Ortho-alkynylation

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

Imidazo[2- ]pyridines bound to solid supports via acid or base labile linkers can be prepared by reaction of resin-bound a-bromoketones with 2-aminopyridines <2003TL6265>. 5-Azaindoles may be prepared by cyclization of ortho-alkynyl aminopyridines in moderate to high yield in the presence of catalytic amounts of Cul <1998TL5159> (Equation 58). 

Iridium(m) hydrides catalyze a 6-endo-dig cyclization of ortho-alkynyl benzoic acids to afford isocoumarins (Equation 323) <2005OL5437>. Likewise, the intramolecular cyclization of ortho-alkynyl benzoic acids can be catalyzed by palladium(ll) and silver(ll) to afford isocoumarins as the major product along with formation of the 5-endo-dig cyclization product (Equation 323) <1999S1145, 2000T2533>. 

Electrophilic cyclization of ortho-alkynyl benzoates using iodine or IC1 affords 4-iodocoumarins in good yield (Scheme 206) <2002TL7401, 2002T5023, 2003JOC5936>. Electrophiles other than iodine can effectively mediate the electrophilic cyclization of ortho-alkynyl benzoates with concomitant incorporation of the electrophile into C-4 of the resulting isocoumarin (Equation 324) <2003JOC5936>. 

Several examples have appeared of diversion of the normal photochemistry of ortho-alkyl aromatic ketones due to apparent interception of the intermediate biradical by an unsaturated group present elsewhere in the molecule.Thus the vinyl aryl ketones (376) are converted to (377) in reasonable yields upon irradiation with ultra-violet light,while irradiation of the ortho-alkynyl acetophenone (378) in methanol yields diastereomers of (379)The latter reaction is thought to proceed by coupling of the initially formed ketyl radical onto the alkyne to give a carbene (380). The photochemistry of the jS-diketone (381) gives a mixture of the benzocyclobutenol (382) and the tetralone (383), and the proportions depend on the identity of the R-substituent in (381). The formation of (383) can be rationalised in terms of interception of the ketyl radical in the initially formed 1,4-biradical by the remote carbonyl group. 

Isoquinolines from ortho-Alkynyl-Araldehyde-Imines... 

Scheme 27. Metal-catalyzed cycloisomerization of ortho-alkynylated biphenyl derivatives feature...

Common model reactions for the title conversion include cyclizations of alkynoic acids to lactones, with variable degrees of regioselectivity [3-5]. Another model-reaction is the cyclization of ortho-alkynyl-phenols to benzofurans. The reaction is... 

Scheme 60 Cu-mediated bidentate directed cross-dehydrogenative ortho-alkynylation of heteroarenes with terminal alkynes.

Several transformations involving CO insertion into a Pd-heteroatom bond have been developed that lead to incorporation of two molecules of CO into the heterocyclic product. This approach to heterocycle synthesis is exemplified by a synthesis of dihydroindolones reported by Gabriele [101]. As shown below, treatment of ortho-alkynyl aniline 157 with a Pd catalyst under CO in methanol afforded 158 in 50% yield (Eq. (1.62)). A similar strategy has been employed for the conversion of alkene 159 to pyrrolidinone 160 (Eq. (1.63)) [102]. 

This reaction manifold has been heavily exploited in the assembly of indoles and benzofurans [2]. For example, Taylor and McKillop reported in 1985 that ortho-alkynyl substituted anilines 1 can undergo cyclization in the presence of PdCl2 catalysts to... 

The N-tert-butyl imine cyclization strategy can also be applied to the synthesis of isoquinolines via non-oxidative addition/reductive ehmination processes. For example, it has been found that the ortho-alkynyl substituted imine 28 can undergo palladium-catalyzed cyclization in an analogous fashion to the ortho-alkynylanilines noted in Section 6.2.1. In this case, the extra carbon unit provides a synthesis of 2-substituted isoquinolines (Scheme 6.52) [71]. This cyclization can be coupled with the formation of 28 from imines and either TMS-substituted or terminal alkynes, providing access to a diverse range of substituted products with perfect regiocontrol. 

A different pathway to substituted quinoUne derivatives 442 involving Meldrum s acid 112 was reported by Verma et al. [183]. This report utilizes a huge library of amines and CH acids that undergo reaction with the ortho-alkynyl aldehyde 440 by cooperative catalysis of AgNOj and proline or... 

Verma et al. [57] synthesized iodine-catalyzed 4-iodo-pyrano[4,3-A]quinoline derivatives 30 and ortho-alkynyl esters selectively from ortho-alkynyl aldehydes by solvent-controlled reaction (Scheme 10.23). 

This is the first report of the iodine-catalyzed selective synthesis of iodo-pyrano [4,3-Z)]-quinolines and ortho-alkynyl esters from ortho-alkynyl aldehydes. The developed novel oxidative esterification process provides a powerful tool for the preparation of a wide range of functionalized pyranoquinolinones as well as isocoumarins. 

Liang et al. [133] developed an iodine-ealalyzed tandem cyclization-cyeloaddi-tion reaction of ortho-alkynyl-substituted benzaldehydes leading to polyoxacyclic ring systems, which represents a useful approach towards the synthesis of the oxabi-... 

Verma AK, Aggarwal T, Rustagi V, Riehard CL (2010) lodine-eatalyzed and solvent-eon-trolled seleetive electrophilie eyelization and oxidative esterifieation of ortho-alkynyl aldehydes. Chem Commun 46 4064-4066... 

When the ortho-alkynyl tether on the iodoarene bears a terminal aryl group the cascade process after the intra-intermolecular carbopalladation sequence may be terminated by an ortho attack of the norbomylpalladium intermediate on the previously terminal aryl group (cf. Scheme 10) to yield an oligocyclic system (Scheme 18). 

Zhu J, Xie H, Chen Z, Id S, Wu Y (2012) A detailed study of the intramolecirlar hydroamination of iV-(ortho-alkynyl)aryl-iV -substituted trifluoroacetamidines and bromodifluoroacetami-dines. Org Biomol Chem 21 516-523... 

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