Letter pubs.acs.org/OrgLett
Decarbonylative Cyanation of Amides by Palladium Catalysis Shicheng Shi and Michal Szostak* Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States S Supporting Information *
ABSTRACT: Transition-metal-catalyzed cyanation of aryl halides is a process of significant importance in the preparation pharmaceuticals, organic materials and agrochemicals. Here, we demonstrate a palladium-catalyzed decarbonylative cyanation of amides by highly selective carbon−nitrogen bond cleavage for the synthesis of a wide range of aryl nitriles. The utility of this technology is demonstrated by the synthesis of isotopically labeled aryl nitriles and orthogonal cross-coupling reactions of bench-stable amides to establish cross-coupling synthons with opposite polarity.
A
romatic nitriles represent extremely useful building blocks in organic synthesis that can be exploited to generate an array of versatile products by standard functional group transformations, including benzoic acid derivatives, amines, aldehydes, ketones, imines, and heterocycles.1 Furthermore, aryl nitriles represent a common structural motif in a large number of pharmaceuticals, bioactive natural products, agrochemicals, dyes, and functional materials (Figure 1).2
Figure 1. Examples of pharmaceutically important benzonitriles. Figure 2. (a) Cross-coupling of amides. (b) Classical cross-coupling of aryl halides and equivalents, and palladium-catalyzed redox-neutral decarbonylative cyanation of amides: a novel strategy for the synthesis of aryl nitriles.
The synthesis of aryl nitriles has been classically achieved by the Rosenmund−von Braun3 or Sandmeyer reactions4 of aryl halides or diazonium salts. In the past decade, significant progress has been made in the development of methods to access aryl nitriles directly by the transition-metal-catalyzed cross-coupling of aryl halides.5 Furthermore, elegant methods for the chelation-assisted cyanation6 and electrophilic cyanation of organometal nucleophiles7 have been developed. Recently, direct cyanation of arenes by a photoredox mechanism has been disclosed.8 Noteworthy progress in the synthesis of alkyl nitriles by transfer hydrocyanation9 and radical relay10 mechanisms has been made.11,12 However, the synthesis of aryl nitriles from carboxylic acid derivatives after direct oxidative addition into the acyl bond13 represents a major challenge. Carboxylic acid derivatives are cheap, readily accessible, and derived from a different pool of precursors than halides, phenols, anilines, or hydrocarbons.14 Of major interest is the development of synthetic methods for the cross-coupling of amide derivatives (Figure 2A).15,16 © 2017 American Chemical Society
Among many advantages of using amides as precursors to acylmetal species is the availability of tricoordinate nitrogen geometry that allows controlled access to additional amide geometries by rational variation of N-substitution.16aa,ab Methods to replace common aryl halide electrophiles with stable carboxylic acid derivatives are rare.16k−m,q,17,18 Here, we describe the first palladium-catalyzed decarbonylative cyanation of amides by carbon−nitrogen bond cleavage for the synthesis of a broad range of aryl nitriles (Figure 2B). Cross-coupling of an alkenyl amide is also reported. Despite elevated temperatures, decarbonylative cross-coupling methods represent an attractive coupling manifold due to (i) the use of Received: April 20, 2017 Published: June 1, 2017 3095
DOI: 10.1021/acs.orglett.7b01199 Org. Lett. 2017, 19, 3095−3098
Letter
Organic Letters common carbonyl-containing substrates, (ii) orthogonal selectivity, (iii) reduction of halide waste.13 The following features of our protocol should be noted: (1) The process constitutes the first example of a palladium-catalyzed decarbonylative cross-coupling of bench-stable carboxylic acid derivatives under ligand-controlled catalysis conditions.13,14 (2) The reaction proceeds with exclusive decarbonylation/acyl selectivity via N−C activation. (3) The reaction proceeds in the absence of external oxidants; (4) the utility has been highlighted by the synthesis of labeled nitriles. Using amide derivatives as aryl electrophiles enables tuning of the acyl bond reactivity for direct oxidative addition.15 Given the pivotal role of amides19 as key building blocks in peptides, polymers, and pharmaceuticals,20 methods that allow cross-coupling of the amide bond are likely to have a broad impact on chemical synthesis. Our development of Pd-,16k,q Ni-,16l and Rh-catalyzed16m decarbonylative reactions by N−C cleavage prompted us to question whether this bond activation platform might be exploited for the development of redox-neutral (cf. oxidative) decarbonylative cyanation of carboxylic acid derivatives.13 Notably, the use of a versatile palladium catalysis platform in the coupling makes this method synthetically appealing.21 After a very extensive survey of various reaction parameters we discovered a catalyst system that promotes the desired cross-coupling [Table 1, Pd(OAc)2, 5 mol %; PCyPh2, 20 mol %; Zn(CN)2, 2 equiv; dioxane, 150 °C]. Under the optimized conditions the cross-coupling of 1 afforded the cyanation product in 91% yield. Key optimization results are shown in Table 1. Various catalysts were tested, and Pd(OAc)2 showed the best activity. The key optimization result involved identification of Zn(CN)2 as the cyanide source. We hypothesize that low concentration of cyanide ions and faster transmetalation of cyanide to the acylpalladium contribute to its high reactivity. Note that zinc cyanide is one of the preferred cyanide sources for industrial development.5a Importantly, a 71% yield of the coupling product was obtained using only 0.5 equiv of Zn(CN)2 (entry 25), providing an entry point for future studies. Control experiments in the absence of catalyst resulted in recovery of 1. Using the less distorted anilides,16a NBoc-carbamates, and N-Ts-sufonamides,15,16 as well as acyl chlorides, benzoates,18a−d and thiobenzoates,18e only a trace or none of the cross-coupled product was formed.16ab Note that N-glutarimide amides are easy to handle, bench-stable, crystalline solids readily prepared from carboxylic acids.15a,b The insertion occurred selectively at the N−C bond, with cleavage of the alternative σ N−C bond and amide deamidation not observed.16y To our knowledge, this transformation represents the first example of decarbonylative cyanation of amides. The successful decarbonylative cross-coupling of 1 highlights the advantageous use of amide derivatives as coupling partners in decarbonylative manifolds.15−17 With the optimized conditions in hand, we explored the preparative scope of the reaction (Scheme 1). As shown, the scope of the reaction is very broad and tolerates the coupling of electron-neutral (2a−2d), electron-rich (2e−2f), and electronwithdrawing (2g−2h) substrates. Steric hindrance is welltolerated (2b). Importantly, fluoro-substituents are readily accommodated (2i−2l). Furthermore, saturated oxygen heterocycles that are prone to Ni-catalyzed C−O cleavage (2m− 2n),22 as well as quinoline (2o) and thiophene heterocycles (2p), provided the corresponding coupling products in moderate to excellent yields. At this stage, other heterocyclic
Table 1. Optimization of Pd-Catalyzed Decarbonylative Cyanation of Amidesa
entry
catalyst
ligand
M(CN)x
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d 17e 18f 19g 20h 21i 22j 23 24 25k
Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 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 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(TFA)2 Pd(dba)2 Pd(OAc)2
− − − − PPh3 P(4-MeO-C6H4)3 P(4-CF3-C6H4)3 dppb dppp Sphos Xphos Xanthphos PCy3HBF4 PCy2Ph PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2 PCyPh2
CuCN KCN NaCN Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2 Zn(CN)2
25 46 51 75 21 81 27 59
