Heterocyclic synthesis alkene reactions

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

Topics of relevance to the content of this chapter which have been reviewed during the year include photoactive [2]rotaxanes and [2]catenanes, photochemical synthesis of macrocycles, phototransformations of phthalimido amino acids, photoaddition reactions of amines with aryl alkenes and arenes, photoreactions between arenenitriles and benzylic donors, photostability of drugs, polycyclic heterocycles from aryl- and heteroaryl-2-propenoic acids, photoreactions of pyrroles, photoamination reactions in heterocyclic synthesis, switching of chirality by light, photochromic diarylethenes for molecular photoionics and solid state bimolecular photoreactions. 

A commoner way to make heterocycles by pericyclic reactions is to use 1,3-dipolar cycloadditions. These often occur without catalysis and so are compatible with many other reactions. The starting material 182 for this asymmetric synthesis of swainsonine was derived from a natural sugar (chiral pool strategy, chapter 23). An exceptionally stereoselective Wittig reaction gave the Z-alkene 183 (chapter 15) and the alcohol was converted into the azide 184 with diphenylphos-phoryl azide.24... 

Vinylsilanes 132 have been reacted with bromomalononitrile to yield the intermediate 133, which was used for the synthesis of cyclopropane derivatives Addition reactions of dichloromalononitrile with substituted alkenes and alkadienes can also be used for the preparation of intermediates in carbo- and heterocyclic synthesis. 2-Arylmalononitriles 135 have been produced by coupling malononitriles with aryllead(IV) triacetates like 134163. 

The Pauson-Khand reaction provides another new approach to the metal-catalyzed synthesis of heterocycles. This reaction involves the interaction of the multiple bonds of an alkyne with an alkene and carbon monoxide in the presence of dicobalt octacarbonyl (Co2(CO)g), or with just this reagent as a source of CO. The overall process has been described as a [2 -h 2 -h 1] cycloaddition. Only a few applications to heterocyclic synthesis have been reported so far. A 2008 paper that is illustrative of the process describes the use of this reaction for the construction of a heterocyclic ring that is part of an azabicy-clo[3.3.1]nonane derivative. This ring system is present in the alkaloid (-)-alstonerine (4.37), which prompted this study. 

The [2+2] cycloaddition is the main method for the synthesis of cyclobutanes and 4-membered ring heterocycles. The thermal reaction between two alkenes is not a synchronous, pericyclic process, which is symmetry forbidden, but is a two-step, Lewis acid-catalysed procedure involving a Michael reaction between an electron-rich alkene and an electron-poor partner followed by cyclisation (Figure 8.7). 

The reaction is an important synthetic route to triazolines and their derivatives [5-7] such as cycUc imines or aziridines and is hence a valuable technique in the synthesis of heterocycles [8]. The reaction rate is dependent on the dipolarophile. Whereas strained olefins, such as norbornene, react readily, terminal alkenes react extremely slowly [9]. 

Alkylidenephosphoranes (a.La. phosphorus yUdes) of the general formula Ph3P=CR R (1) have been frequently used in key steps of heterocycle synthesis. Numerous papers and review articles [1-4] testify their versatility in the construction of rings with sizes ranging from three to well beyond 20 and with virtually any number, kind and distribution of heteroatoms. The Wittig alkenation of carbonyl groups is doubtless the most common, though not the only, reaction of P-ylides that has been employed in the cyclization of bifunctional precursors. The cycloaddition between acyl ylides (1 = H,... 

The argument is closely analogous to that used to explain the regioselectivity of formation of bromoacetoxy compounds (Table 9.2) formed in the addition of bromine to alkenes in acetic acid. Similarly, addition of bromine to alkenes in water produces bromohydrins. Although they are more difficult to synthesize, iodohydrins and fluorohydrins are also known. For a review of the synthesis and reactions of halohydrins, see Rosowsky, A. in Weissberger, A., Ed. Heterocyclic Compounds with Three- and Four-Membered Rings, Part One Wiley-Intersdence New York, 1964 p.l. 

Direct C-H bond functionalization via ruthenium complexes catalysis has been well explored [5]. However, the rapid progress for heterocycle synthesis via ruthenium-catalyzed C-H activation has been only achieved since 2011. By utilizing the less expensive and stable ruthenium(II) complex [RuCl2(/ -cymene)]2, the oxidative cyclization reactions with a series of unsaturated small molecules like alkenes and alkynes proved to be a fast access to heterocycles. Herein, this chapter is intended to provide an overview of reported examples for ruthenium-catalyzed C-H bond activation and cyclization for heterocycle synthesis till the end of 2014, including mechanism presentations... 

PhSSPh with retention/ or photochemically/ Methyl phenyl N-methyl-sulphoximide gives adducts with ketones after conversion into its carban-ion, from which either tertiary alcohols are obtained by Al-Hg reduction under neutral conditions, or alkenes by reduction in aqueous acid, thus providing an alternative to the Wittig methylenation reaction/ Oxosul-phonium ylides formed by N-dimethylation followed by carbanion formation with NaH are useful as alkylidene-transfer reagents/ Uses of sulphoximides in heterocyclic synthesis have been reported methyl phenyl sulphoximide reacts through N with ethoxymethylene malonate esters. ... 

Additions to Electron-Deficient Species. Diazomethane will also add to highly electrophilic species such as sulfenes or im-minium salts to give the corresponding three-membered ring heterocycles. When the reaction is performed on sulfenes, the products are episulfones which are intermediates in the Ramberg-Backlund rearrangement, and are therefore precursors for the synthesis of alkenes via chelotropic extrusion of S02- The sulfenes are typically prepared in situ by treatment of a sulfonyl chloride with a mild base, such as Triethylamine (eq 47). Similarly, the addition of diazomethane to imminium salts has been used to methyle-nate carbonyls. In this case, the intermediate aziridinium salt is treated with a strong base, such as n-Butyllithium, in order to induce elimination (eq 48). 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

Fluorinated alkenes and alkynes are highly activated toward nucleophilic attack and reaction with bifunctional nucleophiles is a fruitful area for the synthesis of heterocycles. A review on perfluoroalkyl(aryl)acety-lenes contains many examples (91RCR501). 

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

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