molecules

Review Recent Advances in Cyanamide Chemistry: Synthesis and Applications

M. R. Ranga Prabhath, Luke Williams, Shreesha V. Bhat and Pallavi Sharma * School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Lincoln LN6 7DL, UK; [email protected] (M.R.R.P.); [email protected] (L.W.); [email protected] (S.V.B.) * Correspondence: [email protected]; Tel.: +44-015-2288-6885

Academic Editor: Margaret A. Brimble Received: 9 March 2017; Accepted: 7 April 2017; Published: 12 April 2017

Abstract: The application of alkyl and aryl substituted cyanamides in synthetic chemistry has diversified multi-fold in recent years. In this review, we discuss recent advances (since 2012) in the chemistry of cyanamides and detail their application in cycloaddition chemistry, aminocyanation reactions, as well as electrophilic cyanide-transfer agents and their unique radical and coordination chemistry.

Keywords: cyanamide; synthesis; aminocyanation; cycloaddition; electrophilic cyanation; radical reaction; coordination chemistry

1. Introduction Cyanamide enjoys a rich chemical history, which can be traced to its unique and chemically promiscuous nitrogen-carbon-nitrogen (NCN) connectivity. The chemistry of the nitrile-substituted amino-group of the ‘cyanamide-moiety’ is dominated by an unusual duality of a nucleophilic sp3-amino nitrogen and an electrophilic nitrile unit. The reported use of unsubstituted cyanamide (NH2CN) and metal cyanamides (MNCN, where M = metal) date back as far as the late 19th century, where the likes of calcium cyanamide (CaNCN) was used as a fertilizer, and later as source of ammonia and nitric acid, which fueled the industrial production of metal cyanamides. In contrast, the reported use of the corresponding substituted organic cyanamides (RNHCN or RR’NCN) gathered pace only in more recent years. The last decade has witnessed a significant increase in the use and application of substituted cyanamides in synthetic chemistry, along with development of more sustainable and robust synthetic routes to these important family of compounds. A number of excellent review articles describing the chemistry of cyanamide have appeared in the literature in recent years, and we encourage the readers to investigate these articles. Nekasarov and co-workers [1] summarized the synthesis and reactions of mono and disubstituted cyanamides in a seminal review article in 2004, whereas the literature from 2004 to 2012 was captured concisely by Fensterbank and Lacôte et al [2]. Thus, in the present review, we limit our discussion to developments appearing in the literature from 2012. The present review is by no means exhaustive and we apologize to authors whose work has been omitted. The present article focuses on some leading topics in cyanamide chemistry such as aminocyanation, electrophilic cyanation, selected cycloaddition reactions, coordination chemistry and radical reactions, whereas more traditional chemistry has not been covered here and we would like to direct the readers to appropriate primary literature.

2. Synthesis of Mono and Disubstituted Cyanamides The direct alkylation of metal cyanamides such as calcium cyanamide is the most straightforward approach to mono and disubstituted derivatives, and reports on these strategies have been previously

Molecules 2017, 22, 615; doi:10.3390/molecules22040615 www.mdpi.com/journal/molecules Molecules 2017, 22, 615 2 of 27 Molecules 2017, 22, 615 2 of 27 2. Synthesis of Mono and Disubstituted Cyanamides 2.Molecules Synthesis2017, 22of, 615Mono and Disubstituted Cyanamides 2 of 28 The direct alkylation of metal cyanamides such as calcium cyanamide is the most straightforward The direct alkylation of metal cyanamides such as calcium cyanamide is the most straightforward approach to mono and disubstituted derivatives, and reports on these strategies have been previously approachcovered [1 to–3 mono]. This and section disubstituted details more derivatives, recent approaches, and reports including on these developmentstrategies have of been new previously reagents to covered [1–3]. This section details more recent approaches, including development of new reagents coveredaccess substituted [1–3]. This cyanamides. section details more recent approaches, including development of new reagents to access substituted cyanamides. to access substituted cyanamides. 2.1. N-Cyanation of Secondary Amine 2.1. N-Cyanation of Secondary Amine 2.1. N-Cyanation of Secondary Amine 2.1.1. Using Electrophilic Nitrile [CN]+ Reagents 2.1.1. Using Electrophilic Nitrile [CN]+ Reagents 2.1.1.The Using electrophilic Electrophilic cyanation Nitrile [CN] of+ secondaryReagents amines is the most prevalent method used to accessThe disubstituted electrophilic cyanamides,cyanation of secondary with cyanogen amines bromideis the most (BrCN) prevalent being method the most used commonto access The electrophilic cyanation of secondary amines is the most prevalent method used to access reagent.disubstituted Though cyanamides, cheap and with effective, cyanogen the bromide toxicity (BrCN) associated being with the thismost reagent common has reagent. prompted Though the disubstituted cyanamides, with cyanogen bromide (BrCN) being the most common reagent. Though developmentcheap and effective, of safer the cyanating toxicity agentsassociated such with as 2-cyanopyridazin-3(2 this reagent has promptedH)-one, cyanobenzimidazole,the development of safer and cheap and effective, the toxicity associated with this reagent has prompted the development of safer 1-cyanoimidazolecyanating agents such [4–6 as]. 2-cyanopyridazin-3(2H)-one, cyanobenzimidazole, and 1-cyanoimidazole [4–6]. cyanating agents such as 2-cyanopyridazin-3(2H)-one, cyanobenzimidazole, and 1-cyanoimidazole [4–6]. In 2014, Chen et et al. al. used used a a combination combination of of hypochlorite hypochlorite and and TMSCN TMSCN for for the the in insitu situ generation generation of In 2014, Chen et al. used a combination of hypochlorite and TMSCN for the in situ generation of ofcyanogen cyanogen chloride chloride (CNCl) (CNCl) to accomplish to accomplish the theN-cyanationN-cyanation of a ofvariety a variety of secondary of secondary amines amines [7]. The [7]. cyanogen chloride (CNCl) to accomplish the N-cyanation of a variety of secondary amines [7]. The Thehypochlorite hypochlorite oxidizes oxidizes the theTMSCN TMSCN to torelease release the the active active CNCl CNCl reagent, reagent, which which then cyanatescyanates hypochlorite oxidizes the TMSCN to release the active CNCl reagent, which then cyanates nucleophilic amines. Both Both dialkyl dialkyl and and alkyl-aryl amines amines were readily cyanated using this method, nucleophilic amines. Both dialkyl and alkyl-aryl amines were readily cyanated using this method, offering the products inin goodgood toto excellentexcellent yieldsyields (Scheme(Scheme1 1).). offering the products in good to excellent yields (Scheme 1).

Scheme 1. In situ generation of CNCl for cyanation. Scheme 1. In situ generation of CNCl for cyanation. Alcarazo and co-workers have developed the thiocyanoimidazolium salt 5 as an electrophilic Alcarazo and co-workers have developed the thiocyanoimidazolium salt salt 55 as an electrophilic cyanation reagent for secondary amines [8]. Halogenation of thiourea led to the hypervalent sulfur cyanation reagent for secondary amines [8]. [8]. Halogena Halogenationtion of of thiourea thiourea led led to to the hypervalent sulfur species 4, which upon treatment with TMSCN provided the active reagent 5. In the presence of an species 44,, which which upon upon treatment treatment with with TMSCN TMSCN provided provided the the active active reagent reagent 5. 5In. the In the presence presence of an of amine base such as diisopropylethylamine (DIPEA), the reagent 5 successfully transferred the active aminean amine base base such such as diisopropylethylamine as diisopropylethylamine (DIPEA), (DIPEA), the reagent the reagent 5 successfully5 successfully transferred transferred the active the [CN]+ to a number of alkyl and aryl sec-amines to give corresponding cyanamides in good yield [CN]active+ to [CN] a number+ to a number of alkyl of and alkyl aryl and sec aryl-aminessec-amines to give to corresponding give corresponding cyanamides cyanamides in good in yield good (Scheme 2). The protocol was deemed to be operationally simple and wide in scope, however (Schemeyield (Scheme 2). The2). Theprotocol protocol was was deemed deemed to tobe beoper operationallyationally simple simple and and wide wide in in scope, howeverhowever precaution must be taken when handling the cyanating reagent 5; just like the isolobal hypervalent precaution must be taken when handling the cy cyanatinganating reagent 5; just like the isolobal hypervalent iodine reagents, they show strong exothermic decomposition upon heating. iodineiodine reagents, they show strong exothermicexothermic decomposition upon heating.

Scheme 2. Thiocyanoimidazolium salts for electrophilic cyanation. SchemeScheme 2. ThiocyanoimidazoliumThiocyanoimidazolium salts fo forr electrophilic cyanation.

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Molecules 2017, 22, 615 3 of 27 The Morrill group reported trichloroacetonitrile (6) as an effective cyanating reagent of sec-amines + followingMolecules aThe one-pot 2017 Morrill, 22, 615 protocol group reported [9]. Though trichloroacetonitrile not strictly ( a6) [CN] as an effectivetransfer cyanating reagent, reagent the two-step-single-pot of sec-amines3 of 27 protocolfollowing involved a one-pot formation protocol of [9]. the Though amidine not 7strictly(Scheme a [CN]3)+ via transfer nucleophilic reagent, the addition two-step-single-pot and its further conversionprotocolThe into Morrillinvolved the group nitrile formation reported mediated of trichloroacetonitrilethe byamidine NaO t7Am (Scheme base(6) as 3) (Schemean via effective nucleophilic3). cyanating Both addition cyclic reagent and and of sec acyclicits-amines further dialkyl followingconversion a one-potinto the protocol nitrile mediated [9]. Though by notNaO strictlytAm base a [CN] (Scheme+ transfer 3). reagent, Both cyclic the two-step-single-potand acyclic dialkyl cyanamides were obtained in good yields. The trichloroacetonitrile reagent 6 allowed the selective protocolcyanamides involved were obtainedformation in of good the amidineyields. The 7 (Scheme trichloroacetonitrile 3) via nucleophilic reagent addition 6 allowed and the its selective further cyanationconversioncyanation of secondary of into secondary the nitrile amines amines mediated in in the the presenceby presence NaOtAm ofof base other (Scheme nucleophilic nucleophilic 3). Both centers, centers, cyclic which and which acyclicis a significant is adialkyl significant benefitcyanamidesbenefit compared compared were to other obtainedto other cyanating cyanating in good reagents. yi reagents.elds. The trichloroacetonitrile reagent 6 allowed the selective cyanation of secondary amines in the presence of other nucleophilic centers, which is a significant benefit compared to other cyanating reagents.

SchemeScheme 3. 3.Trichloroacetonitrile Trichloroacetonitrile for for cyanation. cyanation.

2.1.2. Under Copper CatalysisScheme 3. Trichloroacetonitrile for cyanation. 2.1.2. Under Copper Catalysis Cheng et al. developed a transition metal catalyzed cyanation of sec-amines for N–CN bond 2.1.2. Under Copper Catalysis Chengformation et al.under developed oxidative acoupling transition conditions metal [10], catalyzed using CuCN cyanation as the source of sec-amines of nitrile. forWhen N–CN used bond formationin combinationCheng under et oxidative al. with developed N,N coupling,N’, Na′ -tetramethylethylenediaminetransition conditions metal [10catalyzed], using cyanation CuCN (TMEDA), as of the whichsec-amines source itself of forwas nitrile. N–CN proposed Whenbond to used 0 0 in combinationformationplay the dual under with role oxidativeN of,N a,N ligand, Ncoupling-tetramethylethylenediamine and a conditions base in the [10], catalytic using cycle,CuCN (TMEDA),molecular as the source oxygen which of nitrile. (O itself2) andWhen was sodium used proposed insulfate, combination the sec-amine with N underwent,N,N’,N′-tetramethylethylenediamine cyanation in the presence of (TMEDA), CuBr2 (Scheme which 4). itself The was CuCN proposed was also to to play the dual role of a ligand and a base in the catalytic cycle, molecular oxygen (O2) and sodium playshown the to dual self-catalyze role of a the ligand cyanation and a reactionbase in whenthe catalytic conducted cycle, in molecularthe absence oxygen of any additional(O2) and sodium copper sulfate, the sec-amine underwent cyanation in the presence of CuBr2 (Scheme4). The CuCN was also sulfate,source. theBased sec-amine on the underwentexperimental cyanation evidence in thethe aupresencethors proposed of CuBr2 (Schemethe catalytic 4). The cycle CuCN illustrated was also in shown to self-catalyze the cyanation reaction when conducted in the absence of any additional copper shownScheme to 4, self-catalyze where a Cu(II) the cyanationspecies is thoughtreaction towhen participate conducted in the in thecatalytic absence cycle. of any additional copper source.source. Based Based on theon the experimental experimental evidence evidence the au authorsthors proposed proposed the the catalytic catalytic cycle cycle illustrated illustrated in in SchemeScheme4, where 4, where a Cu(II) a Cu(II) species species is thoughtis thought to to participate participate in in the the catalytic catalytic cycle. cycle.

Scheme 4. Copper catalyzed cyanation of secondary amines.

SchemeScheme 4. 4.Copper Copper catalyzed catalyzed cyanation of of secondary secondary amines. amines.

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Molecules 2017, 22, 615 4 of 27 Continuing their efforts to provide a safer source of cyanide for N–CN bond formation under copperContinuing catalysis, thetheir authors efforts to investigated provide a safer the source use of of the cyanide radical for initiatorN–CN bond azobisisobutyronitrile formation under copperMolecules catalysis, 2017, 22, 615the authors investigated the use of the radical initiator azobisisobutyronitrile4 of 27 (12 , (12, AIBN) [11]. In the presence of CuI, in combination with molecular oxygen and K2CO3, AIBN AIBN) [11]. In the presence of CuI, in combination with molecular oxygen and K2CO3, AIBN efficiently efficiently led to a variety of disubstituted cyanamides starting from both alkyl and aryl secondary led to aContinuing variety of their disubstituted efforts to providecyanamides a safer starting source offrom cyanide both foralkyl N–CN and bond aryl formationsecondary under amines amines (Scheme5). Based on their experimental observations the authors proposed a radical pathway, (Schemecopper 5). catalysis, Based on the their authors experimental investigated observatio the use nsof the radicalauthors initiator proposed azobisisobutyronitrile a radical pathway, which(12, which incorporates the generation of a nitrile radical from AIBN. Molecular oxygen mediated oxidation incorporatesAIBN) [11]. theIn the generation presence of CuI,a nitrile in combination radical from with AIBN. molecular Molecular oxygen oxygen and K2 COmediated3, AIBN oxidationefficiently of of Cu(I) to Cu(II) leads to species 13 in the presence of the base. The generation of nitrile radical from Cu(I)led toto Cu(II)a variety leads of todisubstituted species 13 incyanamides the presence starting of the from base. both The alkyl generation and aryl of secondary nitrile radical amines from AIBNAIBN(Scheme assisted assisted 5). by Based by molecular molecular on their oxygenexperimental oxygen insertinsert observatio intointo 13 tons givethe authors 14.. A A reductive reductiveproposed eliminationa eliminationradical pathway, of of 1414 provideswhichprovides incorporates the generation of a nitrile radical from AIBN. Molecular oxygen mediated oxidation of thethe final finalN -cyanatedN-cyanated product product2 2(Scheme (Scheme5 ).5). Cu(I) to Cu(II) leads to species 13 in the presence of the base. The generation of nitrile radical from AIBN assisted by molecular oxygen insert into 13 to give 14. A reductive elimination of 14 provides the final N-cyanated product 2 (Scheme 5).

SchemeScheme 5. 5.AIBN AIBN mediatedmediated cyanation of of secondary secondary amine. amine. Scheme 5. AIBN mediated cyanation of secondary amine. 2.2.2.2. Cyanamides Cyanamides from from Amidoximes Amidoximes and and Guanidoximes Guanidoximes 2.2.Chauhan Cyanamides and from co-workers Amidoximes reported and Guanidoximes the synthesis of monosubstituted N-arylcyanamides via the Chauhan and co-workers reported the synthesis of monosubstituted N-arylcyanamides via the oxidationChauhan of the andcorresponding co-workers reportedguanidoximes the synthesis in an ionic of monosubstituted liquid (Scheme N 6)-arylcyanamides [12], which is proposedvia the oxidation of the corresponding guanidoximes in an ionic liquid (Scheme6)[ 12], which is proposed to mimicoxidation the of natural the corresponding enzymatic oxidation guanidoximes of oximes in an to ionic nitriles. liquid The (Scheme imidazolium 6) [12], ionicwhich liquid is proposed was used to mimic the natural enzymatic oxidation of oximes to nitriles. The imidazolium ionic liquid was as tothe mimic reaction the natural medium enzymatic for the oxidation H2O2 mediated of oximes oxidation to nitriles. catalyzed The imidazolium by the ionicwater liquid soluble was anionicused used as the reaction medium for the H2O2 mediated oxidation catalyzed by the water soluble anionic iron(III)-porphyrinsas the reaction medium [TAPS for4Fe(III)Cl]. the H2O 2 mediated oxidation catalyzed by the water soluble anionic iron(III)-porphyrinsiron(III)-porphyrins [TAPS [TAPS4Fe(III)Cl].4Fe(III)Cl].

Scheme 6. Cont. SchemeScheme 6. Cont.Cont .

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Scheme 6. Conversion of guanidoximes to monosubstituted cyanamide. Scheme 6. Conversion of guanidoximes to monosubstituted cyanamide. A peroxo-speciesScheme like 21 6. Conversion was proposed of guanidoximes as an intermediate, to monosubstituted itself cyanamide. obtained upon nucleophilic addition Aof peroxo-species iron-peroxo 20like on 21 thewas oximeproposed double as an bond.intermediate, The peroxo-complex itself obtained upon 21 thennucleophilic undergoes A peroxo-species like 21 was proposed as an intermediate, itself obtained upon nucleophilic cyclizationaddition followed of iron-peroxo by selective 20 on ringthe oximeopening double to give bond. 23 , Thefollowed peroxo-complex by the elimination 21 then undergoes of water and addition of iron-peroxo 20 on the oxime double bond. The peroxo-complex 21 then undergoes loss ofcyclization NO to render followed the by target selective cyanamide ring opening 18 (Scheme to give 23 6).The, followed generation by the elimination of cyanamide of water type and species cyclization followed by selective ring opening to give 23, followed by the elimination of water and loss fromloss the ofreaction NO to ofrender amidoxime the target with cyanamide aryl-sulfonyl- 18 (Schemechloride 6).The was generation first observed of cyanamide by Tiemann type in species 1891 [13]. of NO to render the target cyanamide 18 (Scheme6).The generation of cyanamide type species from the from the reaction of amidoxime with aryl-sulfonyl-chloride was first observed by Tiemann in 1891 [13]. In theirreaction seminal of amidoxime report, Tiemann with aryl-sulfonyl-chloride detected a series was of firstdiverse observed mixture by Tiemann of products, in 1891 which [13]. In included their In their seminal report, Tiemann detected a series of diverse mixture of products, which included cyanamide,seminal carbodiimide, report, Tiemann guanidine detected a seriesand benzimidazole of diverse mixture, among of products, others. which In 2014 included Chien cyanamide, et al. revisited cyanamide, carbodiimide, guanidine and benzimidazole, among others. In 2014 Chien et al. revisited this carbodiimide,reaction and guanidine developed and conditions benzimidazole, that among led to others. the Inselective 2014 Chien formation et al. revisited of monosubstituted this reaction this reaction and developed conditions that led to the selective formation of monosubstituted aryl-cyanamideand developed from conditions the corresponding that led to the aryl-amidoxime selective formation [14]. of Upon monosubstituted treatment aryl-cyanamidewith p-TsCl in the aryl-cyanamide from the corresponding aryl-amidoxime [14]. Upon treatment with p-TsCl in the presencefrom of the DIPEA corresponding or pyridine, aryl-amidoxime the amidoximes [14]. Upon were treatment converted with top -TsClcyanamides in the presence in good of to DIPEA excellent presence of DIPEA or pyridine, the amidoximes were converted to cyanamides in good to excellent or pyridine, the amidoximes were converted to cyanamides in good to excellent yields (Scheme7). yieldsyields (Scheme (Scheme 7). The7). The authors authors observed observed that that thethe reaction of of the the amidoxime amidoxime 25 25with with p-TsCl, p-TsCl, and andthe the The authors observed that the reaction of the amidoxime 25 with p-TsCl, and the subsequent product subsequentsubsequent product product distribution, distribution, was was dependent dependent on thee electronicselectronics of of the the substrates. substrates. It was It was observed observed distribution, was dependent on the electronics of the substrates. It was observed that cyanamide that cyanamidethat cyanamide products products were were predominantly predominantly formedformed withwith electron electron rich rich aryl aryl substrates. substrates. The The authors authors products were predominantly formed with electron rich aryl substrates. The authors further observed furtherfurther observed observed that that the the rate rate of of the the key key rearrearrangementrangement stepstep depends depends on on the the crucial crucial N–O N–O bond bond that the rate of the key rearrangement step depends on the crucial N–O bond cleavage and reports cleavagecleavage and and reports reports o-NsCl o-NsCl as as a abetter better leaving leaving groupgroup forfor challenging challenging substrates substrates (electron-deficient (electron-deficient o-NsCl as a better leaving group for challenging substrates (electron-deficient aryl- and alkyl-substrates) aryl- and alkyl-substrates) at elevated reaction temperatures. A variety of aryl, alkyl and vinyl aryl-at and elevated alkyl-substrates) reaction temperatures. at elevated A variety reaction of aryl, temperatures. alkyl and vinyl A cyanamides variety of can aryl, be accessed alkyl and under vinyl cyanamides can be accessed under these conditions. cyanamidesthese conditions. can be accessed under these conditions.

Scheme 7. Amidoximes to substituted cyanamides. SchemeScheme 7. 7.AmidoximesAmidoximes to to substitutedsubstituted cyanamides. cyanamides. 2.3. Cyanamides from Isoselenocyanates 2.3. Cyanamides2.3. CyanamidesThe dehydration from from Isoselenocyanates Isoselenocyanates of urea or desulfurization of thiourea are both well-established methods that areThe used Thedehydration to dehydration access cyanamides of urea of urea or [2]. desulfurization or Similarly, desulfurization cyanamides of ofthiourea thiourea can also are arebe both prepared both well-es well-established by tablishedthe deselenization methods methods of that selenourea. In 2015, Xie and co-workers, described a one-pot hypervalent iodine-mediated deselenization are usedthat to are access used cyanamides to access cyanamides [2]. Similarly, [2]. cyanamides Similarly, cyanamidescan also be prepared can also beby preparedthe deselenization by the of of aryl-isoselenocyanates [15], using the recyclable ionic liquid supported 1-(4-diacetoxyiodobenzyl)- selenourea.deselenization In 2015, ofXie selenourea. and co-workers, In 2015, described Xie and a one-pot co-workers, hypervalent described iodine a-mediated one-pot hypervalent deselenization 3-methylimidazolium tetrafluoroborate ([dibmim]+[BF4]–), which gave a variety of cyanamides of aryl-isoselenocyanatesiodine-mediated deselenization [15], using of the aryl-isoselenocyanates recyclable ionic liquid [15 supported], using the 1-(4-diacetoxyiodobenzyl)- recyclable ionic liquid (Scheme 8). + – supported 1-(4-diacetoxyiodobenzyl)-3-methylimidazolium tetrafluoroborate ([dibmim] [BF4] ), 3-methylimidazolium tetrafluoroborate ([dibmim]+[BF4]–), which gave a variety of cyanamides which gave a variety of cyanamides (Scheme8). (Scheme 8).

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Scheme 8. Isoselenocyanates to aryl-cyanamide. Scheme 8. Isoselenocyanates to aryl-cyanamide. During the syntheses of 5-alkylselanyl-1-aryl-1H-tetrazoles from aryl-isoselenocyanates, the During the syntheses of 5-alkylselanyl-1-aryl-15-alkylselanyl-1-aryl-1H-tetrazoles from aryl-isoselenocyanates, the serendipitous synthesis of N-alkyl-N-aryl-cyanamides was observed by Roh and co-workers [16]. serendipitousserendipitous synthesis synthesis of of N-alkyl--alkyl-NN-aryl-cyanamides-aryl-cyanamides was was observed observed by by Roh Roh and and co-workers co-workers [16]. [16]. The disubstituted cyanamide 30 was formed as predominant product when aryl-isoslelenocyanate The disubstituted cyanamide 30 was formed as predominant product when aryl-isoslelenocyanate 28 was treated with azide followed by an alkyl-halide (Scheme 9). Mechanistically the loss of 28 was treated with azideazide followedfollowed byby anan alkyl-halidealkyl-halide (Scheme(Scheme9 ).9). MechanisticallyMechanistically thethe lossloss ofof elemental selenium and dinitrogen (N2) from the intermediate tetrazole 32 led to the anionic species 33, elemental selenium selenium and and dinitrogen dinitrogen (N (N2) from) from the the intermediate intermediate tetrazole tetrazole 32 32ledled to the to the anionic anionic species species 33, which upon alkylation provided the disubstituted2 cyanamides (Scheme 9). which33, which upon upon alkylation alkylation provided provided the thedisubstituted disubstituted cyanamides cyanamides (Scheme (Scheme 9). 9).

Scheme 9. Synthesis of disubstituted cyanamide by the cycloaddition of azide with isoselenocyanate. SchemeScheme 9. 9. SynthesisSynthesis of of disubstituted disubstituted cyanamide cyanamide by by the the cycloaddition of azide with isoselenocyanate. 3. Synthetic Applications of Substituted Cyanamides 3. Synthetic Synthetic Applications Applications of of Substituted Cyanamides 3.1. Cycloaddition Reactions 3.1. Cycloaddition Cycloaddition Reactions Reactions The carbon-nitrogen triple bond of cyanamides readily undergo [3 + 2] and [2 + 2 + 2] cycloadditions The carbon-nitrogen triple bond of cyanamides readily undergo [3 + 2] and [2 + 2 + 2] cycloadditions whenThe exposed carbon-nitrogen to suitable reacting triple bond partners, of cyanamides which ultimately readily lead undergo to the [3formation + 2] and of [2five + and 2 + six 2] when exposed to suitable reacting partners, which ultimately lead to the formation of five and six cycloadditionsmembered ring when heterocycles, exposed respectively. to suitable reacting partners, which ultimately lead to the formation of memberedfive and six ring membered heterocycles, ring heterocycles, respectively. respectively. 3.1.1. [3 + 2] Cycloaddition 3.1.1. [3 [3 + + 2] 2] Cycloaddition Cycloaddition Cyanamides participate as dipolarophiles in [3 + 2] cycloaddition reactions with dipoles to offer Cyanamides participate participate as as dipolarophiles dipolarophiles in in[3 [3+ 2] + cycloaddition 2] cycloaddition reactions reactions with withdipoles dipoles to offer to cycloadducts; e.g., the reaction with azide dipoles offer 4-aminotetrazole adducts [2]. Recently, cycloadducts;offer cycloadducts; e.g., the e.g., reaction the reaction with with azide azide dipole dipoless offer offer 4-aminotetrazole 4-aminotetrazole adducts adducts [2]. [2]. Recently, Recently, cyanamides have been shown to participate in reactions with alkynes and other dipoles to offer a cyanamides have have been been shown shown to to participate participate in in re reactionsactions with with alkynes alkynes and and other other dipoles dipoles to tooffer offer a variety of heterocyclic products. varietya variety of ofheterocyclic heterocyclic products. products. Kukushkhin et al. applied a gold catalyzed heterocyclization of alkynes with substituted Kukushkhin et al. applied a gold catalyzed heterocyclization of alkynes with substituted cyanamides in the presence of the oxygen donor 2-picoline oxide (35), to give 2-amino-1,3-oxazoles cyanamides in the presence of the oxygen donor 2-picoline oxide (35), to give 2-amino-1,3-oxazoles 36 (Scheme 10) [17]. A variety of terminal alkynes 34 in the presence of Ph3PAuNTf2 and 2-picoline 36 (Scheme 10) [17]. A variety of terminal alkynes 34 in the presence of Ph3PAuNTf2 and 2-picoline

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MoleculesKukushkhin 2017, 22, 615 et al. applied a gold catalyzed heterocyclization of alkynes with substituted7 of 27 cyanamidesMolecules 2017, 22 in, 615 the presence of the oxygen donor 2-picoline oxide (35), to give 2-amino-1,3-oxazoles7 of 27 oxide36 (Scheme in chlorobenzene, 10) [17]. A varietyunderwent of terminal cyclization alkynes with34 dimethylcyanamidein the presence of Ph to3PAuNTf offer the2 and 5-substitued 2-picoline 2- amino-1,3-oxazolesoxide in chlorobenzene, 36. The underwent underwentreaction was cyclization cyclization proposed withwith to proceeddimethylcyanamide dimethylcyanamide through a β to-gold(I)-vinyloxypyridinium tooffer offer the the 5-substitued 5-substitued 2- β intermediate2-amino-1,3-oxazolesamino-1,3-oxazoles 37, which 3636. isThe. Thetrapped reaction reaction by was the was proposedcyanamide proposed to to nitrile.proceed proceed through aa β-gold(I)-vinyloxypyridinium-gold(I)-vinyloxypyridinium intermediateintermediate 3737,, whichwhich isis trappedtrapped byby thethe cyanamide cyanamide nitrile. nitrile.

SchemeScheme 10. 10. 2-Amino-1,3-oxazoles 2-Amino-1,3-oxazoles synthesis synthesis via via cycloadditioncycloaddition ofof alkynes alkynes and and cyanamides. cyanamides.

A cycloaddition protocol for the synthesis of 1,2,4-oxadiazoles 39 was developed utilizing A Acycloaddition cycloaddition protocol protocol for for the the synthesis synthesis of 1,2,4-oxadiazoles1,2,4-oxadiazoles 3939was was developed developed utilizing utilizing cyanamides as core building block by Goldberg and co-workers [18]. A zinc-chloride catalyzed cyanamidescyanamides as as core core buildingbuilding block block by by Goldberg Goldberg and co-workersand co-workers [18]. A [18]. zinc-chloride A zinc-chloride catalyzed catalyzed reverse reverse nucleophilic addition of N-Boc-hydroxylamine (38) to the cyanamide-nitrile, followed by reversenucleophilic nucleophilic addition addition of N-Boc-hydroxylamine of N-Boc-hydroxylamine (38) to the (38 cyanamide-nitrile,) to the cyanamide-nitrile, followed by followed acylation, by acylation, deprotection and ring-closure, mediated by TFAA and TFA, lead to the final cyclized 1,2,4- acylation,deprotection deprotection and ring-closure, and ring-closure, mediated bymediated TFAA and by TFAA TFA, lead and to TFA, the final lead cyclized to the final 1,2,4-oxadiazole cyclized 1,2,4- oxadiazole targets 39 (Scheme 11). oxadiazoletargets 39 targets(Scheme 39 11 (Scheme). 11).

Scheme 11. 1,2,4-Oxadiazoles synthesis from cyanamides. SchemeScheme 11. 11. 1,2,4-Oxadiazoles1,2,4-Oxadiazoles synt synthesishesis fromfrom cyanamides.cyanamides. Recently, we (Sharma and co-workers) investigated the in situ trapping of a cyanamide anion 44 Recently, we (Sharma and co-workers) investigated the in situ trapping of a cyanamide anion 44 with Recently,1,3-dipoles we like (Sharma nitrile oxide and co-workers) 43 for the syntheses investigated of nitrogen the in siturich trappingheterocycles of a via cyanamide a formal [3 anion + 2] with44cycloaddition 1,3-dipoleswith 1,3-dipoles [19].like nitrileUsing like nitrile oxideTBAF oxide 43as afor re43 theagentfor syntheses the for synthesesboth ofthe nitrogen detosylation of nitrogen rich heterocycles richof N heterocycles-tosyl-cyanamide via a via formal a and formal [3 the + 2] cycloaddition[3dehydrochlorination + 2] cycloaddition [19]. Using [of19 chlorooxime,].TBAF Using as TBAF a re allowedagent as a reagentfor the both formation for the both detosylation of the both detosylation complimentary of N-tosyl-cyanamide of N-tosyl-cyanamide reactive species and the dehydrochlorinationandin one the pot. dehydrochlorination The nucleophilic of chlorooxime, addition of chlorooxime, allowed of the cy allowedtheanamide formation the anion formation of to both the ofnitrile-oxidecomplimentary both complimentary followed reactive by reactive 5-speciesexo- in speciesdigone cyclizationpot. in The one nucleophilic pot. gave The the nucleophilic oxadiazol-5-imine addition addition of the productcy ofanamide the cyanamide 41 in anion excellent anionto the yields tonitrile-oxide the (Scheme nitrile-oxide followed12). These followed by novel 5- byexo - dig5-heterocycles, cyclizationexo-dig cyclization gavewhich the gaveare oxadiazol-5-imine theuseful oxadiazol-5-imine but somewhat product product under-represented 41 41in inexcellent excellent inyields yields pharmaceutical (Scheme 12 12).). drugs, These These novelwere novel heterocycles,heterocycles,further converted which which to are the usefuluseful biologic but butally somewhat somewhat relevant under-represented oxadiazol-5-ones under-represented in 42 pharmaceutical uponin pharmaceutical acidic hydrolysis. drugs, were drugs, Further further were furtherconvertedinvestigation converted to the into biologicallyto the the reactions biologic relevant ofally cyanamide oxadiazol-5-onesrelevant anionoxadiazol-5-ones led42 uponto the acidic syntheses 42 hydrolysis.upon of acidic other Further novelhydrolysis. investigationheterocycles Further investigationintounder the trapping reactions into conditionsthe of cyanamidereactions with of aniondipoles cyanamide led like to thenitrile anion syntheses imine. led to of the other syntheses novel heterocycles of other novel under heterocycles trapping underconditions trapping with conditions dipoles like with nitrile dipoles imine. like nitrile imine.

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SchemeScheme 12. 12.1,2,4-oxadizole-5-imines 1,2,4-oxadizole-5-imines synthesis synthesis from from cyanamides. cyanamides.

3.1.2. [2 + 2 + 2] Cycloaddition 3.1.2. [2 + 2 + 2] Cycloaddition The metal-catalyzed [2 + 2 + 2] cyclotrimerization of substituted cyanamides to triazine products Theare metal-catalyzedwell studied reactions [2 + 2that + 2]have cyclotrimerization been previously reviewed of substituted [2]. In contra cyanamidesst, the co-cyclization to triazine productsof are wellthe studied nitrile moiety reactions of cyanamides that have with been dialkyne previously or alkenyl-nitrile reviewed system [2]. In offers contrast, a route the to functionally co-cyclization of the nitrilediverse moiety six membered of cyanamides heterocyclic with systems dialkyne such oras 2-aminopyridine alkenyl-nitrile systemand amin offersopyrimidine a route derivatives. to functionally diverse six memberedScheme heterocyclic 12. 1,2,4-oxadizole-5-imines systems such as 2-aminopyridine synthesis from and cyanamides. aminopyrimidine derivatives. Early reports routinely employed cobalt-based catalysts for such transformations [20,21]. In more 3.1.2. [2 + 2 + 2] Cycloaddition recent years nickel, iron and iridium-based catalysts have been applied for the co-cyclization of cyanamidesThe metal-catalyzed and alkynes [2 to + render 2 + 2] cyclotrimerization 2-aminopyridine withof substituted excellent cyanamides regiocontrol. to Thetriazine Louie products group arereported well studied the use reactions of Ni(cod) that2 in have combination been previously with IMes reviewed ligand as [2]. an In effective contrast, catalyst the co-cyclization system for the of thereaction nitrile of moiety diyne withof cyanamides a variety ofwith dialkyl dialkyne cyanamides or alkenyl-nitrile to give N system,N-disubstituted offers a route 2-aminopyridines to functionally (Schemediverse six 13 membereda) [22]. heterocyclic systems such as 2-aminopyridine and aminopyrimidine derivatives.

Scheme 13. Metal catalyzed [2 + 2 + 2] cycloaddition reactions of cyanamides.

Early reports routinely employed cobalt-based catalysts for such transformations [20,21]. In more recent years nickel, iron and iridium-based catalysts have been applied for the co-cyclization of cyanamides and alkynes to render 2-aminopyridine with excellent regiocontrol. The Louie group reported the use of Ni(cod)2 in combination with IMes ligand as an effective catalyst system for the reaction of diyne with a variety of dialkyl cyanamides to give N,N-disubstituted 2-aminopyridines (Scheme 13a) [22].

Scheme 13. Metal catalyzed [2 + 2 + 2] 2] cycl cycloadditionoaddition reactions reactions of cyanamides.

Early reports routinely employed cobalt-based catalysts for such transformations [20,21]. In more recent years nickel, iron and iridium-based catalysts have been applied for the co-cyclization of cyanamides and alkynes to render 2-aminopyridine with excellent regiocontrol. The Louie group reported the use of Ni(cod)2 in combination with IMes ligand as an effective catalyst system for the reaction of diyne with a variety of dialkyl cyanamides to give N,N-disubstituted 2-aminopyridines (Scheme 13a) [22].

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Later in 2012, the same group demonstrated the effectiveness of an iron based catalyst system [FeCl2/Zn/L1] for the cyclization reaction [23]. In such systems, the Fe(II) salt is reduced by Zn to a low valent Fe catalyst species, followed by the slow addition of diyne (Scheme 13b). The authors also report the successful intermolecular cyclization of terminal aryl acetylenes with cyanamides to offer 2-amino-4,6-aryl pyridines 51 (Scheme 13c) [24]. Further modification of the iron based catalyst system was introduced by Wan et al., wherein FeI2/dppp/Zn realizes the products in comparable yields and regioselectivity but with the benefit of lower reaction temperatures and catalyst loadings [25]. The [2 + 2 + 2] co-cyclization utilizing cyanamide was further applied by Louie et al. to access aminopyrimidines 53 [26]. The cyclization of alkenyl-nitrile 52 with cyanamide under FeI2, iPrPDAI, Zn dust in toluene gave access to the substituted pyrimidines (Scheme 13d). Given the significance and prevalence of substituted aminopyridines in pharmaceutical drugs and natural product cores, more flexible catalyst systems were developed to improve the yield and selectivity. Takeuchi and co-workers found [Ir(cod)Cl]2/BINAP as an efficient catalyst for the [2 + 2 + 2] cycloaddition of α,ω-diynes 54 with cyanamide nitriles (Scheme 13e). The authors argue that the presence of a phosphine-ligand-offered flexibility with respect to the catalytic activity, which could be achieved by choosing the appropriate phosphine ligand [27].

3.2. N-CN Bond Cleavage The cleavage of the N–CN bond of cyanamide offers: (i) an electrophilic cyanating agent; (ii) amino-transfer group (aminating reagent); as well as (iii) the synchronized transfer of both amino and nitrile-groups, could offer routes to difunctionalization of C–C multiple bond aminocyanation. These reactions of cyanamides are accomplished under both metal catalysis and metal-free conditions, offering highly functionalized substrates. The present section will detail recent pioneering work in these subcategories.

3.2.1. Aminocyanation Metal catalyzed aminocyanation involves the simultaneous installment of an amino and nitrile-group on adjacent carbon atoms, commonly in unsaturated systems. Unlike its congeners, oxycyanation, carbocyanation, thiocyanation etc., the field of aminocyanation is relatively unexplored. The first example of aminocyanation via the cleavage of the N–CN bond by a cooperative palladium/triorganoboron catalysis was reported by Nakao et al. in 2014 [28]. An intramolecular insertion of N–CN into the double bond of N-cyano-N-[2-(2-methylallyl)aryl]acetamide 56 was achieved under the catalytic system: CpPd(allyl), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (xantphos), and BEt3. The 5-exo-trig products were obtained in good to excellent yield under elevated temperature (Scheme 14). The same authors also investigated the enantioselective aminocyanation, by replacing the xantphos ligand with an (R,R,R)-Ph-SKP ligand. A catalytic cycle was proposed, wherein the boron Lewis acid coordinated to the N–CN group 58 undergo oxidative addition to a Pd(0)−xantphos complex. Syn-aminopalladation of 59 in an exo-trig fashion followed by C−CN bond-forming reductive elimination generates the boron-bound product (Scheme 14). Chien and Co-workers synthesized a series of 1-sulfonyl-3-cyanoindole (62) products by CuI catalyzed intramolecular aminocyanation of N-(2-ethynylphenyl)-N-sulfonyl-cyanamides 61 (Scheme 15) [29]. In the presence of CuI and Na2CO3, both terminal ethynyl and TMS-ethynyl-N-tosylcyanamide-substituted aryl-derivatives underwent intramolecular aminocyanation across the C–C triple bond leading to the 3-cyanoindole skeleton. Based on the experimental results with internal alkynes, it was postulated that the reaction proceeds via the formation of a key Cu-acetylide intermediate. Molecules 2017, 22, 615 10 of 28 Molecules 2017, 22, 615 10 of 27

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Scheme 14. Palladium/triorganoboron cooperat cooperativeive catalysis catalysis for for aminocyanation. aminocyanation. Scheme 14. Palladium/triorganoboron cooperative catalysis for aminocyanation.

Scheme 15. Copper catalyzed intramolecular aminocyanation. Scheme 15. Copper catalyzed intramolecular aminocyanation. A metal free intramolecularScheme 15. aminocyanationCopper catalyzed was intramolecular achieved under aminocyanation. Lewis acid catalysis by Douglas et al. Awhich metal proceeds free intramolecular via cleavage aminocyanation of the N–CN bond was of ac cyanamidhieved undere [30]. Lewis The coordinationacid catalysis of by the Douglas Lewis A metal free intramolecular aminocyanation was achieved under Lewis acid catalysis by acidet al. catalyst which proceeds with the viasulfonyl-group cleavage of the lead N–CN to the bond weakening of cyanamid of thee key [30]. N–CN The coordination bond, thereby of theinducing Lewis Douglas et al. which proceeds via cleavage of the N–CN bond of cyanamide [30]. The coordination of bondacid catalyst cleavage. with Hence, the sulfonyl-group starting with a lead variety to the of Nweakening-tosylcyanamides of the key 63 ,N–CN the indoline bond, productsthereby inducing 64 were the Lewis acid catalyst with the sulfonyl-group lead to the weakening of the key N–CN bond, thereby obtainedbond cleavage. in good Hence, yields star whenting treatedwith a variety with equivalent of N-tosylcyanamides quantity of B(C 63, 6theF5) 3indoline. The authors products proposed 64 were a mechanisminducing bond consistent cleavage. with Hence, nucleophil startingic withattack a varietyof the alkene of N-tosylcyanamides on the nitrile center,63, the which indoline is supported products obtained in good yields when treated with equivalent quantity of B(C6F5)3. The authors proposed a 64 were obtained in good yields when treated with equivalent quantity of B(C F ) . The authors bymechanism experimental consistent data (Scheme with nucleophil 16). A comparableic attack of theyield alkene was obtainedon the nitrile when center, the reaction which6 5 3 is was supported carried proposed a mechanism consistent with nucleophilic attack of the alkene on the nitrile center, which is outby experimental with 20 mol data% of (Scheme Lewis acid,16). A although comparable extended yield wasreaction obtained times when were the required. reaction Initiallywas carried the supported by experimental data (Scheme 16). A comparable yield was obtained when the reaction was reactionout with was 20 performedmol % of Lewiswith a acid,rhodium although complex, extended but further reaction investigation times were indicated required. that Initially the N–CN the carried out with 20 mol % of Lewis acid, although extended reaction times were required. Initially the bondreaction activation was performed can be achieved with a rhodium without complex,the addition but offurther any transition investigation metal indicated catalysts. that the N–CN reaction was performed with a rhodium complex, but further investigation indicated that the N–CN bond activation can be achieved without the addition of any transition metal catalysts. bond activation can be achieved without the addition of any transition metal catalysts.

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SchemeScheme 16. 16.Lewis Lewis acid acid activated activated cleavage cleavage of N–CN bond bond for for intramolecular intramolecular aminocyanation. aminocyanation. Scheme 16. Lewis acid activated cleavage of N–CN bond for intramolecular aminocyanation. Another example of a metal-free cleavage of the N–CN bond was described by Zeng et al. [31]. Another example of a metal-free cleavage of the N–CN bond was described by Zeng et al. [31]. The AnotherresearchersScheme example 16.demonstrated Lewis of aacid metal-free activated that aryne-insertion cleavage of of N–CN the acrossN–CN bond for thebond intramolecular N–CN was described bond aminocyanation. to bydeliver Zeng the et al. amino [31]. The researchers demonstrated that aryne-insertion across the N–CN bond to deliver the amino Thebenzonitriles researchers (68 )demonstrated could be achieved that byaryne-insertion in situ generation across of arynesthe N–CN 69 and bond an anionic to deliver species the 44 amino from benzonitrilesAnother (68 )example could beof a achieved metal-free by cleavage in situ of generation the N–CN bond of arynes was described69 and by an Zeng anionic et al. species [31]. 44 benzonitrilesthe mono-substituted (68) could cyanamide. be achieved Both by in of situ the generationreactive species of arynes were 69 generated and an anionic simultaneously species 44 fromvia a The researchers demonstrated that aryne-insertion across the N–CN bond to deliver the amino fromthefluoride the mono-substituted mono-substituted ion source (CsF). cyanamide. cyanamide. The aryne Both underwent Both of the of thereac nu reactivetivecleophilic species species additionwere were generated to generated give simultaneouslythe phenyl-anion simultaneously via 70 a, via benzonitriles (68) could be achieved by in situ generation of arynes 69 and an anionic species 44 from a fluoridefluoridewhich on ion ion cyclization source source (CsF). (CsF). gave The Thethe arynehighlyaryne underwent strained four-membered nu nucleophiliccleophilic addition intermediate addition to give to 71 give .the Ring thephenyl-anion opening phenyl-anion of the70, 70, the mono-substituted cyanamide. Both of the reactive species were generated simultaneously via a whichwhichintermediate on cyclizationon cyclization 71 and gave protonation gave the the highly highly led strainedto strained the final four-memberedfour-membered aminocyanated intermediate product intermediate (Scheme 71.71 Ring .17). Ring opening opening of the of the fluoride ion source (CsF). The aryne underwent nucleophilic addition to give the phenyl-anion 70, intermediateintermediate71 and71 and protonation protonation led led to to the thefinal final aminocyanatedaminocyanated product product (Scheme (Scheme 17). 17 ). which on cyclization gave the highly strained four-membered intermediate 71. Ring opening of the intermediate 71 and protonation led to the final aminocyanated product (Scheme 17).

Scheme 17. Aminocyanation of arynes. Scheme 17. Aminocyanation of arynes. 3.2.2. Aminating Agent Scheme 17. Aminocyanation of arynes. Scheme 17. Aminocyanation of arynes. 3.2.2. Aminating Agent 3.2.2. AminatingIn 2014 Nageswar Agent and co-workers reported the amination of 2-halobenzothiazole and benzoxazole 3.2.2. Aminating Agent derivativesIn 2014 on Nageswar reaction andwith co-workers dialkyl cyanamides reported untheder am Ru/Cination catalysis of 2-halobenzothiazole (Scheme 18). The and reaction benzoxazole utilizes derivativescyanamidesIn 2014In 2014 Nageswar on as Nageswar reaction aminating and with and co-workers agent co-workersdialkyl with cyanamides the reported reported concomitant theuntheder am amination Ru/Cinationloss of catalysis nitrileof of 2-halobenzothiazole 2-halobenzothiazole group(Scheme [32]. 18). The and reaction andbenzoxazole benzoxazole utilizes derivativescyanamidesderivatives on on reactionas aminatingreaction with with agent dialkyldialkyl with cyanamides cyanamidesthe concomitant under under Ru/Closs Ru/Cof catalysis nitrile catalysis group(Scheme [32]. (Scheme 18). The reaction 18). The utilizes reaction utilizescyanamides cyanamides as aminating as aminating agent agentwith the with concomitant the concomitant loss of nitrile loss group of nitrile [32]. group [32].

Scheme 18. Cyanamide as aminating agent.

Scheme 18. Cyanamide as aminating agent. Scheme 18. Cyanamide as aminating agent. Scheme 18. Cyanamide as aminating agent.

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Molecules 2017, 22, 615 12 of 27 3.2.3. Electrophilic Cyanation 3.2.3. Electrophilic Cyanation N-Sulfonyl cyanamides viz N-cyano-N-tosyl-sulfonamide (74, NCTS), also known as N-cyano-N-SulfonylN-phenyl- cyanamidesp-methylbenzene-sulfonamide viz N-cyano-N-tosyl-sulfonamide [33], are popular (74, NCTS), cyanamide also known derivatives as N-cyano- with N-phenyl-p-methylbenzene-sulfonamide [33], are popular cyanamide derivatives with significant significant applications in synthetic chemistry. The reactivity and stereoelectronic properties of the applications in synthetic chemistry. The reactivity and stereoelectronic properties of the sulfonyl sulfonyl group have been exploited to orchestrate diverse reactions of cyanamides; e.g., Lewis acid group have been exploited to orchestrate diverse reactions of cyanamides; e.g., Lewis acid assisted assisted aminocyanation [30], generation of cyanamide anion by action of a nucleophilic fluoride aminocyanation [30], generation of cyanamide anion by action of a nucleophilic fluoride ion [19], ion [19], electrophilic cyanation by reaction with Grignard reagents [34] as well as for heterocyclic electrophilic cyanation by reaction with Grignard reagents [34] as well as for heterocyclic ring ring construction [35,36]. Since the re-introduction of NCTS by Beller et al. in 2011 as an efficient construction [35,36]. Since the re-introduction of NCTS by Beller et al. in 2011 as an efficient electrophilic electrophilic cyanation source of aryl- and alkenyl-substrates under rhodium catalysis [37], there has cyanation source of aryl- and alkenyl-substrates under rhodium catalysis [37], there has been a been a growing interest in developing new catalytic metal systems for such reactions [38,39]. growing interest in developing new catalytic metal systems for such reactions [38,39]. Wang and co-workers reported the first example of rhodium-catalyzed intramolecular C–H Wang and co-workers reported the first example of rhodium-catalyzed intramolecular C–H cyanationcyanation in in 2013 2013 [ 40[40].]. TheThe intramolecularintramolecular C–H cyanation of of an an appropriately appropriately decorated decorated styrene styrene substratesubstrate (75 (75)) was was achieved achieved viavia aa rhodium(I)-catalyzedrhodium(I)-catalyzed N–CN cleavage cleavage (Scheme (Scheme 19a). 19a). Good Good substrate substrate tolerancetolerance was was shown shown forfor differentdifferent substituentssubstituents attached attached on on the the arene arene ring ring and and styrene styrene αα-position.-position. Alkyl-substituentsAlkyl-substituents inin thethe olefinicolefinic αα-position-position of the styrene styrene has has led led to to acrylonitriles acrylonitriles in in good good yields, yields, whereaswhereas corresponding corresponding arenearene substitutionsubstitution on the olefinicolefinic α-position,-position, resulted resulted in in moderate moderate yields yields of of thethe cyanated cyanated products. products. TheThe reactionreaction establishesestablishes the the importance importance of of αα-substitution-substitution in in styrene styrene for for the the cyanationcyanation to to be be feasible. feasible.

SchemeScheme 19.19. Rhodium-catalyzedRhodium-catalyzed electrophilic cyanation cyanation with with NCTS. NCTS.

Fu and co-workers reported the syntheses of aromatic nitriles 78 under Rh-catalyzed directed C−HFu cyanation and co-workers using NCTS reported as the synthesescyanating ofagent aromatic (Scheme nitriles 19b)78 [41].under The Rh-catalyzed cyanation was directed first Cdeveloped−H cyanation for acetophenone using NCTS O as-methyl the cyanating oxime substrates agent (Scheme (77) and 19 eventuallyb) [41]. The extended cyanation to different was first developeddirecting groups for acetophenone such as pyridiO-methylnes, pyrazoles, oxime substratesdihydroimidazoles (77) and eventuallyand dihydrooxazoles, extended towhich different all directingresulted groupsin moderate such asto pyridines,good yields pyrazoles, of the nitr dihydroimidazolesile products. The reaction and dihydrooxazoles, was found to tolerate which a all resultedvariety inof moderatesynthetically to gooddemanding yields offunctional the nitrile groups products. (e.g., Theunprotected reaction wasphenol, found Ar-I, to epoxide), tolerate a which variety ofproved synthetically to be challenging demanding with functional other tr groupsansition (e.g., metal unprotected catalysts such phenol, as Pd. Ar-I, epoxide), which proved to be challengingA series of withreports other on transitionthe chelation metal assisted catalysts C–H such activation as Pd. for cyanation under Rh-catalysis withA NCTS series ofhave reports since on appeared. the chelation Anbarasan assisted et C–Hal. described activation the for cyanation cyanation of under phenyl Rh-catalysis pyridines with79 NCTSwith have[RhCp*Cl since2]2appeared. catalyst inAnbarasan the presence et al.of AgSbF described6 (Scheme the cyanation 19c) [42]. of This phenyl method pyridines allowed79 withthe synthesis of various aryl nitrile derivatives in good to excellent yields, while reducing the catalytic loading to 1 mol %.

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[RhCp*Cl2]2 catalyst in the presence of AgSbF6 (Scheme 19c) [42]. This method allowed the synthesis of various aryl nitrile derivatives in good to excellent yields, while reducing the catalytic loading to 1 mol %. The H.-Y. Ding group on the other hand employed the chelation-assisted ortho-cyanation on arylphosphate substrates 81 under rhodium catalysis (Scheme 19d) [43]. The protocol delivered complete ortho-selectivity, thereby hindering the formation of biscyanated aryl-phosphonate byproducts. Zhu and co-workers applied the rhodium based catalytic protocol for C–H cyanation of symmetric azobenzenes (83) at the ortho-position (Scheme 19e) [44]. The protocol was more effective for the cyanation of aromatic azo-compounds having electron donating groups than those with electron withdrawing groups. Chelation assisted C–H functionalization was extended to the indole and indoline scaffolds. Indole and indolines are ubiquitous structural motifs found in natural products and find application in pharmaceuticals, agrochemicals and dyes. The introduction of cyano groups to these structural motifs provides a means of decorating the indole and indoline rings. In particular, selective C-2 cyanation of indoles and C-7 cyanation of indolines have received much attention. In 2015, Kim et al. Molecules 2017, 22, 615 13 of 27 reported site selective, directing group-assisted C−H cyanation of indolines and indoles at the C-7 andThe C-2 H.-Y. positions Ding group respectively, on the viaother rhodium-catalyzed hand employed the reaction chelation-assisted with NCTS ortho (Scheme-cyanation 20a) on [45 ]. Thearylphosphate results indicated substrates that 81N under-carbonyl rhodium or carbamoyl-directing catalysis (Scheme 19d) groups [43]. The act protocol very effectively delivered complete in the C-7 cyanationortho-selectivity,(compounds thereby85 hinderingto 86), whereas the formation C-2, C-3of biscyanated or C-4 substituted aryl-phosphonateN-pivaloyl-indolines byproducts. deliver the C-7Zhu cyanated and co-workers products applied only inthe moderate rhodium based to good catalytic yields. protocol A similar for C–H protocol cyanation was of usedsymmetric in the synthesisazobenzenes of C2-cyanated (83) at the indolesortho-position88, utilizing (Scheme a removable 19e) [44]. The pyrimidyl-directing protocol was more group effective to achieve for the the desiredcyanation product of aromatic in excellent azo-compounds yields. Extending having their electr work,on donating Kim et al. groups reported than the those C-7 cyanation with electron of C-2 substitutedwithdrawing indoles groups.93 and 94 (Scheme 20c) [46].

SchemeScheme 20. 20.Rhodium Rhodium catalyzedcatalyzed electrophilic cyanation cyanation with with NCTS. NCTS.

Chelation assisted C–H functionalization was extended to the indole and indoline scaffolds. Indole and indolines are ubiquitous structural motifs found in natural products and find application in pharmaceuticals, agrochemicals and dyes. The introduction of cyano groups to these structural motifs provides a means of decorating the indole and indoline rings. In particular, selective C-2 cyanation of indoles and C-7 cyanation of indolines have received much attention. In 2015, Kim et al. reported site selective, directing group-assisted C−H cyanation of indolines and indoles at the C-7 and C-2 positions respectively, via rhodium-catalyzed reaction with NCTS (Scheme 20a) [45]. The results indicated that N-carbonyl or carbamoyl-directing groups act very effectively in the C-7 cyanation (compounds 85 to 86), whereas C-2, C-3 or C-4 substituted N-pivaloyl-indolines deliver the C-7 cyanated products only in moderate to good yields. A similar protocol was used in the synthesis of C2-cyanated indoles 88, utilizing a removable pyrimidyl-directing group to achieve the desired product in excellent yields. Extending their work, Kim et al. reported the C-7 cyanation of C-2 substituted indoles 93 and 94 (Scheme 20c) [46]. Appearing at a similar time as Kim’s report, a publication by the Anbarasan group described the electrophilic C-2 selective cyanation of indoles and pyroles (Scheme 20b) [47]. The cyanation process was assisted by a removable directing group such as N-pyridyl, N-quinolyl and N-pyrimidyl. The

Molecules 2017, 22, 615 14 of 28

MoleculesAppearing 2017, 22 at, 615 a similar time as Kim’s report, a publication by the Anbarasan group described14 of 27 the electrophilic2-cyanoindoles C-2and selectivepyrrole products cyanation were ofobtained indoles in andthe presence pyroles of (Scheme low catalyst 20 b)loadings [47]. The(1–3 mol cyanation %) processand wasadditives. assisted by a removable directing group such as N-pyridyl, N-quinolyl and N-pyrimidyl. The 2-cyanoindolesConcurrently andto the pyrrole C–H cyanation products study were of obtained indoles and in thepyrroles, presence Anbarasan of low and catalyst co-workers loadings (1–3also mol reported %) and additives.the C–H cyanation of acrylonitriles/vinyl-nitriles (95) with NCTS via rhodium(III) catalysisConcurrently (Scheme to 20d). the C–H In this cyanation case, Cu(OAc) study2 ofwas indoles used as and an additive pyrroles, [48]. Anbarasan The new andmethod co-workers tolerates also reporteda variety the of C–H functional cyanation groups, of acrylonitriles/vinyl-nitriles thereby allowing the synthesis (95 of) di withverse NCTS substituted via rhodium(III) acrylonitriles catalysis 96. (Scheme Rhodium20d). In this catalyzed case, Cu(OAc) C–H cyanation2 was usedof substituted as an additive vinyl amides [48]. The 97 with new NCTS method to access tolerates alkenyl- a variety of functionalnitriles (98 groups,) was accomplished thereby allowing by Fu the et synthesisal. (Scheme of 20 diversee) [49]. substituted This methodology acrylonitriles exhibited96. good functionalRhodium group catalyzed tolerance C–H and cyanation both acrylamides of substituted and ketoximes vinyl could amides be used97 aswith directing NCTS groups. to access Expanding the scope of the rhodium catalyzed C−H cyanation with NCTS, Yi and co-workers alkenyl-nitriles (98) was accomplished by Fu et al. (Scheme 20e) [49]. This methodology exhibited good reported the C−H cyanation of a wide range of ortho-substituted N-methoxybenzamides 99 (Scheme 20f). functional group tolerance and both acrylamides and ketoximes could be used as directing groups. The reactions showed good substrate and functional group tolerance [50]. The new protocol delivers Expanding the scope of the rhodium catalyzed C−H cyanation with NCTS, Yi and co-workers products with good regioselectivity and under mild reaction conditions. reportedRecently the C− SunH et cyanation al. reported ofthe asynt widehesis rangeof 2-(alkylamino)benzonitriles of ortho-substituted 102N -methoxybenzamidesvia a rhodium catalyzed 99 (Schemearyl C 20−Hf). cyanation The reactions and denitrosation showed of good N-nitrosoarylamines substrate and functional101 with NCTS group (Scheme tolerance 20g) [51]. [50 The]. The new new protocolreaction delivers demonstrated products good with tolerance good regioselectivity to a wide range and of undersubstituents mild reactionon the aryl-ring conditions. and amino- group,Recently while Sun delivering et al. reported the corresponding the synthesis products of 2-(alkylamino)benzonitrilesin moderate to good yields. 102 via a rhodium catalyzedIn addition aryl C− toH rhodium, cyanation cobalt and anddenitrosation ruthenium catalysts of N have-nitrosoarylamines also been developed101 aswith efficient NCTS (Schemetransition 20g) [metal51]. The catalysts new reactionfor the electrophilic demonstrated cyanation good tolerance of C–H bond to a by wide NCTS. range of substituents on the aryl-ringThe and first amino-group, example of whilea cobalt-catalyzed delivering thecyanat correspondingion of C–H bonds products with in NCTS moderate was reported to good by yields. AckermannIn addition and to rhodium,Li in 2014 cobalt(Scheme and 21a) ruthenium [52]. The reaction catalysts was have found also to beenbe dependent developed on asthe efficient co- transitioncatalyst metal AgSbF catalysts6 and carboxylate for the electrophilic additives. Mechanistic cyanation studies of C–H indicate bond by that NCTS. in situ generation of the highly active cationic cobalt(III) acetate is vital for site-selective ortho-cyanation. The methodology is The first example of a cobalt-catalyzed cyanation of C–H bonds with NCTS was reported by also applicable to removable directing groups such as pyridyl, pyrimidyl and pyrazole. Ackermann and Li in 2014 (Scheme 21a) [52]. The reaction was found to be dependent on the co-catalyst In 2014 Glorius and co-workers reported the C–H cyanation of heteroaryls (ortho-cyanation), AgSbFindoles6 and (C-2 carboxylate cyanation), additives. and olefins Mechanistic under cobalt studies catalysis indicate (Scheme that 21b) in [53]. situ The generation method ofexhibited the highly activegood cationic functional cobalt(III) group tolerance acetate isan vitald high for efficacy site-selective when usedortho in combination-cyanation. with The different methodology directing is also applicablegroups to(pyridyl, removable pyrimidyl directing and pyrazole). groups such as pyridyl, pyrimidyl and pyrazole.

Scheme 21. Cobalt catalyzed electrophilic cyanation with NCTS. Scheme 21. Cobalt catalyzed electrophilic cyanation with NCTS. Recently the Gosmini’s group reported the C–H cyanation of aryl-zinc compounds catalyzed by cobalt(II)In 2014 [54]. Glorius The study and co-workers was inspired reported by utilizatio then of C–H mild cyanation reaction conditions of heteroaryls and one-pot (ortho synthesis-cyanation), indolesof aryl-zinc (C-2 cyanation), derivatives and from olefins aryl-halides under and cobalt subsequent catalysis cyanation (Scheme using 21b) the [53 same]. The cobalt(II) method catalyst exhibited good(Scheme functional 21c). group In contrast tolerance to previous and high reports, efficacy Gosmini’s when protocol used in combinationuses low valent with cobalt(II) different catalysts. directing groupsHowever, (pyridyl, in this pyrimidyl case, a catalytic and pyrazole). amount of zinc dust was used to release the reactive cobalt species inRecently the cyanation the Gosmini’s step. Despite group the high reported tolerance the level, C–H the cyanation authors ofreport aryl-zinc that the compounds protocol is ineffective catalyzed by cobalt(II)in the [presence54]. The of study a strong was chelating inspired group by utilization (ketone or of nitrile) mild reaction on the aryl-zinc conditions species. and one-pot synthesis of aryl-zinc derivatives from aryl-halides and subsequent cyanation using the same cobalt(II) catalyst Molecules 2017, 22, 615 15 of 28

(Scheme 21c). In contrast to previous reports, Gosmini’s protocol uses low valent cobalt(II) catalysts. However, in this case, a catalytic amount of zinc dust was used to release the reactive cobalt species in the cyanation step. Despite the high tolerance level, the authors report that the protocol is ineffective in the presence of a strong chelating group (ketone or nitrile) on the aryl-zinc species. RecentlyMolecules 2017 Morandi, 22, 615 et al. described the first cobalt(III) catalyzed C–C bond cleavage of15 secondary of 27 and tertiary alcohols and subsequent electrophilic cyanation by NCTS (Scheme 21d) [55]. In this MoleculesRecently 2017, 22 Morandi, 615 et al. described the first cobalt(III) catalyzed C–C bond cleavage of secondary15 of 27 β protocol,and directing tertiary alcohols groups and such subsequent as pyridyl electrophilic are important cyanation to both by facilitate NCTS (Scheme the -carbon 21d) [55]. elimination In this and + stabilizeprotocol, theRecently cobalt-aryl directing Morandi groups intermediate et al. such described as againstpyridy the lfirst proto-demetallationare cobaltimportant(III) catalyzedto both priorfacilitate C–C tobond electrophile/[CN]the cleavage β-carbon of elimination secondarytrapping. Mechanisticand tertiarystabilize studies alcohols the indicate cobalt-aryl and that subsequent intermediate the cyanation electrophilic against takes proto-demetallationcyanation place directly by NCTS from prior(Scheme the to cobalt-aryl electrophile/[CN] 21d) [55].intermediate In this+ rathertrapping.protocol, than prior directingMechanistic protonation groups studies followedsuch indicate as pyridy by that C–Hl are the activation.important cyanation to takes both place facilitate directly the βfrom-carbon the eliminationcobalt-aryl + Theintermediateand Ackermann stabilize ratherthe groupcobalt-aryl than prior have intermediate protonation also explored followedagainst the proto-demetallation applicabilityby C–H activation. of ruthenium(II) prior to electrophile/[CN] catalysts for C–H trapping. Mechanistic studies indicate that the cyanation takes place directly from the cobalt-aryl cyanationThe with Ackermann NCTS (Scheme group 22havea) [also56]. explored Ackermann the applicability explored the of ruthenium(II) feasibility of catalysts a ruthenium for C–H catalyst cyanationintermediate with rather NCTS than (Scheme prior protonation 22a) [56]. Ackermann followed by explored C–H activation. the feasibility of a ruthenium catalyst with weakly coordinating amide groups for chelation assisted directed C–H cyanation of arenes and with Theweakly Ackermann coordinating group amide have groups also explored for chelation the applicability assisted directed of ruthenium(II) C–H cyanation catalysts of arenes for C–H and heteroarenes.heteroarenes.cyanation The with protocolThe NCTS protocol (Scheme proved proved 22a) to to be[56]. be effective, effective, Ackermann demonstrating explored the good feasibility good substrate substrate of a scope ruthenium scope and tolerance and catalyst tolerance to a widetowith a rangewide weakly range of coordinating functional of functional groups.amide groups. groups for chelation assisted directed C–H cyanation of arenes and heteroarenes. The protocol proved to be effective, demonstrating good substrate scope and tolerance to a wide range of functional groups.

Scheme 22. Ruthenium catalyzed electrophilic cyanation with NCTS. Scheme 22. Ruthenium catalyzed electrophilic cyanation with NCTS. Deb et al. demonstratedScheme 22. Rutheniumruthenium(II) catalyzed catalyzed electrop orthohilic-aryl cyanation C–H withcyanation NCTS. of azoindoles with DebNCTS et (Scheme al. demonstrated 22b) [57]. ruthenium(II) catalyzed ortho-aryl C–H cyanation of azoindoles with NCTS (SchemeADeb general et 22 al.b) mechanismdemonstrated [57]. can ruthenium(II) be proposed forcatalyzed the metal ortho catalyzed-aryl C–H reactions: cyanation Initial of azoindolesC–H metalation with AisNCTS general followed (Scheme mechanism by the 22b) coordination [57]. can be proposedand migratory for theinsertion metal of catalyzed NCTS. Finally, reactions: β-elimination Initial C–Hand proto- metalation A general mechanism can be proposed for the metal catalyzed reactions: Initial C–H metalation is followeddemetallation by the results coordination in the corresponding and migratory produc insertiont and the regenerated of NCTS. cationic Finally, M(II/III)β-elimination catalyst and (Schemeis followed 23). by the coordination and migratory insertion of NCTS. Finally, β-elimination and proto- proto-demetallationdemetallation results results in in the the corresponding corresponding produc productt and and the theregenerated regenerated cationic cationic M(II/III) M(II/III) catalyst catalyst (Scheme(Scheme 23). 23).

Scheme 23. General catalytic cycle for metal catalyzed [Ru, Rh, Co] C–H activation and cyanation.

Scheme 23. General catalytic cycle for metal catalyzed [Ru, Rh, Co] C–H activation and cyanation. Scheme 23. General catalytic cycle for metal catalyzed [Ru, Rh, Co] C–H activation and cyanation.

Molecules 2017, 22, 615 16 of 28

In 2014 Buchwald and Yang reported the copper catalyzed ortho C−H cyanation of vinylarenes (121) with NCTS (Scheme 24a) [58]. Inspired by using π-directing groups instead of strong σ-directing groups, the team developed the reaction with vinyl-arenes. Here, the C–C double bond acts as both a reaction site, which undergoes simultaneous borylation, and as a directing group. The proposed mechanism involves transmetallation of the phosphine-ligated copper catalyst with the diboron reagent, which then undergoes subsequent borocupration to form the benzyl-copper intermediate 131. Electrophilic ortho-cyanation takes place on the benzyl-copper intermediate with NCTS to give the dearomatized cyanation product 132, which transforms to the aromatized product 122 via rapid H-transfer (Scheme 25). The mechanism was further explored by Yang and Liu. Diverse vinyl naphthylenes bearing both electron donating and withdrawing groups undergo this site-selective transformation in good yield. The resulting borylated compounds can be diversified effectively into otherMolecules useful 2017, 22 complex, 615 molecules. 16 of 27

Scheme 24. Copper-catalyzed electrophilic cyanation with NCTS.

ExploringIn 2014 Buchwald the simultaneous and Yang reportedortho-cyanation the copper and catalyzed hydroboration ortho C− ofH styrenecyanation derivatives of vinylarenes with NCTS/(BPin)(121) with NCTS2 system, (Scheme Montgomery 24a) [58]. Inspired et al. disclosed by using the π-directing use of N -heterocyclicgroups instead carbene of strong (NHC)-ligated σ-directing Cu-catalystsgroups, the team (Scheme developed 24b) [59 the]. Thereac protocoltion with required vinyl-arenes. mild reactionHere, the conditions C–C double and bond was acts compatible as both witha reaction a broad site, range which of substituted undergoes styrenes, simultaneous resulting borylation, in selective andortho as -cyanationa directing on group. the least The substituted proposed orthomechanism-position. involves Polycyclic transmetallation substrates with of extendedthe phosphine-ligated conjugation gavecopper the catalyst cyanation with on the adjacentdiboron ringreagent, structure. which then The resultingundergoes products subsequent were borocu furtherpration derivatized to form tothe indanone benzyl-copper derivatives intermediate via a novel 131. AgNOElectrophilic3/Selectfluor-mediated ortho-cyanation takes radical place cyclization. on the benzyl-copper This two-step protocolintermediate provides with an NCTS efficient to give method the fordearomatized cyclopentannulation cyanation ofproduct styrenes. 132, which transforms to the aromatized product 122 via rapid H-transferThe group (Scheme also reported25). The anmechanism unprecedented was copper-NHCfurther explored based by catalyst Yang systemand Liu. for Diverse the cyanation vinyl andnaphthylenes diborylation bearing of terminal both electron allenes donating125 with NCTS/(BPin)and withdrawing2 (Scheme groups 24 undergoc). The protocol this site-selective exhibited exceptionaltransformation chemo-, in good region- yield. and The diastereoslectivity, resulting borylated while compounds being compatible can be diversified with trifunctionalization effectively into ofother a variety useful of complex terminal molecules. allenes [60 ]. MoreExploring recently, the simultaneous Yang applied ortho NCTS-cyanation for cyanation and hydroboration of 1-allyl-2-vinylnaphthalenes of styrene derivatives127 under with copperNCTS/(BPin) catalysis2 system, (Scheme Montgomery 24d) [61]. et Similar al. disclosed to previous the use work, of N-heterocyclic this reaction carbene cascade (NHC)-ligated was initiated byCu-catalysts a copper catalyzed (Scheme electrophilic24b) [59]. The dearomatization protocol required process. mild Thereaction resulting conditions dearomatized and was intermediate compatible undergoeswith a broad a regio range and of stereospecific substituted 1,3-transpositionstyrenes, resulting of anin allyl-fragmentselective ortho via-cyanation a rearomatizing on the Copeleast rearrangementsubstituted ortho to-position. give the Polycyclic final compound substrates128 .with This extended method conjugation also demonstrated gave the promising cyanation resultson the againstadjacent a ring wide structure. range of substratesThe resulting differing products at the we naphthylre further moiety derivatized and the to migratingindanone derivatives allyl fragment. via a novelCyanation AgNO3/Selectfluor-mediated of arene diazonium salts radical are knowncyclization. to be This challenging two-stepdue protocol to homo-coupling provides an efficient at high temperaturesmethod for cyclopentannulation and ready decomposition. of styrenes. Lee et al. reported a palladium based electrophilic cyanation protocolThe forgroup synthetically also reported challenging an unprecedented arenediazonium copper-NHC tetrafluoroborates based catalyst and system aryl halides for the with cyanation NCTS and diborylation of terminal allenes 125 with NCTS/(BPin)2 (Scheme 24c). The protocol exhibited exceptional chemo-, region- and diastereoslectivity, while being compatible with trifunctionalization of a variety of terminal allenes [60]. More recently, Yang applied NCTS for cyanation of 1-allyl-2-vinylnaphthalenes 127 under copper catalysis (Scheme 24d) [61]. Similar to previous work, this reaction cascade was initiated by a copper catalyzed electrophilic dearomatization process. The resulting dearomatized intermediate undergoes a regio and stereospecific 1,3-transposition of an allyl-fragment via a rearomatizing Cope rearrangement to give the final compound 128. This method also demonstrated promising results against a wide range of substrates differing at the naphthyl moiety and the migrating allyl fragment. Cyanation of arene diazonium salts are known to be challenging due to homo-coupling at high temperatures and ready decomposition. Lee et al. reported a palladium based electrophilic cyanation protocol for synthetically challenging arenediazonium tetrafluoroborates and aryl halides with NCTS under mild reaction conditions [62]. The authors emphasized the importance of using a polar solvent (e.g., EtOH) for the reaction, presumably due to its involvement in the reduction of Pd(II) to Pd(0) together with the generation of CH3COOH (Scheme 26).

Molecules 2017, 22, 615 17 of 28 under mild reaction conditions [62]. The authors emphasized the importance of using a polar solvent (e.g., EtOH) for the reaction, presumably due to its involvement in the reduction of Pd(II) to Pd(0) Moleculestogether 2017 with, 22 the, 615 generation of CH3COOH (Scheme 26). 17 of 27 Molecules 2017, 22, 615 17 of 27

Scheme 25. Copper catalytic cycle for C–H cyanation. Scheme 25. Copper catalytic cycle for C–H cyanation.

Scheme 26. Palladium-catalyzed electrophilic cyanation with NCTS. Scheme 26. Palladium-catalyzed electrophilic cyanation withwith NCTS.NCTS. While NCTS is the reagent of choice for many transition metal catalyzed cyanation protocols, While NCTS is the reagent of choice for many transition metal catalyzed cyanation protocols, efforts have also been directed towards the development of transition-metal-free conditions. An early effortsWhile have NCTS also been is the directed reagent towards of choice the fordevelo manypment transition of transition-metal-f metal catalyzedree cyanationconditions. protocols, An early example of NCTS for cyanation under metal-free conditions was reported by the groups of Beller and effortsexample have of NCTS also been for cyanation directed towards under metal-free the development conditions of transition-metal-free was reported by the conditions.groups of Beller An early and Wang [4,63]. Beller and colleagues employed NCTS in the direct cyanation of aryl and heteroaryl- exampleWang [4,63]. of NCTS Beller for and cyanation colleagues under employed metal-free NCTS conditions in the direct was cyanation reported byof thearylgroups and heteroaryl- of Beller halides via in situ generated Grignard reagents, to synthesize a diverse array of benzonitrile derivatives. andhalides Wang via in [4 situ,63]. generated Beller andGrignard colleagues reagents, employed to synthesize NCTS a diverse in the array direct of benzonitrile cyanation of derivatives. aryl and Meanwhile the Wang group demonstrated the applicability of NCTS for the site-selective cyanation heteroaryl-halidesMeanwhile the Wang via ingroup situ generateddemonstrated Grignard the applicab reagents,ility to synthesizeof NCTS for a diverse the site-selective array of benzonitrile cyanation of indoles and pyrroles under Lewis acid catalysis. of indoles and pyrroles under Lewis acid catalysis. In 2016 Minakata et al. reported the cyanation of boron enolates 141 with NCTS [64]. Inspired In 2016 Minakata et al. reported the cyanation of boron enolates 141 with NCTS [64]. Inspired by synthesizing β-ketonitriles 142, which are important building blocks in the synthesis of different by synthesizing β-ketonitriles 142, which are important building blocks in the synthesis of different heterocycles (pyrazoles, pyrimidines, thiophenes), Minakata planned to intercept the electrophilic heterocycles (pyrazoles, pyrimidines, thiophenes), Minakata planned to intercept the electrophilic nitrile (NCTS) with an enolate. Boron enolates were derived from either the ketone 137 or the nitrile (NCTS) with an enolate. Boron enolates were derived from either the ketone 137 or the α,β-unsaturated ketone 138 and the resulting enolate 141 was reacted with NCTS under milder reaction α,β-unsaturated ketone 138 and the resulting enolate 141 was reacted with NCTS under milder reaction conditions. Even though the mechanistic aspect of the reaction is yet not fully resolved, the pathway conditions. Even though the mechanistic aspect of the reaction is yet not fully resolved, the pathway

Molecules 2017, 22, 615 18 of 28 derivatives. Meanwhile the Wang group demonstrated the applicability of NCTS for the site-selective cyanation of indoles and pyrroles under Lewis acid catalysis. In 2016 Minakata et al. reported the cyanation of boron enolates 141 with NCTS [64]. Inspired by synthesizing β-ketonitriles 142, which are important building blocks in the synthesis of different heterocycles (pyrazoles, pyrimidines, thiophenes), Minakata planned to intercept the electrophilic nitrile (NCTS) with an enolate. Boron enolates were derived from either the ketone 137 or the α,β-unsaturated ketone 138 and the resulting enolate 141 was reacted with NCTS under milder Molecules 2017, 22, 615 18 of 27 reaction conditions. Even though the mechanistic aspect of the reaction is yet not fully resolved, theis believed pathway to is be believed initiated to by be the initiated activation by the of NC activationTS via coordination of NCTS via to coordination the Lewis acidic to the boron Lewis center. acidic boronThis coordination center. This is coordination also assumed is to also enhance assumed the tonucleophilicity enhance the nucleophilicity of the boron-enolate, of the boron-enolate,promoting the promotingcyanation. A the diverse cyanation. range A of diverse β-ketonitriles range ofwereβ-ketonitriles synthesized were throug synthesizedh this protocol through exhibiting this protocol ample exhibitingscope for substrates ample scope (Scheme for substrates 27). (Scheme 27).

Scheme 27. Metal free cyanationcyanation of boronenolates.

3.3. Cyanamides in Radical Reactions Cyanamide-based radical cascade reactions are emerging as an important tool to access nitrogen-containing polycyclic frameworks. These compounds are key intermediates in heterocyclic natural products. products. The The radical radical cascade cascade reactions reactions allo alloww rapid rapid access access to complex to complex cores, cores, initiated initiated with withsimple simple starting starting materials, materials, while whilemaintaining maintaining not on notly atom- only and atom- step-economy, and step-economy, but also but high also stereo- high stereo-selectivity.selectivity. The seminal The seminal work in work this inarea this was area reported was reported by Fensterbank by Fensterbank et al [65,66]. et al [65 ,66]. Extending their previously reported radical cascade reactions of N-acyl-cyanamides to generate guanidine derivatives, Fensterbank et al. achieved the syntheses of two natural products; deoxyvasicinone (143) and mackinazolinone (144). The group also synthesized two guanidine analogues, α-methyldeoxyvasicinone (145) and α,α’-dimethyldeoxyvasicinone (146)[67]. The 5,6,6-and 6,6,6-tricyclic guanidine derivatives were successfully synthesized in good yields by reacting N-acylcyanamide with Bu3SnH and AIBN in benzene under reflux conditions (Scheme 28). This protocol was not only effective with the previously reported aminyl- and vinyl-radicals, but also compatible with alkyl-radicals. Alkyl substituted N-acylcyanamides were cyclized in both 5- and 6-exo-dig pathways, although the 6-exo-dig cyclization was comparatively slower. Attempts to achieve tin-free reaction conditions with (TMS)3SiH resulted in substantially lower yields. The mechanism of the reaction was postulated to proceed with the formation of an alkyl radical via the abstraction of phenyl-selenide by a tributyltin-radical. The resulting alkyl-radical undergoes 5- or 6-exo-dig cyclization, forming the amide-iminyl-radical, which itself undergoes a final rearomatization–cyclization through β-hydrogen abstraction by AIBN (Scheme 29).

Scheme 28. Radical reaction of N-acyl-cyanamides for the synthesis of guanidine based natural products.

Extending their previously reported radical cascade reactions of N-acyl-cyanamides to generate guanidine derivatives, Fensterbank et al. achieved the syntheses of two natural products; deoxyvasicinone (143) and mackinazolinone (144). The group also synthesized two guanidine analogues, α-methyldeoxyvasicinone (145) and α,α’-dimethyldeoxyvasicinone (146) [67]. The 5,6,6- and 6,6,6-tricyclic guanidine derivatives were successfully synthesized in good yields by reacting N-acylcyanamide with Bu3SnH and AIBN in benzene under reflux conditions (Scheme 28). This protocol

Molecules 2017, 22, 615 18 of 27 is believed to be initiated by the activation of NCTS via coordination to the Lewis acidic boron center. This coordination is also assumed to enhance the nucleophilicity of the boron-enolate, promoting the cyanation. A diverse range of β-ketonitriles were synthesized through this protocol exhibiting ample scope for substrates (Scheme 27).

Scheme 27. Metal free cyanation of boronenolates.

3.3. Cyanamides in Radical Reactions Cyanamide-based radical cascade reactions are emerging as an important tool to access nitrogen-containing polycyclic frameworks. These compounds are key intermediates in heterocyclic natural products. The radical cascade reactions allow rapid access to complex cores, initiated with Moleculessimple starting2017, 22, 615materials, while maintaining not only atom- and step-economy, but also high stereo-19 of 28 selectivity. The seminal work in this area was reported by Fensterbank et al [65,66].

Molecules 2017, 22, 615 19 of 27 was not only effective with the previously reported aminyl- and vinyl-radicals, but also compatible with alkyl-radicals. Alkyl substituted N-acylcyanamides were cyclized in both 5- and 6-exo-dig pathways, although the 6-exo-dig cyclization was comparatively slower. Attempts to achieve tin-free reaction conditions with (TMS)3SiH resulted in substantially lower yields. The mechanism of the reaction was postulated to proceed with the formation of an alkyl radical via the abstraction of phenyl-selenide by a tributyltin-radical. The resulting alkyl-radical undergoes 5- or 6-exo-dig cyclization, forming the amide-iminyl-radical, which itself undergoes a final rearomatization–cyclization Scheme 28. Radical reaction of N-acyl-cyanamides for the synthesis of guanidine based natural products. throughScheme β-hydrogen 28. Radical abstraction reaction of N by-acyl-cyanamides AIBN (Scheme for 29). the synthesis of guanidine based natural products. Extending their previously reported radical cascade reactions of N-acyl-cyanamides to generate guanidine derivatives, Fensterbank et al. achieved the syntheses of two natural products; deoxyvasicinone (143) and mackinazolinone (144). The group also synthesized two guanidine analogues, α-methyldeoxyvasicinone (145) and α,α’-dimethyldeoxyvasicinone (146) [67]. The 5,6,6- and 6,6,6-tricyclic guanidine derivatives were successfully synthesized in good yields by reacting N-acylcyanamide with Bu3SnH and AIBN in benzene under reflux conditions (Scheme 28). This protocol

Scheme 29. Proposed mechanism for the radical cascade involving N-acyl-cyanamide to generate Scheme 29. Proposed mechanism for the radical cascade involving N-acyl-cyanamide to generate guanidine derivatives. guanidine derivatives. Cui and co-workers applied a radical cascade cyclization protocol to construct dihydroisoquinolinone and 4-quinazolinoneCui and co-workers cores 152 and applied 153. The a methodology radical cascade involved cyclization a silver(I) mediated protocol phosphorylation/ to construct cyclizationdihydroisoquinolinone radical cascade and of 4-quinazolinone N-acyl-cyanamide cores alkenes152 and [68].153 A. wide The methodologyrange of phosphorous involved quinazolinonea silver(I) mediated derivatives phosphorylation/cyclization were achieved in good radicalyields by cascade reacting of NN-acyl-cyanamide-acyl-cyanamide alkenesalkenes [15168]. A wide range of phosphorous quinazolinone derivatives were achieved in good yields by reacting (1 equiv.) and diphenylphosphine oxide (154, 2 equiv.) in the presence of AgNO3 (1 equiv.) in CH3CN. FollowingN-acyl-cyanamide this protocol, alkenes 151the (1para equiv.)-substituted and diphenylphosphine N-acylcyanamidebutenes oxide (154 ,delivered 2 equiv.) in phosphorous the presence 4-quinolinonesof AgNO3 (1 equiv.) in moderate in CH3CN. to Following excellent this yields, protocol, while the paraexhibiting-substituted a broadN-acylcyanamidebutenes functional group compatibilitydelivered phosphorous (Scheme 30). 4-quinolinones When meta-substituted in moderate cyanamides to excellent were subjected yields, while to the exhibiting reaction, a amixture broad offunctional regioisomeric group phosphorous compatibility 4-quinolinones (Scheme 30). resulted When meta. The-substituted protocol was cyanamides also amenable were for subjectedheterocyclic to moietiesthe reaction, such a mixtureas indoles of regioisomericand pyrazoles. phosphorous Di-substituted 4-quinolinones alkenes were resulted. more effective The protocol compared was also to mono-substitutedamenable for heterocyclic alkenes, moietieswhich can such be asattributed indoles andto the pyrazoles. stabilization Di-substituted of the in situ alkenes generated were alkyl- more radicaleffective intermediate. compared to mono-substituted alkenes, which can be attributed to the stabilization of the in situ generatedInterestingly, alkyl-radical the reaction intermediate. of unactivated cyclic internal alkenes resulted in a range of spirocyclic compounds. Dihydroquinolinones were obtained in moderate to good yields when N-acylcyanamide- propenes was subjected to cyclization protocol. The feasibility of both phosphonates and phosphine oxides substrates were investigated with positive outcomes. The phosphonate addition was particularly attractive as it gave access to the phosphonic acid derivatives. The authors reported that the addition of a radical scavenger resulted in the quenching of the reaction, which is indicative of a radical pathway being involved. The reaction is initiated with the formation of a diphenyl-phosphine- oxide-radical 155 and its subsequent trapping by the olefin to form the alkyl radical 156. This undergoes a subsequent cascade reaction with the cyanamide nitrile to offer the final cyclized product 153 (Scheme 30).

Molecules 2017, 22, 615 20 of 28 Molecules 2017, 22, 615 20 of 27

Molecules 2017, 22, 615 20 of 27

SchemeScheme 30. Phosphorylation/cyclization 30. Phosphorylation/cyclization radical cascade cascade of N of-acylN-acyl cyanamide cyanamide alkenes. alkenes. Goswami et al. disclosed a metal and base free protocol for chemo-selective generation of primary Interestingly,amines via ipso the-amination reaction of substituted of unactivated boronic cyclicacids us internaling cyanamide alkenes radicals resulted as the aminating in a range of spirocyclicagent compounds. [69]. They envisaged Dihydroquinolinones that radical transfer wereto the aryl obtained cyanamides in moderate occurred via to succinimidyl- good yields when N-acylcyanamide-propenesradicals, which itself was was generated subjected in situ to cyclizationby the action protocol. of a hypervalent The feasibility iodine derivatives of both such phosphonates as phenyliodine-bis(trifluoroacetate) (PIFA) (Scheme 31). and phosphine oxides substrates were investigated with positive outcomes. The phosphonate Subsequently the cyanamide-radicals reacted with boronic acid derivatives via the nitrile nitrogen additionatom was to particularly give the primary attractive amine products. as it gave The access protoc tool thewas phosphonichighly effective acid with derivatives. both aliphatic The and authors reportedaromatic that the boronic addition acids ofand a could radical tolerate scavenger a variety resulted of functional in thegroups. quenching The likelihood of the of reaction, a radical which Scheme 30. Phosphorylation/cyclization radical cascade of N-acyl cyanamide alkenes. is indicativepathway of was a radical confirmed pathway by the addition being involved.of radical scavengers The reaction to the reaction is initiated medium. with the formation of a diphenyl-phosphine-oxide-radicalGoswami et al. disclosed a metal155 andand base its free subsequent protocol for trappingchemo-selective by the generation olefin to of form primary the alkyl radicalamines156. Thisvia ipso undergoes-amination a subsequentof substituted cascade boronic reaction acids using with cyanamide the cyanamide radicals nitrile as the toaminating offer the final cyclizedagent product [69]. They153 envisaged(Scheme 30that). radical transfer to the aryl cyanamides occurred via succinimidyl- Goswamiradicals, which et al. itself disclosed was generated a metal in situ and by base the action free protocolof a hypervalent for chemo-selective iodine derivatives generation such as of phenyliodine-bis(trifluoroacetate) (PIFA) (Scheme 31). primary amines via ipso-amination of substituted boronic acids using cyanamide radicals as the Subsequently the cyanamide-radicals reacted with boronic acid derivatives via the nitrile nitrogen aminating agent [69]. They envisaged that radical transfer to the aryl cyanamides occurred via atom to giveScheme the primary31. Synthesis amine of primary products. amines The by protoc reactionol ofwas cyanamide-radical highly effective with with boronic both acids. aliphatic and succinimidyl-radicals,aromatic boronic acids which and could itself tolerate was generated a variety of in functional situ by groups. the action The likelihood of a hypervalent of a radical iodine derivativespathway3.4. Coordination such was as confirmed phenyliodine-bis(trifluoroacetate) Chemistry by ofthe Cyanamides addition of radical scavengers (PIFA) (Schemeto the reaction 31). medium. The organometallic complexes of cyanamide find application in materials sciences and more recently in the biological sciences [70,71]. Substituted cyanamides offer multiple coordination sites: (i) end on σ-bonding via the nitrile nitrogen (ii) side on π-bond via the nitrile group (iii) via the amine nitrogen and (iv) via the aromatic π-system in the aryl-substituted cyanamides. The coordination mode and strength of cyanamide bonding depends hugely on their steric and electronic properties; i.e., the number and kind of N-substitution; for example the monoalkyl- and dialkylcyanamides have increased electron density on the NCN system, whereas the aryl-substituted cyanamides offer Scheme 31. Synthesis of primary amines by reaction of cyanamide-radical with boronic acids. extendedScheme 31.π-conjugationSynthesisof into primary the aromatic amines ring. by reaction This provides of cyanamide-radical an energetically with favourable boronic acids.means through which a metal ion can couple into a conjugated organic π-system. 3.4. Coordination Chemistry of Cyanamides In addition, the mono-substituted cyanamides, such as phenylcyanamide (PhNHCN) are known Subsequently the cyanamide-radicals reacted with boronic acid derivatives via the nitrile nitrogen to participateThe organometallic as coordinating complexes ligands of in cyanamide neutral as wellfind asapplication anionic cyanamido in materials form sciences ([PNCN] and−) [72]. more atom torecently give thein the primary biological amine sciences products. [70,71]. TheSubstituted protocol cyanamides was highly offer effective multiple with coordination both aliphatic sites: and aromatic(i) end boronic on σ-bonding acids and via the could nitrile tolerate nitrogen a variety(ii) side on of π functional-bond via the groups. nitrile group The likelihood (iii) via the amine of a radical pathwaynitrogen was confirmedand (iv) via bythe the aromatic addition π-system of radical in the scavengers aryl-substituted to the cyanamides. reaction medium. The coordination mode and strength of cyanamide bonding depends hugely on their steric and electronic properties; 3.4. Coordinationi.e., the number Chemistry and kind of of Cyanamides N-substitution; for example the monoalkyl- and dialkylcyanamides have increased electron density on the NCN system, whereas the aryl-substituted cyanamides offer The organometallic complexes of cyanamide find application in materials sciences and more extended π-conjugation into the aromatic ring. This provides an energetically favourable means recentlythrough in the which biological a metal sciences ion can couple [70,71 into]. Substituted a conjugated cyanamides organic π-system. offer multiple coordination sites: In addition, the mono-substituted cyanamides, such as phenylcyanamide (PhNHCN) are known to participate as coordinating ligands in neutral as well as anionic cyanamido form ([PNCN]−) [72].

Molecules 2017, 22, 615 21 of 28

(i) end on σ-bonding via the nitrile nitrogen (ii) side on π-bond via the nitrile group (iii) via the amine nitrogen and (iv) via the aromatic π-system in the aryl-substituted cyanamides. The coordination mode and strength of cyanamide bonding depends hugely on their steric and electronic properties; i.e., the number and kind of N-substitution; for example the monoalkyl- and dialkylcyanamides have increased electron density on the NCN system, whereas the aryl-substituted cyanamides offer extended π-conjugation into the aromatic ring. This provides an energetically favourable means through which a metalMolecules ion can2017, couple22, 615 into a conjugated organic π-system. 21 of 27 In addition,The coordination the mono-substituted chemistry of cyanamides,alkylcyanamide, such arylcyanamide as phenylcyanamide and dicyanamides (PhNHCN) has arebeen known − to participatepreviously ascovered coordinating in a number ligands of inexcellent neutral reviews as well [73,74]. as anionic The present cyanamido section form will ([PNCN] provide an)[ 72]. overviewThe coordination on the application chemistry of substituted of alkylcyanamide, cyanamide in arylcyanamide coordination chemistry and dicyanamides via a few selected has been previouslyrepresentative covered examples in a number from theof recent excellent literature. reviews A more [73 detailed,74]. The discussion present is beyond section the will scope provide an overviewof this article. on the application of substituted cyanamide in coordination chemistry via a few selected representative examples from the recent literature. A more detailed discussion is beyond the scope of 3.4.1. Dialkyl-Cyanamide Complexes this article. Albertin et al. initiated a program to study the behavior of amino substituted nitriles, such as 3.4.1.cyanamides Dialkyl-Cyanamide and cyanaoguanidines, Complexes and their coordination chemistry with metals like iron, ruthenium and osmium [75,76]. The bivalent metallic bis-cyanamide complex of iron 161 was obtained by mixing Albertin et al. initiated a program to study the behavior of amino substituted nitriles, such as FeCl2 with P(OEt)3 and then treating with dialkyl-cyanamide followed by addition of an excess of cyanamides and cyanaoguanidines, and their coordination chemistry with metals like iron, ruthenium NaBPh4 (Scheme 32A). The corresponding osmium and ruthenium-derived complexes 162a and 162b and osmiumwere obtained [75,76 by]. Thetreating bivalent the corresponding metallic bis-cyanamide metal hydride complex (MH2L4) of with iron one161 equivalentwas obtained of HOTf by or mixing FeClMeOTf2 with P(OEt)followed3 and by addition then treating of excess with of dialkyl-cyanamide dialkylcyanamide (Scheme followed 32B). by additionThe authors of anfurther excess of NaBPhstudied4 (Scheme the reaction 32A). Theof these corresponding complexes with osmium nucleophilic and ruthenium-derived hydrazine. The reactions, complexes in each162a case,and 162b wereproduced obtained a bysolid treating product the characterized corresponding as hydrazinecarboximidamide metal hydride (MH2L4 )complex with one 164 equivalent. The reaction of was HOTf or MeOTfproposed followed to byproceed addition via ofthe excess displacement of dialkylcyanamide of a cyanamide (Scheme ligand 32withB). Thehydrazine authors followed further by studied the reactionintramolecular of these nucleophilic complexes attack with on nucleophilic the neighbor hydrazine.ing nitrile carbon The reactions,by the second in each amino case, group produced of hydrazine leading to the five membered azametallocycle (Scheme 32C). a solid product characterized as hydrazinecarboximidamide complex 164. The reaction was proposed In comparison the reaction of the iron triad with aliphatic amines like iPrNH2 and nPrNH2 led to the to proceed via the displacement of a cyanamide ligand with hydrazine followed by intramolecular mono-substituted mixed ligand product only with no observed nucleophilic attack on the cyanamide nucleophilicnitrile. No attack mixed on ligand the neighboringproduct was observed nitrile carbon upon reaction by thesecond with the amino corresponding group of aromatic hydrazine amine leading to theand five NH membered3. azametallocycle (Scheme 32C).

SchemeScheme 32. 32.Reaction Reaction ofof aminesamines with with cyanamide cyanamide metal metal complex. complex.

Recently Bokach et al. reported the synthesis of two Co(II) (dimethylcyanamide) complexes along with the structural details of their dihydrate complexes trans-[Co(H2O)4(NCNMe2)2]X2·2H2O [77]. A key feature of the X-ray crystal structure was the hydrogen bonding of the counter anion and the ligated water of crystallization. They studied the effect of both chloride and bromide counter ions

Molecules 2017, 22, 615 22 of 28

i n In comparison the reaction of the iron triad with aliphatic amines like PrNH2 and PrNH2 led to the mono-substituted mixed ligand product only with no observed nucleophilic attack on the cyanamide nitrile. No mixed ligand product was observed upon reaction with the corresponding aromatic amine and NH3. Recently Bokach et al. reported the synthesis of two Co(II) (dimethylcyanamide) complexes along with the structural details of their dihydrate complexes trans-[Co(H2O)4(NCNMe2)2]X2·2H2O[77]. A key feature of the X-ray crystal structure was the hydrogen bonding of the counter anion and the ligated water of crystallization. They studied the effect of both chloride and bromide counter ions and associated water molecules on the 3D network of hydrogen bonding, and rationalized the differences observed based on the electronic differences primarily between the counter ions in terms of electrostatics but also depending on the metal center size and electronegativity.

3.4.2. Aryl Cyanamide Complexes The electronic properties of substituted cyanamides are known to play a crucial role as a bridging ligand for metal-metal coupling in dinuclear complexes, which directly affects their magnetic properties [78]. In 2013 Crutchley et al. synthesized a series of nine mononuclear [Ru(Tp)(dppe)L] complexes, (where L is a substituted phenylcyanamide ligand, Tp is hydrotris(pyrazol-1-yl)-borate, dppe 2+ is 1,2-bis[(diphenyl-phosphino)ethane) and a dinuclear complex [{Ru(trpy)(bpy)}2(µ-adpc)] , (where trpy is 2,20:60,200-terpyridine, and bpy is 2,20-bipyridine and adpc2− is azo-4,40-diphenylcyanamide), of ruthenium with substituted phenylcyanamide ligands [79]. The crystal structure of [Ru(Tp)(dppe) (Cl5pcyd)] and [{Ru(Tp)(dppe)}2(µ-adpc)] revealed that the cyanamide coordinates to the ruthenium(II) through the terminal nitrogen. Significant conjugation between the cyanamide and phenyl ring was predicted, given the planarity of the cyanamide group in the complex. A mixed valence complex was observed for these complexes upon oxidation, which showed strong π-interactions between Ru(III) and the cyanamide group, operating through the super exchange mechanism. The authors also investigated the effect of disrupting the strong π-interactions through a scorpionate ligand, which possesses strong π-donor properties via the anionic coordination mode and weakens the inter-metal coupling. This allowed an overall charge reduction, whilst retaining the properties of the original mixed-valence complex. The Chiniforoshan group have been investigating coordination complexes of a range of transition metal with cyanamide derivative ligands and their possible medicinal activity. The group recently reported the synthesis and characterization of Ni(II) and Cd(II) complexes with 4-nitrophenylcyanamido ligands [80,81]. More recently the group reported the synthesis and biological activities of the polymeric coordination complexes of mercury(II), with the anions of a number of arylcyanamides [82]. The complexes were obtained via deprotonation of the relevant arylcyanamide with NaOH, followed by mixing the arylcyanamide anion with Hg(NO3)2·H2O in acetone at reflux temperature. The structural analysis of the solid products revealed that the cyanamide ligand is coordinated through the amine nitrogen, which is relatively rare. The nitrile coordination mode was observed, but was thermodynamically less favorable than the amine isomer. Analysis also revealed that the anion of the acetone, the reaction solvent, was present as a bridging ligand connecting two mercury ions through the carbon atom of one and carbonyl oxygen (C=O) atom of another acetone anion. Antimicrobial assays indicated some inhibition to bacterial growth, but there was no overall improvement when compared the free ligand itself (Figure1). The group also reported the synthesis of trimethyltin(IV) complexes with 4-nitrophenylcyanamide and a biphenyl derivative of cyanamide ligand [83]. The complexes were obtained by mixing the trialkyl-tin with the ligand in an alkali medium (NaOH), and irradiating the mixture under high-intensity ultrasound. In these complexes the cyanamide coordinates to the metal through the nitrile nitrogen; the biphenyl derivative was found to bridge between two trimethyltin metal centers (Figure2). All compounds showed some activity in the antimicrobial/antifungal assay, but did not Molecules 2017, 22, 615 22 of 27 and associated water molecules on the 3D network of hydrogen bonding, and rationalized the differences observed based on the electronic differences primarily between the counter ions in terms of electrostatics but also depending on the metal center size and electronegativity.

3.4.2. Aryl Cyanamide Complexes The electronic properties of substituted cyanamides are known to play a crucial role as a bridging ligand for metal-metal coupling in dinuclear complexes, which directly affects their magnetic properties [78]. In 2013 Crutchley et al. synthesized a series of nine mononuclear [Ru(Tp)(dppe)L] complexes, (where L is a substituted phenylcyanamide ligand, Tp is hydrotris(pyrazol-1-yl)-borate, dppe is 1,2-bis[(diphenyl-phosphino)ethane) and a dinuclear complex [{Ru(trpy)(bpy)}2(μ-adpc)]2+, (where trpy is 2,2′:6′,2″-terpyridine, and bpy is 2,2′-bipyridine and adpc2− is azo-4,4′-diphenylcyanamide), of ruthenium with substituted phenylcyanamide ligands [79]. The crystal structure of [Ru(Tp)(dppe) (Cl5pcyd)] and [{Ru(Tp)(dppe)}2(μ-adpc)] revealed that the cyanamide coordinates to the ruthenium(II) through the terminal nitrogen. Significant conjugation between the cyanamide and phenyl ring was predicted, given the planarity of the cyanamide group in the complex. A mixed valence complex was observed for these complexes upon oxidation, which showed strong π-interactions between Ru(III) and the cyanamide group, operating through the super exchange mechanism. The authors also investigated the effect of disrupting the strong π-interactions through a scorpionate ligand, which possesses strong π-donor properties via the anionic coordination mode and weakens the inter-metal coupling. This allowed an overall charge reduction, whilst retaining the properties of the original mixed-valence complex. The Chiniforoshan group have been investigating coordination complexes of a range of transition metal with cyanamide derivative ligands and their possible medicinal activity. The group recently reported the synthesis and characterization of Ni(II) and Cd(II) complexes with 4-nitrophenylcyanamido ligands [80,81]. More recently the group reported the synthesis and biological activities of the polymeric coordination complexes of mercury(II), with the anions of a number of arylcyanamides [82]. The complexes were obtained via deprotonation of the relevant arylcyanamide with NaOH, followed by mixing the arylcyanamide anion with Hg(NO3)2·H2O in acetone at reflux temperature. The structural analysis of the solid products revealed that the cyanamide ligand is coordinated

Moleculesthrough2017 the, 22amine, 615 nitrogen, which is relatively rare. The nitrile coordination mode was observed,23 of 28 but was thermodynamically less favorable than the amine isomer. Analysis also revealed that the anion of the acetone, the reaction solvent, was present as a bridging ligand connecting two mercury exceedions through the efficacy the carbon of ciprofloxacin atom of one or fluconazoleand carbonyl for oxygen antimicrobial (C=O) oratom antifungal of another activity. acetone However, anion. theAntimicrobial cytotoxic activity assays of indicated these compounds some inhibition were impressive to bacterial against growth, the HeLa but cell there line. was Both no complexes overall hadimprovement similar efficacy when incompared causing cellthe deathfree ligand in the itself MTT (Figure assay, and1). this was comparable to cis-platin.

Molecules 2017, 22, 615 23 of 27 nitrile nitrogen; the biphenyl derivative was found to bridge between two trimethyltin metal centers (Figure 2). All compounds showed some activity in the antimicrobial/antifungal assay, but did not exceed the efficacy of ciprofloxacin or fluconazole for antimicrobial or antifungal activity. However, the cytotoxic activity of these compounds were impressive against the HeLa cell line. Both complexes had similarFigure efficacy 1. A in schematic causing representation cell death in the of Mercury MTT assay, based and polymeric this was coordination comparable complex.complex. to cis-platin.

The group also reported the synthesis of trimethyltin(IV) complexes with 4-nitrophenylcyanamide and a biphenyl derivative of cyanamide ligand [83]. The complexes were obtained by mixing the trialkyl-tin with the ligand in an alkali medium (NaOH), and irradiating the mixture under high-intensity ultrasound. In these complexes the cyanamide coordinates to the metal through the

Figure 2. Structure of trimethyltin derivatives.

Recently, Chiniforoshan et al. synthesized three mononuclear complexes of nickel(II) with 4- Recently, Chiniforoshan et al. synthesized three mononuclear complexes of nickel(II) with nitrophenyl-cyanamide and their antimicrobial and cytotoxic properties were investigated [71]. The 4-nitrophenyl-cyanamide and their antimicrobial and cytotoxic properties were investigated [71]. three complexes [Ni(HIm)4(4-NO2pcyd)2]·CH3OH, [Ni(bpy)2(4-NO2pcyd)2]·CH3CH2OH, and [Ni(phen)2 The three complexes [Ni(HIm)4(4-NO2pcyd)2]·CH3OH, [Ni(bpy)2(4-NO2pcyd)2]·CH3CH2OH, (4-NO2pcyd)2]·CH3OH were readily obtained by the reaction of 4-nitrophenylcyanamide ligand with and [Ni(phen)2(4-NO2pcyd)2]·CH3OH were readily obtained by the reaction of 4-nitrophenylcyanamide Ni(OAc)2·4H2O in the presence of 1,10-phenanthroline (phen), 2,20-bipyridine (bpy), imidazole (HIm) ligand with Ni(OAc) ·4H O in the presence of 1,10-phenanthroline (phen), 2,20-bipyridine (bpy), respectively. X-ray crystallographic2 2 studies of the complexes 168 and 169 revealed that in each case, imidazole (HIm) respectively. X-ray crystallographic studies of the complexes 168 and 169 revealed the cyanamide ligand is coordinated via the terminal nitrile nitrogen rather than the sterically that in each case, the cyanamide ligand is coordinated via the terminal nitrile nitrogen rather than the hindered amine nitrogen (Figure 3). The observed bond angles and bond distances between the sterically hindered amine nitrogen (Figure3). The observed bond angles and bond distances between metal-ligand and those of N–C–N of the cyanamide ligand suggested that the coordination mode of the metal-ligand and those of N–C–N of the cyanamide ligand suggested that the coordination mode of the cyanamide group to Ni(II) ion is approximately linear. This finding helps to confirm the extended the cyanamide group to Ni(II) ion is approximately linear. This finding helps to confirm the extended conjugation of the cyanamide π-electrons into the aromatic ring and thereby the ability of the Ni(II) conjugation of the cyanamide π-electrons into the aromatic ring and thereby the ability of the Ni(II) to to accept π-density into a filled dπ orbital. The authors further conducted biological studies and tested accept π-density into a filled d orbital. The authors further conducted biological studies and tested the the cytotoxicity and antimicrobialπ potential of these complexes. cytotoxicity and antimicrobial potential of these complexes. Efficacy was shown by all of the complexes against human lung adenocarcinoma (A549), prostate (Du145), epithelial carcinoma (HeLa) and breast cancer (MCF-7) cell lines. When compared to cis-platin, higher or equal efficacy was shown by all compounds against Du145 and HeLa cell lines. This suggests that the compounds may be more effective against prostate and cervical cancers respectively. The compounds also had some antibacterial and antifungal activities.

Figure 3. Representative drawing of nickel cyanamide complexes.

Efficacy was shown by all of the complexes against human lung adenocarcinoma (A549), prostate (Du145), epithelial carcinoma (HeLa) and breast cancer (MCF-7) cell lines. When compared to cis-platin, higher or equal efficacy was shown by all compounds against Du145 and HeLa cell lines. This suggests that the compounds may be more effective against prostate and cervical cancers respectively. The compounds also had some antibacterial and antifungal activities.

Molecules 2017, 22, 615 23 of 27 nitrile nitrogen; the biphenyl derivative was found to bridge between two trimethyltin metal centers (Figure 2). All compounds showed some activity in the antimicrobial/antifungal assay, but did not exceed the efficacy of ciprofloxacin or fluconazole for antimicrobial or antifungal activity. However, the cytotoxic activity of these compounds were impressive against the HeLa cell line. Both complexes had similar efficacy in causing cell death in the MTT assay, and this was comparable to cis-platin.

Figure 2. Structure of trimethyltin derivatives.

Recently, Chiniforoshan et al. synthesized three mononuclear complexes of nickel(II) with 4- nitrophenyl-cyanamide and their antimicrobial and cytotoxic properties were investigated [71]. The three complexes [Ni(HIm)4(4-NO2pcyd)2]·CH3OH, [Ni(bpy)2(4-NO2pcyd)2]·CH3CH2OH, and [Ni(phen)2 (4-NO2pcyd)2]·CH3OH were readily obtained by the reaction of 4-nitrophenylcyanamide ligand with Ni(OAc)2·4H2O in the presence of 1,10-phenanthroline (phen), 2,20-bipyridine (bpy), imidazole (HIm) respectively. X-ray crystallographic studies of the complexes 168 and 169 revealed that in each case, the cyanamide ligand is coordinated via the terminal nitrile nitrogen rather than the sterically hindered amine nitrogen (Figure 3). The observed bond angles and bond distances between the metal-ligand and those of N–C–N of the cyanamide ligand suggested that the coordination mode of the cyanamide group to Ni(II) ion is approximately linear. This finding helps to confirm the extended conjugation of the cyanamide π-electrons into the aromatic ring and thereby the ability of the Ni(II)

Moleculesto accept2017 π-density, 22, 615 into a filled dπ orbital. The authors further conducted biological studies and 24tested of 28 the cytotoxicity and antimicrobial potential of these complexes.

Figure 3. Representative drawing of nickel cyanamide complexes.

4. ConclusionsEfficacy was shown by all of the complexes against human lung adenocarcinoma (A549), prostate (Du145), epithelial carcinoma (HeLa) and breast cancer (MCF-7) cell lines. When compared to cis-platin,Since higher the early or equa reportedl efficacy use ofwas cyanamides, shown by all the compounds application against of this Du145 unique and functional HeLa cell moiety lines. haveThis diversifiedsuggests that hugely, the compounds further enriching may be the more field ofeffective amino-substituted against prostate nitrile and chemistry. cervical Herecancers we haverespectively. presented The a compounds selection of recentalso had synthetic some antibacterial methodologies and developedantifungal activities. to access this special group of compounds, along with selected examples of the diverse synthetic applications. The number of reports in the recent years on substituted cyanamide aptly demonstrate the interest that this moiety has generated among synthetic chemists world-over. These new advances in cyanamide chemistry will no doubt attract further studies, thereby widening the applications in the relatively unchartered areas at the interface of chemistry, biology and material science.

Acknowledgments: We wish to thank University of Lincoln, UK for PhD funding to L.W and S.V.B. and EPSRC (Grant No EP/N00969X/1) for financial support to M.R.R.P. and P.S. The authors would also like to thank John E. Moses, La Trobe Institute for Molecular Science, Australia, for helpful discussion and constructive feedback on our manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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