Abstract
Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These N-alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of N-alkynyl azoles mirrors that of the more extensively studied N-alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these N-alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of N-alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting N-alkynyl azoles in synthesis.
Highlights
This review has covered the synthesis and reactions of N-alkynyl azoles, a small subclass of nitrogen-substituted alkynes, which have received a lot of attention over the last several decades
Researchers synthesized these molecules using classical dehydrohalogenation chemistry that limited the scope of accessible substrates; with the discovery of milder catalytic protocols for the synthesis of N-alkynyl amides and azoles the synthesis of more complicated structures containing sensitive functional groups has become possible
N-alkynyl azoles have been used in metal-catalyzed addition reactions, they have found tremendous use in cycloaddition reactions, they have been applied to the total synthesis of several natural products, and have been investigated for their biological activity and use in polymers
Summary
N-Alkynyl azoles, that is, alkynes containing an azole substituent through the ring nitrogen atomN(F-Aiglukryen1y)l, ahzaovleesa,tttrhaactteids, aalskigynniefiscaconnt taaminoinugntaonf ianztoelreesstuobvsetirtutheentlatshtrsoeuvgehratlhdeecriandgesn,iitnropgaernt datuoemto(Ftihgeurseig1n)i,fihcaavneceatotrfatchteedtwa osiginndifiivcaidnut aalmfroaugnmt eonf tisn:tetrheestaozvoeler athnedlathstesaelvkeyrnael .deAclakdyense, sinaprearat fduunedtaomtehnetasligbnuiiflidcainngcebloofckthaentdwfounincdtiiovnidalugarlofurapgtmhaetnitss:inthdeispazeonlseibalnedtothsyenatlhkeytnicec. hAelmkyisntes,swarheilea afuzonldeasmareenetxatlrbemuieldlyincgomblmocoknainndbifoumnoctleiocnualelsgarnodupphtharamt iasceinudtiicsaples.nTsihbelechtoemsyisnttrhyeotifcNc-haelkmyinstysl,awzohlieles raezporleessenartsejuexsttraefmraecltyiocnoomfmthoenniitnrobgieonm-soulbesctuitluestedanadlkpynhearfimeladc.eOutvicearltsh.eTyheearcsh, ethmeirsetrhyavoef bNee-anlkmyannyyl raezvoileews sreopfryesneanmtsinjuesst[a1–f3ra] catniodnyonfatmheidneistr[o3g–e6n],-saunbdstsiotumteedoaf ltkhyensee fhiaelvde. iOnvcleurdtehde Nye-aarlks,ytnhyelreazhoalvese wbeitehninmthaeniyr croenvtieenwt;shoofweyvnearm, tihneeson[l1y–r3e]vaienwd thynatapmriidmeasri[l3y–f6o]c,uasnedd osnomtheis oclfasths eosfecohmavpeouinndclsuwdeads pNu-ballkisyhneydlianz2o0le0s4 w[7i]t,hainndthineitrhceolnastetn1t5; yheoawrsevtheerr, ethheasonbleyenreavsieigwnitfihcaatnptraimmaoruinlyt ofofcwuoserkd pounbtlhisishecdlaisns tohficsoamrepao. unds was published in 2004 [7], and in the last 15 years there has been a significant amount of work published in this area. BBuurrggeerr aanndd DDrreeiieerr’’ss ssyynntthheessiiss ooff aann NN--aallkkyynnyyll ppyyrrrroollee. Their work circumvents elevated reaction temperatures by using 254 nm light to excite the copper catalyst Their method was applicable to the coupling of various vinyl iodides with carbazole and indole (75a–c), and even worked for the N-alkynylation of carbazole with a 1-bromoalkyne (75d). In 2009, Zhang reported an iron-catalyzed synthesis of N-alkynyl amides using 1-bromoalkynes as a coupling partner (Scheme 26) [48].
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