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Palladium-Catalyzed Safe Cyanation of Aryl Iodides with Hexamethylenetetramine Yunjing Yan, Song Sun, and Jiang Cheng* School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou 213164, P. R. China S Supporting Information *
ABSTRACT: A palladium-catalyzed cyanation of aryl halides with hexamethylenetetramine as a safe cyanide source is achieved, providing aromatic nitriles in moderate to good yields. This approach shows good functional group compatibilities and avoids the use of toxic cyanide source.
A
ammonium was well developed.17 Hence, we envisioned the HMTA would take part in the cyanation with aryl halides as a safe cyanide source proceeding with sequential formylation by formaldehyde and transformation of aldehyde to nitrile in the presence of ammonium. Herein, we wish to report it, where HMTA serves as an inexpensive, nontoxic, and easily handling cyanation reagent. Initially, we tested the reaction of 1-iodo-4-methoxybenzene (0.5 mmol), HMTA (2.5 equiv), Pd(OAc)2 (10 mol %), and Cu(OAc)2 (1.2 equiv) in DMF (2.5 mL) under O2 at 140 °C as the model reaction. After 12 h, the cyanation product 4methoxybenzonitrile 3a was isolated in 22% yield (Table 1, entry 1). Among the copper tested, Cu(OAc)2 was the best, and the yield sharply increased to 81% (Table 1, entry 7). Other oxidants, such as CuCl2 (22%), CuI (43%), Cu2S (37%), CuS (35%), CuSO4 (54%), and Cu2O (62%), all decreased the reaction efficiency during this transformation. The reaction efficiency decreased when the reaction was carried out under either N2 (34%) or air (55%). The solvent also played an important role during this procedure. DMSO, DCE, and toluene resulted in lower yields or no reaction (Table 1, entries 8−10). Other Pd sources such as PdCl2 (56%) and Pd2(dba)3 (51%) showed low efficiencies (Table 1, entries 11−12). An inferior result was obtained when the reaction conducted under 120 °C (28%) or 150 °C (67%, Table 1, entries 13). In the absence of palladium, the yield dropped to 27% (Table 1, entry 15), while 3a was isolated in 35% yield without Cu(OAc)2 (Table 1, entry 14). With the optimized condition in hand, a range of aryl iodides were studied in this new protocol, as shown in Table 2. As expected, various functional groups, including methoxy, benzyloxy, chloro, phenyl, free amino, acetyl, ethoxylcarbonyl, and nitro were tolerated under these reaction conditions. The mono-methoxy substrate produced 3a in 81% yield, while diand tri-methoxy analogues provided corresponding cyanation
romatic nitriles are ubiquitous in pharmaceuticals, agrochemicals, pigments, and dyes.1 Moreover, nitriles may be facilely transformed to a series of functional groups, such as amines, aldehydes, amidines, tetrazoles, and amides.2 The Sandmeyer reaction3 and the Rosenmund−von Braun reaction4 are traditional methods toward aromatic nitriles. However, these processes require harsh reaction conditions such as high temperature and stoichiometric toxic copper(I) cyanide. Thus, the development of more practical and efficient procedures by using safe cyanide source remains an area needing intensive research. With the development of organometallics, the transitionmetal-catalyzed direct cyanation of arene C−H bonds represents a useful method to access aryl nitriles, albeit with relative low substrates scope.5 Alternatively, the transitionmetal-catalyzed cyanation of aryl halides represents an efficient pathway to access aromatic nitriles. The cyanide source used in this approach includes alkali cyanides (with toxicity decreased order: KCN,6 NaCN,7 Zn(CN)2,8 CuCN,9 TMSCN, and K3Fe(CN)610), acetone cyanohydrins,11 ethyl cyanoacetate,12 and CH3CN13 (Scheme 1). In addition, Yu reported CH3NO2 as a cyanide source.14 We also developed the combination of DMF and NH4HCO3 as a safe cyanide source for the cyanation of aryl halides.15 Hexamethylenetetramine (HMTA) was known as a formylation reagent in Duff reaction.16 Meanwhile, it serves as the combination of formaldehyde and ammonia upon heating. The transformation of aldehyde to nitrile in the presence of Scheme 1. Cyanation of Aryl Halides
Received: September 19, 2017 Published: November 8, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.joc.7b02373 J. Org. Chem. 2017, 82, 12888−12891
Note
The Journal of Organic Chemistry Table 1. Screening the Optimized Reaction Conditionsa
entry
catalyst
copper
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd2(dba)3 Pd(OAc)2 Pd(OAc)2 −
CuCl2 CuI Cu2S CuS CuSO4 Cu2O Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 − Cu(OAc)2
DMF DMF DMF DMF DMF DMF DMF DMSO DCE toluene DMF DMF DMF DMF DMF
22 43 37 35 54 62 81, 34c, 55d 43
