Cyanide-Free Cyanation of Aryl Iodides with Nitromethane by Using an Amphiphilic Polymer-Supported Palladium Catalyst

Dedicated to Professor Benjamin List in celebration of his Nobel Prize in Chemistry 2021

Abstract

A cyanide-free aromatic cyanation was developed that uses nitromethane as a cyanide source in water with an amphiphilic polystyrene–poly(ethylene glycol) resin-supported palladium catalyst and an alkyl halide (1-iodobutane). The cyanation proceeds through the palladium-catalyzed cross-coupling of an aryl halide with nitromethane, followed by transformation of the resultant (nitromethyl)arene intermediate into a nitrile by 1-iodobutane.

Aromatic nitriles have aroused considerable interest because of their presence in a wide range of biologically and therapeutically active compounds, as well as functional organic materials.[2] They are also among the most versatile synthetic intermediates because the cyano group can be readily transformed into various other functional groups.[3] Thus, the development of efficient routes for preparing aryl nitriles is an essential goal of synthetic organic chemistry. Traditionally, aryl nitriles have been prepared by Sandmeyer–Rosenmund–von Braun reactions[4] that employ stoichiometric amounts of CuCN under thermal conditions (e.g., neat at 260 °C).[5] Catalytic cyanation of aryl halides with inorganic cyanide reagents has also been extensively investigated but often requires the use of toxic metal cyanide salts [e.g., NaCN, KCN, or Zn(CN)₂] (Scheme [1]A).[6] Recently, potassium ferrocyanide {K₄[Fe(CN)₆]} has been used as a nontoxic alternative to inorganic cyanide reagents (Scheme [1]B)[7] prepared from hydrogen cyanide (HCN). Several organic cyanide sources have been developed for catalytic aromatic cyanation under homogeneous conditions (Schemes 1C and 1D).[8] Thus, trimethylsilyl cyanide (TMSCN),[9] acetone cyanohydrin,[10] and butyronitrile[11] have been used in cyanations of aryl halides with transition-metal catalysts. Formamide has also been used as a cyanide source in conjunction with an activating agent such as phosphoryl trichloride (POCl₃),[12] 2,4,6-trichloro-1,3,5-triazine (TCT; cyanuric chloride),[13] and a catalytic nickel bis(acetylacetone)-bipyridyl [Ni(acac)₂-bpy][14] system for catalytic aromatic cyanation. However, these organic cyanide surrogates have been reported to generate toxic cyanide (CN⁻) species in situ; in addition, the activating agents themselves (POCl₃ and TCT) are highly toxic.[15] Recently, a Cu-promoted cyanation of aryl halides was achieved by using nitromethane as a cyanide source (Scheme [1]E); in this reaction, cyanide (CN⁻) species were found to be generated in situ under the catalytic conditions.[16] [17] Thus, the development of a catalytic protocol to introduce a nitrile group onto aromatic rings through a reaction that does not involve potentially toxic cyanide species remains a major challenge. Here, we report a palladium-catalyzed cyanation of aryl halides in water using nitromethane as a cyanide source in the presence of an amphiphilic polymer resin-supported palladium catalyst, where the cyanation occurs via nitromethylarene intermediates, without the generation of CN⁻ species (Scheme [1]F).

We have previously developed an amphiphilic polystyrene–poly(ethylene glycol) (PS–PEG) resin-supported[18] palladium–triarylphosphine complex 1 (Scheme [2]).[19] [20] The polymeric palladium complex 1 efficiently catalyzed a wide variety of palladium-catalyzed organic transformations, including the π-allylic substitution of allyl esters with various nucleophiles.[21] For example, 1,3-diphenylpropenyl ester reacted with nitromethane in water in the presence of lithium carbonate and the polymeric catalyst 1 (5 mol% Pd) to give the desired allylic nitromethylated product in an excellent yield (Scheme [2]A).[22] Although the explosivity of nitromethane under basic conditions is a primary concern, the reaction was safely carried out in water with bases, even upon heating. With a procedure for allylic nitromethylation in hand, we next examined the cross-coupling reaction of aryl halides with nitromethane in water in the presence of the polymeric palladium complex 1 (Scheme [2]B). However, when the reaction of 1-iodonaphthalene (2a) with three equivalents of nitromethane was carried out in water at 100 °C in the presence of lithium carbonate and 5 mol% palladium in the form of polymeric palladium complex 1, the reaction gave a complex crude mixture that produced a convoluted gas chromatogram. Careful GC analysis revealed that a less than 5% GC yield of the nitromethylated product 3a was obtained, along with a trace amount of unexpected naphthalene-1-carbonitrile (4a) (<5%).[23] Although our initial attempt at aromatic nitromethylation failed, these serendipitous findings of aromatic cyanation encouraged us to develop a novel catalytic cyanation system with nitromethane as a cyanide source.

Conditions for the cyanation of 1-iodonaphthalene (2a) were screened; representative results are reported in Table [1]. A wide range of inorganic bases were tested for the cyanation with three equivalents of nitromethane and 5 mol% palladium in the form of the PS–PEG-supported catalyst 1 (Table [1], entries 1–4); among the bases studied, cesium carbonate was found to give a 10% yield of naphthalene-1-carbonitrile (4a; entry 3). When tetrabutylammonium fluoride (TBAF) was used as an additive, the yield of 4a was remarkably improved to 53% (entry 5). Czekelius and Carreira have reported a one-pot transformation of nitroalkanes into cyanoalkanes via the corresponding aldoximes by reaction with benzyl bromide followed by treatment with trifluoroacetic anhydride or sulfurous dichloride, as outlined in Scheme [3].[24] We conjectured that 1-iodonaphthalene (2a) probably coupled with nitromethane to form 1-(nitromethyl)naphthalene (3a), which was then converted in situ into nitrile 4 through O-alkylation by TBAF. Therefore, we next examined the effect of alkyl halides as additional alkylating agents for the aromatic cyanation with nitromethane (Table [1], entries 6–8). (Bromomethyl)benzene exhibited little effect on the efficiency of the cyanation (entry 6). Iodomethane improved the yield of 4a to 81% (entry 7). The best result was obtained when two equivalents of 1-iodobutane were used as the additive, giving a 90% yield of naphthalene-1-carbonitrile (4a) (entry 8). Neither palladium diacetate nor palladium/charcoal promoted the reaction under otherwise similar conditions (entries 9 and 10). Amphiphilic PS–PEG-supported palladium nanoparticles (ARP-Pd)[25] also failed to promote the cyanation under similar conditions (entry 11). The amphiphilic resin-supported palladium catalyst 1 was readily recovered by simple filtration and reused in consecutive catalytic runs (entries 12–14), where a slight loss of catalytic activity was observed as the catalyst was repeatedly recycled.

Table 1 Optimization of Catalytic Cyanation of 1-Iodonaphthalene (2a) with Nitromethane^a

Entry	Catalyst	Base	Additive	Alkyl halide	Yieldb (%)
1	1	Li2CO3	none	none	(<5)
2	1	K2CO3	none	none	(<5)
3	1	Cs2CO3	none	none	10
4	1	KOH	none	none	(<5)
5	1	Cs2CO3	TBAF	none	53
6	1	Cs2CO3	TBAF	BnBr	44
7	1	Cs2CO3	TBAF	MeI	81
8	1	Cs2CO3	TBAF	BuI	90 (95)
9	Pd(OAc)2	Cs2CO3	TBAF	BuI	(<5)
10	Pd/C	Cs2CO3	TBAF	BuI	– c
11	ARP-Pdd	Cs2CO3	TBAF	BuI	(<5)
12e	1	Cs2CO3	TBAF	BuI	82
13f	1	Cs2CO3	TBAF	BuI	80
14g	1	Cs2CO3	TBAF	BuI	63

^a Reaction conditions: 1-iodonaphthalene (2a; 0.4 mmol), MeNO₂ (1.2 mmol), base (1.6 mmol), TBAF (0.4 mmol), alkyl halide (0.8 mmol), 5 mol% Pd in catalyst, H₂O (1 mL), 100 °C, 24 h.

^b Isolated yield (GC yield in parenthesis).

^c No reaction.

^d Amphiphilic resin-supported particles of palladium.[25]

^e Second use of 1 (recycled from entry 8).

^f Third use of 1 (recycled from entry 12).

^g Fourth use of 1 (recycled from entry 13).

Having determined the optimal conditions, we examined the palladium-catalyzed cyanation of various aryl halides (Scheme [4]).[26] Naphthalene-1-carbonitrile (4a) was obtained in 90% isolated yield (Table [1], entry 8); notably, however, 1-bromonaphthalene and 1-chloronaphthalene exhibited little reactivity under the standard catalytic conditions. 2-Iodonaphthalene (2b), 9-iodophenanthrene (2c), and iodobenzene (2d) gave cyanides 4b, 4c, and 4d, respectively, in yields of 51, 88, and 83%. The catalytic cyanation proceeded smoothly with ortho-substituted aromatic iodides, giving the corresponding aromatic cyanides in good-to-high yields. Thus, 2-methylbenzonitrile (4e) and 2-methoxybenzonitrile (4f) were obtained in yields of 41 and 60%, respectively. 1-Chloro-2-iodobenzene (2g) and 1-bromo-2-iodobenzene (2h) underwent cyanation with nitromethane to give nitriles 4c and 4d, respectively, in isolated yields of 80 and 71%, with the aromatic chloride and bromide groups tolerated under the standard catalytic conditions. The meta- and para-substituted iodobenzenes 2i–l afforded the corresponding cyanides 4i–l in yields as high as 85%; however, aryl halides bearing highly electron-withdrawing substituents (e.g., CN or NO₂) were incompatible under the standard conditions and gave complex crude mixtures, presumably because of the instability of the acidic nitromethylated intermediates 3 under the basic catalytic conditions.

To demonstrate the synthetic advantage of our proposed catalytic protocol performed in water, we prepared 5-(1-naphthyl)tetrazole (5a) from 1-iodonaphthalene (2a) in one pot [Scheme [4] (bottom)]. Thus, 2-iodonaphthalene (2a) was subjected to cyanation with nitromethane under the standard catalytic conditions in water. Eight equivalents of sodium azide were then added, and the resultant mixture was stirred at 100 °C for an additional one hour to give 5-(1-naphthyl)tetrazole (5a) in 58% yield.

We speculated that the catalytic cyanation with nitromethane might proceed via a (nitromethyl)arene 3 formed in situ by cross-coupling nitromethylation, and that the (nitromethyl)arene 3 is subsequently transformed into a nitrile through reaction with 1-iodobutane (Scheme [3]). To confirm this plausible reaction pathway for our cyanation, we examined the individual steps possibly involved (Scheme [5]).

When the catalytic cross-coupling of iodobenzene (2d) with nitromethane was carried out with the polymeric palladium complex 1 in water in the absence of any alkylating agent, the cross-coupling afforded a moderate yield of (nitromethyl)benzene (3d), and the analytically pure product 3d was isolated in 10% yield (Scheme [5]A). Product 3d was subsequently treated with 1-iodobutane (1 equiv) and TBAF in water in the presence of the PS–PEG resin TentaGel. The reaction was completed in 10 minutes to give aldoxime 6d in 84% yield (Scheme [5]B). Dehydrative nitrile formation from 6d also occurred under identical conditions with an additional one equivalent of 1-iodobutane within 30 minutes to give nitrile 4d in 70% yield (Scheme [5]C).

In conclusion, we have developed a cyanide-free cyanation of aromatic iodides 2 with nitromethane in water by using the amphiphilic PS–PEG resin-supported phosphine–palladium catalyst 1 in the presence of 1-iodobutane as an alkylating agent. The cyanation proceeded through cross-coupling to form (nitromethyl)arenes 3 in situ, with transformation into aldoximes 6, and subsequent dehydrative nitrile formation affording the desired aromatic nitriles 4. The catalytic cyanation process does not involve a cyanide salt or a cyanide species, thereby offering a novel and safe alternative for aromatic cyanation. The reaction was performed in water with a readily recyclable polymer, resulting in high chemical greenness. The substrate scope as well as the synthetic application of the cyanation system are under investigation in our laboratory and will be reported in due course.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Professor Yasuhiro Uozumi led this project. Dr. Toshimasa Suzuka conducted most of the experiments. Ms. Ryoko Niimi carried out a part of the catalytic condition screenings and optimization of some of the catalytic runs.

• References and Notes

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• 26 Naphthalene-1-carbonitrile (4a) [CAS Reg. No. 86-53-3] Typical Procedure (Table 1Entry 8): To a mixture of polymeric catalyst 1 (74 mg; 0.02 mmol Pd), Cs₂CO₃ (260 mg, 0.8 mmol), TBAF (104 mg, 0.4 mmol), 1-iodobutane (147 mg, 0.8 mmol), and 1-iodonaphthalene (2a; 102 mg, 0.4 mmol) in water (0.8 mL) was added nitromethane (73.2 mg, 1.2 mmol). The resulting mixture was stirred at 100 °C for 24 h, then cooled and filtered. The polymeric resin beads were rinsed successively with EtOAc (3 × 3 mL) and H₂O (3 × 3 mL), and the recovered catalyst beads were used in subsequent recycling runs. The combined filtrates and washings were extracted with MTBE; ICP-OES analysis demonstrated that the extracts were not contaminated with leached Pd species (ICP-OES analysis: detection limit of Pd = 10 ng/mL). The extracts were then washed with brine, dried (MgSO₄), and concentrated in vacuo. The crude residue was purified by chromatography [silica gel, hexane–EtOAc (4:1)] to give a colorless oil; yield: 55 mg (90%). 1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 8.2 Hz, 1 H), 8.09 (d, J = 8.2 Hz, 1 H), 7.95-7.92 (m, 2 H), 7.71 (td, J = 7.7, 1.2 Hz, 1 H), 7.63 (td, J = 7.5, 1.4 Hz, 1 H), 7.54 (dd, J = 8.2, 7.3 Hz, 1 H): 13C NMR (101 MHz, CDCl3): δ = 133.44, 133.08, 132.80, 132.52, 128.80, 128.76, 127.71, 125.32, 125.08, 117.97, 110.35.Naphthalene-2-carbonitrile (4b) [CAS Reg. No. 613-46-7]White solid; yield 31 mg (51%).1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.94-7.89 (m, 3 H), 7.67-7.59 (m, 3 H): 13C NMR (101 MHz, CDCl3): δ = 134.79, 134.32, 132.39, 129.35, 129.19, 128.56, 128.20, 127.80, 126.50, 119.40, 109.52.Phenanthrene-9-carbonitrile (4c) [CAS Reg. No. 2510-55-6]White solid; yield: 71 mg (88%). 1H NMR (400 MHz, CDCl3): δ = 8.75-8.71 (m, 2 H), 8.34-8.31 (m, 1 H), 8.28 (s, 1 H), 7.97-7.95 (m, 1 H), 7.82-7.77 (m, 3 H), 7.72-7.68 (m, 1 H): 13C NMR (101 MHz, CDCl3): δ = 135.83, 131.95, 130.19, 129.99, 129.95, 129.67, 129.03, 128.38, 128.27, 127.80, 126.28, 123.25, 123.03, 118.09, 109.58.

Corresponding Author

Publication History

Received: 08 September 2021

Accepted: 20 October 2021

Accepted Manuscript online:
20 October 2021

Article published online:
16 November 2021

© 2021. Thieme. All rights reserved

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• References and Notes

• 1 Present address; Department of Chemistry, University of the Ryukyus, Okinawa 903-0213, Japan.
• 2a Kleemann A, Engel J, Kutscher B, Reichert D. Pharmaceutical Substances: Syntheses, Patents, Applications of the Most Relevant AIPs, 5th ed. Thieme; Stuttgart: 2001
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• 2b Miller JS, Manson JL. Acc. Chem. Res. 2001; 34: 563
  CrossrefPubMedSearch in Google Scholar
• 3a The Chemistry of the Cyano Group . Rappoport Z. Wiley Interscience; New York: 1970
  CrossrefSearch in Google Scholar
• 3b Friedrich K, Wallenfels K. The Chemistry of the Cyano Group . Rappoport Z. Wiley Interscience; New York: 1970. Chap. 2, 77
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• 4a Sandmeyer T. Ber. Dtsch. Chem. Ges. 1884; 17: 1633
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• 4b Galli C. Chem. Rev. 1988; 88: 765−792
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• 4c Rosenmund KW, Struck E. Ber. Dtsch. Chem. Ges. 1919; 52: 1749
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• 4d von Braun J, Manz G. Liebigs Ann. Chem. 1931; 488: 111
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• 5 Callen JE, Dornfeld CA, Coleman GH. Org. Synth. Coll. Vol. III 1955; 212
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For reviews, see
• 6a Ellis GP, Romney-Alexander TM. Chem. Rev. 1987; 87: 779
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• 6b Anbarasan P, Schareina T, Beller M. Chem. Soc. Rev. 2011; 40: 5049
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• 6c Yan G, Zhang Y, Wang J. Adv. Synth. Catal. 2017; 359: 4068
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For recent examples, see:
• 7a Zhang S, Neumann H, Beller M. Chem. Eur. J. 2018; 24: 67
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• 7b Schareina T, Zapf A, Beller M. Chem. Commun. 2004; 1388
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• 7e Grossman O, Gelman D. Org. Lett. 2006; 8: 1189
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• 7g Schareina T, Jackstell R, Schulz T, Zapf A, Mägerlein W, Cotté A, Gotta M, Beller M. Adv. Synth. Catal. 2009; 351: 643
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• 8 For a review on aromatic cyanation using nonmetallic cyanide sources, see: Kim J, Kim HJ, Chang S. Angew. Chem. Int. Ed. 2012; 51: 11948
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• 9 Sundermeier M, Zapf A, Spannenberg A, Beller M. J. Organomet. Chem. 2003; 684: 50
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• 10a Sundermeier M, Zapf A, Beller M. Angew. Chem. Int. Ed. 2003; 42: 1661
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• 10b Ouchaou K, Georgin D, Taran F. Synlett 2010; 2083
• 10c Park EJ, Lee S, Chang S. J. Org. Chem. 2010; 75: 2760
  CrossrefPubMedSearch in Google Scholar
• 10d Schareina A, Zapf A, Cotté A, Gotta M, Beller M. Adv. Synth. Catal. 2011; 353: 777
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• 10e Burg F, Egger J, Deutsch J, Guimond N. Org. Process Res. Dev. 2016; 20: 1540
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• 11 Yu P, Morandi B. Angew. Chem. Int. Ed. 2017; 56: 15693
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• 12a Sawant DN, Wagh YS, Tambade PJ, Bhatte KD, Bhanage BM. Adv. Synth. Catal. 2011; 353: 781
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• 12b Khemnar AB, Bhanage BM. RSC Adv. 2014; 4: 13405
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• 13 Niknam E, Panahi F, Khalafi-Nezhad A. Eur. J. Org. Chem. 2020; 2699
• 14 Yang L, Liu Y.-T, Park Y, Park S.-W, Chang S. ACS Catal. 2019; 9: 3360
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Examples of toxicity:
• 15a POCl₃, LD₅₀ oral rat: 36 mg/kg; https://www.sigmaaldrich.com/GB/en/sds/aldrich/262099
• 15b Cyanuric chloride, LD₅₀ oral rat: 315 mg/kg; https://www.sigmaaldrich.com/GB/en/sds/aldrich/487570
• 16 Ogiwara Y, Morishita H, Sasaki M, Imai H, Sakai N. Chem. Lett. 2017; 46: 1736
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For other examples of cyanation with nitromethane, see:
• 17a Wang Z.-H, Ji X.-M, Hu M.-L, Tang R.-Y. Tetrahedron Lett. 2015; 56: 5067 ; (S-cyanation via halonitromethane)
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• 17b Nagase Y, Sugiyama T, Nomiyama S, Yonekura K, Tsuchimoto T. Adv. Synth. Catal. 2014; 356: 347 ; (Lewis acid-catalyzed CH cyanation via aci-nitromethane)
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• 18 TentaGel S NH₂ (Rapp Polymere, Tuebingen) was used as a polymer support. Loading value = 0.26 mmol/g.

For reviews, see:
• 19a Uozumi Y. Bull. Chem. Soc. Jpn. 2008; 81: 1183
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• 19b Osako T, Ohtaka A, Uozumi Y. Catalyst Immobilization: Methods and Applications . Benaglia M, Puglisi A. Wiley-VCH; Weinheim: 2019. Chap. 10, 325
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For recent selected examples of catalytic transformations using PS–PEG-supported catalysts, see:
• 20a Koshino S, Hattori S, Hasegawa S, Haraguchi N, Yamamoto T, Suginome M, Uozumi Y, Hayashi Y. Bull. Chem. Soc. Jpn. 2021; 94: 790
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• 20b Osako T, Kaiser R, Torii K, Uozumi Y. Synlett 2019; 30: 931
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• 20c Pan S, Yan S, Osako T, Uozumi Y. Synlett 2018; 29: 1152
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• 20d Hirai Y, Uozumi Y. Synlett 2017; 28: 2966 ; and references cited therein
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For selected examples, see:
• 21a Sarkar S, Uozumi Y, Yamada YM. A. Angew. Chem. Int. Ed. 2011; 50: 9437
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• 23 caution! Notably, the reaction of 2a with nitromethane in THF or CH₂Cl₂ exploded at 40 °C under otherwise similar conditions [1 (5 mol% Pd), Li₂CO₃ (4 mol equiv)].
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For selected examples, see:
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• 25b Osako T, Torii K, Hirata S, Uozumi Y. ACS Catal. 2017; 7: 7371
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• 26 Naphthalene-1-carbonitrile (4a) [CAS Reg. No. 86-53-3] Typical Procedure (Table 1Entry 8): To a mixture of polymeric catalyst 1 (74 mg; 0.02 mmol Pd), Cs₂CO₃ (260 mg, 0.8 mmol), TBAF (104 mg, 0.4 mmol), 1-iodobutane (147 mg, 0.8 mmol), and 1-iodonaphthalene (2a; 102 mg, 0.4 mmol) in water (0.8 mL) was added nitromethane (73.2 mg, 1.2 mmol). The resulting mixture was stirred at 100 °C for 24 h, then cooled and filtered. The polymeric resin beads were rinsed successively with EtOAc (3 × 3 mL) and H₂O (3 × 3 mL), and the recovered catalyst beads were used in subsequent recycling runs. The combined filtrates and washings were extracted with MTBE; ICP-OES analysis demonstrated that the extracts were not contaminated with leached Pd species (ICP-OES analysis: detection limit of Pd = 10 ng/mL). The extracts were then washed with brine, dried (MgSO₄), and concentrated in vacuo. The crude residue was purified by chromatography [silica gel, hexane–EtOAc (4:1)] to give a colorless oil; yield: 55 mg (90%). 1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 8.2 Hz, 1 H), 8.09 (d, J = 8.2 Hz, 1 H), 7.95-7.92 (m, 2 H), 7.71 (td, J = 7.7, 1.2 Hz, 1 H), 7.63 (td, J = 7.5, 1.4 Hz, 1 H), 7.54 (dd, J = 8.2, 7.3 Hz, 1 H): 13C NMR (101 MHz, CDCl3): δ = 133.44, 133.08, 132.80, 132.52, 128.80, 128.76, 127.71, 125.32, 125.08, 117.97, 110.35.Naphthalene-2-carbonitrile (4b) [CAS Reg. No. 613-46-7]White solid; yield 31 mg (51%).1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.94-7.89 (m, 3 H), 7.67-7.59 (m, 3 H): 13C NMR (101 MHz, CDCl3): δ = 134.79, 134.32, 132.39, 129.35, 129.19, 128.56, 128.20, 127.80, 126.50, 119.40, 109.52.Phenanthrene-9-carbonitrile (4c) [CAS Reg. No. 2510-55-6]White solid; yield: 71 mg (88%). 1H NMR (400 MHz, CDCl3): δ = 8.75-8.71 (m, 2 H), 8.34-8.31 (m, 1 H), 8.28 (s, 1 H), 7.97-7.95 (m, 1 H), 7.82-7.77 (m, 3 H), 7.72-7.68 (m, 1 H): 13C NMR (101 MHz, CDCl3): δ = 135.83, 131.95, 130.19, 129.99, 129.95, 129.67, 129.03, 128.38, 128.27, 127.80, 126.28, 123.25, 123.03, 118.09, 109.58.

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