Metal catalyzed, cyanation

Transition-metal-catalyzed cyanation [38] at the C-3 position for the decoration of the pyrazinone scaffold was also reported by the same authors. 

There are many other examples in the literature where sealed-vessel microwave conditions have been employed to heat water as a reaction solvent well above its boiling point. Examples include transition metal catalyzed transformations such as Suzuki [43], Heck [44], Sonogashira [45], and Stille [46] cross-coupling reactions, in addition to cyanation reactions [47], phenylations [48], heterocycle formation [49], and even solid-phase organic syntheses [50] (see Chapters 6 and 7 for details). In many of these studies, reaction temperatures lower than those normally considered near-critical (Table 4.2) have been employed (100-150 °C). This is due in part to the fact that with single-mode microwave reactors (see Section 3.5) 200-220 °C is the current limit to which water can be safely heated under pressure since these instruments generally have a 20 bar pressure limit. For generating truly near-critical conditions around 280 °C, special microwave reactors able to withstand pressures of up to 80 bar have to be utilized (see Section 3.4.4). 

In addition to metal catalysts, organocatalysts could also be used in asymmetric cyanation reactions. Chiral Lewis bases, modified cinchona alkaloids, catalyzed asymmetric cyanation of ketones by using ethyl cyanoformate as the cyanide source (Scheme 5.34)." Similar to metal-catalyzed reactions, ethyl cyanoformate was first activated by chiral Lewis bases to form active nucleophiles. Various acyclic and cyclic dialkyl ketones were transformed into the desired products. Because of using... 

Until recently, the Pd- or Ni-catalyzed cyanation had been performed most frequently with metal cyanides containing alkali metals, such as Na and K21a. More recently, however, the use of Zn(CN)2 in conjugation with DMF has been reported to be a useful alternative216 (Scheme 83). Further delineation of the relative merits and demerits among various metal countercations appears to be desirable. 

For selected excellent contributions of metal-catalyzed asymmetric cyanations, see (a) M. S. Sigman,... 

In contrast to the deactivation observed in the metal-catalyzed process, the photochemical reaction tolerates the use of an excess of KCN, a relatively inexpensive cyanating agent, to generally improve the yield. 

Me3SiCN is a convenient, reactive cyanide donor in transition metal-catalyzed processes. The Pd-catalyzed reaction of aryl iodides with Me3SiCN is useful for the synthesis of aryl cyanides.257 Me3SiCN works also as an effective co-catalyst for the Pd-catalyzed cyanation of aryl iodides with KCN.258 Allylic acetates, carbonates, and the related compounds undergo the Pd-catalyzed cyanation with Me3SiCN.259-261 The tandem cyclization-cyanation reaction of 2-bromo-l,6-heptadienes with Me3SiCN proceeds under catalysis by an Ni complex (Equation (68)).262... 

Asymmetric Cyanation of C=0 Bonds by Metal-Catalyzed Reactions... 

Palladium catalyzed cyanation [71] has recently received a lot of attention in the literature as a cross-coupling which employs cheap, commercially available metal cyanides and incorporates the versatile and synthetically useful cyano group. The development of a domino ort/ o-functionalization/cyanation reaction represents an advance in palladium catalysis as there are very few, if any palladium-catalyzed domino cyanation reactions. The development of the domino ortfto-functionalization/ cyanation [72, 73] by Lautens has led to some of the most significant discoveries of highly functionalized alkyl halides as coupling partners, as well as further development in the selectivity and scope of o/t/to-arylation chemistry. 

Although the Pd(PPh3)4-catalyzed cyanation of aryl bromides with KCN or NaCN does not take place under ordinary conditions, Zn(CN)2 as the cyanide source enables the reaction in DMF at 80 °C. The solubility of Zn(CN)2 is lower than that of KCN or NaCN and the covalency of the Zn-CN bond is higher than that of K-CN or Na-CN. Therefore, the concentration of free CN must be a minimum in the reaction solution using Zn(CN)2 as the metal cyanide. Thus, Zn(CN)2 is probably able to maintain the active form of the Pd° catalyst over a longer period of time than KCN or NaCN (Scheme Zn(CN)2 is also an effective cyanide source for the Pd°-catalyzed reac-... 

Second, the addition of a catalytic amount of second metal salts, especially Cul, to the reaction mixture accelerates the Pd°-catalyzed cyanation.t t f Nitrile solvents are the best reaction media for the Cu+ cocatalyzed processes (Scheme 22). The activating effect of Cu is attributed to the role of vehicle transferring the CN between the poorly soluble cyanide source and the Pd intermediate. The same role exerted by the Pd species is also proposed for the Pd°-catalyzed reaction, CuCN itself is an effective source of cyanide (Scheme 23). ... 

The reaction took place either via the ArSsl or via the AtSn2 mechanism (see Scheme 14.1, paths h,c), and occurred successfully via the first mechanism when using aryl hahdes or esters with electron-donating substituents. Among halides, both aryl chlorides and fluorides underwent photosubstitution when irradiated in an aqueous MeCN solution of KCN (Scheme 14.10, left part) [59]. It should be noted that, in transition metal-catalyzed reactions, the substitution of a chloro- by a cyano-group occurs only under relatively harsh reaction conditions, whereas such a process does not take place at all with aryl fluorides [57]. In the case of aryl esters the photoinduced cyanation occurred conveniently. As esters are easily... 

The exceptional strength of the metal-cyanide linkage makes it challenging to develop catalytic processes that involve excess CN" as reagent. The Pd-catalyzed cyanation of aryl halides discussed in Chapter 19 to form aryl nitriles initially suffered from the formation of catalytically inactive cyanide complexes containing multiple CN" ligands the reaction has been improved by the use of ZnfCN) or Kj[Fe(CN)J as the CN" source. ... 

A Pd-catalyzed cyanation procedure using aryl halides and potassium cyanide was reported in 1973 (Scheme 3.79) [258, 259]. Many studies investigated effective Pd catalysts, metal cyanides, solvents, or additives, intending to provide the efficient catalytic reactions of a variety of carbon electrophiles including aryl halides under rrald conditions. In addition to Zn(CN)2, KCN, and NaCN, several other cyanide sources including NaCN, K4[Fe(CN),5], cyanohydrines, and trimethylsilyl cyanide (TMSCN) have been shown to participate in Pd-catalyzed cyanations [258b]. 

Application of Transition Metal Catalysts in Organic Synthesis, Springer, Berlin, 1998, 149-178. Nickel- and Palladium-Catalyzed Cyanation of sp -Halides and sp -Trillates. 

Due to their importance for research but also for industrial chemistry, transition metal based catalysts are intensively investigated. Ananikov et al. [684] reviewed various appUcatimis of hybrid ONIOM methods within this field. This review involves reaction mechanisms and enantioselective reactions of transition metal complexes, e.g. Ti-catalyzed cyanation of benzaldehyde [685], Cu-catalyzed cyclopropanation [686], Mn-porphyrin catalyzed epoxidation of alkene [687], and Mo-catalyzed nitrogen activation [688]. These approaches involve QM/QM as well as QM/MM approaches. 

Recently, studies in urea synthesis have focused on transition-metal-catalyzed reactions. Buchwald et al. reported a Pd-catalyzed cross-coupling of aryl chlorides with sodium cyanate, which represented a practical way to synthesize unsymmet-rical ureas [50]. The protocol allows for the synthesis of unsymmetrical N,N -di-and A. A. A -trisubstituted ureas in one pot and is tolerant of a wide range of functional groups (Scheme 5.19). Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive... 

For the synthesis of atorvastatin we developed an efficient process that allows for direct cyanation of lactone 2 [21] to cyanomethyl lactone 3 to finally afford the well known atorvastatin precursor 5 (Scheme 6.3) [22]. It is worth pointing out that the two synthetic routes to the advanced statin intermediates 5 and 6 described here avoid ultra-low temperature chemistry, heavy metal catalysts, metal-organic species, and chromatographic purification steps. The DERA-catalyzed chemistry to form the six-carbon chiral unit is cost competitive and operated on a commercial scale. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

Recently, Zhao has described the phosphorylation of adenosine 42 with trimetaphosphate by a wet-dry cycle process performed at neutral pH. Metal ions were able to catalyze the reaction, Ni(II) being the most active catalyst (30% yield of phosphorylated products, twice the yield produced by magnesium ion). 2/,3/-Cyclic AMP 47 (10%) and 5 -adenosinetriphosphate 5 -ATP 50 (13.0%) were obtained as the main reaction products (Scheme 24) [142]. Different prebiotic syntheses are reported for 5 -ATP [143-149]. 5 -ATP 50 has been for instance synthesized by the phosphorylation of 5 -ADP 51 in aqueous solution containing cyanate and insoluble calcium phosphate (Scheme 25) [150]. Similarly, 5 -ADP was synthesized from 5 -AMP. The yield... 

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