Improved Substrate Scope in the Potassium Hexacyanoferrate(II

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Cite This: J. Org. Chem. 2018, 83, 4922−4931

Improved Substrate Scope in the Potassium Hexacyanoferrate(II)Based Cyanation for the Synthesis of Benzonitriles and Their Heterocyclic Analogues Jeffery Richardson*,† and Simon P. Mutton‡ †

Eli Lilly and Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom AMRI UK, Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom

‡

S Supporting Information *

ABSTRACT: The use of Pd(DPEPhos)Cl2 (P26) as a catalyst for the formation of benzonitriles and their heterocyclic analogues provides excellent complementarity to existing catalysts, allowing highly electron-deficient heterocyclic aryl halides to be efficiently converted to the corresponding nitriles using K4[Fe(CN)6]) as cyanide source. This catalyst significantly enhances the scope of this reaction to include a number of substrates that are highly relevant for pharmaceutical and agrochemical applications. Importantly, not only does this cyanation method employ a nontoxic cyanide source, simple semiquantitative testing suggests that, unlike many other methods, no free cyanide is present in the reaction mixture or during a variety of potential workups, thus improving the safety aspects of this method from initial setup through to product isolation. Finally, developing and testing a series of convenient cyanation kits has allowed facile application and broader adoption of this method in our laboratories.

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INTRODUCTION Benzonitriles are versatile intermediates in organic synthesis that undergo a wide variety of transformations as well as being key structural motifs in some highly important substances.1 There are many methods for their synthesis, and one of the most attractive disconnections is the conversion of an aryl halide or pseudohalide to the aryl nitrile. This is typically achieved using a transition-metal catalyst and a cyanide source. Since the first report of Pd-catalyzed methods for the synthesis of benzonitriles,2,3 these have superseded more traditional Cumediated methods. The Pd-catalyzed variants generally operate under milder conditions and are more tolerant of functional groups but ultimately suffer from a common drawback; these methods rely on cyanide sources, such as metal cyanide salts KCN,4−8 NaCN,5,9,10 and Zn(CN)2,11−16 which are highly toxic both to humans and the environment as well as posing additional risk during handling and workup. These metal cyanides are, by design, insoluble under the reaction conditions to maintain a low concentration of “dissolved cyanide” since it is a known catalyst poison, and limiting its concentration allows these reactions to be performed catalytically.10,16−20 This effect has led to cyanation reactions being among the least efficient of the myriad of Pd-catalyzed C−C bond-forming reactions in terms of catalyst turnover, and the insoluble salts can also blight the product isolation.21 The addition of reducing agents has been employed to convert catalytically inactive Pd cyanide species back to Pd(0), but these reductants can further complicate workup operations. While many other reagents have been developed for Pdcatalyzed cyanation of aryl halides, many of them ultimately © 2018 American Chemical Society

generate cyanide in situ and thus must be treated with the same precautions, especially during workup. For example, TMSCN22,23 and acetone cyanohydrin21,24 are both effective cyanation reagents, but they are readily hydrolyzed to HCN and must be added slowly throughout the course of the reaction to avoid catalyst poisoning due to their high solubility and, therefore, high cyanide concentration. To overcome this, methods that do not employ cyanide sources have been developed, for example, tert-butyl isocyanide,25 ethyl nitro acetate/dimethylfumarate,26 butyronitrile,27 and CuSCN28 based methods have been used to effect this transformation. Another noteworthy method involves metalation of the aryl halide, reaction with dimethylmalononitrile, and subsequent rearrangement to form benzonitriles.29 While these methods avoid the use of cyanide, they are each subject to their own specific challenges. Potassium hexacyanoferrate(II) (K4[Fe(CN)6]) has been employed as an inexpensive and nontoxic reagent for the cyanation of aryl halides since its first disclosure by Beller20,30 and Weissman,31 and numerous key developments have been made in terms of its convenience and substrate scope.32−37 These reactions are most commonly catalyzed by palladium complexes, although copper-catalyzed methods are also known for relatively simple substrates at high temperature.38 During a Lilly drug discovery program where several benzonitriles were prepared, the method developed by Buchwald36 was found to be highly effective for the cyanation Received: February 25, 2018 Published: April 9, 2018 4922

DOI: 10.1021/acs.joc.8b00515 J. Org. Chem. 2018, 83, 4922−4931

The Journal of Organic Chemistry

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Scheme 1. Screening of Challenging Aryl Halides in Cyanation Reactions with K4[Fe(CN)6]a

a

Key: (a) X = Br, (b) X = Cl. 4923



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Scheme 2. Screening of Electron-Deficient Arenes and Pyrimidinesa

a

Key: (a) X = Br, (b) X = Cl, (c) 100% conversion of 8 to primary amide, (d) 50% conversion of 8 to primary amide, (e) 16% 2-hydroxyquinoline formed, (f) 8% 2-hydroxyquinoline formed, (g) 10% 2-hydroxyquinoline, (h) 3% 2-hydroxyquinoline formed, (i) 5% 2-hydroxyquinoline formed, (j) mostly recovered aryl halide, (k) complex mixture of products.

various complexes and also if any would allow us to obtain electron deficient pyrimidine 4 (Scheme 1).36 In general, the complexes of Buchwald monodentate phosphines (P1−7) performed well, forming products 1−3 starting from both the corresponding aryl chlorides and bromides. Complexes of XPhos (P2) and tBuXPhos (P4) performed well for nitriles 1− 3 but were unsuccessful for nitrile 4 as had previously been observed. Other ligand classes performed less broadly and relatively few worked well for 2-chloroanisole. Many of the complexes tested performed significantly better for the aryl bromides than the corresponding chlorides, presumably in most instances due to inefficient oxidative addition into the C−Cl bond with those catalysts. The formation of 4 was largely unsuccessful, and this could potentially be attributed to the difficulty of the product-forming reductive elimination step in the catalytic cycle. Buchwald had demonstrated that using ligands that were more sterically demanding at phosphorus, such as L4, helped in some instances to facilitate the key reductive elimination,36 but clearly for these highly electron-deficient arenes this was not sufficient since P2 and P4 were unable to afford 4 in good yield.40 Presumably, reductive elimination is prohibitively difficult in these very electron-deficient heteroarenes. Interestingly, the Pd complexes of bidentate ligands (P12, P13, and P17) were uniquely effective catalysts for cyanation of the electron-deficient pyrimidine to afford 4. This is consistent with the observation that a wide bite angle in bidentate ligands may facilitate reductive elimination.32,41 Since oxidative addition of Pd complexes to electron-deficient arenes is typically facile, these complexes bearing less electron-rich ligands were anticipated to work well across a series of electron-deficient heterocycles. These bidentate ligands did not perform as well as P2 or P4 for the electron-neutral and electron-rich aryl chlorides, and so we

of a range of aryl bromides and chlorides. Despite the practicality, broad scope, and attractive reagents, different conditions were frequently employed in other discovery chemistry efforts that suffered from the drawbacks outlined above. This is a general challenge for high-value, wellestablished transformations in early discovery projects. When faced with hundreds of hits from a literature database, one strategy is to refine the search criteria to make the query closer to the substrate of interest, but for more recently developed methodologies there is a significant probability that the relative lack of exemplification versus older methods will result in the older, potentially less desirable, method being retrieved from the database preferentially.39 If these conditions perform sufficiently for the first substrate tested, then they are likely to become the method of choice for that library or discovery project. In many instances this would not be an issue, but when newer methods exist that extend the scope and overcome the inherent safety or practicality issues of the older methods then this represents a missed opportunity at best. Lowering the “barrier to use” for this chemistry would result in more efficient and safe chemistry being broadly employed and formed a significant component of the work described here. During these projects, the conditions described by Buchwald using XPhos and tBuXPhos precatalysts had performed well across a broad range of substrates but were unsuccessful for some electron-deficient heteroarenes such as halopyrimidines. Given that such heterocycles are common in pharmaceuticals and intermediates, identification of conditions that address this limitation and allow these substrates to be successfully employed would be of significant value. We began by screening a series of Pd complexes under the conditions described by Buchwald in a small set of potentially challenging substrates to understand whether any differentiation occurred between the 4924



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Table 1. Long-Term Stability Testing for Cyanation Kits of Catalysts P2 and P4

test reaction conversionb (%)

a

a

entry

kit

kit contents

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

A A B B C C D D E E F F G G H H I I

KOAc, K4[Fe(CN)6]·3H2O KOAc, K4[Fe(CN)6]·3H2O P2, KOAc, K4[Fe(CN)6]·3H2O P2, KOAc, K4[Fe(CN)6]·3H2O P2, L2, KOAc, K4[Fe(CN)6]·3H2O P2, L2, KOAc, K4[Fe(CN)6]·3H2O P4, KOAc, K4[Fe(CN)6]·3H2O P4, KOAc, K4[Fe(CN)6]·3H2O P4, L4, KOAc, K4[Fe(CN)6]·3H2O P4, L4, KOAc, K4[Fe(CN)6]·3H2O P4, L4, K4[Fe(CN)6]·3H2O P4, L4, K4[Fe(CN)6]·3H2O P4, K4[Fe(CN)6]·3H2O P4, K4[Fe(CN)6]·3H2O P2, L2, K4[Fe(CN)6]·3H2O P2, L2, K4[Fe(CN)6]·3H2O P2, K4[Fe(CN)6]·3H2O P2, K4[Fe(CN)6]·3H2O

storage

1 week

1 month

6 months

glovebox air glovebox air glovebox air glovebox air glovebox air glovebox air glovebox air glovebox air glovebox air

100 100 100 100 100 100 100 100 100 100 100 100

100 100 98 86 100 100 100 100 100 100 100 100 100 100 100 100 100 100

100 100 100 100 99 100 100 100 100 100 100 100 100 100 100 100 100 100

Full details of kit contents and preparation can be found in the Supporting Information. bConversion assessed by LCMS.

benzonitriles. Both L17 and L26 (DPEPhos) were used in the original disclosure by Beller21,30 but did not possess suitably broad substrate scope under mild conditions to be considered general catalysts. However, under these conditions, P26 has excellent complementary with P2 for this transformation and plugs a significant gap in the scope of this transformation. In order to encourage the use of these conditions as a standard method for cyanation of aryl halides in both discovery chemistry laboratories and automated settings (such as the Lilly Automated Synthesis Lab44) the use of premixed “Cat Kits” was investigated, having met with some success for other Pdcatalyzed reactions.45,46 By mixing the inorganic reagent and catalyst, these kits minimize weighing operations and also reduce the weighing error associated with dispensing small quantities of catalyst. A “cyanation kit”, if successful, would achieve both of these goals. Having established that by using P26 and one of either P2 or P4 substantial substrate generality was obtained, we felt that these would represent excellent choices for development as cyanation kits. Kits were prepared in the fumehood by combining all of the solid components. To test robustness, the kits were split in half with half stored under air and half in a glovebox under nitrogen. The catalyst was incorporated into the kit at a level such that when 0.5 equiv of K4[Fe(CN)6] was employed the catalyst loading would be 5 mol %. In many cases, this loading could be lowered, but the 5 mol % kit serves as a practical first pass option for small-scale applications. The kits containing P2 and P4 were periodically tested in the formation of 1 from the corresponding aryl bromide (Table 1). In all instances the kits were stable to long-term storage, giving very good conversion in the test reaction even after 6 months storage in air. Some kits (C, E, F, and H) contained additional ligand to examine whether this conferred any long-term catalyst

felt that these catalysts offered excellent complementarity to the Buchwald ligands. A series of electron-deficient arenes with bidentate ligands were studied to better understand exactly when the complexes P2 or P4 would not suffice and which of the bidentate ligands would be most useful (Scheme 2). The preparation of a series of cyano (hetero)arenes (4−13) was studied using P2, P4, and complexes containing bidentate ligands (P12, P13, P17, and P26). As expected, for simple arenes bearing a single electronwithdrawing group P4 was successful in all cases and P2 worked for some. This is in good agreement with the observations made by Buchwald where the synthesis of 8 had shown this catalyst preference. Interestingly, only when a methoxy group was present (7) on the pyrimidine was P4 successful; however, the bidentate ligands were successful for all such substrates. Highly electron-deficient pyrimidine 5 appeared to be unstable to the reaction conditions, presumably as a result of the nitriles being readily hydrolyzed or displaced, and so for the catalysts where starting materials were consumed, multiple unidentified products were obtained. Again, this substrate was not converted by catalysts P2 or P4, and these reactions returned mostly starting aryl bromide. A similar, but somewhat attenuated, trend was observed for compound 8, although the extent of hydrolysis seemed to be dependent on the catalyst and it may be possible to modulate this by adjustment of the amount of water used.42 In most instances, P17 gave product, but the reaction yields were somewhat variable across the substrates. However, XantPhos (P12), N-XantPhos (P13), and DPEphos (P26) complexes all worked well across the range of electron-deficient substrates. The wide bite angles of these ligands (L12 = 111°, L13 = 114°, and L26 = 102°, compared to L17 = 93°)43 presumably result in more facile reductive elimination to the 4925



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Early methods using K4[Fe(CN)6] required significantly elevated temperatures, and this has been cited as a disadvantage of the method,41 despite the reduction in temperature achieved by Buchwald. The effect of temperature was therefore further studied, and it was found that for the aqueous cyanation kit and P2 the reactions went rapidly to completion at as low as 60 °C, but that for P26 full conversion could only be obtained at 90 °C (see the Supporting Information for full details). While these kits provide a simple and rapid method for (hetero)benzonitrile synthesis, a mixed kit containing both catalysts could potentially provide a single “universal” kit. To test this idea, a 1:1 ratio of kits I and J was combined to afford kit K, which contained 2.5 mol % of catalysts P2 and P26 and was tested under the standard conditions (Scheme 5). In all cases tested, the desired (hetero)benzonitriles were obtained, and it was noted that the isolated yields were typically lower than those where the individual kits were used, although this was likely attributed to the lower catalyst loading in kit K (2.5 mol % of each catalyst) versus kits I or J (5 mol %). It has been suggested that [K 4 [Fe(CN) 6 ] has low dissociation to free cyanide17,36 resulting in slow delivery of cyanide ions to Pd, thereby preventing catalyst deactivation even when the cyanide source is fully dissolved. Beller proposed an alternate, transmetalation-type mechanism shown in Scheme 6, which, if operative, could allow there to be no free cyanide being present during the course of the reaction.20 This would be a significant safety advantage for this method, and so further study was conducted. It is known that high temperatures are required for transmetalation with [K4[Fe(CN)6], suggesting that either this is required to obtain sufficient dissociation of cyanide from Fe or that a different mechanism, such as that proposed by Beller, operates for [K4[Fe(CN)6] versus other cyanide sources. While [K4[Fe(CN)6] is in itself a safe cyanide source, dissociation to free cyanide during the reaction would result in many of the drawbacks of other methods still being relevant for these conditions, especially as pertains to the risk of accidental exposure to cyanide during quenching or workup. Conversely, a mechanism involving no free cyanide would render this method even more attractive. To determine whether a reagent can truly be considered safe, it is important not only to consider the reagent but also its byproducts and potential reactivity/toxicity during workup and disposal. In order to demonstrate that these reactions could be run safely with minimal concerns around cyanide poisoning during setup, reaction, or workup, we tested these reactions at various points to determine if cyanide could be detected. By testing for cyanide both during the reaction and under a variety of workup conditions that could potentially liberate HCN, it was shown that the reactions generate no detectable cyanide in any of these instances (see the Supporting Information) which is consistent with, but not proof of, a mechanism such as that shown in Scheme 6. The reaction mixtures become a deep blue color when they are exposed to air for workup, which rendered the cyanide detection more difficult, and so positive control experiments were undertaken to verify these findings. Interestingly, when NaCN (ca. 5 ppm) is added to the reaction mixture at completion and the blue solids are removed by filtration to aid visualization, no cyanide could be detected, even though this falls into the detectable range for the testing protocol. However, if the blue solids are filtered off before the cyanide is added, the test strips give a result consistent with the amount of cyanide added. This suggests that the Fe species present in the complete reaction are capable of efficiently

stability, but it was found that this was not necessary as the kits without additional ligand performed equally well over a long period. Full details of kit contents can be found in the Supporting Information. There was no difference observed between P2 and P4 in terms of durability over 6 months. While kits A−E maintain good performance and seemingly offer greatest convenience since all components could be dosed simultaneously, the hygroscopic nature of KOAc caused these kits to become difficult to weigh after 6 months. Additionally, the variable water content over time creates ambiguity regarding overall potency of the kit. Those kits stored in the glovebox did not suffer this fate, but storage in the glovebox reduces convenience and accessibility. As such, those kits that did not include KOAc (kits F−I) were preferred since it is operationally no more complex to add aqueous KOAc to the reaction mixture than it is water. Doing so also overcomes the inherent challenge of handling and storing a large container of KOAc under air over a long period. Kit I was therefore selected as the preferred kit for general use with electron-neutral and -rich susbtrates. A similar study was performed for those kits containing bidentate ligands (Table 2). While P12 and P13 provide very Table 2. Cyanation Kits for Electron-Deficient Systems

time point (%) kit

contents

storage

1 month

6 months

J J

P26, K4[Fe(CN)6]·3H2O P26, K4[Fe(CN)6]·3H2O

glovebox air

100 100

100 100

similar scope to P26 with respect to the less electron-deficient arenes, P26 was selected as it was a more economical choice and the overall substrate coverage remained the same.47 This kit also performed well with no reduction in performance over 6 months storage in air. The use of the 6 month old kits I and J for aryl and heteroaryl halides was successful, affording comparable yields to reactions setup using the individual components (Scheme 3). It is worth noting that these kits perform well on a series of molecules that would be particularly challenging with just the original Buchwald conditions alone. Another alternative kit could be conceived where the [K4[Fe(CN)6] and KOAc were transferred to the substrate, catalyst, and solvent as an aqueous solution. While this does not reduce the number of overall dispensing operations, it could be useful in high-throughput catalyst screening to minimize the number of weighing operations. To ascertain the stability of the aqueous cyanation mix, a 0.5 M solution of [K4[Fe(CN)6] and KOAc was prepared in air and periodically tested in a model reaction with no reduction in performance over a 3 month period (Scheme 4). This methodology (method C) would be especially applicable during high-throughput catalyst screening, where the number of solid dispenses could be kept to a minimum. To demonstrate that this method could also be employed preparatively, 3 was be prepared using catalyst P2 in 81% yield and 14 using P26 in 69% yield. 4926



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Scheme 3. Comparison of Isolated Yields for Cyanation Kits and Standard Procedurea

a (a) Method A: All components were charged individually including the catalyst highlighted and K4[Fe(CN)6] (0.5 equiv). (b) Method B: Catalyst and K4[Fe(CN)6] were charged as part of a kit (0.25 g/mmol ArX). The kit used is denoted next to yield. (c) 2.5 mol % of P26, 50 g scale. (d) Conversion measured by LCMS.

Scheme 4. Stability of Aqueous Cyanation Kit (Method C) over a 3 Month Period, Stored under Air

Scheme 5. Cyanation with Combined Cyanation Kit K

sequestering free cyanide but does not rule out either the free cyanide or direct transmetalation mechanisms. Either way, the absence of detectable cyanide in the numerous workup procedures tested makes this method highly attractive from a safety perspective. Interestingly, while no cyanide was observed under the reaction conditions, a slight signal was seen upon storage of the aqueous cyanation kit used in Scheme 4, and although the signal was sufficiently low to consider this mixture safe, it should be noted that aged solutions such as this should be tested periodically to ensure safe handling and storage.

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CONCLUSIONS The use of DPEPhos complex P26 significantly enhances the scope of the cyanation of aryl bromides under Buchwald conditions and thus allows a very broad range of substrates to be cyanated under operationally simple conditions. The excellent complementarity with the catalysts described by

Buchwald further enhance the practicality of this method for the synthesis of small-molecule pharmaceuticals and agrochemicals. This method is rendered even more powerful by the fact that cyanide test strips do not show free cyanide formed at 4927



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Scheme 6. Beller’s Proposed Transmetalation Mechanism

aluminum block at 90 °C for 80 min. In most instances the reactions were complete by LCMS at this point and were then cooled to room temperature, partitioned between satd aq NaCl (20 mL) and EtOAc (20 mL), the layers separated, and the aqueous was extracted with EtOAc (3 × 20 mL). The combined organics were then washed with satd aq NaCl (10 mL), dried over Na2SO4, filtered, and evaporated to afford the aryl nitrile. Products were further purified by flash chromatography if required, employing a prepacked RediSep Rf cartridge (12 g), eluting with EtOAc/n-heptane (0−20% over 16 column volumes) unless otherwise stated. General Procedure for Cyanation with 0.5 M KOAc solution (Method B). Cyanation Kit (either I or J, 0.25 g/mmol aryl halide) and aryl halide (1 g) were charged to a 20 mL microwave vial under air. The vessel was then sealed with a septum cap and evacuated and backfilled with N2 (×5, 5 s evacuation time). 1,4-Dioxane (1 mL/ mmol) and 0.5 M KOAc solution (0.5 equiv) were charged via syringe, and the mixture was then evacuated and backfilled with N2. The mixture was then heated to 90 °C under a N2 atmosphere with stirring (1000 rpm) and monitored by LCMS. Reaction mixtures were worked up and purified using the same procedure as method A. General Procedure for Cyanation with Aqueous Cyanation Kit (Method C). Aqueous cyanation kit was prepared by swirling potassium acetate (9.81 g, 100 mmol) and K4[Fe(CN)6]·3H2O (37.2 g, 100 mmol) in a volumetric flask made up to 200 mL volume with water. This was then stored in a bottle under air. Aryl halide (100 mg) and catalyst (5 mol %) were charged to a 5 mL microwave vial under air. The vessel was then sealed, evacuated, and backfilled with N2. 1,4-Dioxane (1 mL/mmol) and 0.5 M aq cyanation kit (0.5 equiv) were charged via syringe, and the mixture was then evacuated and backfilled with N2. The mixture was then heated to 90 °C under vented N2 with stirring (1000 rpm) and monitored by LCMS. Reaction mixtures were worked up and purified using the same procedure as method A. tert-Butyl 5-Cyanoindoline-1-carboxylate (1). Prepared from the ArCl according to method A (using catalyst P2, 298 mg, 100%) and according to method B using cyanation kit I (896 mg, 93%). Prepared from the ArBr according to method A (using catalyst P2, 229 mg, 93%) and according to method B using cyanation kit I (221 mg, 90%). Obtained as a white solid after trituration with n-heptane: mp 162− 165 °C; 1H NMR (400 MHz, DMSO) 7.95−7.36 (3H, m), 3.95 (2H, t, J = 8.8 Hz), 3.09 (2H, t, J = 8.8 Hz), 1.51 (9H, s); 13C NMR (100 MHz, CDCl3) 152.1, 132.7, 128.2, 119.6, 104.8, 47.9, 28.3, 26.7; IR (neat, cm−1) 2980, 2220, 1708, 1604, 1489, 1433, 1382, 1369, 1317, 1286, 1251 1165, 1138, 1014; LRMS (ESI) m/z [M + H]+ 245.0, [M − tBu]+ 189.0. 2-Methoxybenzonitrile (2).48 Prepared from the ArBr according to Method A (using catalyst P2, 139 mg, 65%) and according to method B using cyanation kit I (152 mg, 71%). Also prepared from the ArCl according to method A (using catalyst P2, 204 mg, 73%) and method B using cyanation kit I (148 mg, 53%). Obtained as a colorless oil: 1H NMR (400 MHz, CDCl3) 7.62−7.42 (2H, m), 7.08−6.85 (2H, m), 3.93 (3H, s); LRMS (ESI) m/z [M + H]+ 134.4. 4-(Dimethylamino)benzonitrile (3).49 Prepared from the ArBr according to method A (using catalyst P2, 237 mg, 85%), according to method B using cyanation kit I (202 mg, 92%) and according to method C (using catalyst P2, 237 mg, 81%). Also prepared from the ArCl according to method A (272 mg, 97%) and method B using cyanation kit I (197 mg, 70%). Obtained as white plates: mp 74−77 °C (lit.50 mp 75−77 °C); 1H NMR (400 MHz, CDCl3) 7.53 (2H, d, J = 9.0 Hz), 6.75 (2H, d, J = 9.0 Hz), 2.99 (6H, s); 13C NMR (100 MHz, CDCl3) 152.5, 133.4, 120.7, 111.4, 97.4, 39.9; LRMS (ESI) m/z [M + H]+ 147.0.+

any point through the reaction or its workup under various conditions. The kits prepared are convenient and stable, avoiding the handling of hygroscopic KOAc These kits have been prepared and distributed throughout Lilly’s discovery laboratories and represent a first choice for the synthesis of benzonitriles from aryl chlorides and bromides.

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EXPERIMENTAL SECTION

General Methods. All reagents were purchased from commercial suppliers and used as received. Solvents were purchased from Aldrich, anhydrous, SureSeal quality, and used with no further purification. Water was degassed by evacuation, sonication (30 s), and backfilling with N2 (×5). The ligands and bases were purchased from commercial sources and stored in a nitrogen filled glovebox. Flash column chromatography was carried out using silica gel columns with a Teledyne ISCO CombiFlash Companion system. 1H and 13C NMR spectra were recorded on a Bruker AV-HD 400 spectrometer. Signal positions were recorded in δ ppm with the abbreviations s, d, t, q, dd, dt, and m denoting singlet, doublet, triplet, quartet, doublet of doublets, doublet of triplets and multiplet, respectively. All 1H NMR chemical shifts were referenced to SiMe4 as an internal standard (0.00 ppm). All 13C NMR chemical shifts in CDCl3 were referenced to the residual solvent peak at 77.00 ppm. All coupling constants, J, are quoted in hertz. Infrared spectra were recorded on a Nexus FT-IR spectrometer with Nicolet OMNI sampler using a neat sample. Melting points were obtained using a DSC 1 STARe system. All LCMS analyses were performed using an Agilent 1200 Infinity Series liquid chromatography (LC) system, consisting of a 1260 HiP degasser (G4225A), 1260 binary pump (G1312B), 1290 autosampler (G4226A), 1290 thermostated column compartment (G1316C), and a 1260 diode array detector (G4212B) coupled to an Agilent 6150 single quadrupole mass spectrometry (MS) detector. The injection volume was set to 1 μL. The UV (DAD) acquisition was performed at 40 Hz, with a scan range of 190−400 nm (in 5 nm steps). A 1:1 flow split was used before the MS detector. The MS was operated with an electro-spray ionization source (ESI) in both positive- and negativeion mode. The nebulizer pressure was set to 50 psi, the drying gas temperature and flow to 350 °C and 12.0 L/min, respectively. The capillary voltages used were 4000 V in positive mode and 3500 V in negative mode. The MS acquisition range was set to 100−800 m/z with a step size of 0.2 m/z in both polarity modes. Fragmentor voltage was set to 70 (ESI+) or 120 (ESI−), gain to 0.40 (ESI+) or 1.00 (ESI−) and the ion count threshold to 4000 (ESI+) or 1000 (ESI−). The overall MS scan cycle time was 0.15 s/cycle. Data acquisition was performed with Agilent Chemstation software. Analyses were carried out on a Waters XBridge C18 column of 50 mm length, 2.1 mm internal diameter, and 3.5 μm particle size, eluting from 95:5 to 5:95 of pH 9 adjusted 10 mM NH4HCO3 (aq) in MeCN over 1.5 min and holding for 0.5 min. General Procedure for the Formation of Cyanation Kits: Cyanation Kit J. K4[Fe(CN)6]·3H2O (98.7 g, 234 mmol) was ground in a pestle and mortar to afford an off-white fine powder. The powder was then mixed with Pd(DPEPhos)Cl2 (16.56 g, 23.13 mmol) under air by rotation until it appeared as a uniform powder. General Procedure for Cyanation Using a Modification of Buchwald’s Procedure (Method A). A 10 mL vial was charged with aryl halide (1.00 mmol), catalyst (P2 or P26) (5 mol %), K4[Fe(CN)6]·3H2O (213 mg, 0.50 mmol), and potassium acetate (49 mg, 0.50 mmol) and sealed with a septum cap. The vial was purged with nitrogen and then 1,4-dioxane (1.0 mL) and water (1.0 mL) were added. The vial was then transferred to a preheated 4928



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Methyl 5-Cyanopyrimidine-2-carboxylate (4).51 Prepared from the ArBr according to method A (using catalyst P26, 126 mg, 40%) and according to method B using cyanation kit J (212 mg, 74%). Obtained as a tan solid: mp 129−132 °C; 1H NMR (400 MHz, CDCl3) 9.20 (2H, s), 4.11 (3H, s); LRMS (ESI) m/z 164.2 [M + H]+. Pyrimidine-5-carbonitrile (6). Prepared from the ArBr according to method A (using catalyst P26, 131 mg, 66%) and according to method B using cyanation kit J (115 mg, 58%). Obtained as a white solid: mp 84−87 °C [lit.52 mp 83.5−84 °C (EtOH)]; 1H NMR (400 MHz, CDCl3) 9.41 (1H, s), 9.03 (2H, s); 13C NMR (100 MHz, CDCl3) 160.5, 159.5, 114.0, 110.2; LRMS (EI) m/z 104.8 [M]+ 2-Methoxypyrimidine-5-carbonitrile (7).53 Prepared from the ArBr according to method A (using catalyst P26, 181 mg, 84%) and according to method B using cyanation kit J (200 mg, 93%). Obtained as white solid: Rf = 0.51 (1:1 v/v EtOAc/isohexane); mp 83−87 °C (lit.54 mp 81−81.5 °C); 1H NMR (400 MHz, CDCl3) 8.79 (1H, s), 4.11 (3H, s); 13C NMR (100 MHz, CDCl3) 166.1, 162.5, 114.8, 102.9, 56.1; LRMS (ESI) m/z 136.0 [M + H]+. Terephthalonitrile (8).55 Prepared from the ArBr according to method A (using catalyst P26, 179 mg, 85%) and according to method B using cyanation kit J (197 mg, 93%). Obtained as white crystalline solid: mp 224−228 °C (lit.56 mp 226−228 °C); 1H NMR (400 MHz, CDCl3) 7.80 (4H, s); 13C NMR (100 MHz, CDCl3) 132.8, 117.0, 116.7; LRMS (EI) m/z 128.0 [M]+. Phthalonitrile (9). Prepared from the ArBr according to method A (using catalyst P26, 193 mg, 91%) and according to method B using cyanation kit J (190 mg, 90%). Obtained as white needles: mp 139− 142 °C (lit.57 mp 139−141 °C); 1H NMR (400 MHz, CDCl3) 7.92− 7.80 (2H, m), 7.80−7.68 (2H, m); 13C NMR (100 MHz, CDCl3) 133.6, 133.1, 116.0, 115.3; LRMS (ESI) m/z [M + H]+ 129.0. 1,3-Dicyanobenzene (10).55 Prepared from the ArBr according to Method A(using catalyst P26, 188 mg, 89%) and according to Method B using cyanation kit J (152 mg, 72%). Obtained as white needles. mp 160−162 °C (lit.58 mp 161−163 °C); 1H NMR (400 MHz, CDCl3) 7.96 (1H, m), 7.91 (2H, dd, J = 8.0, 1.6 Hz), 7.66 (1H, t, J = 8.0 Hz); 13 C NMR (100 MHz, CDCl3) 136.0, 135.4, 130.3, 116.6. 114.2; LRMS (EI) m/z 128.0 [M]+. Methyl 3-Cyanobenzoate (11). Prepared from the ArBr according to method A (using catalyst P2, 187 mg, 83%) and according to method B using cyanation kit I (167 mg, 74%). Also prepared according to method A (using catalyst P26, 187 mg, 83%) and according to method B using cyanation kit J (191 mg, 85%). Obtained as white needles: Rf = 0.51 (1:1 v/v EtOAc/isohexanes); mp 59−63 °C (lit.59 mp 61−62 °C); 1H NMR (400 MHz, CDCl3) 8.33 (1H, s), 8.27 (1H, d, J = 7.8 Hz), 7.84 (1H, d, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 3.96 (3H, s); 13C NMR (100 MHz, CDCl3) 165.1, 136.0, 133.7, 133.3, 131.4, 129.4, 117.9, 113.0, 52.7; LRMS (ESI) m/z [M + H]+ 162.0. 4-Nitrobenzonitrile (12). Prepared from the ArBr according to method A (using catalyst P26, 175 mg, 80%) and according to method B using cyanation kit J (199 mg, 91%). Obtained as off-white needles: Rf = 0.55 (1:1 v/v EtOAc/isohexanes); mp 148−151 °C (lit.60 mp 149−151 °C); 1H NMR (400 MHz, CDCl3) 8.36 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) 150.0, 133.5, 124.3, 118.3, 116.8; LRMS (EI) m/z 148.0 [M]+. Quinoline-2-carbonitrile (13).61 Prepared from the ArBr according to Method A (using catalyst P26, 247 mg, 87%) and according to method B using cyanation kit J (234 mg, 83%). Obtained as white solid: Rf = 0.51 (1:1 v/v EtOAc/isohexanes); mp 94−97 °C (lit.62 mp 94−96 °C); 1H NMR (400 MHz, CDCl3) 8.31 (1H, d J = 8.6 Hz), 8.18 (1H, d, J = 8.6 Hz), 7.90 (1H, d, J = 8.0 Hz), 7.85 (1H, td, J = 8.0, 1.2 Hz), 7.77−7.65 (2H, m); 13C NMR (100 MHz, CDCl3) 148.2, 137.5, 133.7, 131.3, 130.0, 129.5, 126.7, 127.8, 123.3, 117.6; LRMS (ESI) m/z [M + H]+ 155.0. Methyl 5-Cyanopyridine-2-carboxylate (14). Prepared from the ArBr according to method A (using catalyst P26, 170 mg, 76%), according to method B using cyanation kit J (539 mg, 72%) and according to method C (using catalyst P26, 207 mg, 69%). Obtained as white needles: mp 146−149 °C [lit.63 mp 146.6−147 °C (MeOH)]; 1 H NMR (400 MHz, CDCl3) 9.01 (1H, s), 8.26 (1H, d, J = 8.2 Hz),

8.15 (1H, d, J = 8.2 Hz), 4.05 (3H, s); 13C NMR (100 MHz, CDCl3) 164.2, 152.3, 150.4, 140.7, 124.8, 115.7, 113.0, 53.5; LRMS (ESI) m/z [M + H]+ 163.2. 6-Fluoro-2-methyl-1,3-benzothiazole-5-carbonitrile (15). Prepared from the ArBr according to method A (using catalyst P26, 40.9 g, 97%, 93% purity) and according to method B using cyanation kit J (95% conversion by LCMS). Obtained as a beige solid: mp 124− 130 °C; 1H NMR (400 MHz, (CD3)2SO) 8.55 (1H, s), 8.31 (1H, s), 2.83 (3H, s). 19F NMR (376 MHz, (CD3)2SO) −114.69. 13C NMR (100 MHz, (CD3)2SO) 20.3, 99.1 (d, J = 21.0 Hz), 110.5 (d, J = 27.1 Hz), 114.7, 127.3, 142.9. 149.7, 159.0 (d, J = 251.6 Hz), 170.8. LRMS (ESI) m/z [M + H]+ 193.0.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00515. Kit preparation details, reaction temperature studies, cyanide content determination, and spectroscopic data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: richardson_jeff[email protected]. ORCID

Jeffery Richardson: 0000-0002-4450-3828 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Thanks to Iván Collado and Magnus Walter for support of the program and to Peter Lindsay-Scott and Craig Ruble for helpful discussions during manuscript preparation.

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REFERENCES

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Improved Substrate Scope in the Potassium Hexacyanoferrate(II

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