Electrophilic cyclization

Chlorocarbonylphenyl)-ethenyl methyl tellurium cyclizes electrophilically in the presence of aluminum trichloride to yield isotellurocoumarin3. 

Scheme 14.5 Wiemer s total synthesis of (+)-angelichalcone (27) via domino cyclization/ electrophilic aromatic substitution.

The high-valent iron-oxo sites of nonheme iron enzymes catalyze a variety of reactions (halogenation and hydroxylation of alkanes, desaturation and cyclization, electrophilic aromatic substitution, and cis-dihydroxylation of olefins) [lb]. Most of these (and other) reactions have also been achieved and studied with model systems [Ic, 2a-c]. With the bispidine complexes, we have primarily concentrated on olefin epoxidation and dihydroxylation, alkane hydroxylation and halogenation, and sulfoxidation and demethylation processes. The focus in these studies so far has been on a thorough analysis of the reaction mechanisms rather than the substrate scope and catalyst optimization. 

Two equivalents of AICI3 were used to bring about cyclizing electrophilic substitution to make 40 from 39 (Scheme 9) [27]. 

SCHEME 21.28. Amidation/cyclization/electrophilic aromatic substitution cascade for the synthesis of (+)-erysotramidine. 

An interesting catalytic diastereo- and enantioselective tandem transformation via Nazarov cyclization /electrophilic fluorination has been efficiently promoted by a (/ ,/ )-Ph-BOX-Cu(II) complex to afford fluorine-containing 1-indanone derivatives with two new stereocenters with high diastereoselectivity trans/cis up to 49/1) and moderate-to-high enantioselectivities (up to 95.5% ee) (Scheme 44.24). This catalytic enantioselective tandem transformation can be used for synthesis of organofluorine compounds with adjacent carbon- and fluorine-substituted tertiary and quaternary stereocenters. " ... 

SCHEME 44.24. Ph-BOX-Cu(II)-catalyzed tandem Nazarov cyclization/electrophilic fluorination. 

Laurino examined a similar method in which methanesulfonanilides were alkylated with bromoacetaldehyde diethyl acetal and then cyclized with TiCU[4J. 1 hese methods presumably involve generation of an electrophilic intermediate from the acetal functionality, followed by an intramolecular Friedel-Crafts reaction. As a consequence, the cyclization is favoured by ER substituents and retarded by EW groups on the benzene ring. 

Addition of arylhydroxylamines to electrophilic allenes such as methyl propadienoate or l-methancsulfonyl-l,2-propadiene is another route to 0-vinyl derivatives[2]. The addition step is carried out by forming the salt of the hydroxylamine using NaH and the addition is catalysed with LiO CCFj. The intermediate adducts are cyclized by warming in formic acid. Yields are typically 80% or better. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

Electrophilic substitution of thiophene occurs largely at the 2-position and the reactivity of the ring is greater than that of benzene. 3-Substituted derivatives are generally prepared by indirect means or through ring cyclization reactions. 

An oxidative cyclization, (151) -> (152), with azodicarboxylate (78CC764) is balanced by the synthesis of 5-deazaalloxazines from aryl bis(6-aminouracilyl)methanes, which involves azodicarboxylate in an intermediate electrophilic capacity (153 -> 154) (79CPB2507). Other methods involve reductive cyclizations (72AP751). 

Complexation with metals has been observed with a variety of pyridopyridazinones, whilst electrophilic attack at nitrogen is involved in cyclizations to a variety of azolo and azino fused tricyclic systems, e.g. (65CPB586, 7UOC3812). 

The employment of non-protic electrophiles for the foregoing type of cyclizations as illustrated in Scheme 8 has the particular merit of leaving a useful point of departure for further transformations. Comparable cyclizations of 2-allyl-3-aminocyclohexenones with mercury(II) acetate are preceded by dehydrogenation to the corresponding 2-allyl-3-aminophenol as shown in Scheme 9 82TL3591). The preferred direction of cyclization depends upon the nucleophilicity of the amino group. 

Ring closures based upon electrophilic processes are uncommon. The cationic cyclization in Scheme 29a proceeds via transformation of the commencing oxime into a nitrilium ion (81CC568). Schemes 29b (82CB706) and 29c (82CB714) exemplify the application of intramolecular acylation. 

Isothiazole itself is best prepared by the reaction between propynal, ammonia and sodium thiosulfate (see Section 4.17.9.3). A wide range of substituted mononuclear isothiazoles can be obtained by oxidative cyclization of y-iminothiols and related compounds (see Section 4.17.9.1.1). Substituents at the 3-position need to be in place before cyclization, but 4-substituents are readily introduced by electrophilic reagents (see Section 4.17.6.3), and 5-substituents via lithiation (see Section 4.17.6.4). 

Benzisothiazoles are best prepared by oxidative cyclization of o-aminothiobenz-amides (see Section 4.17.9.1.1), reaction of o-toluidines with thionyl chloride (see Section 4.17.9.2.1) or by sulfuration of 2,1-benzisoxazoles (see Section 4.17.10.2). 1,2-Benzisothiazoles can also be prepared from o-disubstituted benzene compounds, cyclodehydration of o-mercaptobenzaldoximes or oxidative cyclization of p-mercaptobenzylamines (see Section 4.17.9.1.1) being the most convenient. Both series of benzo compounds are readily substituted at the 5- and 7-positions by electrophilic reagents. 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

The principal variations on the normal crown synthesis methods were applied in preparing mixed crowns such as those shown in Eq. (3.55) and in forming isomers of the dibinaphthyl-22-crown-6 systems. The latter has been discussed in Sect. 3.5 (see Eq. 3.21) . The binaphthyl unit was prepared to receive a non-naphthyl unit as shown in Eq. (3.57). Binaphthol was allowed to react with the tetrahydropyranyl ether or 2-chloroethoxyethanol. Cleavage of the THP protecting group followed by tosyla-tion of the free hydroxyl afforded a two-armed binaphthyl unit which could serve as an electrophile in the cyclization with catechol. Obviously, the reaction could be accomplished in the opposite direction, beginning with catechol". ... 

Ionic Inflate derivatives of nonmetallic elements such as selenium, sulfur, phosphorus, and iodine form an important class of reagents lor organic chemistry. Highly electrophilic phenylselenyl triflate can be used in the cyclization of 5- and 6-hydroxyalkenes, affording the corresponding tetrahydrofurans and pyrans [132] (equation 68). 

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