Cyclization-cyclopropanation reactions

Nandi, S., Ray, J. K. (2009). Palladium-catalyzed cyclization/cyclopropanation reaction for the synthesis of fused N-containing heterocycles. Tetrahedron Letters, 50,6993-6997. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

Organic halides play a fundamental role in organic chemistry. These compounds are important precursors for carbocations, carbanions, radicals, and carbenes and thus serve as an important platform for organic functional group transformations. Many classical reactions involve the reactions of organic halides. Examples of these reactions include the nucleophilic substitution reactions, elimination reactions, Grignard-type reactions, various transition-metal catalyzed coupling reactions, carbene-related cyclopropanations reactions, and radical cyclization reactions. All these reactions can be carried out in aqueous media. 

Cyclopropanation reactions of chloroalkanes with jt-deficient alkenes under basic phase-transfer catalysed conditions have been observed. Thus, for example, chloroacetic esters and chloroacetonitriles undergo Michael-type reactions with acrylic esters and acrylonitriles, the products of which cyclize to give cyclopropanes (see Section 6.4). 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

Dehydrohalogenation sometimes leads to cyclization which gives cycloalkanes or heterocycles. The fluorinated diester 1 has proved to be a convenient source of polyfluoroalkylated cyclopropanes. Reaction of 1 with aqueous potassium hydroxide gives 2- HA //-hepta-fluorobutyl)cyclopropane-l, 1 -dicarboxylic acid (2) in quantitative yield.120 The diethyl ester 3 ot this acid is obtained in a yield of 87% by the reaction of 1 with sodium ethoxide in anhydrous ethanol.120... 

An unprecedented cyclopropanation reaction was observed during the reaction of ketene alkylsilyl acetals (191) with bromoform-diethylzinc. When monosubstituted acetals were used, cyclopropanecarboxylic esters (195) were formed by a novel C-H insertion. When disubstituted ketene acetals were used, byproducts such as a,)5-ethylenic esters (197) were also formed presumably via 196 (equation 49). This reaction provides a convenient method for the preparation of the bicyclo[3.1.0] hexane system and can be advantageously compared to the copper-catalysed intramolecular cyclization of unsaturated a-diazoketones . 

Grigg et al. [41] first described a cyclization-cyclopropanation process which was later on developed further by de Meijere s group. It is a nice example of a domino process with four C—C bonds being formed in a single transformation [42]. Thus, reaction of 64 with Herrmann-Beller catalyst (15) furnished 66 as the only product. It can be assumed that the palladium compound 65 is an intermediate (Scheme 8.14). 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

Lundurine A could be synthesized from indoloazocine TTT-12 after cycloprop-anation of the indole ring. The intermediate III-12 would be formed by gold(III)-catalyzed cyclization of the alkynylindole ni-13, (See Ref. [118] and [133] in Chap. 1) which arises from III-14 upon conversion of the ester group into a homologated alkyne." Compound III-14 would be assembled from an enantiome-rically pure pyroglutamic ester derivative III-16 and an indole derivative III-15. Two approaches were considered for the cyclopropanation reaction from TTT-12 derivatives (Scheme 4.12) the intermolecular (A) and intramolecular (B). 

The rhodium-catalyzed successive C-C/C-O bond cleavage reaction of a cyclobutanone 77 containing a phenoxymethyl side chain was affected by the employed bidentate diphosphine ligand (Scheme 3.44) [53]. In the presence of [Rh(nbd)(dppe)]PF 5 (nbd, norborna-2,5-diene dppe, l,2-bis(diphenylphos-phino)ethane) (5 mol%) and diphenylacetylene (20 mol%), cyclobutanone 77 was transformed into the alkenoic ester 78 in 88% yield via C-C bond cleavage, P-oxygen elimination, and reductive elimination. In contrast, the [Rh(nbd)(dppp)]PFg-catalyzed (dppp, l,3-bis(diphenylphosphino)propane) reaction afforded cyclopentanone 79 in 81% yield through a rhodacyclohexanone species that was formed by 6-endo cyclization. The reaction of the cyclobutanone 77 catalyzed by [Rh(nbd)(dppb)]PFg (dppb, l,4-bis(diphenylphosphino)butane) led to exclusive formation of cyclopropane 80 via decarbonylation. 

Barluenga and coworkers [32] reported on [2+1]- and [4+3]cyclization reactions of alkyl-, aryl-, and acetoxyfulvenes with Fischer carbene complexes (Scheme 7.31). Unlike the previous cyclopropanation reactions of dienes with Fischer carbene complexes, the cyclopropanation reactions of fulvenes therein... 

Enyne compounds underwent the cyclopropanation reaction in the presence of catalytic amounts of PtCl2. Malacria and coworkers reported that intramolecular cyclization/cyclo-propanation progressed from 1,5-enyne-containing mediumsized rings 365 and 366 to give tiicycUc cyclopropanes 367 and 368, respectively (Scheme 1.174) [246]. 

Cyclic a-diazocarbonyl compounds (59) and enynones (61) have been used as Rh-and Zn-carbenoid precursors, respectively. Cyclic derivatives (59) have been found to favour intermolecular Rh-catalysed cyclopropanation reactions, relative to the formation of conjugated alkene (60) by intramolecular -hydride elimination as is usually observed in the case of a-alkyl-a-diazocarbonyl compounds this high level of chemoselectivity is reported for the first time. Rh-carbenoids derived from (59) have also promoted cyclo-propenation reactions as well as diverse X-H insertion reactions (i.e., X = C, N, O, S). In parallel, highly functionalized cyclopropylfiirans (62) have been successfiilly prepared from an alkene and an enynone (61) by a cyclization/cyclopropanation sequence conducted in the presence of catalytic amounts of ZnCl2, which is cheap and of low toxicity computations support the probable participation of intermediate Fisher-type Zn(II) carbene complexes (63). 

In the reaction with epoxides, y-hydroxysulfones are obtained278-280. For example, Kondo and coworkers279 synthesized various (5-lactols 226 by treating sulfone acetals 225 with terminal epoxides as shown below. Dilithiated phenylsulfonylmethylene reacted with haloepoxide and afforded 3-(phenylsulfonyl)cycloalkanols281. Treatment of y, 5-epoxysulfones 227 and 229 with n-butyllithium resulted in cyclization to form cyclopropane derivatives 228 and bicyclobutane 230, respectively282. 

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