Esters intramolecular cyclization, carbonyl

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2 1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a P-hydrogen elimination. 

Intramolecular alkoxycarbonylation of alkynols is parallel to what has been described for alkenols except that functionalization of the triplebond produces a double bond. No lactone formation is observed in the Pd(II)-catalyzed oxidative cyclization-carbonylation of alkynes. Instead [(methoxycarbonyl)methylene]tetrahydrofurans are selectively formed [134, 135]. Moreover, starting from an enynol, furan-2-acetic ester is obtained resulting from a final aromatization step [136]. 

A further study on six-membered ylide formation examined the use of an aliphatic ester in place of a ketone as the Lewis base donor for carbonyl ylide formation. Although the same keto-substituted system underwent an intramolecular cyclization readily, the ester derivative gave no cycloaddition products. Padwa and co-workers (37,76) points to the major electronic differences between the two carbonyl groups to rationalize the disparity in carbonyl ylide formation. 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Indolo[3,2-3]carbazoles bearing a carbonyl substituent at the 6-position have been synthesized directly by an intramolecular cyclization approach from dichloroacetyl substituted precursors <2004EJO2593>. However, due to a facile decarbonylation under the reaction conditions it was found to be more expedient to employ esters, such as 165, produced by acylation with oxalyl chloride (Equation (79) Table 4). 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

The final example in this section features a rare instance where the electrophilic center is s -hybridized carbon, as most cyclative cleavages involve the attack of carbonyl derivatives. Oxazolidinones are formed cyclatively18 by the displacement of a sulfonate ester by an acylsulfonamide (Fig. 5). In a variant19 of this cyclization, a quasi-meso bis-sulfonate partitions into a pair of quasi-enantiomeric sulfonates, one resin bound and the other cleaved, depending on the direction of intramolecular cyclization. The resin-bound enantiomer can then be displaced by an external nucleophile. 

Bis-acyloxy-substituted 2-butynes 97 in the presence of added carbonyl compound (e.g., acetone) failed to give the corresponding cross-ozonides. Instead, the bicyclo[3.2.1]ozonides 98 were obtained in good yields by intramolecular cyclization of the CO intermediate with only one of the ester carbonyl groups. The bicyclo[2.2.1]ozonide 99 which... 

Several indium-mediated intramolecular carbonyl allylation reactions have been investigated, and it has been found that these reactions provide an easy access to a variety of cyclic compounds. The intramolecular cyclization of 49a-c mediated by indium in aqueous media proceeds smoothly to afford carbocyclic systems containing y-hydroxy-Q -methylene esters 50a-c, which either spontaneously or readily cyclize to give fused o -methylene-y-butyrolactones 51a-c (Scheme 52). The same cyclization of 49d is too slow to compete with the side-reaction, in which the bromide is substituted by a hydroxy group. The ring junction stereochemistry of fused lactones 51 has been found to be cis in all cases. Of the two possible transition states, the one leading to the m-fused compounds is preferred, because the chair-chair conformation is favored over the chair-boat conformation.209... 

First, the intramolecular cyclizations between carbonyl compounds and olefins will be described. This field can be classified into three types as illustrated in O Fig. 13. One is a type of cyclization between carbonyl compounds and a, 8-unsaturated esters (type [A]), the next is a type of cyclization between carbonyl compounds and simple olefins (type [B]), and the last is a type of cyclization between carbonyl compounds and oximes (type [C]) (O Fig. 13). 

Alkyl esters cannot be used for these acylations in place of the carbonyl compounds mentioned above unless an intramolecular cyclization (somewhat analogous to a Dieckmann cyclization) can occur, as, for instance 460... 

In the Dieckmann condensation certain esters having hydrogen on the a-carbon atom which is activated (generally by a carbonyl group) undergo intramolecular cyclization. These reactions may be illustrated by the formation of a-carbethoxy-cyclopentanone from diethyl adipate. 

Surprisingly, methyl esters are also suitable substrates whereby intramolecular cyclization occurs with concomitant loss of methyl iodide. Larock used internal alkynes as coupling partners for lactone synthesis (Scheme 2.33) [74]. The proposed mechanism involves oxidative addition of Pd(0) to the aryl iodide, followed by addition across the alkyne and cyclization of the carbonyl O of the ester to form an oxonium ion. Reductive elimination followed by loss of the methyl group then yields the product [74]. Shen and coworkers also reported a variant utilizing o-2,2-dibromovinylbenzoates (Scheme 2.34) [79]. 

Unlike the cases of alkenes, Wacker-type intermolecular oxypalladation reactions of alkynes have not been extensively investigated, although their intramolecular cyclization reactions have been developed into synthetically useful procedures (Sects. V3.2). In principle, they can proceed by a few alternative paths shown for the cases of terminal alkynes in Scheme 14. In reality, however, alkynyl C—H activation by Pd to give alkynylpalladium derivatives shown in Scheme 3 may well be the dominant path, as suggested by the carbonylative oxidation of terminal alkynes to give alkynoic acid esters shown in Scheme 15. Oxidative dimerization of alkynes is a potentially serious side reaction. Further systematic investigation of this fundamentally important process appears to be highly desirable. 

Early examples of this reaction involved cyclizations of 4-substituted phenols tethered to alkyl sulfonates and halides [3]. CycMzalions involving carbonyl electrophiles (aldehydes, ketones) and imines have been reported as well, but esters are not sufiSciently electrophilic to react [2]. Subsequent studies established that the facility of these so-called Ai-n cyclizations was strongly affected by the size of the newly formed ring in the order 3>5>6 >4. Since the vast majority of alkylative dearomatizations involve intramolecular cyclizations (thereby avoiding competitive 0-aDcylation reactions), stereoelectronic effects operative in the transition states (resembling the TS of an Sjj2 reaction) are crucially important. These sometimes subtle effects can result in differential reactivity of structurally similar substrates [4]. 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

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