Heterocycles from alkynes

Scheme 4.26 Synthesis of seven-membered heterocycles from alkynes.

Trost, B.M., J.-P. Lumb, and J.M. AzzareUi. 2011. An atom-economic synthesis of nitrogen heterocycles from alkynes. J Am Chem Soc 133 740-743. 

RCM of dienes to cycloalkenes provides a useful method for the syntheses of carbo- and heterocycles and thus has been proved to be extremely effective in total synthesis of various natural products. Usually, however, mixtures of (E)- and (Z)-olefms result. In contrast, ring-closing alkyne metathesis provides a reliable route for synthesis of both (E)- and (Z)-macrocycloalkenes in a stereoslective manner taking advantage of stereoselective partial reduction of resulting cycloalkynes. A Lindlar reduction gives (Z)-cycloalkenes, whereas a hydroboration/ protonation sequence afford ( )-cycloalkenes (Equation (23)). Recently, Trost reported an alternative procedure for the synthesis of (E)-olefins from alkynes through hydrosilylation by a ruthenium catalyst. This procedure converts cycloalkyne 130, for example, to vinylsilane 131 and then to (E)-cycloalkene 132 in a stereoselective manner (Scheme 46)7 ... 

Alkynes and ynamines have also been developed as useful participants in RCM approaches to pyrrolidine derivatives (Scheme 13). Mori and co-workers reported the formation of a cyclic dienamide via ene-ynamide RCM <020L803>. They also studied substituent effects on the course of RCM of enynes and reported the formation of both pyrrolidines and piperidines <02MI678>. The syntheses of 5- and 6-ring carbocycles and O-containing heterocycles from appropriate precursors were also reported in that work. Synthetically-useful dienylboronic acids have been prepared from acetylenic boronates <00AG(E)3101>. ... 

The most recent contribution in this area is by Shea who prepared tricyclic oxygen containing heterocycles from acyclic enynes 82 using a combination of intramolecular Nicholas and PKRs. They constructed [5.7.5] and [5.8.5] (83-84) systems involving the formation of a complexed cyclic alkyne. They used several PKR conditions that give different yields and diastereo-selectivities. Due to the strain of the intermediate, [5.6.5] systems (85) were obtained in poor yields (Scheme 24) [121]. 

FOUR-MEMBERED HETEROCYCLES FROM ACTIVATED ALKYNES AND C—X BONDS... 

Heterocycle formation, for example, dihydropyrans from allenes and (Z)-3-iodo-2-propenols, and isoquinolines from alkynes and A-f-butyKo-iodobenzylidenelimines," is an extension of the versatile Heck reaction. 

An alkyne/5-hydroxy-2-pentynoic ester coupling leads to dihydropyran derivatives. Formation of the homologous heterocycle from ethyl 6-hydroxy-2-hexynoate proceeds in two stages, the second stage is promoted by Pd(OCOCF3)2. ... 

Preparation of Heterocycles. As mentioned, heterocycles can be obtained via Schmidt or Curtins reactions. In addition, organic azides react with alkenes to form triazolines (triazoles from alkynes), aziridines, or other heterocycles. In situ triazoline generation and subsequent cleavage can lead to other heterocycles (see eq 15). Reaction of NaNs with other a, 8-unsaturated alkenes (or alkynes) provides different heterocycles dependent on the substituents. Such reactions are too numerous to mention in detail and only selected examples are shown in eqs 16-18. ... 

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... 

The high regio- and stereoselectivities of the process as well as its tolerance of functional groups underline the potential of the methodology. Its wide synthetic applicability is demonstrated by the preparation of a variety of functionalized heterocycles from readily available alkynes. Aryl and alkenyl halides or triflates, alkynyl halides, allyl and... 

Based on the broad-spectrum of activity of PtCl2 in the cycloisomerization of enynes, Fiirstner et al studied the PtCl2-catalyzed cycloisomerization of biaryls bearing an 0-substituted alkyne [227]. The authors found that PtCl2, although efficacious for the synthesis of phenanthrenes from O-alkynylated biphenyls, was not effective for the synthesis of polycyclic heterocycles from the corresponding... 

The direct combination of selenium and acetylene provides the most convenient source of selenophene (76JHC1319). Lesser amounts of many other compounds are formed concurrently and include 2- and 3-alkylselenophenes, benzo[6]selenophene and isomeric selenoloselenophenes (76CS(10)159). The commercial availability of thiophene makes comparable reactions of little interest for the obtention of the parent heterocycle in the laboratory. However, the reaction of substituted acetylenes with morpholinyl disulfide is of some synthetic value. The process, which appears to entail the initial formation of thionitroxyl radicals, converts phenylacetylene into a 3 1 mixture of 2,4- and 2,5-diphenylthiophene, methyl propiolate into dimethyl thiophene-2,5-dicarboxylate, and ethyl phenylpropiolate into diethyl 3,4-diphenylthiophene-2,5-dicarboxylate (Scheme 83a) (77TL3413). Dimethyl thiophene-2,4-dicarboxylate is obtained from methyl propiolate by treatment with dimethyl sulfoxide and thionyl chloride (Scheme 83b) (66CB1558). The rhodium carbonyl catalyzed carbonylation of alkynes in alcohols provides 5-alkoxy-2(5//)-furanones (Scheme 83c) (81CL993). The inclusion of ethylene provides 5-ethyl-2(5//)-furanones instead (82NKK242). The nickel acetate catalyzed addition of r-butyl isocyanide to alkynes provides access to 2-aminopyrroles (Scheme 83d) (70S593). 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

Cyclotrithiazyl chloride is also a useful reagent in organic chemistry in the fusion of 1,2,5-thiadiazoles to quinones as well as the synthesis of (a) isothiazoles from 2,5-disubstituted furans and (b) bis-1,2,5-thiadiazoles from A-alkylpyrroles (Scheme 8.4). Alkenes and alkynes react readily with (NSC1)3 to give 1,2,5-thiadiazoles, while 1,4-diphenyl-1,3-butadiene gives a variety of heterocyclic products including a bis(l, 2,5-thiadiazole). ... 

Metal-mediated reductive coupling of alkenes and alkynes affords access to complicated organic structures, including carbocyclic and heterocyclic molecules, from readily available starting materials. While most of these coupling reactions were initially developed as stoichiometric processes, many selective, catalytic versions have been developed over the past decade these advancements have made reductive coupling much more attractive to synthetic chemists. 

The palladium-catalyzed annulation of alkynes by functionally-substituted aryl and vinylic halides or triflates provides a veiy convenient and efficient approach to a wide variety of heterocycles and carbocycles. This chemistry has lead to the discovery of a number of novel palladium-catalyzed processes in which the palladium migrates from one carbon to another within the molecule providing a unique way to form carbon-carbon bonds in remote locations within the same molecule. 

Another approach to the rapid synthesis of complex polycycles from simple acyclic compounds is via the Ni(COD)2-catalyzed reaction of an enone containing an alkyne moiety to give a carbo- or heterocyclic intermediate, which is quenched with an electrophile. A typical transformation as shown by Montgomery and his group... 

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