Recent Advances in the Addition of Amide/Sulfonamide Bonds to Alkynes

molecules

Review Recent Advances in the Addition of Amide/Sulfonamide Bonds to Alkynes

Fei Zhao 1 , Pinyi Li 1, Xiaoyan Liu 1, Xiuwen Jia 1, Jiang Wang 2,3 and Hong Liu 2,3,*

1 Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, 168 Hua Guan Road, Chengdu 610052, China; [email protected] (F.Z.); [email protected] (P.L.); [email protected] (X.L.); [email protected] (X.J.) 2 State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; [email protected] 3 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China * Correspondence: [email protected]; Tel.: +86-021-5080-7042



Academic Editor: Michal Szostak
 Received: 11 December 2018; Accepted: 27 December 2018; Published: 4 January 2019

Abstract: The addition of amide/sulfonamide bonds to alkynes is not only one of the most important strategies for the direct functionalization of carbon–carbon triple bonds, but also a powerful tool for the downstream transformations of amides/sulfonamides. The present review provides a comprehensive summary of amide/sulfonamide bond addition to alkynes, including direct and metal-free aminoacylation, based-promoted aminoacylation, transition-metal-catalyzed aminoacylation, organocatalytic aminoacylation and transition-metal-catalyzed aminosulfonylation of alkynes up to December 2018. The reaction conditions, regio- and stereoselectivities, and mechanisms are discussed and summarized in detail.

Keywords: amide bond; sulfonamide bond; alkynes; addition reaction; aminoacylation; aminosulfonylation

1. Introduction The addition of atom–atom bonds to alkynes has become an important strategy for the functionalization of carbon–carbon triple bonds [1–16]. These intermolecular and intramolecular addition reactions provide a facile and efficient access to highly functionalized alkenes and cyclic compounds, respectively, in a high atom- and step-economic manner. Considering the large occurrence of amide/sulfonamide motifs in natural products and pharmaceutical agents, the addition of amide/sulfonamide bonds to alkynes, namely aminoacylation/aminosulfonylation of alkynes, is particularly important. Because they allow the direct downstream transformations of amides/sulfonamides by the insertion of carbon–carbon triple bonds into the amide/sulfonamide bonds, they thus produce more complex and skeletally different addition molecules (Scheme1). In addition, the aminoacylation/aminosulfonylation of alkynes also constitutes a tool for the structural modification of compounds carrying amide/sulfonamide bonds, especially for peptides, which are an important class of drugs used in the clinic [17–19]. Besides, amide/sulfonamide bond addition to alkynes, which constructs one C–C/S and one C–N bond in a single step featuring high atom- and step-economy, is in accordance with the concept of “green and sustainable chemistry”. It should be noted that the addition of amide/sulfonamide bonds to alkynes has not been reviewed before. Moreover, amide/sulfonamide bond addition to alkynes has achieved many important developments in recent decades, especially in transition-metal-catalyzed and organocatalytic processes. Therefore, a review focused on the aminoacylation/aminosulfonylation of alkynes

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Molecules 2018, 23, x FOR PEER REVIEW 2 of 22 alkynes would enrich the knowledge of synthetic chemists who are interested in amide/sulfonamide would enrich the knowledge of synthetic chemists who are interested in amide/sulfonamide bond activation. The aim of the present review is to provide a systematical and comprehensive alkynesbond activation. would enrich The the aim knowledge of the present of synthetic review chemists is to provide who are a systematical interested in and amide/sulfonamide comprehensive summary on the addition of amide/sulfonamide bonds to alkynes, including direct and catalyst‐free bondsummary activation. on the additionThe aim of of amide/sulfonamide the present review bonds is to provide to alkynes, a systematical including direct and and comprehensive catalyst-free aminoacylation, based‐promoted aminoacylation, transition‐metal‐catalyzed aminoacylation, summaryaminoacylation, on the addition based-promoted of amide/sulfonamide aminoacylation, bonds transition-metal-catalyzedto alkynes, including direct and aminoacylation, catalyst‐free organocatalytic aminoacylation, and transition‐metal‐catalyzed aminosulfonylation of alkynes up to aminoacylation,organocatalytic aminoacylation, based‐promoted and transition-metal-catalyzedaminoacylation, transition aminosulfonylation‐metal‐catalyzed aminoacylation, of alkynes up to December 2018. We hope this review will serve as a handy reference for chemists interested in the organocatalyticDecember 2018. aminoacylation, We hope this review and transition will serve‐metal as a‐ handycatalyzed reference aminosulfonylation for chemists interestedof alkynes inup the to addition of amide/sulfonamide bonds to alkynes, and will encourage further developments in this Decemberaddition of 2018. amide/sulfonamide We hope this review bonds will to alkynes, serve as anda handy will encouragereference for further chemists developments interested inin thisthe field in overcoming the remaining challenges. additionfield in overcoming of amide/sulfonamide the remaining bonds challenges. to alkynes, and will encourage further developments in this field in overcoming the remaining challenges.

Scheme 1. The addition of amide/sulfonamide bonds to alkynes. Scheme 1.1. The addition of amide/sulfonamide bonds bonds to to alkynes. alkynes. 2. Addition of Amide Bonds to Alkynes 2. Addition of Amide Bonds to Alkynes 2. Addition of Amide Bonds to Alkynes 2.1. Direct Addition of Amide Bonds to Alkynes without Catalysts and Additives 2.1. Direct Addition of Amide Bonds to Alkynes without Catalysts and Additives 2.1. DirectThe first Addition example of Amide of amide Bonds bond to Alkynes addition without to alkynes Catalysts was and a catalyst Additives‐ and additive‐free process as The first example of amide bond addition to alkynes was a catalyst- and additive-free process as reportedThe firstby E exampleğe’s group of inamide 1976 bond [20]. Theyaddition found to alkynes the treatment was a catalystof active‐ and2‐phenylpyrazolidin additive‐free process‐3‐ones as reported by E˘ge’sgroup in 1976 [20]. They found the treatment of active 2-phenylpyrazolidin-3-ones 4 reported4 with dimethyl by Eğe’s groupacetylenedicarboxylate in 1976 [20]. They 5found in CH the3CN treatment under ofreflux active led 2‐phenylpyrazolidin to the formation‐ 3of‐ones the with dimethyl acetylenedicarboxylate 5 in CH3CN under reflux led to the formation of the interesting 4interesting with dimethyl ring expansion acetylenedicarboxylate products 1,2‐diazepin 5 in CH‐5‐3onesCN 6under, albeit reflux with unsatisfactoryled to the formation selectivities of andthe ring expansion products 1,2-diazepin-5-ones 6, albeit with unsatisfactory selectivities and yields interestingyields (Scheme ring 2).expansion The main products byproducts 1,2‐diazepin of this reaction‐5‐ones were 6, albeit the ciswith‐ and unsatisfactory trans‐ Michael selectivities‐type addition and (Scheme2). The main byproducts of this reaction were the cis- and trans- Michael-type addition yieldsproducts. (Scheme Besides, 2). The this main transformation byproducts of was this stronglyreaction wereinfluenced the cis‐ andby the trans solvent‐ Michael used.‐type Polar addition but products. Besides, this transformation was strongly influenced by the solvent used. Polar but nonprotic products.nonprotic Besides,solvents suchthis transformationas acetone and wasacetonitrile strongly gave influenced the best byresults the whilesolvent few used. products Polar were but solvents such as acetone and acetonitrile gave the best results while few products were obtained nonproticobtained insolvents protic suchsolvents as acetone such asand ethanol. acetonitrile Similar gave results the best were results also while observed few products in Svete were and in protic solvents such as ethanol. Similar results were also observed in Svete and Stanovnik’s obtainedStanovnik in′s proticresearch solvents on thesuch additionas ethanol. reactions Similar resultsbetween were 5,5 ‐alsodimethyl observed‐2‐(1H in‐indenyl Svete ‐2)and‐3‐ research on the addition reactions between 5,5-dimethyl-2-(1H-indenyl-2)-3-pyrazolidinones 7 and Stanovnikpyrazolidinones′s research 7 and acetylenedicarboxylateson the addition reactions 8 (Scheme between 3) [21]. 5,5A plausible‐dimethyl ‐reaction2‐(1H‐indenyl mechanism‐2)‐3‐ acetylenedicarboxylates 8 (Scheme3)[ 21]. A plausible reaction mechanism was outlined in Scheme4. pyrazolidinoneswas outlined in7 andScheme acetylenedicarboxylates 4. The Michael 8 (Schemeaddition 3) of[21]. N1 A plausibleof the reactionpyrazolidinones mechanism to The Michael addition of N1 of the pyrazolidinones to acetylenedicarboxylate generates the carbanionic wasacetylenedicarboxylate outlined in Scheme generates 4. theThe carbanionic Michael intermediateaddition of 11N1, which of attacksthe pyrazolidinones the carbonyl group to intermediate 11, which attacks the carbonyl group across the ring to give the bicyclic amino-acetal acetylenedicarboxylateacross the ring to give generatesthe bicyclic the amino carbanionic‐acetal intermediateintermediate 1211., whichThe following attacks thering carbonyl opening group of 12 intermediate 12. The following ring opening of 12 affords the zwitterionic intermediate 13, which acrossaffords the the ring zwitterionic to give the intermediate bicyclic amino 13, ‐whichacetal undergoesintermediate ring 12 .expansion The following to produce ring opening the addition of 12 undergoes ring expansion to produce the addition products 6. affordsproducts the 6. zwitterionic intermediate 13, which undergoes ring expansion to produce the addition products 6. R3 R2 R3 CO2Me R2 O CH CN, reflux R R1R R CO Me 3 R1R 3 2 3 O + 2 2 O CO Me HN HN 2 R1 N CH3CN,1-5 reflux d R1 O + CO Me N CO Me Ph 2 HN CO Me2 HN N 1-5 d Ph 2 CO Me N 4 5 2 CO Me Ph 6Ph, 25-56% 2 4 5 6, 25-56% O O O O O O CO Me CO Me CO Me HN 2 HN 2 HN 2 N N CO Me N CO Me COCOMe2Me CO Me2 CO Me2 HNPh 2 HNPh 2 HNPh 2 N N N CO Me CO Me CO Me Ph 56%2 Ph 25% 2 Ph 34% 2 Scheme56% 2. Insertion of 2-phenylpyrazolidin-3-ones 25% into amide34% bonds. Scheme 2. Insertion of 2‐phenylpyrazolidin‐3‐ones into amide bonds. Scheme 2. Insertion of 2‐phenylpyrazolidin‐3‐ones into amide bonds.

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Scheme 3. Catalyst‐ and additive‐free amide bond addition to alkynes. Scheme 3. Catalyst‐ and additive‐free amide bond addition to alkynes. Scheme 3. CatalystCatalyst-‐ and additive additive-free‐free amide bond addition to alkynes.

SchemeScheme 4. 4. ProposedProposed mechanism mechanism for for the the insertion insertion of of 2 2-phenylpyrazolidin-3-ones‐phenylpyrazolidin‐3‐ones into into amide amide bonds. bonds. Scheme 4. Proposed mechanism for the insertion of 2‐phenylpyrazolidin‐3‐ones into amide bonds. Scheme 4. Proposed mechanism for the insertion of 2‐phenylpyrazolidin‐3‐ones into amide bonds. InIn contrast, contrast, Hanack Hanack’s′s group group developed developed a a more more general general and and practical practical addition addition of of amide amide bonds bonds to to In contrast, Hanack′s group developed a more general and practical addition of amide bonds to carbon–carboncarbon–carbonIn contrast, triple triple Hanack bonds bonds′s group without without developed any any catalysts catalysts a more and and general additives additives and in inpractical 1989 1989 [22]. [22 addition]. Amides Amides of 15 15amide werewere bonds directly directly to carbon–carbon triple bonds without any catalysts and additives in 1989 [22]. Amides 15 were directly addedaddedcarbon–carbon toto alkynyl alkynyl triple trifluoromethyl trifluoromethyl bonds without sulfones anysulfones catalysts14 to afford14 and to the additivesaffordcis-adducts the in 1989 cis16‐ adductswith[22]. Amides excellent 16 15with regioselectivity were excellent directly added to alkynyl trifluoromethyl sulfones 14 to afford the cis‐adducts 16 with excellent regioselectivityandadded good to yields,alkynyl and despite goodtrifluoromethyl yields, the fact despite that sulfones a longthe fact reaction 14 that to a time longafford wasreaction the required cis time‐adducts (Schemewas required 165 ).with This (Scheme protocolexcellent 5). regioselectivity and good yields, despite the fact that a long reaction time was required (Scheme 5). Thisshowedregioselectivity protocol advantages showed and suchgood advantages as yields, simple suchdespite operation, as simplethe fact broad operation, that substrate a long broad reaction scope, substrate and time the wasscope, avoidance required and the of (Scheme metalsavoidance and 5). This protocol showed advantages such as simple operation, broad substrate scope, and the avoidance ofadditives.This metals protocol and A plausible showedadditives. mechanismadvantages A plausible wassuch mechanism proposed as simple in wasoperation, Scheme proposed6. broad The in Michael Schemesubstrate reaction 6. scope, The Michael of and nitrogen the reaction avoidance atom of of metals and additives. A plausible mechanism was proposed in Scheme 6. The Michael reaction of nitrogentheof metals amides atom and to alkynyladditives. of the trifluoromethylamides A plausible to alkynyl mechanism sulfones trifluoromethyl yields was aproposed zwitterion sulfones in 17Scheme ,yields which 6. undergoesa The zwitterion Michael cyclization reaction17, which toof nitrogen atom of the amides to alkynyl trifluoromethyl sulfones yields a zwitterion 17, which undergoesformnitrogen intermediate atom cyclization of 18the. Theto amides form subsequent intermediate to alkynyl rupture trifluoromethyl18. of The the subsequent carbon–nitrogen sulfones rupture bondyields of the of a18 carbon–nitrogen zwitteriongives the products 17, whichbond16 . undergoes cyclization to form intermediate 18. The subsequent rupture of the carbon–nitrogen bond ofTheundergoes 18 regio- gives andthecyclization products stereoselectivity to 16form. The intermediate observed regio‐ and in stereoselectivity18 this. The reaction subsequent could observed be rupture well in explained of this the reaction carbon–nitrogen by this could mechanism. be bondwell of 18 gives the products 16. The regio‐ and stereoselectivity observed in this reaction could be well explainedof 18 gives by the this products mechanism. 16. The regio‐ and stereoselectivity observed in this reaction could be well explained by this mechanism. explained by this mechanism.

SchemeScheme 5. 5. DirectDirect aminoacylation aminoacylation of of alkynyl alkynyl trifluoromethyl trifluoromethyl sulfones. sulfones. Scheme 5. Direct aminoacylation of alkynyl trifluoromethyl sulfones. Scheme 5. Direct aminoacylation of alkynyl trifluoromethyl sulfones.

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Scheme 6. Proposed mechanism for the direct aminoacylation of alkynyl trifluoromethyl sulfones. SchemeScheme 6.6. ProposedProposed mechanismmechanism forfor thethe directdirect aminoacylationaminoacylation ofof alkynylalkynyl trifluoromethyltrifluoromethyl sulfones.sulfones. What seems particularly interesting is the addition of 1,10-carbonyldiimidazole (CDI) 19 What seems particularly interesting is the addition of 1,1′‐carbonyldiimidazole (CDI) 19 to to alkynoicWhat seems acids particularly20 with the interestinginteresting release of isis CO thethe2, asaddition reported of 1,1 by′‐′‐ Knölkercarbonyldiimidazole and co-workers (CDI)(CDI) in 19 1993 toto alkynoic(Schemealkynoic 7 acidsacids)[ 23 20].20 Thiswithwith reactionthethe releaserelease proceeded ofof COCO22,,, asas well reportedreported under byby mild KnölkerKnölker conditions andand coco to‐‐workersworkers provide inin the 19931993E-adducts (Scheme(Scheme 237)7) [23].[23].in moderate ThisThis reactionreaction yields. proceededproceeded The reaction wellwell of underunder CDI mild19mildwith conditionsconditions alkynoic toto acids provideprovide20 generated thethe EE‐‐adductsadducts intermediate 2323 inin moderatemoderate21 and yields. The reaction of CDI 19 with alkynoic acids 20 generated intermediate 21 and imidazole 22 yields.imidazole The22 reactionwith the of release CDI 19 of with CO2 ,alkynoic and the subsequentacids 20 generated addition intermediateintermediate of the imidazole 21 and22 to imidazoleimidazole the electron 22 withdeficientwith thethe release alkynerelease 21ofof stereoselectivelyCOCO22,,, andand thethe subsequentsubsequent produced additionaddition the products ofof thethe23 .imidazoleimidazole 2222 toto thethe electronelectron deficientdeficient alkynealkyne 2121 stereoselectivelystereoselectively producedproduced thethe productsproducts 2323...

Scheme 7. Direct addition of 1,10-carbonyldiimidazole to alkynes. SchemeScheme 7.7. DirectDirect additionaddition ofof 1,11,1′‐′‐′‐carbonyldiimidazolecarbonyldiimidazole toto alkynes.alkynes. 2.2. Base-Promoted Addition of Amide Bonds to Alkynes 2.2.2.2. BaseBase‐‐PromotedPromoted AdditionAddition ofof AmideAmide BondsBonds toto AlkynesAlkynes In 1987, Suzuki and Tsuchihashi disclosed a sequential process for the preparation of enaminones 27 throughInIn 1987,1987, the SuzukiSuzuki insertion andand of Tsuchihashi lithiumTsuchihashi (triphenylsilyl)acetylide discloseddisclosed aa sequentialsequential into amidesprocessprocess (Schemeforfor thethe 8 )[preparationpreparation24]. Acyclic ofof enaminonesamidesenaminones reacted 2727 throughthrough smoothly thethe to insertioninsertion give the ofEof-enaminones lithiumlithium (triphenylsilyl)acetylide(triphenylsilyl)acetylide in high yields, while intointo lower amidesamides yields (Scheme(Scheme of the desired 8)8) [24].[24]. AcyclicringAcyclic expansion amidesamides reacted productsreacted smoothlysmoothly were obtained toto givegive when thethe EE‐‐ cyclicenaminonesenaminones amides inin were highhigh used yields,yields, as the whilewhile substrates. lowerlower yieldsyields It is worthofof thethe desirednotingdesired that ringring the expansionexpansion triphenyl productsproducts group on werewere silicon obtainedobtained was essential whenwhen cycliccyclic for the amidesamides transformation werewere usedused as asas other thethe substrates.substrates. silylacetylides ItIt isis worthfailedworth to notingnoting give the thatthat enaminone thethe triphenyltriphenyl products. groupgroup The onon possible siliconsilicon reaction waswas essentialessential pathway forfor may thethe involve transformationtransformation the initial formation asas otherother silylacetylidesofsilylacetylides the silylalkynone, failedfailed toto the givegive subsequent thethe enaminoneenaminone Michael products.products. addition TheThe possible ofpossible in situ-formed reactionreaction pathwaypathway lithium maymay amide involveinvolve and the the initialinitialfinal protiodesilylation. formationformation ofof thethe silylalkynone,silylalkynone, thethe subsequentsubsequent MichaelMichael additionaddition ofof inin situsitu‐‐formedformed lithiumlithium amideamide andand thethe finalfinal protiodesilylation.protiodesilylation.

− ◦ SchemeScheme 8. 8. TheThe insertioninsertioninsertion of of lithiumlithium lithium (triphenylsilyl)acetylide (triphenylsilyl)acetylide intointointo amides.amides. MethodMethod AA:::: THF,THF, − − −4545 °C,°C,C, 55 h,h, then quenching with MeOH. Method B: BF ·OEt (1.2 equiv.), THF:Hexane = 1:5 (v/v), −45 ◦C, 5 h, thenthen quenchingquenching withwith MeOH.MeOH. MethodMethod BB::: BFBF333∙∙∙OEt3OEt222 (1.2(1.22 equiv.),equiv.), THF:HexaneTHF:Hexane == 1:51:5 ((vv//vv),), − − −4545 °C,°C, 55 h,h, thenthen quenchingthenquenching quenching withwith 50% with50% aqueousaqueous 50% aqueous TFA.TFA. TFA. Subsequently, Jeong et al. successfully realized the addition of Weinreb amides 29 to the Subsequently,Subsequently, JeongJeong etet al.al. successfullysuccessfully realizedrealized thethe additionaddition ofof WeinrebWeinreb amidesamides 2929 toto thethe carbon–carbon– carbon–carbon triple bond of trifluoropropynyl lithium 30 in a one-pot two-step pathway [25–27], carboncarbon tripletriple bondbond ofof trifluoropropynyltrifluoropropynyl lithiumlithium 3030 inin aa oneone‐‐potpot twotwo‐‐stepstep pathwaypathway [25–27],[25–27], providingproviding aa ZZ//EE mixturemixture ofof β‐ β‐ β‐trifluoromethyltrifluoromethyl enaminonesenaminones 3434 inin moderatemoderate yieldsyields (Scheme(Scheme 9).9). ItIt shouldshould bebe noticednoticed

Molecules 2019, 24, 164 5 of 22 providingMolecules 2018 a, 23Z, /x EFORmixture PEER REVIEW of β -trifluoromethyl enaminones 34 in moderate yields (Scheme5 of9 ).22 It should be noticed that an excessive amount of trifluoropropynyl lithium was required to consume that an excessive amount of trifluoropropynyl lithium was required to consume Weinreb amides Weinreb amides completely. The reaction temperature had a decisive impact on the outcome of completely. The reaction temperature had a decisive impact on the outcome of this transformation this transformation since quenching the reaction with H2O at room temperature failed to give the since quenching the reaction with H2O at room temperature failed to give the enaminones but gave enaminones but gave recovery of Weinreb amides. Besides, the use of N,N-dimethylbenzamide instead recovery of Weinreb amides. Besides, the use of N,N‐dimethylbenzamide instead of N‐methoxy‐N‐ of N-methoxy-N-methylbenzamide under optimal conditions did not provide the desired product methylbenzamide under optimal conditions did not provide the desired product at all, only the at all, only the recovery of starting material. This indicated that the N-methoxy group in Weinreb recovery of starting material. This indicated that the N‐methoxy group in Weinreb amides played an amides played an indispensable role in this reaction. The proposed mechanism involved the key indispensable role in this reaction. The proposed mechanism involved the key intermediate 31, which intermediate 31, which was formed from the addition of trifluoropropynyl lithium with Weinreb was formed from the addition of trifluoropropynyl lithium with Weinreb amides. Then 31 was amides. Then 31 was quenched by H2O to give the ynone intermediate 32, which rapidly reacted with quenched by H2O to give the ynone intermediate 32, which rapidly reacted with N‐methoxy‐N‐ N-methoxy-N-methylamine 33 generated from the reaction to give the products 34. The N-methoxy methylamine 33 generated from the reaction to give the products 34. The N‐methoxy group in group in Weinreb amides was essential because the oxygen could coordinate with the lithium cation to Weinreb amides was essential because the oxygen could coordinate with the lithium cation to stabilize the key intermediate 31. Particularly, the fact that trapping 31 with trimethylsilyl chloride stabilize the key intermediate 31. Particularly, the fact that trapping 31 with trimethylsilyl chloride afforded the corresponding siloxane derivative in a high yield further demonstrated the mechanism. afforded the corresponding siloxane derivative in a high yield further demonstrated the mechanism.

Scheme 9. Addition of Weinreb amides to trifluoropropynyl lithium. Scheme 9. Addition of Weinreb amides to trifluoropropynyl lithium. Soon afterwards, the group of Nielsen reported the insertion of sodium acetylide of ethyl propynoateSoon afterwards,35 into Weinreb the group amides of29 Nielsento produce reported the 1,2-addition the insertion products of sodium37 as theacetylide major productsof ethyl (Schemepropynoate 10 a)35 [into28]. Weinreb The selectivity amides 29 of to the produce 1,2-addition the 1,2 products‐addition 37productsover 1,1-addition 37 as the major products products38 depended(Scheme 10a) on the[28]. R The group selectivity of the Weinreb of the 1,2 amides.‐addition Substrates products with 37 over bigger 1,1 R‐addition substituents products showed 38 higherdepended selectivity on the thanR group those of with the Weinreb smaller ones. amides. For Substrates example, substituentswith bigger suchR substituents as phenyl showed excellenthigher selectivity selectivity, than providing those with the 1,2-additionsmaller ones. adduct For example, as the single substituents product such in high as yield.phenyl However, showed substratesexcellent selectivity, carrying bulky providing substituents the 1,2‐ suchaddition as tert-butyl adduct as or the 2,4-dimethoxyphenyl single product in high did notyield. undergo However, this transformation.substrates carrying Notably, bulky the substituents tertiary enaminones such as tert37‐butylpreferentially or 2,4‐dimethoxyphenyl adopted E-geometry did not in allundergo cases, suggestingthis transformation. the 1,2-addition Notably, reactions the tertiary proceeded enaminones in a highly 37 preferentially trans-selective adopted manner. E‐geometry In addition, in theall βcases,-enaminoketoesters suggesting the 1,237‐wereaddition employed reactions by proceeded the authors in to a reacthighly with trans hydrazines‐selective 39manner.under In microwave addition, irradiationthe β‐enaminoketoesters to construct pyrazoles37 were employed40 through by a the regioselective authors to cyclocondensationreact with hydrazines (Scheme 39 under 10b). Similarly,microwave Choudhury’s irradiation to groupconstruct reported pyrazoles a one-pot 40 through sequential a regioselective process cyclocondensation consisting of nucleophilic (Scheme substitution10b). Similarly, of Choudhury the lithiated′s group acetylides reported with a Weinreb one‐pot sequential amides, and process a following consisting Michael of nucleophilic reaction ofsubstitution the extruded of theN -methoxy-lithiated acetylidesN-methylamine with Weinreb to a carbon–carbon amides, and a triple following bond Michael after quenching reaction of with the extruded N‐methoxy‐N‐methylamine to a carbon–carbon triple bond after quenching with saturated saturated NH4Cl, producing the E-β-enamino ketones 43 as the single geometrical isomer in high yieldsNH4Cl, (Scheme producing 11)[ 29the]. E‐β‐enamino ketones 43 as the single geometrical isomer in high yields (Scheme 11) [29].

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Scheme 10. (a) Insertion of sodium acetylide of ethyl propynoate into Weinreb amides. (b) Synthesis Scheme 10. (a) Insertion of sodium acetylide of ethyl propynoate into Weinreb amides. (b) Synthesis Schemeof pyrazoles 10. ( aemploying) Insertion β‐ ofenaminoketoesters. sodium acetylide of ethyl propynoate into Weinreb amides. (b) Synthesis of pyrazoles employing β-enaminoketoesters. of pyrazoles employing β‐enaminoketoesters.

Scheme 11. One-pot sequential transformation of Weinreb amides to enamino ketones. Scheme 11. One‐pot sequential transformation of Weinreb amides to enamino ketones. Very recently,Scheme 11. Li One and‐pot co-workers sequential reported transformation the addition of Weinreb of amides the amide to enamino bond of ketones. imides 45 to the carbon–carbonVery recently, triple Li bond and co of‐workers alkynones reported44 under the basic addition conditions of the (Schemeamide bond 12)[ of30 imides]. This 45 addition to the carbon–carbon triple bond of alkynones 44 under basic conditions (Scheme 12) [30]. This addition reactionVery proceeded recently, Li smoothly and co‐workers with the reported addition the ofaddition a base of such the amide as K 2bondCO3 ofin imides DMSO 45 at to high the carbon–carbontemperature,reaction proceeded affording triple smoothly bond the of corresponding with alkynones the addition 44 tetra-substituted under of a basebasic such conditions enamidesas K2CO (Scheme3 in46 DMSOin good12) at [30]. high yields. This temperature, Although addition reactionthisaffording transformation proceeded the corresponding smoothly suffered fromwith tetra the unsatisfactory‐ substitutedaddition of a stereoselectivities, baseenamides such as46 K 2COin excellent3 goodin DMSO yields. regioselectivities at high Although temperature, werethis affordingobserved.transformation the The correspondingsuffered acyl group from and unsatisfactorytetra amide‐substituted group stereoselectivities, wereenamides dominantly 46 inexcellent locatedgood yields.regioselectivities at the αAlthough-position were andthis transformationβobserved.-position The of the acyl suffered carbonyl, group andfrom respectively. amide unsatisfactory group Interestingly, were stereoselectivities, dominantly in the located reactions excellent at the of α‐ alkynones positionregioselectivities and47 bearing β‐position were an observed.orthoof the-bromo-substituted carbonyl, The acyl respectively. group aryl and ring,Interestingly,amide highly group functional werein the dominantly reactions chromones of located alkynones48 were at the 47 selectively α‐ bearingposition an formed and ortho β‐position‐ inbromo good‐ oftosubstituted the high carbonyl, yields aryl via respectively.ring, the highlyO-cyclization functional Interestingly, pathway chromones in the (Scheme reactions 48 were 13). selectivelyof Controlalkynones experimentsformed 47 bearing in good showed an toortho high‐ thatbromo yields the‐ substitutedbasevia the played O‐cyclization aryl an importantring, highlypathway role. functional (Scheme It could chromones deprotonate13). Control 48 thewereexperiments imides selectively45 showedto formed form athat nitrogenin goodthe base to anion, high played whichyields an viaundergoesimportant the O‐ cyclizationrole. a Michael-type It could pathway deprotonate addition (Scheme to the the 13). imides alkynones Control 45 to49experiments formto produce a nitrogen showed the anion anion, that intermediate whichthe base undergoes played50. Then an a importantintermediateMichael‐type role.50 addition undergoesIt could to deprotonatethe an alkynones intramolecular the 49 imides to nucleophilic produce 45 to the form addition/ring-opening anion a nitrogen intermediate anion, 50 which sequence. Then intermediateundergoes to provide a Michaelintermediate50 undergoes‐type 52addition .an Hydrolysis intramolecular to the alkynones of intermediate nucleophilic 49 to produce52 generates addition/ring the anion enamides intermediate‐opening46 (X =sequence H),50. Then or imine–enamine intermediateto provide 50intermediate undergoes 52 . anHydrolysis intramolecular of intermediate nucleophilic 52 generates addition/ring enamides‐opening 46 (X = sequenceH), or imine–enamine to provide intermediate 52. Hydrolysis of intermediate 52 generates enamides 46 (X = H), or imine–enamine

Molecules 2018, 23, x FOR PEER REVIEW 7 of 22 Molecules 2019, 24, 164 7 of 22 Molecules 2018, 23, x FOR PEER REVIEW 7 of 22 tautomerization of intermediate 52 followed by nucleophilic aromatic substitution (SNAr) to give the Molecules 2018, 23, x FOR PEER REVIEW 7 of 22 chromones 48 (X = Br) (Scheme 14). tautomerization of intermediate 52 followed by nucleophilic aromatic substitution (SNAr) to give the tautomerization of intermediate 52 followed by nucleophilic aromatic substitution (SNAr) to give the tautomerizationchromoneschromones 4848 (X(X of == intermediate Br) (Scheme(Scheme 14 14).52). followed by nucleophilic aromatic substitution (SNAr) to give the chromones 48 (X = Br) (Scheme 14).

Scheme 12. Addition of imides to alkynones promoted by K2CO3 to synthesize enamides.

Scheme 12. Addition of imides to alkynones promoted by K2CO3 to synthesize enamides. Scheme 12. Scheme 12. Addition of imides to alkynones promoted by K22CO3 toto synthesize synthesize enamides. enamides.

Scheme 13. Addition of imides to alkynones promoted by K2CO3 to synthesize chromones. Scheme 13. Addition of imides to alkynones promoted by K2CO3 to synthesize chromones. Scheme 13. Addition of imides to alkynones promoted by K2CO3 to synthesize chromones. Scheme 13. Addition of imides to alkynones promoted by K2CO3 to synthesize chromones.

Scheme 14. Proposed catalytic cycle for the addition of imides to alkynones promoted by K 2CO3. Scheme 14. Proposed catalytic cycle for the addition of imides to alkynones promoted by K2CO3.

Soon afterwards, Li and co-workers presented the insertion of alkynones 53 into the amide bond Scheme 14. Proposed catalytic cycle for the addition of imides to alkynones promoted by K2CO3. of amideScheme54 promoted 14. Proposed by Cs catalytic2CO3 (Scheme cycle for 15the), addition providing of imides the functionalized to alkynones promoted enaminones by K552COwith3. high

Molecules 2018, 23, x FOR PEER REVIEW 8 of 22 Molecules 2018, 23, x FOR PEER REVIEW 8 of 22 Molecules 2019, 24, 164 8 of 22 Soon afterwards, Li and co‐workers presented the insertion of alkynones 53 into the amide bond of amideSoon 54 afterwards, promoted Liby and Cs2 COco‐3workers (Scheme presented 15), providing the insertion the functionalized of alkynones enaminones 53 into the 55amide with bond high of amide 54 promoted by Cs2CO3 (Scheme 15), providing the functionalized enaminones 55 with high stereoselectivity andand excellentexcellent regioselectivityregioselectivity [ [31].31]. ItIt shouldshould bebe notednoted thatthat thethe combinationcombination of of Cs Cs22COCO33 stereoselectivity and excellent regioselectivity [31]. It should be noted that the combination of Cs2CO3 and 1,10 1,10-phenanthroline‐phenanthroline hydrate hydrate (Phen (Phen∙H·H2O)2O) is isessential essential to obtain to obtain good good yields yields in a inshort a short reaction reaction time. andThetime. 1,10authors The‐phenanthroline authors hypothesized hypothesized hydrate that 1,10 (Phen that‐phenanthroline 1,10-phenanthroline∙H2O) is essential hydrate to obtain hydrate may good act may as yields a act metal as in a ion short metal chelator, reaction ion chelator, which time. The authors hypothesized that 1,10‐phenanthroline hydrate may act as a metal ion chelator, which whichincreased increased the basicity the basicity of Cs2 ofCO Cs3 2toCO accelerate3 to accelerate the reaction. the reaction. Similarly, Similarly, 3‐carbonyl 3-carbonyl-4-quinolinones‐4‐quinolinones 58 increasedwere58 were selectively selectively the basicity formed formed of via Cs a2 viaCO subsequent3 a to subsequent accelerate N‐cyclization theN-cyclization reaction. pathway Similarly, pathway in the 3cases in‐carbonyl the of cases alkynones‐4‐ ofquinolinones alkynones 56 bearing 5856 wereanbearing ortho selectively‐ anbromoortho‐ substitutedformed-bromo-substituted via aaryl subsequent ring aryl(Scheme N ring‐cyclization 16). (Scheme The pathwayproposed 16). The in reaction proposed the cases mechanism of reaction alkynones mechanismis outlined 56 bearing in is anSchemeoutlined ortho ‐17.bromo in SchemeThe‐ Michaelsubstituted 17. The‐type Michael-type aryl addition ring (Scheme of addition amides 16). 57 of The amidesto alkynones proposed57 to alkynones 59reaction under mechanismbasic59 under conditions basic is outlined conditions yields anin Schemeyieldsallenol an intermediate 17. allenol The Michael intermediate 60. ‐Thetype subsequent addition60. The subsequent of intramolecular amides 57 intramolecular to alkynones nucleophilic nucleophilic59 under addition basic additiongives conditions a highly gives yields areactive highly an allenolcyclobutenolreactive intermediate cyclobutenol intermediate 60 intermediate. The 61 subsequent, which61 undergoes, which intramolecular undergoes ring opening nucleophilic ring to opening produce addition to a produce formal gives aalkyne a highly formal insertion reactive alkyne cyclobutenolintermediateinsertion intermediate intermediate62. Then62 .intermediate Then 61, which intermediate undergoes 62 undergoes62 undergoes ring openingimine imine-enamine‐enamine to produce tautomerization tautomerization a formal alkyne to to insertionprovide intermediate 62. Then intermediate 62 undergoes imine‐enamine tautomerization to provide intermediate 6363, which, which undergoes undergoes a nucleophilic a nucleophilic aromatic aromatic substitution substitution (SNAr) to (S affordNAr) theto quinolinoneafford the intermediateproductsquinolinone64 (Y products63 =, Br). which In 64 contrast, (Yundergoes = Br). the In protonation contrast,a nucleophilic the of protonation intermediate aromatic of62substitution intermediateor 63 leads (S to 62N theAr) or formation 63to leadsafford to of the quinolinoneformationenaminone of products productsthe enaminone65 64(Y (Y = =products H). Br). In contrast, 65 (Y = H). the protonation of intermediate 62 or 63 leads to the formation of the enaminone products 65 (Y = H).

Scheme 15. Insertion of alkynones into amides to synthesize enaminones promoted by Cs2CO3. Scheme 15. Insertion of alkynones into amides to synthesize enaminones promoted by Cs2CO3. Scheme 15. Insertion of alkynones into amides to synthesize enaminones promoted by Cs2CO3.

Scheme 16. Insertion of alkynones intointo amides toto synthesizesynthesize quinolinonesquinolinones promotedpromoted byby CsCs22CO3.. Scheme 16. Insertion of alkynones into amides to synthesize quinolinones promoted by Cs2CO3.

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O O R 4 O R4 R3 N N R1 R3 R2 Cs CO O R Y 2 3 2 O R 59 2 + Y Y O R 4 R1 R1 R3 N H 60 61 57

R4 R3 N R1 R O R2 Y 1 R4 Y R4 Y=Br N O N O R2 O R2 R1 R3 O 62 R3 O 63 64

Y=H

R4 R3 HN

O R2 O

65 R1

SchemeScheme 17. 17.Proposed Proposed reaction reaction mechanism mechanism for thefor insertionthe insertion of alkynones of alkynones into amidesinto amides promoted promoted by Cs by2CO 3.

Cs2CO3. 2.3. Transition-Metal-Catalyzed Addition of Amide Bonds to Alkynes 2.3. TransitionIn 2004, Yamamoto’s‐Metal‐Catalyzed group Addition reported of Amide the platinum Bonds to catalyzed Alkynes synthesis of highly functional indoles through an intramolecular amide C–N bond addition to alkynes with the [1,3]-migration of acyl groups In 2004, Yamamoto′s group reported the platinum catalyzed synthesis of highly functional (Scheme 18)[32]. PtCl showed the highest catalytic activity compared with other platinum catalysts indoles through an intramolecular2 amide C–N bond addition to alkynes with the [1,3]‐migration of such as PtCl2(CH3CN)2, PtBr2, and Pt(PPh3)4. Various ortho-alkynylanilides 66 bearing diverse alkyl acyl groups (Scheme 18) [32]. PtCl2 showed the highest catalytic activity compared with other or aryl groups at R1 could be converted into the corresponding indole products 67 with good to high platinum catalysts such as PtCl2(CH3CN)2, PtBr2, and Pt(PPh3)4. Various ortho‐alkynylanilides 66 yields with PtCl2. Notably, a variety of acyl groups could undergo intramolecular [1,3]-migration bearing diverse alkyl or aryl groups at R1 could be converted into the corresponding indole products to give 3-acyl-indoles 67. The main drawback of this method is that the desired products 67 are 67 with good to high yields with PtCl2. Notably, a variety of acyl groups could undergo 68 intramoleculartogether with deacylated[1,3]‐migration byproducts to give 3‐acylin most‐indoles cases. 67. BasedThe main on thedrawback results of deuterium-labelingthis method is that theexperiments desired products and crossover 67 are experiments, together with the deacylated authors proposed byproducts a catalytic 68 in cyclemost of cases. this intramolecular Based on the resultsaminoacylation of deuterium of alkynes.‐labeling As shownexperiments in Scheme and 19 crossover, coordination experiments, of alkyne moietythe authors to PtCl proposed2 yields the a π 69 catalytic-complex cycle ,of followed this intramolecular by nucleophilic aminoacylation attack of nitrogen of alkynes. to the As shown alkyne, in affording Scheme 19, the coordination zwitterionic intermediate 70. An intramolecular [1,3]-migration of the acyl group then gives intermediate 71, which of alkyne moiety to PtCl2 yields the π‐complex 69, followed by nucleophilic attack of nitrogen to the 68 alkyne,affords theaffording product the and zwitterionic regenerates intermediate the catalyst. The70. 3-deacylatedAn intramolecular byproducts [1,3]‐migrationmay attribute of the to acyl the 70 groupdeacylation then gives which intermediate takes place through 71, which the affords protonolysis the product of the C–Pt and bondregenerates of intermediate the catalyst.. The 3‐ deacylated byproducts 68 may attribute to the deacylation which takes place through the protonolysis of the C–Pt bond of intermediate 70.

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Scheme 18. PtCl2‐catalyzed intramolecular aminoacylation of alkynes. Scheme 18. PtCl2-catalyzed intramolecular aminoacylation of alkynes. Scheme 18. PtCl2‐catalyzed intramolecular aminoacylation of alkynes.

Scheme 19. Proposed catalytic cycle of PtCl2-catalyzed intramolecular aminoacylation of alkynes. Scheme 19. Proposed catalytic cycle of PtCl2‐catalyzed intramolecular aminoacylation of alkynes.

EncouragedScheme 19. Proposed by the catalytic excellent cycle catalytic of PtCl2‐catalyzed performance intramolecular of platinum aminoacylation catalysts of alkynes. towards the intramolecularEncouraged aminoacylation by the excellent of alkynes, catalytic Nakamura’s performance group of platinum further studied catalysts similar towards reactions the intramolecularusingEncouragedortho-alkynylphenylureas aminoacylation by the excellent of or alkynes,ortho catalytic-alkynylphenyl Nakamura performance′s group carbamates furtherof platinum asstudied substrates catalysts similar (Scheme reactions towards 20 using)[ 33the]. Theorthointramolecular reactions‐alkynylphenylureas of aminoacylationortho-alkynylphenylureas or ortho of alkynes,‐alkynylphenyl72 Nakamurahaving carbamates a′ carbamoyls group further as group substrates studied attached (Schemesimilar to the reactions nitrogen20) [33]. using atom The reactionsortho‐alkynylphenylureas of ortho‐alkynylphenylureas or ortho‐alkynylphenyl 72 having a carbamatescarbamoyl groupas substrates attached (Scheme to the nitrogen 20) [33]. atom The proceeded successfully under the catalysis of PtI4, providing the desired indole-3-carbamides 73 in proceededmoderatereactions of to successfully highortho‐ yieldsalkynylphenylureas alongunder with the catalysis the 3-protonated72 having of PtI 4a, providingcarbamoyl byproducts the group68 desired. Interestingly, attached indole to‐ortho3 the‐carbamides -alkynylphenylnitrogen atom73 in moderatecarbamatesproceeded tosuccessfully74 highcould yields be under converted along the catalysis intowith the the of corresponding PtI3‐protonated4, providing indole-3-carboxylates byproductsthe desired indole68. Interestingly,‐3‐75carbamidesin good yields ortho73 in‐ withoutalkynylphenylmoderate the to generation highcarbamates yields of 3-protonated 74 along could bewith converted byproducts the 3‐ protonatedinto76. the The corresponding authors byproducts proposed indole 68 a. similar‐Interestingly,3‐carboxylates mechanism ortho 75 in to‐ goodthatalkynylphenyl of yields Yamamoto’s without carbamates group the generation [ 3274]. could They beof assumed 3converted‐protonated the generationinto byproducts the corresponding of the 76 3-protonated. The authorsindole‐ byproducts3 proposed‐carboxylates a68 similarin 75 the in mechanismreactionsgood yields of orthotowithout that-alkynylphenylureas of the Yamamoto’s generation ofgroup72 3may‐protonated [32]. be attributed They byproducts assumed to protodemetalation the76. Thegeneration authors ofof proposed intermediate the 3‐protonated a similar78 by byproductsamechanism proton from 68to the inthat the methyl ofreactions Yamamoto’s moiety of ortho of intermediategroup‐alkynylphenylureas [32]. They79, which assumed 72 was may extruded the be generationattributed in the to reactionof protodemetalation the 3 (Scheme‐protonated 21). ofNotably,byproducts intermediate this 68 work in 78 the by proved reactions a proton that offrom amide ortho the‐alkynylphenylureas and methyl ester moiety groups of could intermediate 72 may be used be attributed 79 as, the which migrating to was protodemetalation extruded groups, in thus the reactionof intermediate (Scheme 78 21). by aNotably, proton from this thework methyl proved moiety that amideof intermediate and ester 79 groups, which could was extruded be used asin the migratingreaction (Scheme groups, 21). Notably,thus providingthis work provedan thatefficient amide methodand ester groupsto synthesize could be usedindole as the‐3‐ migrating groups, thus providing an efficient method to synthesize indole‐3‐

Molecules 2019, 24, 164 11 of 22 Molecules 2018, 23, x FOR PEER REVIEW 11 of 22 Molecules 2018,, 23,, x FOR PEER REVIEW 11 of 22 providingcarbamides/carboxylates an efficient method which to could synthesize not be indole-3-carbamides/carboxylates prepared via Friedel–Crafts electrophilic which could substitution not be carbamides/carboxylates which could not be prepared via Friedel–Crafts electrophilic substitution preparedinto the C3 via‐position Friedel–Crafts of the indole electrophilic ring. substitution into the C3-position of the indole ring. into the C3‐position of the indole ring.

Scheme 20. Platinum‐catalyzed intramolecular carboamination. Scheme 20. PlatinumPlatinum-catalyzed‐catalyzed intramolecular carboamination.

Scheme 21. Proposed pathway for the generation of 3-protonated byproducts. Scheme 21. Proposed pathway for the generation of 3‐protonated byproducts. Scheme 21. Proposed pathway for the generation of 3‐protonated byproducts. In 2007, Nakamura’s group revealed that PdBr2 could also catalyze the intramolecular amide In 2007, Nakamura’s group revealed that PdBr2 could also catalyze the intramolecular amide C– In 2007, Nakamura’s group revealed that PdBr2 could also catalyze the intramolecular amide C– C–NIn bond 2007, addition Nakamura’s to alkynes group (Scheme revealed 22 that), affording PdBr2 could the indole also catalyze adduct the82 fromintramolecularortho-alkynylanilide amide C– N bond addition to alkynes (Scheme 22), affording the indole adduct 82 from ortho‐alkynylanilide 81 N81 bondin 52% addition yield [ 34to]. alkynes Encouraged (Scheme by 22), the catalyticaffording performance the indole adduct of PdBr 822 fromtowards ortho the‐alkynylanilide intramolecular 81 in 52% yield [34]. Encouraged by the catalytic performance of PdBr2 towards the intramolecular in 52% yield [34]. Encouraged by the catalytic performance of PdBr2 towards the intramolecular inaminoacylation 52% yield [34]. of alkynes,Encouraged Liu’s by group the furthercatalytic screened performance a series of of PdBr palladium2 towards complexes. the intramolecular They found aminoacylation of alkynes, Liu′s group further screened a series of palladium complexes. They found aminoacylationthat PdCl2(CH 3ofCN) alkynes,2 showed Liu′s excellentgroup further catalytic screened activity a series (Scheme of palladium 23)[35 complexes.]. Substrates They83 foundwith that PdCl2(CH3CN)2 showed excellent catalytic activity (Scheme 23) [35]. Substrates 83 with alkyl/aryl that PdCl2(CH3CN)2 showed excellent catalytic activity (Scheme 23) [35]. Substrates 83 with alkyl/aryl thatalkyl/aryl PdCl2(CH groups3CN)2 at showed R1 furnished excellent the catalytic corresponding activity (Scheme products 23) [35].84 in Substrates good to 83 excellent with alkyl/aryl yields. groups at R1 furnished the corresponding products 84 in good to excellent yields. The protocol was groups at R1 furnished the corresponding products 84 in good to excellent yields. The protocol was Thegroups protocol at R1 furnished was also compatible the corresponding with substrates products83 84bearing in good electron-donating to excellent yields. substituents, The protocol halides, was also compatible with substrates 83 bearing electron‐donating substituents, halides, and electron‐ alsoand electron-withdrawingcompatible with substrates substituents 83 bearing at R2, whichelectron produced‐donating the substituents, corresponding halides, products and 84electronin high‐ withdrawing substituents at R2, which produced the corresponding products 84 in high yields. In withdrawing substituents at R2, which produced the corresponding products 84 in high yields. In yields.withdrawing In addition, substituents the reactions at R2, ofwhich substrates produced83 with the different corresponding alkyl substituents products 84 at Rin3 highalso tookyields. place In addition, the reactions of substrates 83 with different alkyl substituents at R3 also took place smoothly, addition, the reactions of substrates 83 with different alkyl substituents at R3 also took place smoothly, addition,smoothly, the providing reactions the of desired substrates products 83 with84 differentin high yields. alkyl substituents More importantly, at R3 also various took place acyl and smoothly, amide providing the desired products 84 in high yields. More importantly, various acyl and amide groups providinggroups could the migratedesired smoothlyproducts 84 and in be high conveniently yields. More introduced importantly, at the various C3-position acyl and of indoles. amide groups could migrate smoothly and be conveniently introduced at the C3‐position of indoles. could migrate smoothly and be conveniently introduced at the C3‐position of indoles.

Scheme 22. PdBr2‐catalyzed intramolecular aminoacylation of alkynes. Scheme 22. PdBr2‐-catalyzedcatalyzed intramolecular intramolecular aminoacylation aminoacylation of of alkynes. alkynes. Scheme 22. PdBr2‐catalyzed intramolecular aminoacylation of alkynes.

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O R1 R4 PdCl2(CH3CN)2 (5 mol%) O R R R 2 CH CN or toluene 2 1 N R 3 N 4 o 90-110 C, 8 h R R3 3 83 84, 26-99%

O O O O H H H O

N N N N Bn 99% 97% 93% 85%

O O O O H Bn N

N N N N

26% 80% 84% 32% Scheme 23. PdCl2(CH3CN)2-catalyzed intramolecular aminoacylation of alkynes. Scheme 23. PdCl2(CH3CN)2‐catalyzed intramolecular aminoacylation of alkynes. Subsequently, Liu and coworkers further extended their palladium catalytic system to the synthesisSubsequently, of 3-diketoindoles Liu and coworkers86 from ortho further-alkynyl- extendedN-α-ketoacylanilines their palladium85 catalyticvia the intramolecularsystem to the amidesynthesis bond of addition3‐diketoindoles to alkynes 86 (Schemefrom ortho 24)[‐alkynyl36]. Notably,‐N‐α‐ketoacylanilines this addition reaction 85 via proceeded the intramolecular smoothly toamide give bond the high addition functional to alkynes 3-diketoindoles (Scheme 24) 86[36].with Notably, the [1, this3]-migration addition reaction of α-ketoacyl proceeded groups, smoothly which wereto give used the ashigh migrating functional groups 3‐diketoindoles for the first 86 time. with the Compared [1,3]‐migration with previously of α‐ketoacyl reported groups, protocols which weresuch asused Friedel–Crafts as migrating acylation groups for [37 the], Glyoxylation/Stephens–Castro first time. Compared with previously coupling reported sequence protocols [38], and such the as Friedel–Crafts acylation [37], Glyoxylation/Stephens–Castro coupling sequence [38], and the oxidative cross-coupling of indoles [39–41], which achieved the synthesis of 3-diketoindoles through oxidative cross‐coupling of indoles [39–41], which achieved the synthesis of 3‐diketoindoles through the modification of the indole ring, but suffered from poor selectivity, operational complexity, the the modification of the indole ring, but suffered from poor selectivity, operational complexity, the requirement of strict exclusion of moisture, limited substrate scope and low atom economy, this new requirement of strict exclusion of moisture, limited substrate scope and low atom economy, this new method successfully prepared 3-diketoindoles via the construction of an indole ring with valuable method successfully prepared 3‐diketoindoles via the construction of an indole ring with valuable features such as operational simplicity, high atom economy, broad substrate scope and high yields. features such as operational simplicity, high atom economy, broad substrate scope and high yields. Interestingly, a 3-diketoindole dimer 88 was synthesized in a high yield when substrate 87 was Interestingly, a 3‐diketoindole dimer 88 was synthesized in a high yield when substrate 87 was subjected to the optimal reaction conditions (Scheme 25). Finally, the authors proposed a reaction subjected to the optimal reaction conditions (Scheme 25). Finally, the authors proposed a reaction mechanism which is similar to that proposed by Yamamoto’s group [32]. mechanism which is similar to that proposed by Yamamoto′s group [32].

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Scheme 24. PdCl2(CH3CN)2‐catalyzed synthesis of 3‐diketoindoles via the intramolecular amide bond Scheme 24. PdCl2(CH3CN)2-catalyzed synthesis of 3-diketoindoles via the intramolecular amide bond Schemeaddition 24.to alkynes.PdCl2(CH 3CN)2‐catalyzed synthesis of 3‐diketoindoles via the intramolecular amide bond addition to alkynes. addition to alkynes.

Scheme 25. PdCl2(CH3CN)2-catalyzed synthesis of 3-diketoindole dimer via the intramolecular amide Scheme 25. PdCl2(CH3CN)2‐catalyzed synthesis of 3‐diketoindole dimer via the intramolecular amide bond addition to alkynes. bondScheme addition 25. PdCl to 2alkynes.(CH3CN) 2‐catalyzed synthesis of 3‐diketoindole dimer via the intramolecular amide Rutheniumbond addition complexes to alkynes. were also found to be efficient catalysts for the intramolecular amide bond additionRuthenium to alkynes, complexes as was reported were also by found Li’s group to be in efficient 2012 (Scheme catalysts 26)[ for42 ].the Their intramolecular study showed amide that bond addition to alkynes, as was reported by Li′s group in 2012 (Scheme 26) [42]. Their study showed [RuClRuthenium2(p-cym)]2 complexesdisplayed thewere highest also found catalytic to activity,be efficient with catalysts which ortho for the-alkynylanilides intramolecular83 amidecould undergobondthat [RuCl addition intramolecular2(p‐ cym)]to alkynes,2 displayed annulation as was the reported throughhighest by amide catalyticLi′s group bond activity, in addition 2012 (Schemewith to thewhich 26) alkyne [42].ortho moiety Their‐alkynylanilides study to synthesize showed 83 highlycouldthat [RuCl undergo functional2(p‐cym)] intramolecular indoles2 displayed84. A annulationthe variety highest of substratesthrough catalytic amide 83activity,carrying bond with diverseaddition which functional toortho the‐alkynylanilides alkyne groups moiety such 83 asto olefin,couldsynthesize undergo ester, highly aldehyde intramolecular functional were indoles well annulation tolerated 84. A variety through and could of substratesamide be converted bond 83 carryingaddition into thediverse to correspondingthe functionalalkyne moiety groups indole to productssuchsynthesize as olefin,84 highlyin ester, moderate functional aldehyde to highindoles were yields. 84well. A Despitevarietytolerated of the andsubstrates fact could that 83be a longer carryingconverted reaction diverse into timethe functional corresponding was required groups comparedindolesuch as products olefin, with platinumester, 84 in aldehyde moderate or palladium were to highwell catalytic toleratedyields. systems, Despite and it could is the worth factbe notingconverted that a that longer into no 3-deacylated thereaction corresponding time indoles was wererequiredindole observed products compared in 84 all in examples.with moderate platinum However, to orhigh palladium theyields. main Despite shortcomingcatalytic the systems, fact of thisthat it method ais longerworth is thatreactionnoting unsatisfactory thattime no was 3‐ yieldsrequireddeacylated were compared indoles obtained were with when observed platinum bigger acylin orall groups palladiumexamples. such However,catalytic as acetyl were systems,the main employed itshortcoming is worth as the noting migrating of this thatmethod groups. no 3is‐ Basedthatdeacylated unsatisfactory on the indoles mechanistic wereyields observed study were results obtained in all with examples. when deuterium-labeling bigger However, acyl groups the experiments, main such shortcoming as acetyl the authors were of this hypothesizedemployed method asis thatthe migrating theunsatisfactory reaction groups. mechanism yields Based were may on obtainedthe involve mechanistic when the complexation bigger study acylresults ofgroups substrateswith suchdeuterium withas acetyl ruthenium‐labeling were experiments,employed catalyst, the as subsequentthe migratingauthors oxidativehypothesized groups. additionBased that on the of the ruthenium reaction mechanistic mechanism catalyst study across results may theinvolve with amide deuterium the bond, complexation the‐labeling following experiments,of substrates addition ofthewith the authors ruthenium N–Ru hypothesized bond catalyst, to carbon–carbon the that subsequent the reaction triple oxidative bonds, mechanism and addition the may final ofinvolve reductiveruthenium the complexation elimination catalyst across to of produce thesubstrates amide the productsbond,with ruthenium the and following regenerate catalyst, addition the the catalyst ofsubsequent the N–Ru (Scheme bondoxidative 27 to). carbon–carbon addition of ruthenium triple bonds, catalyst and the across final the reductive amide eliminationbond, the following to produce addition the products of the N–Ru and regeneratebond to carbon–carbon the catalyst (Scheme triple bonds, 27). and the final reductive elimination to produce the products and regenerate the catalyst (Scheme 27).

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Scheme 26. [RuCl2(p‐cym)]2 catalyzed intramolecular aminoacylation of alkynes. Scheme 26. [RuCl2(p-cym)]2 catalyzed intramolecular aminoacylation of alkynes. Scheme 26. [RuCl2(p‐cym)]2 catalyzed intramolecular aminoacylation of alkynes.

Scheme 27. Possible mechanism of [RuCl2(p-cym)]2 catalyzed intramolecular aminoacylation of alkynes. Scheme 27. Possible mechanism of [RuCl2(p‐cym)]2 catalyzed intramolecular aminoacylation of

2.4. AdditionSchemealkynes. of 27. Amide Possible Bonds mechanism to Alkynes of through [RuCl2( Organocatalysisp‐cym)]2 catalyzed intramolecular aminoacylation of alkynes. 2.4.In Addition addition of Amide to the Bonds metal-catalyzed to Alkynes through processes, Organocatalysis methods utilizing organocatalysis, which feature advantages2.4. Addition such of Amide as low Bonds cost, to environmentalAlkynes through Organocatalysis economy, and the avoidance of metal contamination, have alsoIn addition been developed to the metal in recent‐catalyzed years. processes, What seems methods particularly utilizing interesting organocatalysis, is the which insertion feature of an electron-deficientadvantagesIn addition such to alkyneas the low metal 5cost,into‐ catalyzedenvironmental the amide processes, bond economy, of methods an acyl-onio and utilizing the avoidance salt organocatalysis,92 (Scheme of metal 28 ),contamination, which as reported feature by have also been developed in recent years. What seems particularly interesting is the insertion of an Weissadvantages and Huber such [ 43as ].low This cost, reaction environmental could be achievedeconomy, in and the the presence avoidance of a catalyticof metal amountcontamination, of small haveelectron also‐deficient been developed alkyne 5 in into recent the amideyears. Whatbond seemsof an acyl particularly‐onio salt interesting 92 (Scheme is 28),the insertionas reported of anby organic molecules such as PPh3 or DMAP, providing the desired β-oniovinylation products 93 in Weiss and Huber [43]. This reaction could be achieved in the presence of a catalytic amount of small goodelectron yields.‐deficient The stereochemistry alkyne 5 into the of thisamide process bond dependsof an acyl on‐onio the reactionsalt 92 (Scheme conditions, 28), as preferentially reported byE - Weissorganic and molecules Huber [43]. such This as PPhreaction3 or DMAP,could be providing achieved inthe the desired presence β‐oniovinylation of a catalytic amount products of small93 in or Z-stereochemistry was observed, and the Z-isomer is the thermodynamically more stable isomer. organicgood yields. molecules The stereochemistry such as PPh3 orof thisDMAP, process providing depends the on desired the reaction β‐oniovinylation conditions, preferentially products 93 Ein‐ More importantly, the onio substituent in the products 93 could be selectively replaced by a number goodor Z‐stereochemistry yields. The stereochemistry was observed, of this and process the Z‐isomer depends is the on thethermodynamically reaction conditions, more preferentially stable isomer. E‐ of nucleophiles, such as anilines, phenols, and thiophenols, to prepare Michael systems with donor or Z‐stereochemistry was observed, and the Z‐isomer is the thermodynamically more stable isomer.

Molecules 2018, 23, x FOR PEER REVIEW 15 of 22 Molecules 2018, 23, x FOR PEER REVIEW 15 of 22 Molecules 2019, 24, 164 15 of 22 More importantly, the onio substituent in the products 93 could be selectively replaced by a number Moreof nucleophiles, importantly, such the as onio anilines, substituent phenols, in the and products thiophenols, 93 could to prepare be selectively Michael replaced systems by with a number donor functionsoffunctions nucleophiles, in in the theβ β‐such-position,position, as anilines, whichwhich phenols, couldcould bebe and furtherfurther thiophenols, converted to prepareinto into quinolones, quinolones, Michael thiochromones,systems thiochromones, with donor and and pyrazolesfunctionspyrazoles by inby intramolecular the β‐intramolecularposition, cyclization. which cyclization. could The be authorsfurtherThe authors proposedconverted proposed ainto catalytic quinolones, a cycle catalytic for thiochromones, this cycle organocatalytic for andthis pyrazoles by intramolecular cyclization. The authors proposed a catalytic cycle for this process.organocatalytic Taking process. the transformation Taking the transformation catalyzed by PPhcatalyzed3 as the by examplePPh3 as the (Scheme example 29 (Scheme), the conjugate 29), the organocatalytic process. Taking the transformation catalyzed by PPh3 as the example (Scheme 29), the additionconjugate of PPhaddition3 to alkyne of PPh53 toproduces alkyne 5 the produces zwitterionic the zwitterionic intermediate intermediate94, which attacks 94, which the electrophilicattacks the carbonylconjugateelectrophilic center addition carbonyl of 92 ofto PPh provide center3 to alkyne intermediate of 592 produces to 95providewith the zwitterionic liberation intermediate of intermediate 4-dimethylaminopyridine 95 with 94 , liberationwhich attacks (DMAP).of the4‐ Thenelectrophilicdimethylaminopyridine intermediate carbonyl95 reacts (DMAP).center with of Then the 92 liberated intermediateto provide DMAP 95 intermediatereacts to give with the the products95 liberated with 93DMAPliberationand to regenerates giveof the4‐ dimethylaminopyridine (DMAP). Then intermediate 95 reacts with the liberated DMAP to give the theproducts catalyst. 93 and regenerates the catalyst. products 93 and regenerates the catalyst.

Scheme 28. The addition of amide bonds of acyl‐onio salts to alkynes through PPh3 or 4‐ Scheme 28. The addition of amide bonds of acyl-onio salts to alkynes through PPh3 or Schemedimethylaminopyridine 28. The addition (DMAP) of amide organocatalysis. bonds of acyl‐onio salts to alkynes through PPh3 or 4‐ 4-dimethylaminopyridine (DMAP) organocatalysis. dimethylaminopyridine (DMAP) organocatalysis.

SchemeScheme 29. 29.Proposed Proposed catalytic catalytic cyclecycle forfor the addition of amide bond bond of of acyl acyl-onio‐onio salts salts to to alkynes. alkynes. Scheme 29. Proposed catalytic cycle for the addition of amide bond of acyl‐onio salts to alkynes. Recently,Recently, Doi’s Doi′s group group reported reported an an exampleexample of amide addition to to alkynes alkynes through through tertiary tertiary amine amine organocatalysisorganocatalysisRecently, Doi (Scheme (Scheme′s group 3030) reported)[ [44].44]. TheyThey an example foundfound that of amide o‐-alkynoylanilinealkynoylaniline addition to alkynes derivatives derivatives through 9696 could tertiarycould undergo undergo amine intramolecularorganocatalysisintramolecular aminoacylation aminoacylation (Scheme 30) [44]. ofof the theThey carbon–carboncarbon–carbon found that o ‐triple alkynoylaniline bonds bonds successfully successfully derivatives under under 96 couldthe the catalysis catalysis undergo of of 9-azajulolidineintramolecular9‐azajulolidine (9-AJ) aminoacylation(9‐AJ) to to afford afford the theof 3-acyl-4-quinolinones the3‐acyl carbon–carbon‐4‐quinolinones triple 97 bondsinin moderate moderate successfully to to good good under yields yields the with with catalysis excellent excellent of regioselectivity.9regioselectivity.‐azajulolidine (9 Notably,Notably,‐AJ) to afford aa varietyvariety the 3‐ acyl of acyl‐4‐quinolinones groups including 97 in moderate ester ester groups groups to good could could yields act act with as as migrating excellent migrating groupsregioselectivity.groups to to be be transferred transferred Notably, to to a the the variety C3-positon C3‐positon of acyl of groups the quinolinones. including esterParticularly, Particularly, groups thecould the synthesis synthesis act as ofmigrating of pyrrolyl pyrrolyl 4-quinolinonegroups to be transferred alkaloid, quinolactacide, to the C3‐positon and of its the analogues quinolinones. were Particularly, successfully the achieved synthesis by of the pyrrolyl authors employing this organocatalytic process. Finally, a plausible reaction mechanism was outlined in

Molecules 2018, 23, x FOR PEER REVIEW 16 of 22 MoleculesMolecules2019 2018, 24, 23, 164, x FOR PEER REVIEW 16 16of of22 22 4‐quinolinone alkaloid, quinolactacide, and its analogues were successfully achieved by the authors 4‐quinolinone alkaloid, quinolactacide, and its analogues were successfully achieved by the authors employing this organocatalytic process. Finally, a plausible reaction mechanism was outlined in Schemeemploying 31. 1,4-addition this organocatalytic of 9-AJ to process. substrates Finally,96 takes a plausible place at reaction first, and mechanism the subsequent was nucleophilicoutlined in Scheme 31. 1,4‐addition of 9‐AJ to substrates 96 takes place at first, and the subsequent nucleophilic attackScheme of the 31. resulting1,4‐addition anion of to9‐AJ the to acyl substrates group provides 96 takes place intermediate at first, 98and, which the subsequent could be converted nucleophilic into attack of the resulting anion to the acyl group provides intermediate 98, which could be converted theattack intermediate of the resulting99. Then anion the acylto the group acyl ingroup allenolate provides99 couldintermediate be transferred 98, which to thecould C3-position, be converted thus into the intermediate 99. Then the acyl group in allenolate 99 could be transferred to the C3‐position, leadinginto the to intermediate the formation 99 of. Then enone the100 acyl, which group undergoes in allenolate 6-endo 99 could cyclization be transferred to provide to the the C3 products‐position,97 thus leading to the formation of enone 100, which undergoes 6‐endo cyclization to provide the withthus the leading regeneration to the formation of 9-AJ. of enone 100, which undergoes 6‐endo cyclization to provide the products 97 with the regeneration of 9‐AJ. products 97 with the regeneration of 9‐AJ.

Scheme 30. The 9‐azajulolidine‐catalyzed intramolecular amide addition to alkynes. SchemeScheme 30. 30.The The 9-azajulolidine-catalyzed 9‐azajulolidine‐catalyzed intramolecular amide amide addition addition to to alkynes. alkynes.

Scheme 31. SchemeProposed 31. Proposed mechanism mechanism for the for 9-azajulolidine-catalyzed the 9‐azajulolidine‐catalyzed intramolecular intramolecular amide amide addition addition to alkynes. to Scheme 31. Proposed mechanism for the 9‐azajulolidine‐catalyzed intramolecular amide addition to alkynes. 3. Transition-Metal-Catalyzedalkynes. Addition of Sulfonamide Bonds to Alkynes 3. TransitionThe group‐Metal of Nakamura‐Catalyzed reported Addition the of first Sulfonamide example of Bonds the addition to Alkynes of sulfonamides to alkynes in 3. Transition‐Metal‐Catalyzed Addition of Sulfonamide Bonds to Alkynes 2007. As shown in Scheme 32, ortho-alkynyl-N-sulfonylanilines 101 could undergo the intramolecular The group of Nakamura reported the first example of the addition of sulfonamides to alkynes aminosulfonylationThe group of Nakamura of carbon–carbon reported triplethe first bonds example successfully of the addition under of the sulfonamides catalysis of to AuBralkynesto in 2007. As shown in Scheme 32, ortho‐alkynyl‐N‐sulfonylanilines 101 could undergo the3 givein the2007. 3-sulfonylindoles As shown in Scheme102 in good 32, toortho high‐alkynyl yields‐N [‐45sulfonylanilines,46]. Although 101 small could amounts undergo of 4- the and intramolecular aminosulfonylation of carbon–carbon triple bonds successfully under the catalysis of 6-sulfonylindolesintramolecular aminosulfonylation were obtained as the of byproducts carbon–carbon in some triple examples, bonds successfully this process under provides the catalysis a facile andof AuBr3 to give the 3‐sulfonylindoles 102 in good to high yields [45,46]. Although small amounts of 4‐ AuBr3 to give the 3‐sulfonylindoles 102 in good to high yields [45,46]. Although small amounts of 4‐ efficientand 6‐sulfonylindoles method for the were synthesis obtained of 3-sulfonylindoles, as the byproducts which in some cannot examples, be synthesized this process directly provides from thea and 6‐sulfonylindoles were obtained as the byproducts in some examples, this process provides a corresponding unsubstituted indoles by electrophilic substitution because the electrophilicity of the

Molecules 2018, 23, x FOR PEER REVIEW 17 of 22 Molecules 2018, 23, x FOR PEER REVIEW 17 of 22 Moleculesfacile and2019, 24efficient, 164 method for the synthesis of 3‐sulfonylindoles, which cannot be synthesized17 of 22 faciledirectly and from efficient the corresponding method for the unsubstituted synthesis of indoles3‐sulfonylindoles, by electrophilic which substitution cannot be synthesizedbecause the directlyelectrophilicity from the of thecorresponding sulfonyl groups unsubstituted is much lower indoles than thatby ofelectrophilic the acyl groups substitution and halogens because [47,48]. the sulfonylelectrophilicityInterestingly, groups when of is muchthe 2 sulfonyl‐alkynyl lower groups‐ than6‐methoxy that is much of‐N the‐sulfonylanilines lower acyl groupsthan that and of105 the halogens were acyl groupsemployed [47,48 and]. Interestingly,as halogens the substrates, [47,48]. when 2-alkynyl-6-methoxy-Interestingly,this transformation when 2couldN‐alkynyl-sulfonylanilines also‐6 ‐methoxyoccur under105‐N‐sulfonylanilines werethe catalysis employed of 105 asInBr thewere3. substrates,However, employed the this as theintramolecular transformation substrates, couldthisaminosulfonylation transformation also occur under productscould the also catalysis 106 occur were ofunder obtained InBr 3the. However, ascatalysis minor products,of the InBr intramolecular3. whereasHowever, 6‐ sulfonylindolesthe aminosulfonylation intramolecular 107 productsaminosulfonylationwere observed106 were as obtainedthe products major as products106 minor were products,obtained(Scheme 33).as whereas minor The reactionproducts, 6-sulfonylindoles mechanism whereas 6107 ‐ofsulfonylindoles thiswere process observed may107 as thewereinvolve major observed the products initial as coordinationthe (Scheme major 33products ).of Thethe catalyst reaction(Scheme to mechanism 33).the alkyneThe reaction moiety, of this mechanism processsubsequent may of nucleophilic this involve process the attack initialmay coordinationinvolveof the nitrogen the initial of the atom coordination catalyst to the tocarbon–carbon the of alkyne the catalyst moiety, triple to bond, subsequent the alkyne the following moiety, nucleophilic migrationsubsequent attack of ofnucleophilic the the sulfonyl nitrogen attackgroup atom toofto the thethe carbon–carbon nitrogenC3‐position atom of triple tothe the indole bond, carbon–carbon skeleton, the following and triple the migration bond, final generationthe of following the sulfonyl of the migration groupproducts to of the withthe C3-position sulfonyl elimination group of of the indoletothe the catalyst skeleton,C3‐position (Scheme and of the the34). final indole generation skeleton, ofand the the products final generation with elimination of the products of the catalystwith elimination (Scheme of34 ). the catalyst (Scheme 34).

Scheme 32. AuBr3‐catalyzed intramolecular aminosulfonylation of alkynes. Scheme 32. AuBr -catalyzed intramolecular aminosulfonylation of alkynes. Scheme 32. AuBr33‐catalyzed intramolecular aminosulfonylation of alkynes.

Molecules 2018, 23, x FOR PEER REVIEW 18 of 22 Scheme 33. InBr3-catalyzed intramolecular aminosulfonylation of alkynes. Scheme 33. InBr3‐catalyzed intramolecular aminosulfonylation of alkynes. Scheme 33. InBr3‐catalyzed intramolecular aminosulfonylation of alkynes. SO2R2 R1

R1 N MBr3 SO2R2 R3 N 102 M=Au,In R3 101

MBr3 R1 Br M 3 SO2R2 SO2R2 R1 N N R3 MBr3 110 R3 108

R1 N SO2R2 R3 109

Scheme 34. Proposed mechanism for AuBr3/InBr3-catalyzed intramolecular aminosulfonylation of alkynes. Scheme 34. Proposed mechanism for AuBr3/InBr3‐catalyzed intramolecular aminosulfonylation of alkynes.

Subsequently, Chan′s group presented a gold‐catalyzed domino aminocyclization/1,3‐sulfonyl migration of N‐substituted N‐sulfonyl‐aminobut‐3‐yn‐2‐ols 111 to synthesize highly functional pyrroles 112 (Scheme 35) [49]. A screening of gold catalysts disclosed that the NHC (N‐heterocyclic carbene)‐gold(I) complex 113 was found to be the most effective catalyst for this intramolecular aminosulfonylation of alkynes. It could catalyze the conversion of various substrates 111 carrying electron‐withdrawing, electron‐donating, and sterically demanding groups to the corresponding pyrroles 112 in moderate to high yields. It is worth noting that this method provides an efficient and convenient tool to prepare penta‐substituted highly functional pyrroles. The mechanism of this transformation is outlined in Scheme 36. The coordination of gold cation to the alkyne moiety of the substrates gives intermediate 114, which undergoes a nucleophilic attack of the nitrogen atom to the alkynes to produce intermediate 115. At this juncture, dehydration of intermediate 115 yields cationic pyrrole–gold adduct 116, subsequent 1,3‐sulfonyl migration of intermediate 116 then results in deauration with the regeneration of the gold catalyst and delivery of the products 112. Alternatively, intermediate 115 could undergo the deaurative 1,3‐sulfonyl migration first to afford intermediate 117, which undergoes dehydrative aromatization to produce the products 112.

Molecules 2018, 23, x FOR PEER REVIEW 18 of 22

SO2R2 R1

R1 N MBr3 SO2R2 R3 N 102 M=Au,In R3 101

MBr3 R1 Br M 3 SO2R2 SO2R2 R1 N N R3 MBr3 110 R3 108

R1 N SO2R2 R3 109 Molecules 2019, 24, 164 18 of 22 Scheme 34. Proposed mechanism for AuBr3/InBr3‐catalyzed intramolecular aminosulfonylation of alkynes. Subsequently, Chan’s group presented a gold-catalyzed domino aminocyclization/1,3-sulfonyl migrationSubsequently, of N-substituted Chan′s groupN-sulfonyl-aminobut-3-yn-2-ols presented a gold‐catalyzed domino111 to aminocyclization/1,3 synthesize highly functional‐sulfonyl migrationpyrroles 112 of (SchemeN‐substituted 35)[49 ].N A‐sulfonyl screening‐aminobut of gold‐3 catalysts‐yn‐2‐ols disclosed 111 to synthesize that the NHC highly (N-heterocyclic functional pyrrolescarbene)-gold(I) 112 (Scheme complex 35) [49].113 Awas screening found toof begold the catalysts most effective disclosed catalyst that the for NHC this ( intramolecularN‐heterocyclic carbene)aminosulfonylation‐gold(I) complex of alkynes. 113 was It couldfound catalyze to be the the most conversion effective of catalyst various for substrates this intramolecular111 carrying aminosulfonylationelectron-withdrawing, of alkynes. electron-donating, It could catalyze and sterically the conversion demanding of various groups substrates to the corresponding 111 carrying electronpyrroles‐withdrawing,112 in moderate electron to high‐donating, yields. Itand is worthsterically noting demanding that this groups method to provides the corresponding an efficient pyrrolesand convenient 112 in moderate tool to prepare to high penta-substituted yields. It is worth highly noting functional that this method pyrroles. provides The mechanism an efficient of and this convenienttransformation tool isto outlined prepare inpenta Scheme‐substituted 36. The highly coordination functional of gold pyrroles. cation The to the mechanism alkyne moiety of this of transformationthe substrates givesis outlined intermediate in Scheme114 36., which The coordination undergoes a of nucleophilic gold cation attackto the ofalkyne the nitrogen moiety of atom the substratesto the alkynes gives to intermediate produce intermediate 114, which115 undergoes. At this juncture,a nucleophilic dehydration attack of of the intermediate nitrogen atom115 yieldsto the alkynescationic to pyrrole–gold produce intermediate adduct 116 115, subsequent. At this juncture, 1,3-sulfonyl dehydration migration of intermediate of intermediate 115116 yieldsthen cationic results pyrrole–goldin deauration withadduct the 116 regeneration, subsequent of the 1,3 gold‐sulfonyl catalyst migration and delivery of intermediate of the products 116112 then. Alternatively, results in deaurationintermediate with115 thecould regeneration undergo the of the deaurative gold catalyst 1,3-sulfonyl and delivery migration of the first products to afford 112 intermediate. Alternatively,117 , intermediatewhich undergoes 115 could dehydrative undergo aromatization the deaurative to 1,3 produce‐sulfonyl the migration products first112. to afford intermediate 117, which undergoes dehydrative aromatization to produce the products 112.

Molecules 2018, 23, x FOR PEER REVIEW 19 of 22

Scheme 35. Gold‐catalyzed intramolecular aminosulfonylation of N‐substituted N‐sulfonyl‐ Scheme 35. Gold-catalyzed intramolecular aminosulfonylation of N-substituted N-sulfonyl-aminobut- aminobut‐3‐yn‐2‐ols. 3-yn-2-ols.

Scheme 36. 36. PossiblePossible reaction reaction mechanism mechanism for for gold gold-catalyzed‐catalyzed intramolecular intramolecular aminosulfonylation aminosulfonylation of N of‐ substitutedN-substituted N‐sulfonylN-sulfonyl-aminobut-3-yn-2-ols.‐aminobut‐3‐yn‐2‐ols.

Soon afterwards, Liu′s group reported a more general and efficient intramolecular aminosulfonylation of alkynes to synthesize 3‐sulfonylindoles 119 through palladium catalysis (Scheme 37) [35,50]. The reactions took place smoothly with PdCl2(CH3CN)2 in CH3CN at 90 °C to afford 3‐sulfonylindoles 119 as the single products without the generation of 4‐ and 6‐sulfonylindole regioisomers, which were obtained as the byproducts in the gold‐ and indium‐catalyzed process. In addition, this protocol features broad substrate scope, good functional group tolerance, and moderate to high yields, thus providing a practical access to functional 3‐sulfonylindoles. A plausible mechanism, which is similar to gold‐ or indium‐catalyzed aminosulfonylation of alkynes [45,46], was also proposed by the authors.

Scheme 37. PdCl2(CH3CN)2‐catalyzed intramolecular aminosulfonylation of alkynes.

4. Conclusions and Perspectives In this review, we presented a summary of the addition of amide/sulfonamide bonds to alkynes, which has emerged as a highly important tool to functionalize carbon–carbon triple bonds. The aminoacylation/aminosulfonylation of alkynes, which is characterized by high atom‐ and step‐ economy in an environmentally‐friendly manner, has also become a remarkable method for the downstream transformations of amide/sulfonamides compounds. Notably, the intramolecular

Molecules 2018, 23, x FOR PEER REVIEW 19 of 22

Scheme 35. Gold‐catalyzed intramolecular aminosulfonylation of N‐substituted N‐sulfonyl‐ aminobut‐3‐yn‐2‐ols.

MoleculesScheme2019, 2436., 164 Possible reaction mechanism for gold‐catalyzed intramolecular aminosulfonylation of N19‐ of 22 substituted N‐sulfonyl‐aminobut‐3‐yn‐2‐ols. Soon afterwards, Liu’s group reported a more general and efficient intramolecular Soon afterwards, Liu′s group reported a more general and efficient intramolecular aminosulfonylation of alkynes to synthesize 3-sulfonylindoles 119 through palladium catalysis aminosulfonylation of alkynes to synthesize 3‐sulfonylindoles 119 through palladium catalysis◦ (Scheme 37)[35,50]. The reactions took place smoothly with PdCl2(CH3CN)2 in CH3CN at 90 C to (Scheme 37) [35,50]. The reactions took place smoothly with PdCl2(CH3CN)2 in CH3CN at 90 °C to afford 3-sulfonylindoles 119 as the single products without the generation of 4- and 6-sulfonylindole afford 3‐sulfonylindoles 119 as the single products without the generation of 4‐ and 6‐sulfonylindole regioisomers, which were obtained as the byproducts in the gold- and indium-catalyzed process. regioisomers, which were obtained as the byproducts in the gold‐ and indium‐catalyzed process. In In addition, this protocol features broad substrate scope, good functional group tolerance, and addition, this protocol features broad substrate scope, good functional group tolerance, and moderate moderate to high yields, thus providing a practical access to functional 3-sulfonylindoles. A plausible to high yields, thus providing a practical access to functional 3‐sulfonylindoles. A plausible mechanism, which is similar to gold- or indium-catalyzed aminosulfonylation of alkynes [45,46], was mechanism, which is similar to gold‐ or indium‐catalyzed aminosulfonylation of alkynes [45,46], was also proposed by the authors. also proposed by the authors.

Scheme 37. PdCl2(CH3CN)2-catalyzed intramolecular aminosulfonylation of alkynes. Scheme 37. PdCl2(CH3CN)2‐catalyzed intramolecular aminosulfonylation of alkynes. 4. Conclusions and Perspectives 4. Conclusions and Perspectives In this review, we presented a summary of the addition of amide/sulfonamide bonds to alkynes,In this which review, has we emerged presented as a a highly summary important of the addition tool to functionalize of amide/sulfonamide carbon–carbon bonds triple to alkynes, bonds. Thewhich aminoacylation/aminosulfonylation has emerged as a highly important of tool alkynes, to functionalize which is characterized carbon–carbon by triple high bonds. atom- andThe step-economyaminoacylation/aminosulfonylation in an environmentally-friendly of alkynes, manner, which hasis characterized also become by a remarkable high atom‐ methodand step for‐ theeconomy downstream in an environmentally transformations‐friendly of amide/sulfonamides manner, has also compounds. become a Notably,remarkable the method intramolecular for the aminoacylation/aminosulfonylationdownstream transformations of amide/sulfonamides of alkynes has provided compounds. a facile Notably, and efficient the protocolintramolecular for the synthesis of valuable heterocycles such as chromones, quinolinones, indoles, and pyrroles. Despite the remarkable achievements made, there are at least three areas where some critical advances are necessary to make the aminoacylation/aminosulfonylation of alkynes more general and powerful: (a) the intermolecular addition of unactivated amide/sulfonamide bonds to alkynes is still in high demand; (b) as the reported metal-catalyzed process employed expensive metals, the development of cheap metal catalysis as well as organocatalysis, will be a good direction to take; (c) the exploration of tandem reactions involving aminoacylation/aminosulfonylation of alkynes will continue to drive this field considering their efficiency and step-economy in constructing complex heterocyclic compounds.

Author Contributions: F.Z. wrote the manuscript; P.L. and X.L. collected the literature references; X.J. and J.W. drew the schemes and contributed to the editing; H.L. conceived this review and made major revisions and edits. Funding: This research was funded by National Natural Science Foundation of China (grant 21602022, 81620108027 and 21632008), Sichuan Science and Technology Program (grant 2018JY0345) and Chengdu University New Faculty Start-up Funding (grant 2081915037). Acknowledgments: F.Z. gratefully acknowledge the support from 1000 Talents Program of Sichuan Province and Chengdu Talents Program. Conflicts of Interest: The authors declare no conflict of interest. Molecules 2019, 24, 164 20 of 22

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