Dicarbonyl coupling intramolecular

Oxo esters undergo an intramolecular dicarbonyl coupling reaction on treatment with a low-valent titanium reagent to form a ketone. This was used in the synthesis of (Z)-7,l0,10-trimethyl-bicyclo[7.2.0]undec-6-en-2-one (4) from ethyl ( )-6-methyl-7-(4,4-dimethyl-2-oxocyclobutyl)-hept-5-enoate,108 Interestingly, the configuration of the isolated C -C double bond in the isolated product is sensitive to the reaction conditions. 

Motherwell and Roberts dicarbonyl coupling reaction19 can be improved by substituting l,2-bis(chlorodimethylsilyl)ethane for TMSC1. The intermediate organozinc carbenoids can be trapped with alkenes to produce cyclopropanes, as exemplified in the intramolecular case in equation 3. 

The proposed catalytic mechanism for intramolecular McMurry reaction begins with the reduction of TiCl3 by zinc metal to generate the activated titanium species A-19. Reductive cyclization of the dicarbonyl substrate forms the McMurry coupling product, along with titanium oxide complex B-15. To close the catalytic cycle, the oxide complex B-15 is converted to TiCl3 by Me3SiCl (Scheme 63).8d,8e... 

Reduction of dicarbonyl compounds can be expected to lead to a cyclic 1,2-glycol formed by the intramolecular coupling of radical intermediates. 

Several bicyclo[2.2.1]heptane derivatives with a 1,4-dicarbonyl moiety undergo C—C bond cleavage via intramolecular pinacol coupling, promoted by samar-ium(II) iodide.190... 

In the intermolecular mode, this reaction has been utilized for the preparation of products 28 from various nucleophiles, including C-nucleophiles (e. g. (3-dicarbonyl compounds). A similar reaction in the intramolecular mode provides a powerful synthetic tool for the preparation of various polycyclic compounds via oxidative biaryl coupling [21,27 - 30]. Several examples of these C-C bond forming reactions are shown in Schemes 13-15. Specifically, various dibenzoheterocyclic compounds 30 have been prepared by the oxidation of phenol ether derivatives 29 with [bis(trifluoroacetoxy)iodo]benzene in the presence of BF3-etherate in dichloromethane (Scheme 13) [27-29]. 

The primary adduct 53 (Eq. (117) ) of the anodically generated radical R undergoes a series of follow-up reactions a) hydrogen abstraction to 54, b) dimerization to additive dimers 55, c) coupling with R to 1,2-disubsti-tuted monomers56, d) le-oxidation to a carbonium ion that either solvolyzes to 57 or, when 1,3-dicarbonyl compounds are added cyclizes intramolecularly to tetra (58) - or dihydrofuran derivatives (59). Product control is possible in some cases by suitable choice of the anode potential. With a high anode potential,... 

In 1977, McMurry and Kees [152] developed a titanium-induced intramolecular coupling procedure to form cycloalkenes from dicarbonyl compounds. Mechanistically, as shown in Scheme 85, the coupling reaction proceeds by an initial pinacol dimerization of the dicarbonyl 253 to 254, followed by titanium-induced deoxygenation to afford alkene 255. 

Ti[0]-linduced intramolecular pinacol coupling and olefination-coupling of dicarbonyl compounds... 

Li et al. reported on the total synthesis of cembrene C from geraniol (137) or trans, frani-famesol (91) by using the titantium-induced intramolecular coupling of the dicarbonyl precursor keto enal 176 as the key macrocyclization step (Scheme 6-17). 

Exploration of the reduction of dicarbonyl compounds has centered on attempts to achieve intramolecular coupling of radical intermediates to give a cyclic 1,2-diol. A mechanistic study of the production of cyclopropanediols, during the reduction of 1,3-dibenzoylpropane in acetonitrile, has been made [110]. It is suggested that the ratedetermining cyclization step is the addition of the radical anion from one ketone function onto the second carbonyl group in the same molecule. 

Intramolecular free radical cyclization of dicarboxylic esters leads to a-hydroxy ketones (acyloins). Reductive coupling of dicarbonyl compounds provides 1,2-diols ipinacols) and further reaction of these yields cycloalkenes (McMurry reaction). These cyclization reactions are especially valuable for the preparation of medium and large rings that are not readily accessible by other methods. 

Tin. Bu3SnH has recently been demonstrated to effect the intramolecular pinacol coupling of 1,5- and 1,6-dialdehydes and keto aldehydes (Eqs. 3.24 and 3.25) [41]. 1,5-Dicarbonyl compounds undergo cyclization with consistently excellent (> 20 1) cis selectivity, whereas 1,6-dicarbonyl compounds provide variable stereoselection. Mechanistic studies furnish evidence for an interesting new pathway for pinacol coupling, involving homolytic substitution as a key step (Fig. 3-2). 

An intramolecular variation of the arylation reaction of a p-diketone led to cyclised products (24). The reaction involved the treatment of an a-(aryl)alkyl p-dicarbonyl derivative (22) with phenyl-iodine(in) bistrifluoroacetate (23), followed by base catalysed ligand coupling reaction. 2... 

Radically induced coupling of two t-systems also provides a synthetically useful route to cyclohexanes. The 6-endo-tng cyclization of the vinyl radical generated by Bu3Sn radical addition to the carbohydrate alkyne 147 provided a novel route to carbasugar 148 [93]. The intramolecular pinacol coupling of 1,6-dicarbonyl compounds such as 149 provides a direct synthesis of the inositol 150 [94] (Scheme 24). 

Carbonyl couplings. Many variations of cross couplings are possible these include aldehydes with a-dicarbonyl compounds. Ketyl radicals derived from carbonyl compounds also add to alkenes such as acrylonitrile " or N-allyl moieties. Intramolecular cyclizations on terminal alkenes or allene species have also been exploited for synthetic purposes. 

Previously, tin-ketyl radicals have been added to alkenes only in an intramolecular fashion. [9] In recent publications, however, pinacols and amino alcohols have been prepared by cyclisation of dicarbonyl compounds [10] or keto-oximes [11] with tributyltin hydride. Cyclisation of 1,5-ketoaldehydes 1 and 1,5-dialdehydes with tributyltin hydride yields cw-diols 2 with excellent stereoselectivities, whereas the keto-oxime 4 with four benzyloxy-substituents affords a 58 42 cis trans) mixture. The tran -product was transformed in two more steps to the potent glycosidase inhibitor 1-deoxynojirimycin (6). [lib] The reversibility of both the addition of the tributyltin-radical to the carbonyl group and the intramolecular radical C-C bond formation is believed to be responsible for the high selectivity in the formation of 2. In the cyclisation of 1,5-pentanedial the unhydrolyzed coupling product 3 could be isolated, therefore providing evidence for a new mechanistic variant of the pinacol reaction, in which only 1.2 equivalent of the reducing agent are necessary. 

In a related study, intramolecular oxidative coupling of enolate derivatives has been investigated by Schmittel and co-workers [167]. The intermolecular version of this reaction provides a useful route to 1,4-dicarbonyl compounds but typically suffers from low levels of stereoselectivity. Furthermore, in mixed systems, the desired heterocoupling products are often accompanied by appreciable amounts of homocoupling products. It was hoped that the use of a single metal for both enolate precursors with concomitant intramolecularization of the bond-forming event might overcome some of these problems. 

Cycloalkenes. McMurry and Kees have described an intramolecular coupling of dicarbonyl compounds to cycloalkenes. In the intermolecular version of this reaction titanium(O) powder obtained by reduction with potassium or lithium is used (7, 368). In the intramolecular reaction a superior coupling reagent is prepared by reduction of TiClg with a zinc/copper couple in DME. 

Mixed coupling reactions, using two different carbonyl compounds, can be effected, but they generally lead to mixtures of products and are of limited use in synthesis. Intramolecular reactions with dicarbonyl compounds, on the other hand, provide a good route to cyclic alkenes. The keto-aldehyde 80, for example, gave the cyclic diterpene kempene-2, despite the presence of a saturated ketone... 

General Methods.—The intramolecular coupling of dicarbonyl compounds to cycloalkenes by low-valent titanium is an exceptionally mild and useful route to 4—16-membered ring carbocycles. Baumstark et ai have now shown that, in... 

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