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. 2020 Mar 9;5(10):4719–4724. doi: 10.1021/acsomega.9b04073

Nucleophilic Isocyanation

Taiga Yurino 1,*, Takeshi Ohkuma 1,*
PMCID: PMC7081272  PMID: 32201756

Abstract

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Isonitriles are frequently employed as both substrates for organic transformations and ligands for organometallic chemistry. However, despite the wide application of the isonitriles, their synthesis generally depends on the traditional dehydration of N-formamide. “Nucleophilic isocyanation” using cyanide as an N-nucleophile is another straightforward strategy affording the corresponding isonitriles. This method has been available since the 19th century but is still an immature procedure and is therefore more rarely used. In this review, we summarize the concepts and recent progress in nucleophilic isocyanation, including the relatively rare examples of catalytic isocyanation.

1. Introduction

Isonitrile (A: R–NC) is a regioisomer of the corresponding nitrile (R–CN) (Figure 1). The structure of C–NC is almost linear. The bond length of the isocyano group (−NC) is slightly longer than that of the cyano group (−CN) because of a postulating contribution of resonance structure B. For example, the NC bond length of methyl isonitrile (MeNC) is reported to be 116.7 pm, while the CN bond length of acetonitrile (MeCN) is 115.8 pm.1 Isonitriles are well-known surrogates of carbon monoxide in organometallic chemistry, whose C termini show carbene-like reactivity (structure B in Figure 1). These compounds are also regarded as unique and important building blocks in organic transformations because they can react with both nucleophiles and electrophiles at their C sites.2 A number of researchers have focused on the attractive characteristics of isonitriles, and the applications of these compounds have been notably expanded. For example, organometallic complexes coordinated by isonitriles have been prepared to investigate their specific chemical properties.2,3 The isonitriles in these complexes are convertible to many other organic ligands. In addition, organic synthesis reactions using isonitriles, such as specific heterocyclizations and multicomponent condensations, have enabled the construction of highly functionalized compounds (right part of Figure 1).2,4 However, in contrast to the versatility of isonitriles, methods for synthesizing these compounds are quite limited. Indeed, most isonitriles are prepared according to a single protocol: dehydration of the corresponding formamides.5

Figure 1.

Figure 1

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Properties and applicability of isonitriles.1−4

An alternative, traditional protocol affording isonitriles is nucleophilic isocyanation using cyanide as an N-nucleophile. In 1888, Schneidewind published the pioneering study on this strategy using benzyl iodide 1 and AgCN to afford benzylic isonitrile 2 (Scheme 1).6 Cyanide is one of the most typical ambident nucleophiles, and its C- and N-termini are both reactive. In general, however, the C-terminus preferentially reacts with several electrophiles to form the corresponding nitriles. In this mini-review, we will discuss several efficient strategies for obtaining the less-accessible isonitriles by nucleophilic substitution or addition of cyanide reagents. The nucleophilic reactions have traditionally utilized stoichiometrically activated cyanide reagents or less-reactive cyanide sources with stoichiometric activators. Recently, however, some efficient nucleophilic isocyanations with catalytic amounts of activators have been reported.

Scheme 1. Pioneering Study on Nucleophilic Isocyanation Using AgCN6.

Scheme 1

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2. Concept of Chemoselectivity for Nucleophilic Cyanation and Isocyanation

Kornblum and co-workers proposed a chemoselectivity preference for the nucleophilic substitutions using ambident reagents (Kornblum’s rule): The “harder” terminus tends to react through the SN1 pathway, while the “softer” terminus reacts in an SN2 fashion.7 According to this rule, isocyanation proceeds through an SN1-type mechanism, since the N-terminus of cyanide is harder than the C-terminus. However, there are some exceptions to explain the selectivity of cyanide: (1) Methylation using very hard reagents trimethyloxonium tetrafluoroborate and methyl triflate with tetrabutylammonium cyanide exclusively gave acetonitrile, a C-terminus-substituted product (Scheme 2).8 (2) When erythro-2-bromo-3-(methylthio)butane 3 was applied as an electrophile, the erythro isomers of nitrile and isonitrile, 4 and 5, were selectively obtained by using NaCN and AgCN as nucleophiles, respectively, although both reactions occurred through the same trans-thiiranium intermediate, 6 (Scheme 3).9 These substitution reactions using the threo isomer of 3 afforded the corresponding threo products.

Scheme 2. Selective Formation of Acetonitrile with Very Hard Methylation Reagents8.

Scheme 2

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Scheme 3. Control of the Reaction Pathway between Cyanation and Isocyanation Based on the Reactivity of Cyanide Sources9.

Scheme 3

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Today, Kornblum’s rule is regarded as an outdated principle for explaining the selectivity of ambident cyanide. Mayr and co-workers carefully analyzed the preference of the reaction site (C or N) selectivity based on the reported observations and some experimental data by themselves and consequently proposed the following revised hypotheses. (a) A free cyanide preferentially reacts at the C-terminus regardless of whether the reaction proceeds through the SN1 or SN2 pathway. (b) Isocyanation with free cyanide occurs only in the case in which C-addition reaches the diffusion limit, affording a mixture of nitrile and isonitrile. (c) When the C-terminus is blocked by another group, such as Me3Si+ or Ag+, the N-terminus exclusively reacts to afford the corresponding isonitriles.8

3. Isocyanation with a Stoichiometric Activator

As mentioned above, the combination of alkyl halides, especially alkyl iodides, and AgCN (a C-terminus-blocked cyanide) is the most typical approach affording the alkylisonitriles.6 Tu and co-workers applied the procedure to the isocyanation of an in-situ-generated allylic iodide during the final step in the synthesis of 7-epi-14-isocyano-isodauc-5-ene 8, which is the epimer of the natural product isolated from marine sponge Acantkella acuta (Scheme 4).10

Scheme 4. Allylic Isocyanation Using AgCN in the Synthesis of an Isocyano Sesquiterpene10.

Scheme 4

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Benzoyl iodide 9 was rapidly consumed (within 10 min) with an excess amount of AgCN to afford N-benzoylisonitrile 10, which was regarded as an electrophilic carbene surrogate, in 73% yield.11 This compound reacted with both electron-rich and -poor alkynes, giving complex molecules of completely different types from each other (Scheme 5).

Scheme 5. Formation of Benzoyl Isonitrile and Further Transformations11.

Scheme 5

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Some alkyl bromides are also applicable to the transformation using stoichiometric silver reagents. For the synthesis of 1-isocyano sugars, as reported by Descotes and co-workers, the combination of 1-bromosugar and AgCN is effective.12 Kitano and co-workers discovered an efficient method that furnished benzylic isonitriles using primary benzylic bromides and trimethylsilyl cyanide (TMSCN) in the presence of AgClO4 as a stoichiometric activator (Scheme 6).13 In this reaction, they proposed that highly reactive benzylic perchlorate was generated in situ, and the following substitution by TMSCN as a C-blocked cyanide formed the isonitrile.

Scheme 6. Stoichiometric Isocyanation of Primary Benzylic Bromide13.

Scheme 6

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Songstad and co-workers focused on easily isolable onium dicyanoargentates (Q+[Ag(CN)2]−) as nucleophiles.14,15 High nucleophilicity was expected due to their anionic character. In fact, benzhydryl bromide 15 was transformed to isonitrile 16 in 88% yield by using (Ph4As)[Ag(CN)2] in acetonitrile (Scheme 7).14 (Me4N)[Ag(CN)2] reacted even with an alkyl chloride, although the reaction rate was slow. Then they proposed the rate dependency upon the alkyl groups of halides and the leaving groups for this isocyanation as follows: tert-RX > sec-RX > prime-RX and RI > RBr > RCl.15

Scheme 7. Isocyanation of Benzhydryl Bromide with Tetraphenylarsonium Dicyanoargentate14.

Scheme 7

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The modified procedure was reported by El Kaim, Grimaud, and co-workers.16 In the presence of 20 mol % Et3NBnCl (TEBAC), benzylic isonitriles were obtained through the reaction of benzylic bromides and in-situ-prepared KAg(CN)2 from KCN and AgCN (Scheme 8).16a The yield of the product obviously decreased without using phase-transfer catalyst TEBAC. This method was applied to a one-pot sequential transformation affording oxazoles or Ugi-type adducts, without the isolation of the stinking isonitriles.

Scheme 8. Benzylic Isocyanation with In-Situ-Generated KAg(CN)2 in the Presence of a Catalytic Amount of TEBAC16a.

Scheme 8

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As Songstad reported,15 isocyanation of tertiary alkyl halides including chlorides through the formation of stable tertiary alkyl cations is relatively easy. Sasaki and co-workers reported that adamantyl isonitrile 18 was furnished by the reaction of adamantyl chloride 17 and TMSCN with the stoichiometric activation of TiCl4 (Scheme 9).17 A modified method was employed as the key step in the total synthesis of 7,10-diisocyanoadociane reported by Corey and co-workers (Scheme 10).18 In this case, readily prepared trifluoroacetate was used as a leaving group instead of halide. In the presence of excess amounts of TMSCN and TiCl4, double isocyanation product 20 as a mixture of four diastereomers was obtained in 70% yield from 19. The diastereomeric ratio of the diaxial/axial–equatorial and equatorial–axial/diequatorial isomers was 30:55:15.

Scheme 9. TiCl4-Mediated Transformation of 1-Chloroada-mantane to the Corresponding Isonitrile17.

Scheme 9

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Scheme 10. Total Synthesis of 7,10-Diisocyanoadocian through TiCl4-Assisted Double Isocyanation18.

Scheme 10

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Kitano and co-workers reported the direct isocyanation of tertiary alcohols. Both ZnBr2 and AgClO4 efficiently promoted the reaction using TMSCN as a cyanide source.19 The reaction of 1-adamantanol 21 with AgClO4 quantitatively afforded the desired product (Scheme 11).19b The Brønsted acid-assisted one-pot (three steps) formal isocyanation of tertiary alcohols was also reported (Scheme 12).20 This procedure without metallic species was applied to the formation of benzylic isonitriles with medium yield.

Scheme 11. AgClO4-Mediated Isocyanation of Tertiary Alcohols19b.

Scheme 11

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Scheme 12. MsOH-Mediated Formal Isocyanation of Alcohols20.

Scheme 12

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Mukaiyama’s oxidation–reduction condensation is a potent strategy for the synthesis of secondary alkyl isonitriles (Scheme 13).21 An alkoxy diphenylphosphine is a suitable electrophile under the oxidative condition when using 2,6-dimethyl-1,4-benzoquinone (DMBQ) and (EtO)2P(O)CN as a cyanide source. In the presence of soft metal oxides such as ZnO and CdO, the corresponding isonitriles are obtained preferentially, while the nitriles are obtained without the addition of these metal oxides. Notably, the optically active secondary alkoxy diphenylphosphine is converted to the isonitrile with almost perfect stereoinversion.

Scheme 13. Isocyanation through Oxidation–Reduction Condensation with the DMBQ/(EtO)2P(O)CN/ZnO Protocol21.

Scheme 13

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The AgClO4-promoted isocyanation of alkenes was reported by Kitano and co-workers (Scheme 14).22 This is the only example affording the hydroisocyanation products from alkenes through the nucleophilic addition of cyanide. AgClO4 acts as a π-Lewis acid to activate alkenes, and the isocyanation proceeds on the positive site in accordance with the Markovnikov rule.

Scheme 14. AgClO4-Promoted Isocyanation of Alkenes through the Nucleophilic Addition of Cyanide22.

Scheme 14

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4. Catalytic Nucleophilic Isocyanation

The first catalytic isocyanation was reported by Gassman and co-workers through the ring-opening reaction of epoxides (Scheme 15).23 Only 0.5 mol % ZnI2 was sufficient to promote the reaction between epoxides and TMSCN affording the β-hydroxyisonitrile derivatives. Isocyanation selectively occurred at the most substituted carbon center with stereoinversion. Utimoto and co-workers discovered a similar isocyanation that proceeds with Pd(CN)2, SnCl2, or Me3Ga as a catalyst, while the nitriles were obtained when an aluminum-based catalyst, such as Et2AlCl or (iBu)2AlOiPr, was employed.24 Oxetanes were also converted to the corresponding γ-hydroxyisonitriles in the presence of a relatively larger amount of ZnI2 than in the case of epoxides.25

Scheme 15. ZnI2-Catalyzed Ring-Opening Isocyanation of Epoxides23.

Scheme 15

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The only example to date of catalytic enantioselective isocyanation was reported by Zhu, Pan, and co-workers.26 They demonstrated the desymmetrization of meso-epoxides with chiral BINOL–Ga(III) complex 31 as a catalyst (Scheme 16). Although the substrate scope was limited, the chiral β-hydroxyisonitriles were obtained in up to 95% ee after desilylation.

Scheme 16. Ga(III)-Catalyzed Desymmetrization of meso-Epoxides through Nucleophilic Isocyanation26.

Scheme 16

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Shenvi and co-workers reported the catalytic conversion of tertiary alkyl trifluoroacetates with TMSCN into the isonitriles catalyzed by Sc(OTf)3 (Scheme 17).27 It is well known that the nucleophilic substitution of tertiary alcohol derivatives usually proceeds through an SN1-type mechanism; therefore, the chiral information on the substrates is lost through the reaction. However, the titled isocyanation preferentially occurs with stereoinversion because of the formation of a contact ion pair upon substitution. The Sc(OTf)3-catalyzed isocyanation has been employed as the key step in the total synthesis of isocyanoterpenoids, which have antiplasmodial and antimalarial activities. Some examples are shown in Figure 2.28

Scheme 17. Sc(OTf)3-Catalyzed Isocyanation of Tertiary Alcohol Derivatives with Stereoinversion27.

Scheme 17

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Figure 2.

Figure 2

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Antiplasmodial and antimalarial compounds synthesized by using catalytic isocyanation as a key step.28

Recently, Yurino, Ohkuma, and co-workers reported a new strategy for the catalytic isocyanation. The reaction of allylic phosphates and TMSCN with a catalytic amount of Pd(OAc)2 selectively afforded the linear-type allylic isonitriles in high yield (Scheme 18).29 The mechanistic studies suggested that the Pd(II) catalyst plays multiple roles in this reaction. (Me3Si)[Pd(CN)3] and/or (Me3Si)2[Pd(CN)4] generated in situ may function as Lewis acid catalysts for the activation of the allylic phosphate to form a relatively stable allylic cation intermediate. TMSCN, [Pd(CN)3]−, and [Pd(CN)4]2– function as C-blocked cyanide reagents affording both linear and branch allylic isonitriles. The Pd(II) catalyst in the reaction has another role, i.e., transferring the branch product to a linear one. Thus, Pd(II)-catalyzed isocyanation proceeds without the formation of a π-allyl-Pd(II) species.

Scheme 18. Pd(II)-Catalyzed Allylic Isocyanation29.

Scheme 18

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5. Conclusions

Herein, we summarized the basic concepts and representative examples of nucleophilic isocyanation, which is a traditional but immature strategy for the synthesis of isonitriles. Nucleophilic isocyanation was first described in the late 19th century, but the advancement and extension of this chemistry are still limited. This is probably due to the difficulty in the selective formation of isonitrile over the thermodynamically and kinetically favored isomer, nitrile. Moreover, excess amounts of toxic metal cyanides are usually required for this transformation. Currently, the relatively reliable dehydration of formamides is most often chosen for the synthesis of isonitriles. However, this procedure also has unignorable drawbacks, such as the use of excess amounts of harmful dehydration reagents and the inevitable isolation of isonitriles with offensive odors. In contrast, some nucleophilic isocyanations are included in the sequential one-pot process to afford more complex molecules without the isolation of the isonitriles. Recently, several catalytic systems for the nucleophilic isocyanation using less toxic TMSCN have been developed. We believe that these new protocols will solve many of the pending problems and finally open the door to the progression of the chemistry of isonitriles to the next stage.

Acknowledgments

This work was supported by Grants-in-Aid from the Japan Society for the Promotion of Science (JSPS) (nos. 19H02706, 16K17900, and 19K15548). T.Y. also acknowledges the support of the Sumitomo Foundation in the form of a Grant for Basic Science Research Projects (no. 171018) and the support of the Feasibility Study Program of the Frontier Chemistry Center, Faculty of Engineering, Hokkaido University.

Biographies

Taiga Yurino graduated from Kyoto University (Kyoto, Japan) in 2008. He received his Ph.D. from the Graduate School of Science, Kyoto University, in 2013 under the supervision of Professor Keiji Maruoka. He then joined Professor Kazushi Mashima’s group in the Graduate School of Engineering Science, Osaka University, as a research associate. In December 2015, he moved to the Faculty of Engineering, Hokkaido University, as an assistant professor in Professor Takeshi Ohkuma’s group. His current research interests are transition-metal catalysis, highly efficient catalytic systems, asymmetric synthesis, and bioconjugation.

Takeshi Ohkuma has been a professor in the Faculty of Engineering since 2004 and the Director of the Frontier Chemistry Center at Hokkaido University since 2013. His research focuses on the development of novel catalytic reactions that achieve a high level of reactivity and selectivity. He received the Progress Award in Synthetic Organic Chemistry, Japan, in 1997, the JSPS Prize in 2007, and the Japan Chemical Society Award for Creative Work in 2018. For further information, please see http://labs.eng.hokudai.ac.jp/labo/orgsynth/.

The authors declare no competing financial interest.

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