Heterocycles from alkenes

DCA reactions are an important means of synthesis of a wide variety of heterocyclic molecules, some of which are useful intermediates in multistage syntheses. Pyrazolines, which are formed from alkenes and diazo compounds, for example, can be pyrolyzed or photolyzed to give cyclopropanes. 

Electrohydrodimerization is well known for its application in the preparation of adiponitrile [82]. The method was successfully used in the preparation of heterocycles from reductions of activated bis-alkenes (Scheme 60 and vide supra Scheme 6) [10, 83] or bis-imines affording substituted piperazines in good yields, in the presence of proton donors (Scheme 61) [84]. 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

Scheme 33 N-Amino heterocycles which yield aziiidines from alkenes and Pb(OAc)4...

In addition to the most important 1,2-difunctionalization assisted or catalyzed by palladium(II) complexes, a catalytic 1,1-arylamination process of alkenes, applied to the construction of nitrogen heterocycles from 4-pentenylamides, was realized29,30. The mechanism involves the formation of arylpalladium chloride from alkyl(aryl)stannanes, the addition to the alkene, the isomerization of the adduct to the more stable benzylic palladium complex, and the displacement of palladium by an internal nitrogen nucleophile. In the presence of a substituent, mixtures of diastereomers were generally obtained. 

Three such tests have been made [77, 78, 85] and good correlations between the theoretical and experimental relative yields were obtained for the O-heterocycles formed from 2-methylpentane [77] and from 3-ethyl-pentane [85] at sub-atmospheric pressures. The most exhaustive test was carried out for the oxidation of 2-methylpentane [78] at 525 °C and 19.7 atm and considered the relative yields of O-heterocycles, conjugate alkenes and j3-scission products. The reaction scheme considered is shown below. 

There are reviews dealing with conjugated nitroalkenes in organic synthesis, " nitroenamines, the oxyalkylation of carbonyl compounds with conjugated nitroalkenes and the use of conjugated nitroalkenes in the synthesis of heterocyclic compounds. In this section mainly the preparation of nitroalkenes starting from alkenes is described. 

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. 

Chemically, 1. a. are often alcohols or carboxylic acids and esters derived from alkenes or alkadienes but also terpenoid or heterocyclic compounds may have I. a. activity. In many cases the ratio of ciVfrani-isomers or, in the case of chiral compounds, the enantiomer ratio often plays a decisive role for the effectiveness of La. Many other substances occurring in the environment also have an attracting effect on insects, especially those associated with the search for food examples the typical odors of certain plants (e.g., arum), flower and fruit odors, emanations from animals and humans [CO2, lactic acid, (-)-(/ )-l-octen-3-ol] or carrion. 

SYNTHESIS OF SF5-SUBSTITUTED AROMATIC HETEROCYCLES FROM SF5CL (SF5BR) APPLICATION OF SF5-SUBSTITUTED ALKENES AND SF5-SUBSTITUTED ALKYNES TO THE SYNTHESIS OF SF5-SUBSTITUTED HETEROARENES... 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

More recently, a palladium-catalyzed tandem protocol for the synthesis of cyclopentene fused heterocycles from diazabicyclic alkenes and ortho-functionalized atyl iodides was elaborated. A number of cyclopentene fused dihydrobenzofurans and indolines were prepared by this procedure (Scheme 2.50). The reaction can he tuned toward the formation of either... 

Very recently unusual approach to 4-fluoropyrimidine N-oxides from alkenes was elaborated in Moscow State University. The method based on three-component heterocyclization involving gem-bromofluorocyclopropanes 113 or 116, nitrosyl tetrafluoroborate, and a molecule of the solvent (nitrile) yielding previously unknown fluorinated pyrimidine N-oxides 114 or 117 (Scheme 25) [127]. 

The formation of heterocyclic organoboranes from alkenes and alkylated diboranes has been recently reviewed 22b). 

SCHEME 39.4. Chiral Br0nsted-acid-catalyzed synthesis heterocycles from amino-alkene. ... 

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. 

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