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. 2026 Oct 5. Online ahead of print. doi: 10.1039/d6ra06539b

Desulfurative cyanation of organosulfur compounds

Esmail Vessally a,b,✉, Ali Zal Zalov c, Hawraa Hussein Al-Mayal d, Chingiz Kinyaz Rasulov e, Khudayar Hasanov f,g, Asmat Azizova f,g, Adila Y Suleymanova h, Khalig M Hashimov h, Mehriban M Maharramova h
PMCID: PMC13637678  PMID: 42836154

Abstract

This review presents an overview of the reported methods for the synthesis of nitriles through the direct cyanation of organosulfur compounds via C–S bond activation. It is intended to serve as a practical guide for chemists seeking suitable desulfurative cyanation protocols for synthetic applications, while also providing inspiration for the development of new protocols in this rapidly evolving field.

Recent strategies for the direct cyanation of organosulfur compounds via C–S bond activation are reviewed, providing insights into catalytic approaches and future directions for nitrile synthesis.graphic file with name d6ra06539b-ga.webp

1. Introduction

The cyano (–C Created by potrace 1.16, written by Peter Selinger 2001-2019 N) group is one of the most versatile functional groups in organic chemistry that can be transformed into a broad range of valuable functionalities, including amines,1 amides,2 imines,3 aldehydes,4 ketones,5 esters,6 carboxylic acids,7 and alcohols,8 as well as heterocycles such as triazoles and tetrazoles.9 In addition to its remarkable synthetic versatility, the cyano group is a common structural motif in pharmaceuticals,10 agrochemicals,11 dyes,12 and natural products.13 Interestingly, this functional group is present in more than 60 marketed small-molecule drugs (Scheme 1)14 and over 20 additional drug candidates currently in clinical development.15 Although the first cyano-containing drug, verapamil, was approved in 1981, the importance of the cyano group in drug discovery has grown markedly in recent years. Nearly 80% of FDA-approved cyano-containing drugs have been approved within the past 15 years, and since 2010, the United States Food and Drug Administration (US FDA) has approved at least one cyano-containing drug each year.16,17 This growing significance has prompted extensive efforts to develop efficient and selective approaches for the synthesis of nitrile-containing compounds.18 These methods can generally be divided into two broad categories: (i) direct cyanation using cyanating agents18a–e and (ii) conversion of other functional groups into nitriles.18f Among these approaches, direct cyanation is particularly appealing because it allows the cyano group to be introduced in a single step, avoiding additional prefunctionalization and thereby providing a more concise synthetic route. Accordingly, the development of efficient, practical, and selective direct cyanation methods has attracted considerable attention in recent years.

Scheme 1. Selected examples of newly developed nitrile-containing drugs.

Scheme 1

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The widespread availability, structural diversity, and synthetic versatility of organosulfur compounds make them attractive precursors for molecular diversification. Owing to the relatively low bond dissociation energy of the C–S bond, desulfurative functionalization via selective C–S bond cleavage has emerged as a powerful synthetic strategy for the efficient construction of a broad range of valuable chemical bonds and functional groups.19,20 In this context, desulfurative cyanation of organosulfur compounds has recently emerged as a straightforward and efficient approach for the synthesis of nitriles (Fig. 1). This review aims to summarize the most significant advances and developments in this emerging area, with particular emphasis on reaction mechanisms.

Fig. 1. Cyanation of organosulfur compounds via C–S activation.

Fig. 1

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2. Cyanation of sulfonyl chlorides

The first and, thus far, only example of the desulfitative cyanation of sulfonyl chlorides was reported by Cheng and co-workers in 2012.21 They showed that a series of electron-rich and electron-deficient arenesulfonyl chlorides 1 underwent selective cyanation via C–S bond cleavage upon treatment with CuCN in the presence of a Pd(MeCN)2Cl2/Cu(acac)2/Na2CO3 catalytic system in refluxing 1,4-dioxane, affording the corresponding aryl nitriles 2 in poor to excellent yields (Scheme 2). The results showed that the reaction outcome was largely insensitive to the electronic nature of substituents on the aromatic rings of arenesulfonyl chlorides, as substrates bearing either electron-donating groups (e.g., OMe and tBu) or electron-withdrawing groups (e.g., Br and NO2) were well tolerated. In contrast, steric effects had a pronounced influence on the reaction, as sterically hindered substrates such as 2-nitrobenzenesulfonyl chloride and 2,4,6-triisopropylbenzene-1-sulfonyl chloride failed to afford the desired products. NH-containing functional groups also appeared to be poorly tolerated under the reaction conditions. Notably, para-CF3- and CN-substituted arenesulfonyl chlorides failed to furnish the corresponding cyanated products and instead underwent homocoupling to give symmetrical biaryl products. Control experiments revealed that the reaction still proceeded in the absence of Cu(acac)2, albeit with diminished yields, whereas omission of either Pd(MeCN)2Cl2 or Na2CO3 resulted in only trace amounts of the desired product. Furthermore, replacing Pd(MeCN)2Cl2 with other palladium precatalysts, including PdCl2, Pd(OAc)2, and Pd(acac)2, led to very low yields, highlighting the superior catalytic performance of Pd(MeCN)2Cl2 in this transformation. Notably, the optimized catalytic system was almost equally effective for the desulfitative cyanation of sodium aryl sulfinates. The mechanism proposed for this desulfitative cyanation reaction is illustrated in Scheme 3 and involves the following key steps: (i) coordination of the aryl sulfonyl chloride 1 to the PdII complex to generate palladium aryl sulfinate intermediate A; (ii) extrusion of SO2 from intermediate A to furnish the aryl–palladium species B; (iii) coordination of the cyanide (CN) to B, leading to palladium intermediate C; and (iv) reductive elimination from C to afford the desired aryl nitrile 2, accompanied by formation of a Pd0 species, which is subsequently reoxidized to PdII by CuII and/or air oxygen.

Scheme 2. Pd-catalyzed desulfitative cyanation of arenesulfonyl chlorides 1 with CuCN.

Scheme 2

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Scheme 3. Mechanistic proposal for the formation of aryl nitriles 2.

Scheme 3

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3. Cyanation of sodium sulfinates

In 2012, in the same paper describing Pd-catalyzed desulfitative cyanation of arenesulfonyl chlorides with CuCN,21 Cheng's research group21 unraveled the preparation of a small series of aryl nitriles 4 in synthetically usefull yields via the desulfitative cyanation of corresponding sodium aryl sulfinates 3 under their standard conditions. As shown in Scheme 4, sodium aryl sulfinates bearing either electron-donating groups (e.g., Me, OMe) or electron-withdrawing groups (e.g., NO2) showed broadly similar reactivity under the standard conditions. However, consistent with the results obtained for 2-nitrobenzenesulfonyl chloride and 2,4,6-triisopropylbenzene-1-sulfonyl chloride, the corresponding sodium 2-nitrobenzenesulfinate and sodium 2,4,6-triisopropylbenzene-1-sulfinate also failed to deliver the cyanated products. Unfortunately, the applicability of sodium alkyl sulfinates was not examined in this study. The mechanism proposed for this transformation is analogous to that illustrated for the cyanation of arenesulfonyl chlorides.

Scheme 4. Pd-catalyzed desulfitative cyanation of sodium aryl sulfinates 3 with CuCN.

Scheme 4

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4. Cyanation of sulfoxides

Desulfinylative cyanation of sulfoxides via C–S bond cleavage represents a largely unexplored approach to the synthesis of nitriles. To the best of our knowledge, only a single example has been reported to date. Very recently, Shi and co-workers demonstrated that treatment of diaryl sulfoxides 5 with bench-stable Zn(CN)2 in the presence catalytic amounts of Pd(OAc)2 and PCy3, together with 1.5 equiv. of tBuONa as the base, in refluxing 1,4-dioxane furnished the corresponding aryl nitriles 6 in poor to high yields (Scheme 5).22 A clear dependence on the electronic nature of the substrates was observed, as electron-rich diaryl sulfoxides generally exhibited superior reactivity and afforded the corresponding aryl nitriles in higher yields than electron-deficient analogues. Steric effects were also significant; while 4,4″-sulfinyldi-1,1′-biphenyl afforded the corresponding nitrile in 73% yield, the 3,3″- and 2,2″-isomers afforded the products in lower yields of 58% and 30%, respectively. The authors also investigated regioselective cyanation of unsymmetric sulfoxides for the electronic or steric bias of diaryl groups. For the sterically biased 2,6-dimethylphenyl phenyl sulfoxide, cyanation afforded the nitrile derived from the more hindered 2,6-dimethylphenyl group in a 2 : 1 product ratio relative to that derived from the less hindered phenyl group. Likewise, cyanation of electronically biased phenyl(4-methoxyphenyl) sulfoxide preferentially furnished the nitrile originating from the electron-deficient phenyl group over that derived from the electron-rich 4-methoxyphenyl group, with a 2.8 : 1 product ratio. Unfortunately, extension of the protocol to aryl alkyl sulfoxides was unsuccessful, affording only trace amounts of benzonitrile, while the corresponding alkyl nitriles were not detected. The authors also evaluated the reactivity of several sulfur-containing electrophilic reagents, including diphenyl sulfide, sodium benzenesulfonate, diphenyl sulfone, benzenesulfonyl chloride, and phenylthionium salts, under the optimized reaction conditions. Among these substrates, only diphenyl sulfide displayed measurable reactivity, affording benzonitrile in 23% yield, whereas all of the remaining sulfur-containing electrophiles were unreactive. Based on control experiments and literature precedents, a catalytic cycle was proposed involving sequential oxidative addition, transmetalation, and reductive elimination sequential steps (Scheme 6).

Scheme 5. Pd-catalyzed desulfinylative cyanation of diaryl sulfoxides 5 with Zn(CN)2.

Scheme 5

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Scheme 6. Proposed mechanism for the formation of aryl nitriles 6.

Scheme 6

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5. Cyanation of sulfides

Building on the pioneering work of Jarvis and co-workers, who in 1980 demonstrated the one-pot conversion of benzyl phenyl sulfides into the corresponding benzonitriles via sequential chlorination with sulfuryl chloride, azidation with sodium azide, and base-induced elimination,23 Morandi and co-workers developed in 2021 the first general strategy for the direct conversion of aryl sulfides into aryl nitriles.24 Their methodology relied on a Ni(COD)2/dcype (1,2-bis(dicyclohexylphosphino)ethane) catalytic system to promote the reversible functional-group metathesis between (hetero)aryl methyl sulfides 7 and aryl nitriles 8 to afford a wide range of (hetero)aryl nitriles 9 in moderate to excellent yields (Scheme 7). Methyl 4-cyanobenzoate 8a proved to be an effective nitrile transfer reagent for electron-neutral and electron-rich aryl sulfides, whereas the more electron-deficient 1,4-dicyanobenzene 8b was required to achieve efficient conversion of electron-poor aryl sulfide substrates. The protocol displayed broad functional-group compatibility, tolerating halides, ethers, ketones, esters, amides, and sulfoxides, thereby providing access to structurally diverse aryl nitriles amenable to further synthetic elaboration. Moreover, the authors demonstrated the synthetic utility of the methodology through the late-stage functionalization of a range of structurally complex medicinally relevant molecules, as well as by the high-yielding synthesis of nitrile-containing pharmaceuticals, including letrozole, a clinically used anticancer agent. However, the applicability of this method to the synthesis of aliphatic nitriles was not investigated in this study. Comprehensive mechanistic investigations, including in situ NMR spectroscopy, X-ray crystallography, stoichiometric organometallic experiments with putative catalytic intermediates, kinetic studies, and density functional theory (DFT) calculations, enabled the authors to propose a detailed catalytic cycle for this transformation as depicted in Scheme 8.25

Scheme 7. Nickel-catalyzed metathesis between (hetero)arylmethyl sulfides 7 and aryl nitriles 8.

Scheme 7

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Scheme 8. Proposed mechanistic pathway for the formation of (hetero)aryl nitriles 9.

Scheme 8

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Almost concurrently, the same research group also described the direct conversion of a diverse range of (hetero)aryl methyl sulfides 11 into the corresponding (hetero)aryl nitriles 12via desulfitative cyanation using Zn(CN)2 as a cyanide source under the same catalytic system in combination with KOAc as a base (Scheme 9).26 Notably, compared with their previously reported method, this protocol generally afforded higher yields of the desired nitriles. Furthermore, the method was inert toward aliphatic thioethers, allowing the selective cyanation of aryl sulfides in the presence of alkyl sulfides. A possible mechanism for this Ni-catalyzed cyanation is illustrated in Scheme 10. The reaction starts with the generation of NiII-complex B through the oxidative addition of sulfide 11 to active catalyst A. Subsequently, this intermediate undergoes transmetalation with M–CN to give the complex C and the generation of M–SMe salt. Finally, reduction of this complex with the help of an extra ligand leads to the formation of observed aryl nitrile 12 and regenerates complex A.

Scheme 9. Nickel-catalyzed desulfitative cyanation of (hetero)aryl methyl sulfides 11 with Zn(CN)2.

Scheme 9

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Scheme 10. Plausible mechanism for the formation of aryl nitriles 12.

Scheme 10

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Very recently, He and co-workers reported an elegant Ni-catalyzed desulfurative cyanation of sulfides, in which CO2 and NH3 served as the carbon and nitrogen sources for in situ generation of the cyanide functionality.27 The transformation was conducted in NMP at 150 °C using NiCl2 as the catalyst, dppp as the ligand, ZnF2 as an additive, and a combination of zinc powder and PhSiH3 as the reducing system. Under optimized conditions, twenty-two (hetero)aryl nitriles 14 were prepared in relatively poor to excellent yields from the corresponding (hetero)aryl methyl sulfides 13 (Scheme 11). Besides, ethyl phenyl sulfide and benzyl phenyl sulfide were also found to be compatible with this catalytic system, giving the corresponding products in 86% and 52% yields, respectively. More significantly, the authors demonstrated that the protocol could be extended to readily accessible diaryl sulfides, thereby considerably expanding the substrate scope of this page of aryl nitrile synthesis. Notably, the conversion of polyphenylene sulfide to benzonitrile was also demonstrated, although the desired product was obtained in only 17% yield. However, attempts to extend the reaction to sulfones were unsuccessful. In addition, functional groups such as ketones and thiophene rings were not tolerated under the reaction conditions. Scheme 12 depicts the proposed catalytic cycle for this transformation. Initially, the NiII precursor is reduced in the presence of dppp and silane to generate the active Ni0 species A. Subsequent oxidative addition of A into the C–S bond of the aryl sulfide 13 affords intermediate B, which is then reduced to a NiI species C. In an alternative pathway, intermediate B may undergo chloride–ligand exchange with Cl− to form a NiII–Cl species B′, which is subsequently reduced by Zn powder to the same NiI intermediate C. In parallel, CO2 and NH3, under silane-mediated conditions, generate a silyl isocyanate intermediate, which inserts into the NiI–C bond of C to afford a Ni–amidate species D. This is followed by a 1,3-silyl N-to-O migration to deliver the target nitrile 14, along with formation of intermediate E. Finally, reduction of E by zinc and silane regenerates the Ni0 species A, thereby completing the catalytic cycle.

Scheme 11. He's synthesis27 of (hetero)aryl nitriles 14.

Scheme 11

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Scheme 12. Mechanistic proposal for the reaction in Scheme 11.

Scheme 12

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6. Cyanation of sulfonium salts

Although Ritter and co-workers first established the feasibility of cyanation of sulfonium salts via C–S bond cleavage in 2019,28 the transformation was exemplified by only a single substrate, with no investigation of its substrate scope. The first general protocol on this transformation was subsequently developed by Procter's research group in 2022.29 Their strategy involved the regioselective Pummerer reaction of arenes 15 with diaryl sulfoxide 16, providing the corresponding triaryl sulfonium salts 17. These species formed electron donor–acceptor (EDA) complexes A with the triarylamine donor (4-Br-C6H4)3N. Irradiation with visible light promoted homolytic cleavage of the C–S bond, generating aryl radicals that were intercepted by the electron-rich tert-butyl isocyanide 18. Subsequent radical fragmentation delivered the corresponding aryl nitriles 19 in synthetically useful overall yields, ranging from 23% to 65% (Scheme 13). The reaction tolerated a broad range of functional groups, including fluoro, chloro, bromo, iodo, amido, sulfonamido, cyano, trifluoromethyl, ether, ester, ketone, and sulfonyl groups, highlighting the versatility of this method for the synthesis of functionalized aryl nitriles and providing opportunities for further product modification. However, the generation of at least one equivalent of phenoxathiine, together with other waste products, represents a significant drawback that may limit the practical applicability of this method, particularly on a larger scale.

Scheme 13. Procter's synthesis29 of aryl nitriles 19.

Scheme 13

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Subsequently, by means of the same strategy and using the combination of NiCl2·6H2/xantphos/Zn/CuBr2 as the catalytic system, Ding and colleagues were able to synthesize a large library of (hetero)aryl nitriles 21 through desulfurative cyanation of corresponding thianthrenium salts 20 (TTs) using Zn(CN)2 as cyanating agent (Scheme 14).30 Importantly, the TTs were generated in situ through the regioselective thianthrenation of the corresponding (hetero)arenes, thereby streamlining the overall synthetic sequence. The reaction exhibited excellent tolerance toward steric hindrance, as substrates bearing ortho-, meta-, or para-substituents on the aryl ring all afforded the desired nitriles in good yields. In contrast, fused (hetero)aromatic substrates generally proved less efficient, giving lower yields than simple monocyclic arenes. Interestingly, allyl-substituted substrates underwent isomerization under the reaction conditions to give the corresponding β-styrene-derived nitriles, while no products resulting from direct allyl addition were observed. The practicality of the method was further demonstrated through the late-stage cyanation of the bioactive molecules pyriproxyfen and famoxadone, both of which furnished the corresponding nitrile derivatives in moderate to good yields. A plausible mechanism for the desulfurative cyanation is outlined in Scheme 15. The catalytic cycle is proposed to begin with the reduction of the NiII precatalyst by zinc to generate the active NiI–Cl species A. Transmetallation of A with Zn(CN)2 then furnishes the NiI–CN intermediate B. This species undergoes single-electron transfer to thianthrenium salt 20, resulting in C–S bond cleavage and the formation of aryl cationic complex [NiIICN–(X)]+C, accompanied by an aryl radical and thianthrene. Afterwards, capture of aryl radical by the NiII species gives the NiIII intermediate D, which subsequently undergoes reductive elimination to afford aryl nitrile 2 and regenerate the catalytically active NiI–Cl species (Scheme 15, path A). An alternative pathway involving copper catalysis has also been proposed (Scheme 15, path B). In this scenario, aryl radical is trapped by CuBr2 to generate the CuIII–Br intermediate E, which undergoes transmetallation with Zn(CN)2 to form the corresponding CuIII–CN complex F. Reductive elimination from F then yields the desired aryl nitrile 21, completing the catalytic cycle.

Scheme 14. Ding's synthesis30 of aryl nitriles 21.

Scheme 14

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Scheme 15. Plausible mechanism for the formation of aryl nitriles 21.

Scheme 15

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Subsequently, Shi, Dang, Cao, and co-workers developed an alternative Pd-catalyzed desulfurative cyanation of aryl sulfonium salts.31 They showed that the treatment of various (hetero)aryl dimethylsulfonium salts 22 with cheap, nontoxic, and bench-stable K4[Fe–(CN)6]·3H2O as the cyanating reagent in the presence of Pd(OAc)2 as the catalyst and BerttPhos as a ligand in refluxing MeCN, resulted in the formation of the corresponding (hetero)aryl nitriles 23 in poor to excellent yields (Scheme 16). The reaction was relatively insensitive to the electronic effects of the substituents; however, steric effects had a more pronounced influence on the reaction outcome, and ortho-substituted substrates were generally poorly tolerated. Another limitation of this protocol is the relatively high catalyst loading required, which may reduce its practicality for larger-scale applications. Notably, control experiments revealed that nickel catalysts such as Ni(COD)2 and Ni(PPh3)2Cl2 were ineffective, with no detectable product formation under the same conditions. Based on DFT calculations, the authors proposed a mechanistic sequence comprising oxidative addition, ligand exchange, reductive elimination, and regeneration of the active Pd species to afford the observed products.

Scheme 16. Pd-catalyzed desulfurative cyanation of aryl dimethylsulfonium salts 22.

Scheme 16

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In 2024, Sanford, Scott, and co-workers expanded the applicability of this synthetic strategy to the preparation of 11C-radiolabeled nitriles.32 In the presence of stoichiometric Cu(MeCN)4PF6 and 1,10-phen, the reaction of various (hetero)aryl thianthrenium salts 24 with hydrogen [11C]cyanide ([11C]HCN) at room temperature under irradiation with 395 nm light furnished the corresponding 11C-labeled nitriles 25 in good radiochemical yields (Scheme 17). The protocol was also successfully applied to the cyanation of heteroaryl thianthrenium salts derived from pyridine, pyrimidine, pyrazole, quinoline, thiophene, and carbazole scaffolds. Its synthetic utility was further demonstrated through the late-stage radiocyanation of several pharmaceutically relevant molecules, including febuxostat, clopidogrel, gemfibrozil, and meclofenamic acid.

Scheme 17. Photo- and Cu-mediated 11C-cyanation of aryl thianthrenium salts 24, reported by Sanford and Scott.

Scheme 17

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7. Conclusion

As discussed in this review, the direct cyanation of organosulfur compounds via C–S bond activation has emerged as an efficient and valuable approach for the synthesis of biologically and synthetically important nitriles (Table 1). Despite the considerable progress achieved in recent years, several challenges still remain to be overcome: (i) most of the reported methods require elevated reaction temperatures, highlighting the need for new catalytic systems that can promote these transformations under milder conditions; (ii) the reported transformations are predominantly dependent on transition-metal catalysts, whereas metal-free approaches remain largely unexplored; (iii) electrochemical strategies for C–S bond activation in nitrile synthesis have received little attention and represent an interesting area for future investigation; (iv) only a limited number of cyanating reagents have been employed so far, and the use of readily available cyanide sources such as KCN, NaCN, and TMSCN should be further explored; (v) the applicability of other common organosulfur compounds, such as sulfonyl hydrazines, sulfonamides, sulfones, thiols, and disulfides, remains to be explored; (vi) further studies are needed to expand the substrate scope and define the limitations of existing methodologies for organosulfur substrates such as sulfonyl chlorides and sodium sulfinates; and (vii) the development of sequential one-pot strategies that combine C–S bond formation with subsequent C–S cyanation would provide a particularly attractive and practical direction for future research.

Table 1. Comparison of results of desulfurative cyanation of organosulfur compounds.

Entry Organosulfur compound CN reagent Conditions Number of examples Yield (%) Ref.
1 Sulfonyl chlorides CuCN Pd(CH3CN)2Cl2, Cu(acac)2, Na2CO3, 1,4-dioxane, air, 130 °C, 24 h 11 27–93 21
2 Sodium sulfinates CuCN Pd(CH3CN)2Cl2, Cu(acac)2, Na2CO3, 1,4-dioxane, air, 130 °C, 24 h 5 46–65 21
3 Sulfoxides Zn(CN)2 Pd(OAc)2, PCy3, tBuONa, 1,4-dioxane, 150 °C, 12 h 28 10–88 22
4 Sulfides Ar–CN Ni(COD)2, dcype, o-xylene, 140 °C, 24 h 33 37–95 24
5 Sulfides Zn(CN)2 Ni(COD)2, dcype, KOAc, 1,4-dioxane, 110 °C, 16 h 41 41–97 26
6 Sulfides CO2 + NH3 NiCl2, Dppp, PhSiH3, Zn, ZnF2, NMP, 150 °C, 16 h 22 23–92 27
7 Sulfonium salts MeNC (4-Br-C6H4)3N, NaOAc, DMSO, blue LEDs, r.t., 20 h 23 23–65 29
8 Sulfonium salts Zn(CN)2 NiCl3·6H2O, xantphos, Zn, CuBr2, DMF, 120 °C, 12 h 20 31–87 30
9 Sulfonium salts K4[Fe(CN)6]·3H2O Pd(OAc)2, BettPhos, MeCN, 110 °C, 8 h 31 11–92 31
10 Sulfonium salts [11C]HCN-pyridine Cu(MeCN)4PF6, 1,10-phen, MeCN, 395 nm LEDs, r.t., 5 min 16 13–90 32
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Conflicts of interest

There are no conflicts to declare.

Data availability

This article is a review of previously published literature. No new experimental or computational data were generated or analyzed during this study. Consequently, there are no datasets associated with this manuscript.

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Data Availability Statement

This article is a review of previously published literature. No new experimental or computational data were generated or analyzed during this study. Consequently, there are no datasets associated with this manuscript.

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