Dihalides cyclization

The dihalide cyclization method has been used to make the two isomeric tetrahydrodithiocins (394) and (395), as well as the benzo derivative (396). Oxidation of (394) and (395) gives rise to crystalline disulfones (m.p. 227 and 130 °C respectively), while (395) behaves as a dienophile towards cyclopentadiene (64ZC302) (cf. 255, Section 5.19.4.4). 

The 1,3-dianions formed across the sulfone of ) -ketosulfones may be selectively dialkylated with an a, co-dihalide and thus cyclize to give 2-ketothiane dioxides . Due to its polarity, the 2-keto-substituent (or other polar group in the 2-position) adopts the axial orientation (equation 124). 

Synthesis. These macrocycles are prepared from seven-membered ring dinitrile complexes, 84a-84c (Scheme 17), which contain either methylene, sulfur or oxygen in the five position (129). These cyclic dinitriles are synthesized by alkylating maleonitrile dithiolate or derivatives thereof with the corresponding dihalide. The dinitriles 84a-84c can be cyclized in magnesium propoxide to form porphyrazines 85a (33%), 85b (19%), and 85c (27%) (Scheme 17), which can be demetalated with trifluoroacetic to form 86a-86c. Additionally, 86a has been remetalated with nickel (87a, 92%), copper (88a, 95%), and zinc (89a, 94%). The sulfur and oxygen derivatives 85b, 85c, 86b, and 86c are of low solubility and are not suitable for further manipulation. 

This has been applied to the cyclization of dihalides [45, 46], nonconjugated, unsaturated ketones [47] and esters [48], oxoalkylpyridinium salts [49], aldehydes and unsaturated nitriles [50], halides, and unsaturated esters [51], The umpoled acceptors, mostly radical anions or carban-ions (see Scheme 1), can also be used in intermolecular reactions such as acylation, alkylation, or carboxylation (Eq. 5). 

Cyclization of diallylic halides 0-90 Cyclization of 1,3-diols 0-94 Internal malonic ester synthesis 0-102 Carbonylation of 1,4-dihalides 0-108 Internal condensation of diesters (Dieckmann)... 

Cyclization of haloamines (cyclic amines) dealkylation of quaternary salts of nitrogen heterocycles 0-45 Reaction between dihalides and cy-anamide (cyclic amines)... 

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

The preparation of three-, five- and six-membered rings in modest yield by the elec-trochemically induced coupling of activated olefins with dihalides has been reported (equation 35)98. Use of an aluminum anode was critical for the formation of cyclized product. Application of this technique to the preparation of four-membered rings was unsuccessful. 

Many important cyclization reactions have been performed by alkylation of a-carbonyl (and related) anions. These reactions may be performed intramolecularly with suitably functionalized halo-containing carbonyl compounds or can be performed intermolecular-ly by the use of a,co-dihalides. These are discussed below. 

A new cyclization process was published in 2003 <2003PS1295>, where dithiols are substituted by dithioiminium salts, which can be created by reacting thioacteamide 5 with a,o -dihalides. In a second step, the dithioiminium salts 6 are treated with (different) a,tu-dihalides adding sodium hydroxide, as base, and tetrabutylammonium bromide, as phase-transfer catalyst (Scheme 2). Thus, two kinds of macrocycles are found in the final reaction mixture XS2 (1 1 ratio) 7 and (2X)S4 (2 2 ratio) 8. 

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