Non-toxic cyanide sources and cyanating agents

Abstract

The present review gives an overview over non-toxic cyanation agents and cyanide sources used in the synthesis of structurally diverse products containing the nitrile function. Nucleophilic as well as electrophilic agents/systems that transfer the entire CN-group were taken in consideration. Reactions in which a preexisting carbon functionality is transformed into a nitrile function by addition of nitrogen are however not covered here.

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1. Introduction

By treating potassium ferrocyanide with sulfuric acid, the famous Swedish–German chemist Carl Wilhelm Scheele produced a hitherto unknown chemical compound in 1782. Since the hydrogen cyanide evolved under the formation of Prussian blue, he called this new compound “Blausäure” (“blue acid”, prussic acid). Over the years, hydrogen cyanide – free or in form of its salts – became one of the most important C₁ building blocks in chemical industry.¹ It is essential for the synthesis of α-amino acids like methionine² or chelators like ETDA,³ NTA⁴ and is needed for case hardening,⁵ electroplating⁶ and the processing of gold ore.⁷

For chemical companies, the handling of the highly toxic hydrogen cyanide requires closed reactors and substantial safety regulations but is still favored due to cost minimization. For smaller enterprises or research labs, free HCN is often not an option and commercial cyanide sources like metal cyanides, ketone cyanohydrins or trimethylsilyl cyanide are employed instead. Nevertheless, these compounds are still highly toxic and safer alternatives are highly welcome. Over the years, many approaches towards non-toxic alternatives for cyanation reactions have been reported. All these approaches fall into two classes. One class of cyanide sources contains a tightly bound cyano group that needs to be liberated for the reaction to occur. In the other class the cyanide moiety is formed during the reaction from a carbon and a nitrogen atom of any oxidation state.

Several aspects of cyanide sources and cyanating agents have already been discussed in the literature.⁸ In the focus of these reviews were cyanation reactions with palladium,^9,10 copper^11,12 or diverse transition metals,^13–15 metal free cyanations,^16,17 the synthesis of aryl nitriles,^18,19 the formation of N/S/O–CN bonds²⁰ or cyanations by C–H activation.²¹ Here, we intend to give an overview with a particular emphasis on agents that exhibit a low(er) toxicity. Toxic cyanide sources like KCN, NaCN, TMSCN, CuCN, Zn(CN)₂, Bu₄NCN, malononitriles, DDQ and cyanohydrins are therefore not discussed here.

2. Reagents with tightly bound CN

The first group of non-toxic cyanide sources already contain a CN-group that is tightly bound so that no significant concentrations of cyanide are released from these reagents under normal circumstances. For activation, the X–CN bond needs to be cleaved and the cyanide is transferred to the cyanide acceptor. Depending on the electronegativity of the α-atom and the bonding properties CN-group can be an electrophilic, nucleophilic or radical cyanation agent (Fig. 1).

Fig. 1 Overview of the 1. group of non-toxic sources.

Ferro-/ferricyanide

In 1877, Merz and Weith heated ferrocyanide and quartz sand in a furnace and passed a stream of vaporized halobenzene through the mixture. The collected condensate contained the corresponding aryl nitrile. Therefore, Merz and Weith were first to use ferrocyanide as a non-toxic cyanide source for a (nucleophilic) cyanation reaction.²² For a long time, the use of these iron complexes as non-toxic cyanide sources lay dormant until Beller and coworkers rediscovered it in form of an efficient palladium-catalyzed reaction at much lower temperature in 2004 (Scheme 1).²³ Since then, a huge variety of reactions have been reported, in particular for the synthesis of aromatic nitriles from aromatic compounds containing a good nucleofuge. The reported reactions can be grouped by their reaction temperature and the catalyst used. For temperatures below 70 °C, two palladium catalyzed processes have been reported by Kwong (2011)²⁴ and by Jian Li (2012).²⁵ Some palladium^26–32 and one copper³³ catalyzed reaction have been reported to operate below 100 °C while the majority of reactions require higher reaction temperatures. Here, reports with palladium,^23,34–62 copper,^63–72 a palladium/copper co-catalysis,^73,74 and nanoparticles or polymers^75–92 can be found.

Scheme 1 Cyanation with ferro-/ferricyanide of aromatic compounds containing a nucleofugic substituent.

Besides the nucleophilic aromatic cyanation, ferro- and ferricyanide can also be used to convert other aromatic compounds to their corresponding nitriles. In 2010, the Kwong group reported the conversion of mesylates under palladium catalysis with suitable ligands (Scheme 2).⁹³ Recently, Qin and coworkers were able to cyanate phenols by converting the OH-group to a better leaving group with sulfuryl fluoride.⁹⁴ This reaction might enable an alternative way to use fossil- or biomass-based phenols for the chemical industry, even though DMF was used as a solvent. The conversion of aldehydes to the corresponding nitriles with different nanoparticles and ferricyande have been shown by the groups of Karak (2016)⁹⁵ and Nasrollahzadeh (2017).⁹⁶ Unfortunately, they did not investigate the reaction mechanism and it remains unclear if the nitrile is formed by decarbonylation/cyanation or by a nitrogen transfer. In other reports, oxidative cyanations of electron rich benzenes or heterocycles were described as well. The group of Cheng described in 2009 the palladium catalyzed formation of aromatic nitriles from benzene derivatives with stoichiometric quantities of copper(II)salts as an terminal oxidant.⁹⁷ In 2010, Jianbo Wang and coworkers used this reaction to cyanate indoles in 3-position.⁹⁸ Since they used ferrocyanide in contrast to Cheng, the equivalents of the copper(II) salt were increased. By adding iodine and using ferricyanide, Jianji Wang was able to drastically decrease the copper equivalents again.⁹⁹

Scheme 2 Cyanation of different aromatic compounds with ferro-/ferricyanide, RGO = reduced graphene oxide.¹⁰⁰

The cyanation of aliphatic compounds with ferro- or ferricyanide was investigated less extensively but some examples were reported nevertheless. The group of Jianji Wang reported in 2011 and 2012 the cyanation of different benzylic chlorides by palladium and copper catalysis (Scheme 3).^101,102 Other leaving groups in α-carbonyl- or benzylic-position can be substituted by cyanide as shown by Gribble (2013)¹⁰³ and Z. Li (2014).¹⁰⁴ More recently, it was demonstrated that tertiary amines can be used in oxidative cyanation to produce α-amino nitriles. The Opatz group reported an environmentally benign thermal cyanation of different N-arylamines in water/alcohol mixtures in 2015¹⁰⁵ and the conversion of aliphatic amines in a catalyst-free photooxidation in 2017.¹⁰⁶ The addition to electrophilic C=C double bonds, carbonyl groups, imines or iminium ions have been studied by J. Zhu in 2007,¹⁰⁷ by Z. Li et al. (2010–2014)^108–112 as well as by Opatz et al. since 2015.^105,106,113 Very recently, Bolm and coworkers were the first to report a Strecker reaction with ferric-/ferrocyanide or Prussian blue in a ball mill.¹¹⁴

Scheme 3 Cyanation of different aromatic compounds with ferro-/ferricyanide.

Nitriles

Nitriles are another compound class containing strongly bound cyano groups. In contrast to the coordinative bonding in metal complexes, a covalent C–C bond prevents the undesired spontaneous liberation of cyanide. Due to the high dissociation energy of this bond, most reactions require harsh conditions to proceed. The first report on the use of nitriles as a cyanide source was published in 1998 by C.-H. Cheng and coworkers (Scheme 4). They described the formation of aromatic nitriles from aryl bromines with benzyl cyanide or acetonitrile with an excess of zinc and in the presence of palladium or nickel catalysts.¹¹⁵ Since 2012, the cyanation with nitriles has moved into the focus of several research groups. In 2012 and 2013, Y. Wang worked on the cyanation with benzyl cyanide and was able to showcase the cyanation of aryl halides by palladium- or copper-catalysis,^116,117 as well as the oxidative cyanation of 2-arylpyridines by copper-catalysis using air as terminal oxidant.¹¹⁸ In parallel, a remarkable synthesis of α-amino nitriles from arylamines with benzyl cyanide and tert-butyl hydroperoxide as an oxidant was reported by Wan (2013).¹¹⁹ Even though the oxidant and the cyanide source are still classified as toxic (although they are less dangerous than free cyanide), the oxidative cyanation of amines is standing out from all other syntheses of aromatic nitriles. While the cleavage of a benzylic nitrile function is aided by the benzylic stabilization of reaction intermediates, the activation of aliphatic nitriles is even more challenging. In 2012, the cyanation of aryl iodides with acetonitrile through copper-catalysis in the presence of silver oxide and air was reported by Jin-Heng Li.¹²⁰ Based on this publication, Jizhen Li extended the reaction to arenediazonium salts in 2015.¹²¹ Apart from functionalized arenes carrying a leaving group, unsubstituted aromatic or heteroaromatic compounds can also be cyanated by copper catalysis in the presence of oxygen and N-iodosuccinimide or silver salts. These reactions were reported by C. Zhu in 2013¹²² and by Shen in 2013 and 2015.^123–125 Just recently, the Opatz group described a new strategy to use benzylic and aliphatic nitriles as universal cyanide sources through activation by manganese catalysis. In this reaction, the nitriles were oxidized to their corresponding cyanohydrins with peroxodisulfate and cleaved under acidic conditions to release HCN.¹¹³ Another nitrile used for cyanation is the relatively inexpensive ethyl cyanoacetate. This cyanide source has been used by Shen et al. in a palladium-catalysis of aryl halides to yield the aryl nitriles in 2012.¹²⁶ Diaminomaleonitrile (DAMN, the tetramer of HCN) has also been used as a cyanide source in a palladium-catalysis by Goswami in 2013.¹²⁷ It should however be noted that the price of DAMN is substantial.

Scheme 4 Cyanation of different compounds with nitriles.

Cyanates

Another class of cyanating agents are cyano chalcogenides such as cyanate and thiocyanate. In 1992, the Niclas group reported the first acidic transfer cyanation with aluminium chloride and hydrogen chloride for the cyanation of arenes with aryl cyanates (Scheme 5).¹²⁸ This idea was used by Sato and coworkers who described the cyanation of different aromatic compounds by initial lithiation with ^n/tbutyl lithium and subsequent reaction with phenyl cyanate in 2002 and 2003.^129,130

Scheme 5 Cyanation of different compounds with cyanates.

Since aryl cyanates are usually synthesized from phenols and cyanogen bromide (which is substantially more expensive and more toxic than free cyanide),¹³¹ this compound class was not widely applied. Notably, Fu-Xue Chen used 4-acetylphenyl cyanate in 2017 for an asymmetric cyanation of 1,3-dicarbonyls¹³² and amides.¹³³

Thiocyanates

Compared to the cyanates, organic and inorganic thiocyanates have attracted more attention as cyanide sources. In 1977, Kita and coworkers reported on thiocyanations of different aromatic and aliphatic alcohols with Ph₃P(SCN)₂ (Scheme 6). Under identical conditions, they however observed the formation of aryl nitriles for indoles and pyrrole in good yields.¹³⁴ Six years later, Cava used 2-chlorobenzyl thiocyanate for the synthesis of 2-arylmalononitriles from aryl nitriles.¹³⁵ More recently arylboronic acids and aryl halides were cyanated under palladium catalysis with equimolar amounts of copper(I) thiophene-2-carboxylate and organic or inorganic thiocyanates by the groups of Liebeskind (2006),^136,137 J. Cheng (2013)¹³⁸ and Vaghasiya (2018).¹³⁹ Based on the work of Wan (2013),¹¹⁹ Ofial and coworkers reported a catalyst-free synthesis of α-amino nitriles from tertiary amines and potassium thiocyanate by oxidation with tert-butyl hydroperoxide in 2015.¹⁴⁰ Even though the oxidant is classified as toxic, the application of KSCN instead of the more expensive benzyl cyanide¹¹⁹ is a significant improvement of this reaction. In 2017, the Jiang group presented a copper-catalyzed benzylic cyanation of N-tosylhydrazones which enables a unique two-step reductive cyanation of ketones or aldehydes.¹⁴¹

Scheme 6 Cyanation of different compounds with thiocyanates.

Tosyl cyanide

In 2011, Inoue reported an oxidative photocyanation with benzophenone as an organic photocatalyst. Via a PHAT (photon induced hydrogen abstraction)-mechanism, ethers, alcohols, carbamates and aliphatic compounds were successfully cyanated using tosyl cyanide as the CN source (Scheme 7).^142,143 Apart from this process involving free radicals, TsCN can also be used as an electrophilic cyanating agent. As an example, the group of Ibrahim demonstrated an electrophilic cyanation of 1,3-dicarbonlys under basic conditions in 2013.¹⁴⁴

Scheme 7 Cyanation of different compounds with tosyl cyanide.

CN-containing iodine(III) compounds

Some cyanation reactions were also performed with different CN-iodine species, like cyanobenziodoxoles or the more reactive aryl(cyano)-iodonium triflates. In 1995, the Zhdankin lab used for the first time cyanobenziodoxoles as electrophilic cyanation agents for the conversion of dimethylanilines under basic conditions (Scheme 8).¹⁴⁵ It took approximately 20 years before the use of these agents was reported again. The groups of M. Waser (2015),¹⁴⁶ Zheng (2015),¹⁴⁷ and X. Liu (2017)¹⁴⁸ described a enantioselective α-cyanation of β-keto esters with different chiral ligands. Fu-Xue Chen (2015) described a racemic variant without chiral ligands.¹⁴⁹ Cyanobenziodoxoles were also applied for the cyanation of thiophenes by J. Waser in 2015¹⁵⁰ and of silyl enol ethers by Minakata in 2017.¹⁵¹

Scheme 8 Cyanation of different compounds with cyanobenziodoxoles.

The more reactive aryl(cyano)iodonium triflates developed by Zhdankin and Stang^152,153 have been further studied by Jianbo Wang (2014),¹⁵⁴ L. Shi (2015)¹⁵⁵ and Studer (2016)¹⁵⁶ Unfortunately, they are not yet classified in terms of toxicity and are therefore not discussed in further detail here.

Cyanamides

Electrophilic cyanation can also be performed using cyanamide derivatives. One of the most important reagents of this class is N-cyano-N-phenyl-p-toluenesulfonamide (NCTS). This cyanating agent can be synthesized by a procedure of Kurzer et al. from N-phenylurea and p-toluenesulfonyl chloride.^157–159 In 2011, Beller reported for the first time the application of NCTS as a non-toxic electrophilic cyanating agent (Scheme 9). It was used for the synthesis of aromatic nitriles from aryl bromides through the intermediate formation of Grignard reagents¹⁶⁰ or from arylboronic acids through rhodium catalysis.¹⁶¹ In parallel, Jianbo Wang et al. were also able to cyanate indoles and pyrroles using a Lewis acid as the catalyst.¹⁶² In the following years, a variety of different catalysts were used for the cyanation of different aromatic compounds with NCTS by cleaving C–H or C–halogen bonds. In 2013, Anbarasan presented the cyanation of aromatic C–H bonds with a ruthenium catalyst using AgSbF₆.¹⁶³ Based on this research, Glorius and coworkers optimized the reaction and were able to exchange the catalyst for a cobalt complex in 2014.¹⁶⁴ Buchwald published a copper-catalyzed cyanation of β-vinylnaphthalene derivatives with (BPin)₂ in the same year.¹⁶⁵ His former co-worker Yang continued the work (P. Liu, 2015) in this area.¹⁶⁶ Gosmini (2015) and Jizhen Li (2016) used NCTS to cyanate aromatic compounds containing leaving groups like bromine or iodine, as well as arenediazonium salts. For this reaction, copper- or palladium-catalysis in combination with zinc or silver oxide were used.^167,168 Since these substrates are electrophilic it is understandable that zinc as a reductant enables the cyanation with the electrophilic cyanating agent NCTS. It is less obvious why silver oxide or silver salts in DMSO leads to the same outcome. NCTS can also be used for the α-functionalization of simple and α,β-unsaturated carbonyl compounds as demonstrated by Minakata in 2016.¹⁶⁹ In contrast to all these applications, Song and coworkers were able to generate aromatic nitriles from arenecarboxylic acids by a catalytic decarboxylation (2017).¹⁷⁰

Scheme 9 Cyanation of different compounds with NCTS.

Other N–CN-based cyanating agents were also employed in the literature. Unfortunately, they all require prior synthesis from an amine or N-chloroamine with another electrophilic or nucleophilic cyanide source (Scheme 10). As early as in 1985, the Crossley group reported an aliphatic C-cyanation with N,N-diisopropyl cyanamide after deprotonation of a benzylic position.¹⁷¹ In 1998 and 1999, the cyanation of benzylic nitriles with 1-cyanobenzotriazole to form aryl malononitriles under basic conditions was reported by Cava et al.^172,173 The Katritzky group also used 1-cyanobenzotriazole as a cyanating agent under basic conditions for benzylic or aliphatic carbon center substituted with an electron withdrawing group in 2007.¹⁷⁴ In another approach, N-cyanoimidazole was used by Yong-qian Wu and coworkers in 2000 to achieve the cyanation of amines, thiols, Grignard reagents or alkynes.¹⁷⁵ Based on this work, Beller reported in 2010 the cyanation of aryl bromides with magnesium via the Grignard-pathway with the modified cyanating agent N-cyanobenzimidazole.¹⁷⁶ A detailed optimization of N-cyanohetarenes was performed by Yoon in 2005. He varied the substitution pattern of 2-cyanopyridazin-3(2H)-ones to cyanate amines, thiols and 1,3-dicarbonyls and found 4,5-dichloro- and 5-chloro-4-methoxy-6-oxopyridazine-1(6H)-carbonitrile to be the optimum cyanating agents.¹⁷⁷

Scheme 10 Cyanation of different compounds with other N–CN sources.

Isocyanides

A less frequently used group of alternative cyanating agents are the isocyanides. B. Xu and coworkers used tert-butyl isonitrile for the first time for a cyanation of heteroarenes in a palladium catalysis (Scheme 11).¹⁷⁸ Disadvantages of this procedure were the use of copper(II) as terminal oxidant and the low yields for starting materials devoid of electron donating substituents. In 2015, the group of Y.-M. Zhu adopted the procedure for the cyanation of aryl iodides.¹⁷⁹ Tosylmethyl isocyanide (TosMIC) and its derivates as less toxic alternatives to tert-butylisonitrile were applied to different 2-bromobenzyl bromides by Vaquero in 2013. In this case, not only the cyano group but also other parts of the cyanating agent are transferred to the substrate and a the structural diversity of the products is larger than with most other procedures.¹⁸⁰

Scheme 11 Cyanation of different compounds with isocyanides.

Cyanocarbonyls

Cyanocarbonyls are labile sources of cyanide and can release HCN upon aqueous hydrolysis. This was utilized in parallel by the working groups of Nageswar and Lingaiah in 2012 (Scheme 12).^181,182 They used ethyl cyanoformate in combination with TBHP to synthesize α-aminonitriles from N,N-dialkylanilines with ruthenium on charcoal or a niobia-supported iron molybdophosphate as the catalysts. While industry takes specific precautions to handle HCN safely in a well-defined setting, its use in research labs is often refrained from although a safe handling is doubtlessly also possible in this environment. In an attempt to make lab applications of HCN safer, Ley and coworkers reduced the free inventory of this reagent by using a flow setup. In a biocatalytic approach, they achieved the synthesis of chiral O-acetyl cyanohydrins from aldehydes in 2016.¹⁸³ In 2012, the use of pyruvonitrile as a cyanating agent for synthesis of α-ketiminophosphonates was shown by Palacios.¹⁸⁴

Scheme 12 Cyanation of different compounds with cyanocarbonyles.

AIBN

Apart from its well-known application as a radical starter, azobis(isobutyronitrile) (AIBN) and its derivatives can also be used for cyanation reactions. Here, the labile compound breaks down in a radical dediazotation to generate 2-cyanopropan-2-yl radicals. Han and coworkers suggested in a publication of 2013 that these radicals form acetone and cyanide radicals in the presence of oxygen. They described a copper-mediated direct aryl C–H cyanation via this free radical pathway. However the scope was limited to 2-arylpyridines due to the copper coordination by the nitrogen (Scheme 13).¹⁸⁵ The idea of a free radical cyanation through AIBN was also proposed by Jiang Cheng in 2014¹⁸⁶ for their cleavage of disulfides to form thiocyanates as well as for their synthesis of cyano amides from amines (2015).¹⁸⁷ In the same year, X. Xu et al. used AIBN and AMBN (azobisisoamylonitrile) for the cyanation of terminal alkynes. By variation of the equivalents, they were able to either perform the cyanation or an addition of isobutyronitrile.¹⁸⁸ He and coworkers optimized the reaction further in 2017 and were able to forgo the use of any metal. They applied their procedure to an oxidative α-cyanation of arylamines.¹⁸⁹

Scheme 13 Cyanation of different compounds with AIBN.

Miscellaneous

In other works, insoluble polymers were used as ion exchange resins for nucleophilic cyanations. In 2008, Tajima used a cyanide loaded polystyrene-based ion exchange resin in an electrochemical oxidative cyanation of carbamates, amides, and ethers (Scheme 14).¹⁹⁰ Similar resins have been used 2012 by the Ebrahimi group in a Sandmeyer-type deaminative cyanation of anilines through the corresponding diazonium salts.¹⁹¹ A transfer cyanation in which arenes containing a nucleofuge are subjected to an O/C-exchange with α-amino nitriles as cyanide donors was reported by Yamaguchi in 2016. In this nickel-catalyzed process, the starting material can also contain less reactive leaving groups such as carbamates or phenol esters, while an impressive chemoselectivity could be observed.¹⁹²

Scheme 14 Cyanation with different cyanide sources.

Some less frequently used cyanating agents can also be found in the literature. Many of them have not yet been assessed toxicologically and are not discussed in detail. These include diethyl phosphorocyanidate (DEPC, classified as toxic), 1-cyano-4-dimethylaminopyridinium bromide (CAP, potential BrCN releasing agent), and cyanoethyl zinc bromide (potential cyanide releasing agent). Surprisingly, the latter reagent is only classified as harmful. Two interesting reagents are N-cyanosuccinimide¹⁹³ and cyano halo (imidazolium) sulfuranes (analogues to the iodine(III) reagents).¹⁹⁴ Although not yet investigated, they might turn out to exhibit acceptable toxicity values in the future.

3. Group of non-toxic sources: formation of the C≡N-bond

In the second and smaller group of non-toxic cyanide sources, the cyano group is formed during the reaction itself (Scheme 15). Different oxidation states of the carbon and the nitrogen atom source have been employed.

Scheme 15 Schematic representation of the formation of the cyano group from different carbon and nitrogen sources.

Formamides

A relatively large group of cyanide sources developed in the last years comprises simple formamides such as DMF or formamide itself. Two major reaction pathways were established for the cyanide formation. In the first case, the cyano carbon originates from the carbonyl group of DMF or formamide and activation with phosphoryl chloride is required. Here, the group of Pelcman described in 1986 the cyanation of electron rich aromatics like indole or veratrole with Viehe's salt, N-(dichloromethylene)dimethyliminium chloride, prepared from DMF (Scheme 16).¹⁹⁵ Based on the palladium-catalyzed aminocarbonylation with the Vilsmeier–Haack-reagent, N-(chloromethylene)dimethyliminium phosphorodichloridate, published by Hiyama,¹⁹⁶ the group of Bhanage developed palladium- or rhodium-catalyzed nucleophilic cyanations of aryl halides in 2011 and 2013.^197,198 By using an analogue of the Vilsmeier reagent synthesized from formamide (N-(chloromethylene)iminium phosphorodichloridate), they were able to achieve a cyanation instead of an amidation.

Scheme 16 Cyanation of different compounds with formamides.

For DMF, a second reaction pathway is also possible. Here, the methyl group functions as the carbon source for the cyanide generation. The nitrogen can either originate from the DMF itself or from an external source. The former pathway has been reported in 2011 by Jiao and coworkers.¹⁹⁹ In a complex catalysis using iron(II), palladium(II), and copper(II), they were able to achieve the electrophilic cyanation of indoles or benzofurans. By isotope labeling, they could prove the origin of the carbon and the nitrogen atom forming the cyano group. In a series of papers, palladium or copper catalysis were used to turn DMF in combination with ammonium salts into a binary cyanide source. The groups of Chang (2010–2014) and J. Cheng (2011) were able to apply this procedure to arenes, heteroarenes,²⁰⁰ aryl halides,^201,202 arylboronate esters, arylboronic acids,²⁰³ and organosilanes.²⁰⁴ Even though the general procedures of all reports are quite similar (oxygen, 130–150 °C and optionally some additives), the protocol is capable of cyanating both electrophilic and nucleophilic starting materials in very high yields.

Miscellaneous

In 2006, the J.-Q. Yu laboratory investigated a cyanative C–H functionalization of aromatic compounds. After the assumed oxidation of the π-system with air under copper catalysis, they trapped the intermediate radical cation with different nucleophiles. In a blank-experiment, they observed the formation an aryl nitrile without any additional cyanide source in nitromethane as the solvent (Scheme 17).²⁰⁵ In analogy to the cyanations with formamides, DMSO has also been used as a carbon source to form cyanide. By employing ammonium carbonate as the nitrogen source, J. Cheng reported an oxidative cyanation of indoles with dual palladium/copper catalysis.²⁰⁶ Fan Chen and coworkers were able to extend the substrate spectrum to the cyanation of aryl iodides with urea as the CN-nitrogen source in 2013. An extension of the substrate spectrum was achieved by choosing phenanthroline as the ligand on copper. In ¹³C-labeling experiments, the origin of the carbon could be identified.²⁰⁷ In a recent publication, the Opatz group reported the use of α-amino acids and even protein hydrolysates as a source of HCN with the aid of manganese catalysis. To this end, the amino acids were first converted in their corresponding nitrile by an oxidative decarboxylation with the inexpensive sodium dichloroisocyanurate (NaDCC). In a second step, the nitriles were oxidized with ammonium peroxodisulfate under manganese catalysis to the corresponding cyanohydrins. Their degradation released HCN even under acidic conditions.¹¹³

Scheme 17 Cyanations with miscellaneous cyanide sources.

Toxicity of cyanide sources and cyanating agents

All reagents and reagent systems described in the present review are less toxic than cyanide itself by definition. They provide additional safety during handling, transportation and often also during their use, while the health risks associated with the respective reagents differ largely. The sources can be subdivided into groups of different toxicity. In the first column of Table 1, sources are listed that are still classified as toxic or at least as harmful. The sources listed in the second column require toxic chemicals for their activation or the overall process. Many of the systems require for their synthesis toxic starting materials such as alkali cyanides or cyanogen halides. These are listed in the third column. Finally, there are reagents or systems that are entirely non-toxic in every way and should be considered as the ideal cyanide sources for future reactions.

Table 1 Overall toxicity of all cyanide sources

Toxic	Toxic reagents required for activation	Toxic reagents required for preparation	Low toxicity
α-Amino nitriles	Formamide	Ferro-/ferricyanide^208	α-Amino acids/proteins
Nitromethane	KSCN	AIBN	DMSO
DMF		TsCN	NCTS
PhSCN		PhOCN	BnSCN
Ph3P(SCN)2		NC–CH2–COOEt	CuSCN
BnCN		DAMN	CH3CN
CH3COCN		Ion exchanging polymer	Ferro-/ferricyanide^209

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Conflicts of interest

There are no conflicts to declare.

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