 32 %. 2-142 was transformed into mycophenolic acid (2-143) in only a few additional steps [68]. 

Besides the Michael addition-initiated domino reactions presented here, a multitude of other anionic domino reactions exist. Many of these take advantage of an incipient SN-type reaction (for a discussion, see above). In addition to the presented SN/Michael transformations [97, 98, 100], a SN/retro-Dieckmann condensation was described by Rodriguez and coworkers, which can be used for the construction of substituted cycloheptanes as well as octanes [123]. Various twofold SN-type domino... 

The two major routes to 3,4-dihydro-2JT-l,5-benzodioxepins (274) from (273) and (275) are applicable to a wide range of substituted derivatives. The 3-oxo derivative, important as a perfume odorant, can be prepared via the reaction of 1,2-dihydroxybenzene with chloroacetonitrile (75CJC2279) or via a Dieckmann cyclization (74USP3799892). 

This synthetic route is based on ring closure by Dieckmann condensation of 1,2-bis-carbalkoxyalkylpyrrolidines. It has gained special importance during the last few years, after application to several total syntheses of naturally occurring pyrrol izidine bases. The usual starting compounds employed in this route are esters of a-pyrrolidineacetic acid, proline, and their homologues, which are converted into N-substituted dialkyl dicarboxylates. The esters of the dicarboxylic acids are subjected to Dieckmann condensation and subsequent ketonic hydrolysis the resultant ketones are used in further reactions. 

A very useful method for generating 3 (2H)- dihydrofuranones is based on the Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates (Scheme 82). The intermediate anion attacks the adjacent ester moiety via a Dieckmann condensation reaction to produce a substituted furanone ring which usually bears useful functionality. Overall yields of 45-60% have been obtained for this reaction. 

An interesting variation of the Dieckmann cyclization involves vinylogous activation of a methyl group in a 2-butenyl ester. Reaction of an a-halo ester with the enethiol formed by treatment of an acetoacetic ester, which may be substituted at the a-position, with hydrogen sulfide produces (92) in satisfactory yield. Treatment of these compounds with sodium in benzene produced the 4-hydroxythiophene-2-acetic acids (94) (40JCS1385). The product undoubtedly involved the intermediate (93), in which the activated methyl goup has condensed with the ethoxycarbonyl group in typical Claisen fashion. 

A variety of hydroxythiophenedicarboxylic acids have been prepared via the Hinsberg reaction (Section 3.15.3.5.1), and these may be decarboxylated to hydroxythiophenes. Refluxing 3,4-dihydroxythiophene-2,5-dicarboxylic acid in pyridine led to the formation of 3,4-dihydroxythiophene in high yield (equation 63). The Dieckmann cyclization (Section 3.15.2.2.2) has been used to prepare 3-hydroxythiophene derivatives (equation 64), and again the free acid can be decarboxylated to form the 3-hydroxythiophene substituted in the 5-position. 

From the retrosynthetic perspective (Fig. 2), the tetracyclic structure is expected to be accessible by tandem Michael-Dieckmann type reaction of 59 with 60. The suitably substituted chiral intermediate 59 would be synthesized by Diels-Alder reaction of the cyclohexenone 57 and the silyloxybutadiene 58. The regio- and stereoselectivities are established as a consequence of the dienophile geometry according to Gleiter s theory (29). Compound 57 could be obtained from 51 through Ferrier reaction of 54. 

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