Note pubs.acs.org/joc
Metal-Free Aerobic Oxidative Cyanation of Tertiary Amines: Azobis(isobutyronitrile) (AIBN) as a Sole Cyanide Source Peng-Yu Liu,§ Chao Zhang,§ Shi-Chen Zhao, Fang Yu, Fei Li, and Yu-Peng He* College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, China S Supporting Information *
ABSTRACT: An aerobic oxidative cyanation for the synthesis of α-aminonitriles was reported. The formation of C(sp3)-CN bonds was achieved under a metal-free condition by utilizing azobis(isobutyronitrile) as a sole organic cyanide source with the combination of pivalic acid and sodium acetate as additives. Herein, we report for the first time on the generation of the “CN” unit from AIBN without adding either transition-metal catalysts or an additional cyanide source, while efficiently delivering α-aminonitriles from tertiary amines in the presence of air as an oxidant under mild conditions. (Figure 1)
α-Aminonitriles are highly useful precursors for constructing nitrogen-containing bioactive compounds, such as α-amino acids and alkaloids.1−4 These bifunctional compounds show versatile reactivity by generating both iminium ions (electrophilic reagents) and carbon anions (nucleophilic reagents),5 which have been utilized to synthesize various valuable functionalities, including α-amino aldehydes, ketones, and αamino alcohols.6,7 Therefore, the development of clean and efficient methods for the synthesis of α-aminonitriles has gained much interest. Compared to the well-documented Strecker reaction,6,8−10 transition-metal-catalyzed direct C−CN bond-forming reactions via the C−H bond functionalization of tertiary amines are presently the most straightforward strategies to assemble αaminonitriles, including utilizing Ru,11−17 Cu,18−20 V,21 Au,22,23 Mo,24 Re,25 Fe,26−33 and Ir34 catalysts and stoichiometric amounts of oxidants. Regarding the existing CN sources, widely used metal−cyanide (CN) sources (KCN, NaCN, etc.)11−15,21,24,27,34−38 have been shown to be highly efficient for C−CN bond formations. Alternatively, multiple organic CN sources,39−54 such as cyanohydrin,39−41 malononitrile,42 ethylcyanoformate,43,44 phenylacetonitrile,45 acetonitrile,13,46,47 trimethylsilyl cyanide,23,48−50 cyanoacetic acid,51 and combined CN sources52−55 have been intensively investigated. However, most of these protocols employ transition-metal catalytic systems and produce hazardous metal−CN waste. It is, therefore, highly demanding to develop an easily available less-toxic CN source that can be used for a metal-free cyanation of tertiary amines. 2,2′-Azobis(isobutyronitrile) (AIBN) is generally used as a radical initiator. In 2012, Fu and co-workers reported an elegant approach for the AIBN-initiated cyanation of tertiary amines.56 In 2013, for the first time, the Han group published a pioneering work on the copper-mediated direct C(sp2)cyanation of 2-arylpyridine using AIBN as the CN source.57 Recently, the Cheng group successfully developed the coppercatalyzed S-cyanation and N-cyanation using AIBN as an organic CN source.58,59 To the best of our knowledge, no report on the direct cyanation of the C(sp3)-H bond of tertiary amines adopting AIBN as a CN source has been disclosed. © 2017 American Chemical Society
Figure 1. CN sources in cyanation reactions.
As indicated in Table 1, we chose N,N-dimethylaniline 1a as a model substrate to explore the suitable conditions for the aerobic oxidative cyanation. Initial trials showed that the reaction proceeded to give the desired product 2a in a moderate yield when AIBN was used as the cyanation reagent at 90 °C for 8−12 h in the absence of an additive (entries 1−3). The yield of 2a was improved to 65−72%, and the starting material was almost completely consumed with 1.5 equiv of a Brønsted acid used as an additive (entries 4−7), indicating that the addition of a Brønsted acid was crucial to ensure good conversion. A brief comparison of acids showed that pivalic acid (tBuCO2H) was slightly better than the others (entries 4−7). Received: August 16, 2017 Published: November 7, 2017 12786
DOI: 10.1021/acs.joc.7b02021 J. Org. Chem. 2017, 82, 12786−12790
Note
The Journal of Organic Chemistry Table 1. Optimization of the Oxidative Cyanation of Aniline 1aa
entry
AIBN (equiv)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19e
3 3 5 3 3 3 3 3 3 3 3 3 2 5 3 3 3 3 3
acid (1.5 equiv)
base (1.5 equiv)
atm
temp (°C)
time (h)
yieldb (%)
AcONa AcOK AcONa AcONa AcONa AcONa AcONa AcONa AcONa AcONa AcONa AcONa
air air air air air air air air air air O2 Ar air air air air air air air
90 90 90 90 90 90 90 90 90 90 90 90 90 90 70 110 90 90 90
8 12 8 8 8 8 8 8 8 8 8 8 8 8 8 8 4 12 8
46 45 48 70 68 65 72 52 48 84 (72)c 46
